basic neurologic life support

BASIC NEUROLOGIC

LIFE SUPPORT

James J. Corbett, MDMcCarty Professor and Chair

Department of NeurologyUniversity of Mississippi Medical Center

Jackson, Mississippi

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice ofdrugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research andregulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package ofeach drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infre-quently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on acase-by-case basis against the benefits anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten;the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment.

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This book is dedicated to patients whose lives, or livelihood, are threatened by treatableneurologic problems, and to physicians who

recognize these illnesses and take action.

Foreword ix

Preface xi

Contributors xiii

1. Headache as an Emergency 1James J. Corbett, MD

2. Giant Cell Arteritis 20James J. Corbett, MD

3. Approach to the Comatose Patient 32Michael DeGeorgia, MD and John Andrefsky, MD

4. Approach to Status Epilepticus 62Michael DeGeorgia, MD and John Andrefsky, MD

5. Spinal Cord Emergency Conditions 76Robert M. Herndon, MD

6. Respiratory Failure Due to Neuromuscular Disease 89Robert M. Pascuzzi, MD

7. Ischemic Stroke 133Patrick S. Reynolds, MD and Terrence W. Bruner, MD, MBA

v

CONTENTS

8. Neuroleptic Malignant Syndrome 167Robert L. Rodnitzky, MD

9. Encephalitis 182Karen L. Roos, MD

10. Bacterial Meningitis 190Karen L. Roos, MD

11. Cerebellar Hemorrhage and Infarction 210John B. Selhorst, MD

12. Wernicke’s Encephalopathy 220John B. Selhorst, MD

13. Tips on the Neurologic Evaluation 236James D. Fleck, MD and José Biller, MD

Index 258

Contents

vi

Neurology has long been considered a field rich in phe-nomenology and bereft of treatment, but dramatic recentadvances have changed all of that. Nearly every categoryof neurologic disease is yielding to the insights of neuro-science translated into new approaches to the diagnosisand management of human illness. Among the mostimportant areas is the field of neurologic emergency med-icine where modern knowledge may spell the differencebetween horrible disability and remarkable recovery. It iscritical for patients’ well-being that physicians are up todate and facile with the best evidence-based techniquesfor the rapid, accurate diagnosis and treatment of criticalillnesses affecting the nervous system. This new informa-tion is important not only for the students who are thephysicians of tomorrow, but also for the currently practic-ing neurologists, internists, family doctors, and emergencyphysicians. Of all the areas of emergency and critical caremedicine, neurology has been the most neglected in thepast,making the continuing education of practicing physi-cians even more vital.

Under the auspices of the Association of UniversityProfessors of Neurology, which represents the leadershipof American neurology, James J.Corbett has assembled thehandbook of Basic Neurologic Life Support analogous to thatwhich is already available for cardiac catastrophes. Usingthe talents of some of the leading lights in neurology, thebook systematically covers the most important and fre-quently encountered neurologic emergencies. The book’s

vii

FOREWORD

12 subject chapters include headache emergencies, giantcell arteritis, coma, status epilepticus, myelopathies,neuromuscular emergencies, ischemic stroke, neurolepticmalignant syndrome, encephalitis, bacterial meningitis,cerebellar hemorrhage and infarction, and Wernicke’sencephalopathy. The book concludes with a chapter ontips on the neurologic examination in the emergencysetting.

The content of this book should be required knowl-edge for all medical students and for any physician or sur-geon who encounters patients, because one of the mostimportant aspects of an emergency is to recognize that itexists. For those who actually manage patients with neu-rologic emergencies, such as neurologists, emergencyphysicians, and neurosurgeons, the authoritative nature ofthe chapters written by some of the foremost experts ineach field will be a welcome addition to their personallibrary. Dr. Corbett has done us all an enormous serviceby spearheading this effort to put neurologic emergenciesin the prominent position they deserve.

Martin A. Samuels, MD, FAAN, MACPPresident,Association of University Professors of

Neurology, 2004–2006Chairman, Department of Neurology

Brigham and Women’s HospitalProfessor of Neurology, Harvard Medical School,

Boston, Massachusetts

Foreword

viii

Medical emergencies are conditions that, if recognized,can be treated to restore health, or at the very least, pre-vent progression to life-threatening or livlielihood-threat-ening results. Key information about acutely evolvingmedical emergencies is scattered throughout years oftraining and is never concentrated in one place.

In the past few years, cardiopulmonary arrest has takenthe center spotlight as the quintessential emergency thateveryone should know about. Cardiac resuscitation istaught everywhere.Basic cardiac life support and advancedcardiac life support courses are available to everyone, anda cottage industry that provides this training has devel-oped. The neurologic emergencies have not been similarlyhighlighted in medical education, yet they are frequentlyencountered, misdiagnosed, and commonly treated incor-rectly even if the diagnosis is made.

This book is an easy-to-use guide to all the majorneurological emergencies, providing key informationabout, and examples of, their typical presentations, whereuseful their pathogenisis, and, finally, characteristic patienthistories with currently recognized and approved treat-ment of the condition.A brief bibliography accompanieseach condition. Neurologic disease has long been consid-ered arcane, difficult to diagnose, and, above all, untreat-able.Every one of the conditions we highlight here is neu-rologic and, if recognized, eminently treatable. We hopethat this book, produced with the Association of Univer-sity Professors of Neurology, will be the beginning of a

ix

PREFACE

move to familiarize all physicians with basic neurologiclife support in the same way that they have become famil-iar with cardiorespiratory failure.

James J. Corbett, MD2004

Preface

x

John Andrefsky, MD Department of NeurologyCleveland Clinic Foundation Cleveland, Ohio

José Biller, MDDepartment of Neurology Loyola UniversityMaywood, Illinois

Terrence W. Bruner, MD, MBADepartment of Plastic SurgeryBaylor College of MedicineHouston,Texas

James J. Corbett, MDDepartment of NeurologyUniversity of Mississippi Medical CenterJackson, Mississippi

Michael DeGeorgia, MDDepartment of Neurology Cleveland Clinic Foundation Cleveland, Ohio

James D. Fleck, MDDepartment of NeurologyIndiana University School of MedicineIndianapolis, Indiana

xi

CONTR IBUTOR S

Robert M. Herndon, MDDepartment of NeurologyUniversity of Mississippi Medical CenterJackson, Mississippi

Robert M. Pascuzzi, MDDepartment of NeurologyIndiana University School of MedicineIndianapolis, Indiana

Patrick S. Reynolds, MDDepartment of NeurologyWake Forest University School of MedicineWinston-Salem, North Carolina

Robert L. Rodnitzky, MDDepartment of NeurologyUniversity of IowaIowa City, Iowa

Karen L. Roos, MDDepartment of NeurologyIndiana University School of MedicineIndianapolis, Indiana

John B. Selhorst, MDDepartment of NeurologySaint Louis UniversitySt. Louis, Missouri

Contr ibutors

xii

Headaches result in an enormous amount of lost pro-ductivity, but they are benign by and large.The diagnosisis made almost entirely by the patient’s individualheadache attack history, personal lifelong headache his-tory, and family headache history.To a much lesser degree,headaches can be characterized by physical examination,although physical findings usually are not very specific andinclude facial erythema or pallor, intermittent ptosis, andHorner’s syndrome in cluster headache.The tendency ofthe patient to rub or squeeze his or her head and photo-phobia is seen in migraine and other common headaches.Headache histories that should cause concern and consti-tute potential emergencies fall into six distinct categories:

• New headaches in an individual who has never beenheadache prone in the past. Although these may be totallybenign in the young adult who is beginning to havemigraines, new headaches in older patients deservespecial scrutiny. In this circumstance, a computedtomographic (CT) scan with and without contrastmay be warranted and, in older patients, sedimentationrate and C-reactive protein.1

• New headaches or a change of headache characteristics in aheadache-prone individual. “I have had headaches, butthis is a different kind of headache.” Patients who arefamiliar with headaches know how their usual

1

CHAPTER 1

HEADACHE AS AN EMERGENCY

James J. Corbett, MD

headache feels. If headaches that a patient usually haschange in character, location,duration,or severity, theydeserve special attention. In this instance, CT or mag-netic resonance imaging (MRI) may be used. Pay spe-cial attention to the sphenoid sinus for evidence ofsinusitis and look for enlarged ventricles, a subduralhematoma, or intracerebral mass lesion.

• Headache occurring with loss of consciousness or in the pres-ence of fever or other systemic symptoms.This may repre-sent central nervous system infection, inflammation,orarteritis, or the headache may be the residue of unrec-ognized complex partial seizures. Electroencephalog-raphy may be of help in this setting. Pulsatile tinnitusor roaring in the ears, visual blurring, horizontaldiplopia, and transient visual obscurations suggest ele-vated cerebrospinal fluid (CSF) pressure. CT or MRIand possible lumbar puncture (LP) are called for in theevaluation.

• Headache arising de novo in a patient over the age of 50years. This suggests possible giant cell arteritis andrequires an immediate erythrocyte sedimentation rateand C-reactive protein and very likely will need a tem-poral artery biopsy.Abrupt onset of monocular visual losswith or without preceding spells of transient monocularvisual loss should prompt careful examination of thepatient’s optic fundus and pupils to look for a relativeafferent pupil defect (Chapter 2,“Giant Cell Arteritis”).

• Abrupt onset of the worst headache of the patient’s life.Thismay herald a subarachnoid hemorrhage (Figure 1-1).2

A “first headache” is less useful as an indicator of aneurologic emergency, particularly in young adults,

Basic Neurologic L i fe Suppor t

2

Headache as an Emergency

3

Figure 1-1 Blood in the anterior interhemispheric fissure (arrow),sylvian fissures (arrowheads), and suprasellar cistern in apatient with a ruptured anterior cerebral artery aneurysm.

because patients who develop migraine and otherbenign headaches have to start sometime, and an oth-erwise benign-sounding first headache is unlikely tobe a problem.Such patients need immediate referral toa neurosurgeon in a hospital setting. Do not delayreferral beyond obtaining a CT without contrast tolook for blood in the cerebrospinal fluid (Figure 1-1).3,4

If in doubt, properly perform LP (see below).• Long-standing (72 hours or more) headaches. These may

signal increased CSF pressure, infection,or mass lesion.Chronic forms of meningitis such as tuberculosis orcryptococcal or coccidioidal meningitides may presentonly with chronic headache or headache and opticdisk swelling5 but no stiff neck.These patients need tobe studied with MRI with and without contrast.

Neurologic examination of headache patients shouldemphasize palpation of temporal arteries and ophthalmo-scopic examination, if necessary dilated with tropicamide(Mydriacyl) drops, to look for papilledema or a swollenischemic optic nerve head. (Figures 1-2 to 1-6 at the endof this Chapter.These figures can be viewed in color onthe CD-ROM.) Ocular motility examination shouldfocus on ptosis and unilateral pupil constriction or dila-tion. Stiff neck (Kernig’s and Brudzinski’s signs), drift of anoutstretched arm, asymmetry of reflexes, evidence of anextensor plantar response, and Romberg’s testing all helpto identify key features of headaches that are true treatableemergencies. The examination should be recorded in itsentirety, and specific written comments should be madeabout these findings. Abbreviations of cranial nerves II


4

through XII (WNL) without specific mention of pupil,ocular motility, and fundus findings leave subsequentexaminers wondering whether the examinations wereever really done.

Headache occurring with subarachnoid hemorrhageis usually abrupt in onset and severe, and depending on thelocation of the aneurysm, there are frequently other com-plaints or physical findings:

• Abrupt loss of consciousness or weakness of the legsand/or loss of bladder control suggest anterior cerebralor anterior communicating artery aneurysm.

• Third nerve palsy, either partial with or without pupilinvolvement, or complete with pupil involvement,may occur as a result of intra- or extracavernousaneurysms but usually suggests an internal carotid–posterior communicator aneurysm.

• Neck,back, arm, and leg pain (any or all of these),withor without headache, if abrupt in onset, suggests bleed-ing of an aneurysm in the posterior fossa and downinto the spinal canal.

NOTES AND TIPS ON THE SPECIFIC DETAILS OF DOINGA LUMBAR PUNCTURE

Positioning the Patient

The patient is placed in the lateral decubitus position.Knees and hips are flexed into the abdomen. It is not nec-essary, and it is actually undesirable to flex the neck for-ward. Flexion of the lumbar spine opens L3–4 and L4–5


5


6

interspaces. Flexion of the neck does not further open thelumbar interspaces, which are already wide open. Cervi-cal flexion not only does not increase the width of thelumbar interspace openings, it also potentially compressesthe jugular veins, thereby blocking cerebral venousdrainage, increasing cerebral venous sinus pressure, andeventually elevating CSF pressure.

Preparing the Site

Mark the interspace into which you want to place theneedle.Clean the skin with iodine and wipe the skin cleanwith 4 � 4 gauze. Drape the areas above and below thelumbar puncture (LP) site. Infiltrate the skin and subcuta-neous tissue with 1% lidocaine at the level at which youwish to place the needle. Using a Quincke (spinal) needle,place the bevel to the left or right side of the body, notcrossways.This way, the fibers will be separated, not cut,and this presumably lessens the risk of post-LP headache.

Placing the Needle

Advance the 3.5-inch 22-gauge needle directly in andslightly upward using the upper surface of the lower of thetwo vertebrae that form the interspace as your landmark.With the stylet in place, you prevent the introduction ofepidermal or dermal elements into the subarachnoidspace. Once the needle is in a centimeter or so, you mayeither remove the stylet or advance the needle with thestylet in place as you wish.

Years ago, when reusable LP needles were used, theybecame dull.There was a perceptible “pop”when the nee-dle passed through the dura; however, with the advent ofthe one-use sharp cutting needles of today, that pop maybe imperceptible.

Preparation of the Patient to Measure LP Pressure

Once the needle is through the interspace and in the sub-arachnoid space and there is a flow of CSF, replace thestylet and have an assistant passively extend the patient’slegs and place the head in a “neutral” (neither flexed norextended) position. Encourage the patient to relax and totake one or two deep breaths. Encourage the patient tobreathe regularly and be attentive to the patient who maybe hyperventilating (or crying), holding his or her breath,or straining. Changes in PCO2 rapidly alter CSF pressure,as does any Valsalva maneuver.

Measurement of CSF pressure in the lateral decubitusposition is straightforward and can be accomplished withor without the attachment of a short tube to the petcockand manometer that is incorporated in the LP kit. Mea-surement of CSF pressure in the prone position, as per-formed by radiologists, provides the same pressure asfound in the lateral decubitus position (Dan Jacobson,per-sonal communication, 2003). LP can be done safely in thesitting position, but there is no reliable, accurate way tomeasure CSF pressure in the sitting position.Thus, if fluidis needed for cytology and pressure is not an issue, thespinal puncture may be accomplished in the sitting posi-tion more easily than in the recumbent position.


7

Fluid collection should provide quantities sufficient toperform CSF glucose, protein, cell count,Venereal DiseaseResearch Laboratories (VDRL) test, polymerase chainreaction (PCR) (rapid meningitis panel), a large aliquot forcytology (when necessary), or special stain for tuberculo-sis (TB). Do not take small amounts of CSF. Take as muchas you need because CSF regenerates at a rate of 1 ccevery 3 minutes or 20 cc/h.

Post-LP headache is a fact of life and, even in the bestof hands, occurs in one of three patients.5 If hydration anda couple of intravenous or intramuscular doses of 500 mgcaffeine sodium benzoate do not stop the headache, ablood patch should be done. No special precautionsregarding bed rest, reverse Trendelenburg’s position, intra-venous or oral fluids, and other such mantras have everbeen shown to reliably treat or prevent post-LPheadaches.

Do you need to have a CT scan before an LP? A CTscan is not required if the patient is awake, alert, and coop-erative and has no focal neurologic findings.A CT scan isrequired if there are focal lateralized signs or if the patientis febrile or unconscious. CT is required if meningitis isbeing considered, and this has been studied extensively.6

If you suspect bacterial meningitis, start intravenouscorticosteroids and appropriate antibiotics; draw blood forcomplete blood cell count, prothrombin time, partialthromboplastin time, blood cultures, and internationalnormalized ratio (INR); do a CT scan, and then do theLP.Organisms survive 4 to 6 hours after antibiotic therapyhas been initiated (Table 1.1).


8

PATIENT WITH SUSPECTED SUBARACHNOIDHEMORRHAGE

A patient who presents to the emergency departmentwith a headache owing to a ruptured berry aneurysm has“made the cut” and is in the emergency department alive,for the time being. Rapid recognition of the cause of theheadache depends on history taking, physical findings, and


9

Table 1-1 Risk Factors for Uncal and CerebellarHerniation at Time of Lumbar Puncture in

Meningitis

Immunosuppression

Dilated or poorly reactive pupils

Papilledema

Oculomotor palsies

Hemiparesis

Recent focal seizures

Rapid or major depression of consciousness

Bradycardia

Tonic seizures

Irregular respirations

Decerebrate or decorticate posturing

Adapted from Mellor DH.7

rapid performance of CT scan with and without contrastto look for evidence of subarachnoid blood. Blood in thesubarachnoid space will appear immediately (Figure 1-1)and, depending on the quantity of blood, will disappearwithin 4 to 7 days. If no evidence of blood is found on CTscan and subarachnoid hemorrhage is still being consid-ered as the most likely cause of the patient’s headache, thenLP needs to be performed immediately. Table 1-2 listscontraindications to doing an LP.

If you are convinced that the result of the LP was a“bloody tap” (Table 1-3), repeat LP should be done onespinal interspace higher.The bloody CSF should be spundown and the supernatant CSF fluid examined for xan-thochromia in good light, against a white background.8,9

The task of doing the LP and examining the fluid is nottrivial. If you are not going to do it yourself, you shouldbe sure that the LP, done by an anesthesiologist or radiol-ogist under radiographic guidance, includes opening pres-sure and that the CSF fluid is collected and sent immedi-ately for protein, glucose, and cell count, as well as a VDRLtest. Fresh bleeding of a subarachnoid hemorrhage may,onoccasion, cause the CSF glucose to be depressed (hypo-glycorrhachia). Be sure also that CSF is sent for bacterio-logic and fungal cultures and that a rapid PCR screen ofthe fluid is done. Ruptured mycotic aneurysms may havemore white cells than expected when there is bleedingowing to either a ruptured aneurysm or from a bloody tap.There are other causes of subarachnoid hemorrhage,including pituitary apoplexy,which may have abrupt onsetof visual loss in one or both eyes and/or ocular motilitydisturbances owing to the effects on the cavernous sinuses,


10

intracerebral and cerebellar hemorrhage, hemorrhage intometastasis, and arteriovenous malformations. All of thesewill be obvious on CT or MRI.

If you have serious reasons to believe that the patienthas ruptured a berry aneurysm, immediate consultation


11

Table 1-2 Contraindications to Lumbar Puncture

Infection of overlying skin

Known intracerebral mass lesion, especially brain abscessor mass lesion with shift

Known spinal cord compression

Relative contraindication to LP: generalized septicemiahas been reported rarely as a cause of meningitisfollowing LP. If LP is being done for suspectedmeningitis, it should not be withheld because of theconcerns regarding septicemia.

Bleeding disorder or use of anticoagulants: all patientswho undergo LP should have CBC with plateletcount, PT, and PTT and INR drawn. LP is safe if thereare 40,000 or more platelets.After LP, anticoagulationshould be delayed for 1 hour.

Papilledema by itself with none of the other above-mentioned factors is NOT a contraindication for LP.

CBC = complete blood cell count; INR = international nor-malized ratio; LP = lumbar puncture; PT = prothrombin time;PTT = partial thromboplastin time.


12

Table 1-3 Differential Features of SubarachnoidHemorrhage and Traumatic Puncture: The Three-

Tube Test

CSF Subarachnoid Traumatic Finding Hemorrhage Puncture

Pressure Increased or Normalnormal

Appearance Equal blood in First or last tube all tubes is bloodier,

others are clearer

Supernatant Pigment in excess Clear, nofluid color of protein level pigment

RBC count and Variable in Gradual decreasehematocrit different tubes from first to

last tube

WBC count Proportional to Proportional toRBC count in RBC countearliest stages;relatively increased later

Clot formation Absent Occurs rarely

Repeat puncture Findings similar Usually clearat higher to those at interspace initial tap

CSF = cerebrospinal fluid; RBC = red blood cell count;WBC = white blood cell count. Adapted from Fishman RA.8

with a neurosurgeon is indicated. Remember, upward of halfof all patients who have a ruptured berry aneurysm die of the sub-arachnoid hemorrhage before they ever reach the hospital. Havea low threshold of suspicion when considering the diag-nosis. Anyone with an abrupt-onset, severe headacheoccurring like a “thunderclap” or during coitus may wellhave a benign condition, but they should be treated as ifthey have a subarachnoid hemorrhage until proven other-wise.10,11,12

Long-standing headache may occur, particularly withgeneralized malaise or systemic disease with loweredimmunity. Chronic meningitis,most often fungal (crypto-coccus or coccidioidomycosis), but, occasionally, low-grade pathogens such as diphtheroids and low-virulencestreptococcal species may be the culprit. Here again, CTscan and LP are indicated.

SWELLING OF THE OPTIC DISKS

The finding of swollen optic discs is an indication of rel-atively subacute to chronic increased CSF pressure.Swelling of the optic disks owing to increased spinal fluidpressure is called papilledema. Disks may swell for otherreasons, such as unilateral optic neuritis or ischemic opticneuropathy. Rarely are these bilateral, and visual loss istheir primary symptom. Recognition of papilledemarequires familiarity with normal optic disk appearance andhow swelling of the nerve fibers on the disk alters its con-figuration.Lars Frisén has devised a staging scheme for therecognition of papilledema (see Table 1-4 and Figures 1-2to 1-6 at the end of this chapter.)13


13

If florid or even low-grade papilledema is detected inthe emergency department on a background of recent(same day or 2 to 4 days later) head trauma, the diskswelling is never related to the recent head injury. Suddenonset of papilledema (within days) occurs in the setting ofa massive increase in intracranial pressure and coma and isusually very hemorrhagic, with preretinal hemorrhagesand nerve fiber layer infarcts. Sustained high pressures seenin closed head injury rarely produce papilledema evenafter 5 to 7 days of continuously increased pressure.14 Ifdisks are swollen as soon as the patient is seen shortly afterthe onset of headache or after injury, almost certainly theyhave been swollen for at least 2 or more weeks.

The presence of hemorrhages and nerve fiber layerinfarcts (soft exudates) does not influence the grading ofpapilledema because these findings are all quite variableand nonessential. Nerve fiber layer infarcts probably con-tribute to visual loss, but they are not used in gradingpapilledema severity.


14


15

Figure 1-2 Grade I papilledema: C-shaped swelling of both diskswith preserved cup and sharp temporal margin.

Figure 1-3 Grade II papilledema: 360° swelling of the disk mar-gins, which are gray and indistinct.

Figures 1-2 through 1-6 can be viewed in color on theCD-ROM.

OD OS

OD OS


16

Figure 1-5 Grade IV papilledema: 360° swollen marginspapilledema with complete obscuration of some vessels are thehead.

Figure 1-4 Grade III papilledema: 360° swelling of the disk mar-gins and partial obscuration of blood vessels on the disk. Veins,especially OD, are tortuous.

OD OS

OD OS


17

Figure 1-6 Grade V papilledema: dome-shaped 360° swellingwith no cup, completely obscured vessels, sphincter hemor-rhages and circumpapillary hard exudates.

Table 1-4 Frisén Scale of papilledema

Grade I Grade IIBlurring of disk 360° swelling

margins all of disk margins but temporally. but only slight “C-shaped partial obscuration swelling”. of blood vessels.

Cup is preserved.

Grade III Grade IV Grade VSame as II but Same as III but many Smooth dome-

vessels partially vessels are totally shaped swelling obscured. obscured as and obscured Blurring is the cup fills in vessels. No cup isseen at margin and is no longer visible. Gliosisof disk. Cup visible. is beginningis partially to occur.obscured.

OD OS

Adapted from Digre KB, Corbett JJ.13

REFERENCES

1. Edmeads JG. Headache in the elderly. In: Olesen J, Tfelt-Hansen P, Welch KMA, editors.The headaches. Philadel-phia: Lippincott Williams and Wilkins; 2000. p. 947–52.

2. Duffy GB.The warning leak in spontaneous subarachnoidhemorrhage. Med J Aust 1983;28:514–6.

3. Bonita R, Thompson S. Subarachnoid hemorrhage: epi-demiology, diagnosis, management and outcome. Stroke1985;16:591–4.

4. Fontanorosa PB. Recognition of subarachnoid hemorrhage.Ann Emerg Med 1989;18:1199–205.

5. Mokri B. Headache associated with abnormalities in struc-ture or function: low cerebral spinal fluid pressure headache.In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolf ’sheadache and other head pain. 7th ed. USA: Oxford Uni-versity Press; 2001.

6. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computedtomography of the head before lumbar puncture in adultswith suspected meningitis. N Engl J Med 2001;345:1727–33.

7. Mellor DH.The place of computed tomography and lum-bar puncture in suspected bacterial meningitis. Arch DisChild 1992;67:1417–9.

8. Fishman RA. Cerebrospinal fluid in diseases of the nervoussystem. 2nd ed. Philadelphia:WB Saunders; 1992.

9. MacDonald A, Mendchow AD. Xanthochromia revisited: are-evaluation of lumbar puncture and CT scanning in thediagnosis of subarachnoid hemorrhage. J Neurol NeurosurgPsychiatry 1988;51:342–4.

10. Newman LB, Lipton RB. Emergency department evalua-tion of headache.Neurol Clin North Am 1995;16:285–303.

11. Silberstein SD. Evaluation and emergency treatment ofheadache. Headache 1992;32:369–404.


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12. van Crevel H, Hijdra A, de Gans J. Lumbar puncture and therisk of herniation: when should we first perform CT? JNeurol 2002;249:129–37.

13. Digre KB, Corbett JJ. Practical viewing of the optic disc.Burlington (MA): Butterworth Heinemann; 2003.

14. Steffen H, Eifert B, Aschoff A, et al. Diagnostic value ofoptic disc evaluation in actute elevated intracranial pres-sure. Ophthalmology 1996;103:1229–32.


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20

G iant cell arteritis (GCA), also known as temporalarteritis, consists of an inflammatory arteritis of medium-to large-sized arteries that have an elastic membrane.1–4 Itoccurs in patients almost exclusively over the age of50 years and progressively increases in frequency eachdecade to the ninth decade, where it occurs in about onepatient per thousand. A clinical variation of GCA ispolymyalgia rheumatica (PMR), which does not alwayshave the ominous implication for visual loss that is true ofGCA.3,4 The symptom complex of PMR and GCA over-laps.Thus, there is an occult form of GCA identified whenthe dreaded arteritic anterior ischemic optic neuropathyblinds one or both eyes without premonitory symptoms.5,6

There is GCA with symptoms of transient visual loss ordiplopia, headache, fever, and night sweats. GCA mayoccur with PMR where, in addition to the symptoms ofGCA, there is pain in the neck, shoulders, and hips, andPMR may occur alone with no visual loss, stroke, or othervascular complication.The syndromes can only roughly bedivided, and PMR symptoms even without headachemust be considered an important red flag for GCA and apotential cause of anterior ischemic visual loss.3,5,7

SYMPTOMS

The patient with GCA is usually over 60, much less com-

CHAPTER 2

GIANT CELL ARTERITIS

James J. Corbett, MD

monly in the early fifties, and will develop a new type ofheadache that is different from the patient’s previousheadaches. Usually, it is a generalized headache, and itcauses the scalp to be tender. The tenderness is greatenough that brushing or combing the hair is painful andplacing the head on a pillow is uncomfortable. Theheadache is constant but may vary in severity over time,and it may be accentuated by palpation tenderness of thetemporal arteries or other scalp vessels.

Neck pain was found by Hayreh and colleagues to beeven more common than headache in patients withGCA.8 In one large series, they found that 90% of patientswith biopsy-proven GCA had severe neck pain withouttenderness.

Pain occurs in the shoulders (yoke) and hips and upperthighs,8 which are also nontender to palpation. Elec-tromyography and muscle biopsy show no abnormalities.The polymyalgia is constant and enervating and is part ofthe overall feeling of malaise and being unwell but may beso gradual in onset that it is written off by the patient as asymptom of “old age.” 9

Appetite is poor, and weight loss is common.2,3 Some-times loss of appetite is made worse by jaw, tongue, andthroat (swallowing) claudication. Premonitory symptomsinclude transient monocular or binocular visual loss that isindistinguishable from embolic amaurosis fugax. Lesscommon symptoms include tongue and throat pain, chestpain, postprandial abdominal pain, and exertional leg pain.Confusion, frank memory loss, and dementia arereported,10 and it is likely that mental confusion is occa-sionally responsible for delays in diagnosis.

Giant Cel l Ar ter i t is

21

SIGNS

Occasionally, the scalp over the temporal artery willbecome erythematous and swollen.3,8 Rarely, there will betrue ischemic gangrenous breakdown of the skin. Thescalp arteries are frequently locally tender; they may benonpulsatile and ropey, but even grossly arteritic vesselsmay be soft, compressible, pulsatile, and nontender.

Fever is rarely more than 100°F, but night sweats arecommon.3 Night sweats are also common with serotoninreuptake inhibitors, which are ubiquitous.This may con-found the use of night sweats as a sign.

Diplopia may occur owing to ischemic damage toeither oculomotor nerves or muscles.3This weakness tendsto resolve within 3 to 6 months.The most feared compli-cation of GCA is infarction of the anterior optic nerveowing to occlusion of the short posterior ciliary arteriesby the arteritis (Figure 2-1). Peripheral neuropathy, bothsymmetric distal polyneuropathy and mononeuritis mul-tiplex,occurs more commonly than previously recognizedbecause the neuropathies are frequently asymptomatic.10

Muscles are not tender to palpation, but strength testingmay be impaired slightly by pain.

CLINICAL DIAGNOSIS

GCA should be suspected in patients over the age of 50who have any or all of the following: onset of a new typeof headache, scalp tenderness, aching pain in the shouldersand hips, transient monocular or binocular transient visualloss, anterior ischemic optic neuropathy, fever, malaise,


22

night sweats, anorexia and/or weight loss. Patients maydeny any symptoms because the condition has slowlycrept up on them. They may recognize that they hadsymptoms only when the symptoms disappear on corti-costeroid treatment. Furthermore, an insidious ischemicconfusional state may prevent the patient from giving acoherent history, and it may be the family that has noticedthat the patient is having trouble with memory, sleep,appetite, and weight loss or has complained of headache.12

One should have a high level of suspicion for GCA in allelderly patients.

LABORATORY DIAGNOSIS

GCA has characteristically been associated with an ele-vated erythrocyte sedimentation rate (ESR) (Westergrenmethod),with only about 5 to 10% having a normal ESR.Whereas the ESR is characteristically elevated in GCA, anelevated ESR is also commonplace as a nonspecific acute-phase reactant. GCA is in the lower ranks in frequency onthe list of causes of elevated ESR. Furthermore, the ESRmay be depressed by the common use of nonsteroidalanti-inflammatory drugs being used to treat the arthriticsymptoms of PMR.Although it is the most widely avail-able study, the ESR is not the most accurate test, largelyowing to variability produced by time, temperature, andvibration in the laboratory. C-reactive protein (CRP) isanother one of many acute-phase reactants that are ele-vated in GCA. CRP is a more accurate test because it isnot subject to the above-mentioned effects, and inexpen-sive kits are available, in contrast to other, much more


23


24

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xia,

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nd s

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, ja

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icat

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ain

in a

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an 5

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ars

of a

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SP

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T g

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cor

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Bio

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Pos

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Neg

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tinue

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ent

• C

ontin

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ent

• B

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25

Hea

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es a

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ids;

sys

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ove

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Hea

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and

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R s

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oms

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Con

tinue

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ase,

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Con

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and

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opsy

Neg

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opsy

Pos

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re 2

-1R

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. As

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-rea

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. Pa

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CR

P =

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; IV

= in

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26

expensive, acute-phase reactants. Thus, a sedimentationrate and CRP test should be performed on any patientsuspected of having GCA.

Other laboratory tests that may be abnormal includeliver function studies, which may show elevated enzymesbut no change in bilirubin. Blood counts may be low, anda modest microcytic, hypochromic anemia is common.

TEMPORAL ARTERY BIOPSY

To Biopsy or Not To Biopsy?1,3,8

GCA is a chronic disease.1 The exact reasons that move aphysician to treat the patient with corticosteroids are oftenlost in the mists of time and are further obscured bypatients,who may be persistent and insistent in their desireto be taken off the corticosteroids. It is reassuring to thephysician to have a positive temporal artery biopsy in therecords that justifies such treatment.8 There may be scarsof old arteritis rather than active arteritis, and it has beenshown that these arteritic remnants have the same diag-nostic significance as acute active arteritis. The issue ofwhether to treat does not rest entirely on the biopsyresults.A positive biopsy is a relief and justification, but anegative biopsy performed on one side may be followedby a positive biopsy performed on the opposite side. Fur-thermore, a negative biopsy with an elevated ESR maysuggest diabetes mellitus, infection, or malignancy as analternative diagnosis.14


27

When To Biopsy

It is obvious that a biopsy should be done as soon as pos-sible. However, in the event that the performance of abiopsy is delayed, there should be no delay in beginningcorticosteroid treatment if you are serious about the diag-nosis.There is little or no risk of masking the biopsy evi-dence of arteritis by treatment.4,9 Furthermore, promptimprovement of symptoms with the use of corticosteroidsis evidence in favor of the diagnosis of GCA.Ten to 15%of patients with negative biopsies are subsequently foundto have GCA. Biopsy is not a risk factor for scalp necrosisor brain ischemia.

Treatment of GCA consists of oral corticosteroids.2,3 Ithas been suggested that patients with GCA who presentwith transient visual loss or arteritic anterior ischemicoptic neuropathy should be treated with high-dose corti-costeroids (1,000 mg intravenous methylprednisolonedaily for a week) rather than oral corticosteroids.Althoughthis has not been subjected to a prospective randomizedtreatment trial, the potential for blindness as an end pointwith GCA makes it unlikely that any such study will everbe carried out.

How To Treat GCA

The corticosteroid dosage regimen remains controversial,but two things are clear. First, the dose of corticosteroid(usually prednisone) should be adequate to relieve allsymptoms and to rapidly lower the ESR and CRP tonormal. Second, every other day steroids are not effective in the

treatment of GCA and should never be used either initiallyor in the tapering phase.10 Initially, the patient should beseen monthly, and ESR and CRP should be done at eachvisit. Review the patient’s symptoms and begin a very slowtaper only after the patient’s ESR, CRP, and symptomshave been stable for 2 to 3 months.3,11 You may want toturn the patient over to the care of a physician who isfamiliar with the treatment of patients with GCA. Thelong-term treatment and management of GCA with non-steroidal alternative medications are not within the scopeof a neurologic emergency text. Consider GCA to be achronic disease and that it may need to be treated for 2 ormore years.11 Clearly, the treatment of other diseases maybe affected adversely by the chronic use of corticosteroids.Furthermore, these are older patients who are at risk ofosteoporosis and hip and vertebral fractures that maydevelop rapidly after being treated with oral cortico-steroids.

TYPICAL CASE

Figure 2 shows the optic discs of an 83-year old womanwho had abrupt onset of painless visual loss (left eye) withnormal vision (right eye). She complained of “trash” inthe eye. She had no pain in her shoulders or hips and nofever, night sweats, or weight loss. She had, however,recent onset of pain in the neck and pain in the jawswhen she chewed meat. She had been given COX-2inhibitors for arthritis. Despite a normal erythrocyte sed-imentation rate of 13, a temporal artery biopsy was done.The results of the biopsy were positive.


28


29

Figure 2-2A and 2-2B Typical appearance of ischemic optic neu-ropathy caused by giant cell arteritis. The left disc is pale andswollen, and there are a few splinter hemorrhages. Of specialnote in the right eye are the nerve fiber layer infarcts superiorlyand nasally from the disc. This is a sign of retinal ischemia in the“nonaffected” right eye and the infarcted disc in the left eye. Thelack of clarity of both discs and vessels is due to cataracts.

A

B

OD

OS


30

CONCLUSION

The key to prevention of crippling visual loss owing toGCA is immediately starting the patient on oral or intra-venous corticosteroids.Treatment should be begun beforethe temporal artery biopsy; even if the ESR is normal, thepatient should be given corticosteroids if the clinical pic-ture is strongly in favor of the diagnosis. Furthermore, ifthe patient has transient monocular visual loss or anteriorischemic optic neuropathy, round the clock, four times perday, intravenous 250 mg doses of methylprednisoloneshould be used to prevent infarction or to prevent the sec-ond eye from being infarcted.15

REFERENCES

1. Caselli RJ, Hunder GG,Whisnant JP. Neurologic disease inbiopsy-proven giant cell (temporal) arteritis. Neurology1988;38:352–9.

2. Corbett JJ, Melms A. Giant cell arteritis and polymyalgiarheumatica. In: Brandt T, Caplan LR, Dichgans J, et al, edi-tors. Neurological disorders: course and treatment. Acade-mic Press; 2003. p. 475–81.

3. Goodwin J.Temporal arteritis. In: Pinken PJ, Bruyn G, edi-tors. Handbook of clinical neurology. Vol. 39. New York:American Elsevier Co. p. 313–42.

4. Guevara RA, Newman NJ, Grossniklaus HE. Positive tem-poral artery biopsy 6 months after prednisone treatment.Arch Ophthalmol 1998;116:1252–3.

5. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifes-tations of giant cell arteritis. Am J Ophthalmol 1998;125:509–20.

6. Desmet GD, Knockaert DC, Bobbaers HJ.Temporal arteri-tis: the silent presentation and delay in diagnosis. J InternMed 1990; 227:237–40.

7. Ghanchi FD, Dutton GN. Current concepts in giant cell(temporal) arteritis. Surv Ophthalmol 1997;42:99–123.

8. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giantcell arteritis: validity and reliability of various diagnostic cri-teria.Am J Ophthalmol 1997;123:285–95.

9. Beevers DG, Harpur JE,Turk KAD. Giant cell arteritis.Theneed for prolonged treatment. J Chron Dis 1973;26:571–84.

10. Caselli RJ, Daube JR, Hunder GG,Whisnant JP. Peripheralneuropathic syndromes in giant cell (temporal) arteritis.Neurology 1988;38:685–9.

11. Caselli RJ. Giant cell (temporal) arteritis: a treatable cause ofmulti-infarct dementia. Neurology 1990;40:753–5.

12. Hall S, Hunder GG. Is temporal artery biopsy prudent?Mayo Clin Proc 1984;59:793–6.

13. Achkar AA, Lie JT, Hunder GG, et al. How does previouscorticosteroid treatment affect the biopsy findings in giantcell (temporal) arteritis? Ann Intern Med 1994;120:987–92.

14. Hunder GG, Sheps SG,Allen GL, Joyce JW. Daily and alter-nate day regimens in treatment of giant cell arteritis: com-parison in a prospective study. Ann Intern Med 1975;82:613–8.

15. Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cellarteritis: ocular manifestations. Am J Ophthalmol 1998;125:521–6.


31

32

CASE

C. P. is a 47-year-old woman who suddenly developedleft hemiplegia. On examination, she was alert and ori-ented and her eyes tended to the right, but she was able tocross midline.There was a dense left facial weakness, lefthemiplegia, and profound neglect of the left side.A Babin-ski’s sign was present on the left.A noncontrast head com-puted tomographic (CT) scan showed hypodensity of theright frontal and parietal lobes with edema, and a toxicol-ogy screen revealed the presence of cocaine.TranscranialDoppler ultrasonography demonstrated markedly reducedmean flow velocities of the right middle cerebral artery(MCA) and reversal of flow in the right anterior cerebralartery suggestive of a carotid occlusion, which was con-firmed by carotid ultrasonography.The following day, shewas lethargic but still arousable and able to follow simplecommands.That evening, a second CT scan of the headshowed a massive right MCA territory infarct. She wasmoved into the neurologic intensive care unit, where at4:00 am she was minimally responsive. Examinationrevealed her right pupil to be dilated to 6 mm and notreactive to light; her left pupil was dilated to 4 mm andsluggishly reactive to light. She withdrew her right armand leg normally to pain, adducted and flexed her leftarm, and showed a triple flexion response of the left leg.Both toes were upgoing. She was intubated, hyperventi-

CHAPTER 3

APPROACH TO THE COMATOSE PATIENT

Michael De Georgia, MD, and John Andrefsky, MD

lated, and treated with mannitol.A head CT scan demon-strated a massive right MCA territory infarct with 1.8 cmof anterior septal shift and temporal lobe herniation. Adecompressive right hemicraniectomy was done immedi-ately. Postoperatively, she was arousable but followed nocommands.

INTRODUCTION

Consciousness is difficult to define but may be thought ofas the awareness of self and the environment. Physiciansare often called on to evaluate reduced level of conscious-ness, the extreme of which is coma or no awareness of selfor environment. Coma is not a disease in itself but isalways a symptom of an underlying disorder. Sometimesthe underlying disorder is obvious (eg, severe headtrauma).More often the patient is found comatose, and lit-tle information is available. The evaluation must beapproached methodically, leaving none of the commonand treatable causes of coma unexplored.The following isa review of the anatomy of consciousness, terms used todescribe consciousness, and a general approach to thecomatose patient, including a review of brain herniation.

ANATOMY OF CONSCIOUSNESS

The ascending reticular activating system is a poorlydefined group of neurons that make up the central core ofthe brainstem, extending from the lower medulla to theupper midbrain and diencephalon.These neurons projectwidely to the entire cerebral cortex. Consciousness comesfrom the cortex (Figure 3-1).To cause coma, there must

Approach to the Comatose Pat ient

33

be bilateral and diffuse cortical disease or brainstem diseasethat disrupts the ascending reticular activating system(Table 3-1). Bilateral and diffuse cortical disease can occurfrom a number of different causes, for example, bilateralinfarcts (cardiac sources of emboli) or bilateral hemor-rhages (subdural hemorrhages following trauma or associ-ated with anticoagulation). Patients with metabolic disor-ders are included in this category of “bilateral disease”because both hemispheres are subjected to the chemicalalteration.Patients with bilateral and diffuse cortical diseaseoften do not have focal or lateralizing neurologic signs.


34

Figure 3-1 The ascending reticular activating system.


35

Large space-occupying unilateral lesions of the hemi-spheres (ischemic infarcts with edema, hemorrhages,tumors) can impair consciousness by directly extendinginto the diencephalon or by causing horizontal and down-ward displacement of the diencephalon–upper brainstemstructures.This displacement may occur with or withoutactual “herniation” of brain tissue (see “Brain HerniationSyndromes”). Patients with unilateral hemispheric lesionsdo have lateralizing neurologic signs.A number of lesionsthat directly affect the ascending reticular activating systemin the brainstem (infarct, hemorrhage) can result in coma.In this group of patients, the focality of signs, such as

Table 3-1 Two Mechanisms of Coma:Bihemispheric versus Brainstem

Bihemispheric disease

Bilateral or diffuse lesions

Directly affect both hemispheres (including metabolic and systemic disorders)

Unilateral lesions

Directly extend into the diencephalon or indirectly cause lateral and downward displacement of thediencephalon

Brainstem disease

Directly impair the ascending reticular activating system

abnormal pupillary reactions and eye movements, pointsto the presence of a serious brainstem structural lesion.

GRADING LEVELS OF CONSCIOUSNESS

Terms such as “confusion,”“lethargy,”“obtundation,” and“clouding of consciousness” can be ambiguous. Althoughthere are infinite degrees of depressed consciousness, it issimplest to use four categories: alert, somnolent, stuporous,and comatose. Somnolent patients are sleepy and apatheticand often have difficulty cooperating with the examina-tion. Stupor denotes the inability to sustain a wakeful statewithout some external stimulation. Comatose patientscannot be aroused even by strong, painful stimuli.

DIAGNOSIS AND MANAGEMENT OF COMA

General Medical Examination

When evaluating a comatose patient, the physician mustalways begin by doing a quick general medical examina-tion: airway, breathing, and circulation (Figure 3-2). Doesthe patient have an adequate airway? Is the patient breath-ing on his/her own? Endotracheal intubation should bedone in patients without an adequate airway to preventupper airway obstruction or aspiration. Mechanical venti-lation is needed in those with no spontaneous respirationor ineffective respiration (shallow breathing). Does thepatient have a pulse and an adequate blood pressure?Ensuring hemodynamic stability takes precedence overdetermining the cause of coma in the first few minutes.


36


37

Figure 3-2 General medical examination. IV= intravenous.

Neurologic examination

No

Begin cardiopulmonaryresuscitation

Yes

Draw blood and start IVThiamine 1−2 mg/kg IV push

D50W 1 amp IV pushNaloxone 0.01 mg/kg IV push

No

Beginrescue breathing

Yes

Does patienthave a pulse?

No

Create an airway

Yes

Is patient breathing?

Does patient have an airway?

Patient is comatose


38

The head should be inspected for any signs of trauma.Basilar skull fractures may be accompanied by periorbitalecchymoses (“raccoon eyes”), ecchymosis behind the ear(Battle’s sign), hemotympanum, and cerebrospinal fluid(CSF) rhinorrhea or otorrhea. Examination of the opticfundi may demonstrate papilledema with increasedintracranial pressure or subhyaloid hemorrhages in the set-ting of subarachnoid hemorrhage. Common reversiblecauses of coma include hypoglycemia and drug intoxica-tion. Signs of meningeal irritation (neck stiffness on for-ward bending,Kernig’s and Brudzinski’s signs) can be seenin both bacterial meningitis and subarachnoid hemor-rhage but may be absent in deeply comatose patients.Patients in the emergency department about whom youknow little should receive a bolus of 50% glucose (alwaysdrawing off a blood sample before) and thiamine; glucoseinfusion in the setting of thiamine deficiency (such as inan alcoholic patient) can precipitate Wernicke’s en-cephalopathy. Naloxone (Narcan) can be used to reverseopiates if a narcotic overdose is a possibility, and flumaze-nil (Romazicon) can be used to reverse benzodiazepines.

Neurologic Examination

The neurologic examination is critical and should bedirected at differentiating between the two main mecha-nisms of coma: bihemispheric disease and brainstem dis-ease (Figure 3-3). Simply watching the patient for aminute yields considerable information. The brainstemsets posture: the position of the head and eyes; the rate,depth, and rhythm of respiration; and postures of the limbs


39

and body.Therefore, patients who look comfortable andare moving spontaneously and breathing easily likely donot have significant brainstem involvement. Patients wholook uncomfortable and have unnatural posturing move-ments and abnormal breathing patterns are likely to havebrainstem disease.

The state of responsiveness should be estimated bynoting the patient’s reaction to calling his/her name,simple commands, or noxious stimuli. Focal lesions canusually be detected, even in comatose patients. A lack ofrestless movements on one side, for example, suggestshemiparesis. With hemispheric lesions, the eyes may beturned away from the paralyzed side (toward the lesion),and with brainstem lesions, the eyes may be turned towardthe paralyzed side (away from the lesion).The most usefulindicators of brainstem function are pupillary size andreactivity, eye movements, and breathing patterns. Thesefunctions are largely dependent on the integrity of themidbrain and upper pons and can be used, when com-bined with motor responses, to differentiate betweenbihemispheric disease, in which they will be normal, andbrainstem disease, in which they will be abnormal.

Pupils

Pupil reactivity to light, symmetry, and size should beobserved. Pupil size is a balance between parasympatheti-cally mediated constriction and sympathetically mediateddilation. Pupils that are reactive to light, symmetric, and ofnormal size (roughly 3–5 mm in diameter) in a comatosepatient generally suggest bihemispheric disease. Pupillary


40

Pu

pils

• R

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ive

to li

ght

• S

ymm

etric

• N

orm

al s

ize

• S

pont

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)•

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r oc

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uch

• C

ough

/gag

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• N

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tern

• S

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• W

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Bra

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n: i

s th

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rain

stem

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Figu

re 3

-3N

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amin

atio

n.


41

• N

ot r

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ive

to li

ght

• A

sym

met

ric•

Abn

orm

al s

ize

(ver

y la

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or v

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• N

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neou

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ents

•

Dys

conj

ugat

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Abn

orm

al o

culo

ceph

alic

or

ocu

love

stib

ular

ref

lexe

s•

No

blin

k to

cor

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touc

h•

No

coug

h/ga

g pr

esen

t•

Abn

orm

al r

espi

rato

ry p

atte

rn (

cent

ral n

euro

geni

c hy

perv

entil

atio

n,

apn

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)

• N

o sp

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• F

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on o

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Bra

inst

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(Bra

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ause

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oma)

Pu

pils

Eye

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ents

an

d o

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b

rain

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re

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Mo

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ion

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Figu

re 3

-3C

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reactions are usually normal with coma owing to drugintoxications, but important exceptions include opiates,which cause pinpoint pupils, and barbiturates,which causesmall pupils, around 1 to 2 mm in size. Poisoning withatropine or atropine-like drugs (including tricyclic anti-depressants) is characterized by dilated and fixed pupils.

Pupils that are not reactive to light or are asymmetricin size, very large, or very small are likely to occur inpatients with brainstem disease. A unilaterally enlargedpupil (> 5 mm diameter) is the most important and local-izing sign of brainstem involvement, usually signifyingprogressive displacement of the midbrain and stretching orcompression of the oculomotor nerve (see “Brain Herni-ation Syndromes”). With massive midbrain lesions thatdisrupt both parasympathetic and sympathetic fibers, bothpupils become fixed at about 4 mm (midposition).Pontinetegmental lesions cause extremely small pupils (< 1 mm),with only a slight reaction to strong light.

Eye Movements and Other Brainstem Reflexes

Eye movements come from the brainstem.Therefore, if theeyes are moving, the brainstem (from the vestibular nucleiin the upper medulla–lower pons to the oculomotornucleus in the midbrain), at least to some degree, must beintact. Eyes that spontaneously rove back and forth pointto a bihemispheric cause of coma. Lateral and downwarddeviation of one eye suggests an oculomotor nerve palsy,and medial deviation suggests an abducens nerve palsy.Commonly, latent strabismus can be unmasked in stu-porous patients, and the eyes may appear dysconjugate


42

(“wall-eyed”). Conjugate deviation of the eyes away fromthe paralyzed limbs can be seen with large hemisphericlesions and toward the paralyzed limbs with unilateralpontine lesions.The eyes turn toward the convulsing sideof the body during a seizure (pushed away from theseizure focus) and may be turned down and inward (look-ing at the tip of the nose) with thalamic lesions and uppermidbrain lesions (Parinaud’s syndrome).

If the eyes are not moving on their own, then the physi-cian should try to make them move reflexively.The oculo-cephalic reflex (doll’s-eyes maneuver) is elicited by quicklyturning the head and consists of conjugate movement of theeyes in the opposite direction. This demonstrates theintegrity of all the ocular motor nerves and brainstem struc-tures and loss of cortical inhibition that normally suppressesthese movements. Remember to never rotate the neck of anunconscious patient unless you are absolutely sure that thereis no cervical fracture. If the eyes do not move with headturning or if a cervical fracture has not been excluded, astronger stimulus, such as instilling cold water into the ears(oculovestibular reflex or ice-water cold calorics), may beused. After making sure that the tympanic membrane isintact, the oculovestibular reflex is elicited by irrigating eachear canal with 10 mL of ice water.This will normally causeslow conjugate deviation of the eyes toward the irrigated earand compensatory nystagmus (fast component) away fromthe irrigated ear. In coma from bihemispheric disease, thefast “corrective” phase of nystagmus is lost, and the eyesremain tonically deviated toward the side irrigated withcold water. In coma from brainstem disease, no eye move-ment occurs and the eyes remain straight ahead.


43

The presence of other brainstem reflexes (blink at thepontine level and cough/gag at the medullary level) andnormal or Cheyne-Stokes respiration suggests an intactbrainstem.Cheyne-Stokes respiration is characterized by acrescendo-decrescendo pattern of periodic breathing reg-ularly alternating with periods of apnea.This pattern usu-ally indicates bilateral deep hemispheric or diencephalicdisease and has been attributed to an increased ventilatoryresponse to carbon dioxide causing hyperventilation.As aresult, the carbon dioxide concentration drops below thatrequired to stimulate the forebrain respiratory center andbreathing stops. Carbon dioxide then reaccumulates untilit exceeds the respiratory threshold, and the cycle repeatsitself. Cheyne-Stokes respiration is a complicated respira-tory pattern, and its presence generally indicates an intactbrainstem.

The absence of these brainstem reflexes or the pres-ence of abnormal breathing patterns (such as central neu-rogenic hyperventilation, apneustic breathing, or ataxicbreathing) suggests brainstem disease. Central neurogenichyperventilation is characterized by an increase in the rateand depth of respiration, which, at times, can seemmechanical. Central neurogenic hyperventilation localizesto the lower midbrain–upper pontine tegmentum and isthought to represent a release of respiratory control. Milddegrees of hyperventilation are common after any acuteneurologic event and in the setting of medical illness(pneumonia, atelectasis,metabolic acidosis and severe liverfailure) so that the diagnosis of central neurogenic hyper-ventilation is always one of exclusion.Apneustic breathing,characterized by a few rapid deep breaths followed by a


44

2- to 3-second pause at full inspiration, is usually seen inlow pontine lesions.Ataxic or Biot’s breathing, character-ized by chaotic and irregularly interrupted breathing withvarying rate and depth, is usually seen in medullary lesions.

Motor Responses

Spontaneous movements or normal withdrawal andabduction of the limbs to pain generally suggest an intactbrainstem. No spontaneous movement or abnormalextension and adduction of the limbs to pain (so-called“decerebrate posturing”) suggest brainstem disease. In itsfull form, decerebrate posturing consists of opisthotonos,tight clenching of the jaws, stiff extension and internalrotation of the arms and legs, and plantar flexion of thefeet. Bilateral midbrain or pontine lesions cause decere-brate posturing. Abnormal stereotypical flexion andadduction of the arms with extension and internal rota-tion of the legs (so-called “decorticate posturing”) are lesslocalizing but generally occur in hemispheric disease orupper midbrain lesions (classically above the red nucleus).Essentially, this is the same as spastic hemiplegia.

BRAIN HERNIATION SYNDROMES

When bilateral hemispheric mass lesions develop withinthe cranium, such as diffuse cerebral edema, bilateral sub-dural hematomas, or bilateral infarcts, the only availabledirection of expansion, given the symmetry of pressuresbetween the two sides, is downward toward the ten-torial opening (Figure 3-4A). The thalamus and upper


45

midbrain are then forced, en bloc, through the tentorialopening.This is referred to as “central herniation” (Figure3-4B). Conversely, when a unilateral hemispheric massdevelops within the cranium, such as an intracerebralhemorrhage or massive infarct, the direction of expansionis toward the opposite hemicranium through the subfalcialwindow. The more anterior structures are relatively free tomove, but the more posterior structures, close to the ten-torial opening, are confined; a shift of only a few millime-ters results in midbrain compression against the unyield-ing tentorial edge.With continued expansion of the mass,eventually the medial temporal lobe (uncus) can slip downthrough the tentorial opening to lie next to the midbrain.This is referred to as “uncal herniation” (Figure 3-4C). Inboth cases, actual herniation of brain tissue is probably arelatively late event. Similarly, an infratentorial mass, suchas a hemorrhage or tumor in the cerebellum, can expandupward and push the cerebellum up through the tentorialopening.

In patients with central herniation, there is often arostral-caudal deterioration of function. Early, there isconfusion, poor concentration, and drowsiness and eithernormal or Cheyne-Stokes respiration from compression ofthe diencephalon. The pupils become small and poorlyreactive to light. Eye movements and other brainstemreflexes, however, are generally preserved initially.BilateralBabinski’s signs and increased muscle tone can bedetected, and, later, patients may develop decorticate pos-turing. These signs then give way to more threateningsigns of brainstem disease: coma;fixed,midposition pupils;loss of oculocephalic and oculovestibular reflexes; central


46

neurogenic hyperventilation; decerebrate posturing; ataxicbreathing; and death.

Uncal herniation differs in that early unilateral pupil-lary dilatation (as the oculomotor nerve becomes trappedor compressed) accompanies or even precedes drowsiness.Subtle anisocoria with a sluggish light reaction or an ovalpupil can sometimes be seen hours before other signs


47

Figure 3-4 Brain herniation syndromes. A, Normal; B, centralherniation; C, uncal herniation.

A

B

C

appear. Eventually, consciousness worsens, and the uppermidbrain, particularly the cerebral peduncle, may bepushed against the opposite side of the tentorium, causinga Babinksi’s sign ipsilateral to the hemispheric lesion (theKernohan-Woltman phenomenon).

MANAGEMENT OF THE COMATOSE PATIENT

The main goal is to determine the mechanism of coma(bihemispheric versus brainstem) and underlying cause(eg, infarct, hemorrhage, metabolic). Diagnosis and treat-ment must proceed concurrently (Figure 3-5).The man-agement of airway and blood pressure takes precedenceover all other diagnostic and treatment measures. Shallowand irregular respirations, upper airway obstruction, andhypoxia require the establishment of a clear airway anddelivery of oxygen.Arterial blood gases and pulse oxime-tery should be done in all patients. Comatose patientsshould be placed on their side to prevent aspiration ofsecretions and emesis.The inability to protect against aspi-ration and the presence of hypoventilation or hypoxia arereasons for endotracheal intubation and mechanical ven-tilation.There is sometimes a tendency to delay intubationas long as possible in the hope that it will not be necessaryor to not “lose the neurologic examination.” It is alwaysbetter to intubate early rather than later, after the patienthas aspirated.

Two large-bore intravenous lines should be placedearly. In patients with tenuous venous access, a centralvenous catheter should be inserted (the femoral vein is the


48

quickest and safest route). A medical history should beobtained if possible, and blood samples should be drawnfor the determination of glucose, electrolytes, renal andliver function tests, coagulation studies, arterial blood gas,and a drug toxicology screen.Naloxone (Narcan), 0.4 mg,should be given intravenously if a narcotic overdose is sus-pected and flumazenil (Romazicon), 0.2 mg, if a benzodi-azepine overdose is possible. Infusion of 50% glucose(1 ampule or 50 mL of D50W) should be done empiricallyfor hypoglycemia; this must be supplemented with thi-amine.

Once the patient is hemodynamically stable, a briefneurologic examination should be able to differentiatepatients with a bihemispheric mechanism of coma, inwhom brainstem function will be normal, from those witha brainstem mechanism of coma, in whom brainstemfunction will be abnormal. Patients with bihemisphere-type coma should undergo a CT scan as soon as possible.Abnormal scans will fall into one of two categories: abnor-mal with operable lesions (such as a large intracerebralhemorrhage with mass effect amenable to evacuation;Table 3-2 and Figure 3-6) and abnormal with nonopera-ble lesions (such as diffuse cerebral edema without masseffect; Table 3-3 and Figure 3-7). If the CT scan is normal,a lumbar puncture should be performed to excludemeningitis and subarachnoid hemorrhage. If the CSF isnormal, further workup, including electroencephalogra-phy, may be necessary to exclude nonconvulsive statusepilepticus (Table 3-4 and Figure 3-8; see Chapter 4,“Approach to Status Epilepticus”).


49


50

Abnormal Normal

CT scan*

Brainstem is working(bihemispheric cause of coma)

Operable lesion(s) —consult neurosurgery

• Ischemic infarct(s) with mass effect (unilateral or bilateral)• Intracerebral hemorrhage(s) with mass effect (unilateral or bilateral)• Subdural or epidural hemorrhage(s) with mass effect (unilateral or bilateral)• Abscess(es) with mass effect (unilateral or bilateral)• Hydrocephalus• Subarachnoid hemorrhage

Inoperable lesion(s)—medical therapy

• Bilateral ischemic infarcts• Diffuse cerebral edema• Multiple abscesses without mass effect

*If CT scan is abnormal, then appropriate action should be taken (consult neurosurgeon, start antibiotics or corticosteroids, etc)

*If CT scan is normal, then further investigation is warranted, including lumbar puncture for cerebrospinal fluid analysis, toxicology screen, and electroencephalogram. The cause may still be bihemispheric disease, but the physician should re-examine the patient to make sure that brainstem function is indeed normal.

• Meningoencephalitis• Bilateral ischemic infarcts• Subarachnoid hemorrhage• Head trauma• Venous sinus thrombosis• Hypoxic/ischemic injury• Drugs and toxins• Electrolyte disturbances• Postictal state or nonconvulsive status epilepticus

Bihemispheric comawith normal CT scan

Figure 3-5 Diagnosis and treatment algorithm. CT = computedtomography; MRI = magnetic resonance imaging.


51

Abnormal Normal

Signs of herniation?

CT scan* MRI

No

Yes

Brainstem is not working(Brainstem cause of coma)

1. Call neurosurgeon2. Intubate and hyperventilate to Pco2 25–30 mm Hg3. Mannitol 20% 1 g/kg IV

Operable lesion(s)—consult neurosurgeon

• Ischemic infarct (basilar artery occlusion)• Abscess(es) with mass effect• Tumor• Hydrocephalus

Inoperable lesion(s)—medical therapy

• Ischemic infarcts• Intracerebral hemorrhage• Head trauma

*If CT scan is abnormal, then appropriate action should be taken (consult neurosurgeon, start antibiotics or corticosteroids, etc)

*If CT scan is normal, then further investigation is warranted, including lumbar puncture for cerebrospinal fluid analysis, toxicology screen, and electroencephalogram. The cause may still be bihemispheric disease, but the physician should re-examine the patient to make sure that brainstem function is indeed normal.

• Early ischemic infarct (basilar artery occlusion)• Meningoencephalitis• Subarachnoid hemorrhage• Diffuse axonal injury

Brainstem comawith normal CT scan

Figure 3-5 Continued.


52

Table 3-2 Bihemispheric Cause of Coma:CT Scan Abnormal with Operable Lesion

Disease Etiology Action to Take

Ischemic infarct(s) May be cardioembolic Define source and with mass effect or large artery disease treat accordingly (unilateral or (anticoagulation,bilateral) antiplatelet agent)

Consult neurosurgery forpossible ICP; monitorplacement and/orpossible decompressivecraniectomy

Intracerebral Multiple causes Define cause and treat hemorrhage(s) with including hyper- accordingly (manage mass effect (unilateral tension, arteriovenous hypertension, corrector bilateral) malformation, coagulopathy)

aneurysm, amyloid If sinus venous throm-angiopathy, bosis considered,coagulopathy, obtain MRI/MRV or trauma catheter angiography

Consult neurosurgery for possible evacuation

Subdural or epidural Most often from Define cause and treat hemorrhage(s) with trauma or accordingly (correct mass effect (unilateral coagulopathy coagulopathy)or bilateral) Consult neurosurgery

for evacuation anddrainage

Abscess(es) with Multiple causes, Define cause and treat mass effect including bacterial, accordingly (antibiotics)(unilateral or fungal, tuberculous, Consult neurosurgery bilateral) parasitic for possible drainage

and resection

Hydrocephalus May have multiple Define causecauses Consult neurosurgery

for ventriculostomyand drainage

Subarachnoid Most often from Consult neurosurgery hemorrhage aneurysm or trauma for management

CT = computed tomography; ICP = intracranial pressure; MRI = mag-netic resonance imaging; MRV = magnetic resonance venography.


53

Figure 3-6 Subdural hematoma with mass effect.

Table 3-3 Bihemispheric Cause of Coma:CT Scan Abnormal with Nonoperable Lesion


Bilateral ischemic Most often from Define source and infarcts cardiac source; treat accordingly

diffuse large artery (anticoagulation,disease (vasculitis) or antiplatelet agent)hypercoagulable state

Diffuse cerebral May have multiple Define cause and edema causes (infarct, treat accordingly

infection, trauma, (intubation, mannitol,anoxia, rapid corticosteroids)correction of hyperosmolar state)

Multiple abscesses Multiple causes, Define cause and treat without mass effect including bacterial, accordingly (antibiotics)

fungal, tuberculous,parasitic

CT = computed tomography.


54

Figure 3-7 Diffuse cerebral edema.

Table 3-4 Bihemispheric Cause of Coma:CT Scan Normal


Meningoencephalitis Bacterial, fungal, Define cause and treat tuberculous, viral, accordinglycarcinomatous,lymphomatous

Bilateral ischemic Most often from cardiac Define source and infarcts or hypercoagulable state. treat accordingly

CT scan may be normal (anticoagulation,early in course antiplatelet agent).

CT scan may benormal early.Diffusion-weightedMRI more sensitive

Continued


55

Subarachnoid Most often from aneurysm CT scan can be hemorrhage or trauma. CT scan my be normal. Requires

normal lumbar puncture andCSF analysis fordiagnosis

Consult neurosurgery for management

Head trauma Consult neurosurgery for management

Venous sinus Most often hypercoagulable Confirm diagnosis thrombosis state with MRI/MRV or

catheter angiography

Consult cerebrovascular specialist and/or inter-ventional neuroradiol-ogist and treat accord-ingly (eg, anticoagula-tion, local thromboly-sis)

Hypoxix/ischemic Most often after cardiac Supportive careinjury arrest

Drugs and toxins Multiple drugs Define cause (history,toxicology screen)and treat accordingly


Electrolyte Most common hypo- Define cause disturbances natremia, hypo- and (laboratory tests) and

hyperglycemia treat accordingly

Postictal state or Multiple causes EEG necessary for nonconvulsive diagnosisstatus epilepticus

Table 3-4 (continued)

CSF = cerebrospinal fluid; CT = computed tomography; EEG = elec-

troencephalogram; MRI = magnetic resonance imaging; MRV = mag-

netic resonance venography.


56

Figure 3-8 Nonconvulsive status epilepticus.

If the brainstem is abnormal (asymmetric, nonreactivepupils, dysconjugate eyes, irregular breathing, extensorposturing), then the cause is most likely related to brain-stem involvement. Brain herniation is a life-threateningemergency, and any sign of herniation (eg, a unilaterallydilating pupil) should prompt immediate treatment and acall to neurosurgery. The patient should be intubated (ifnot already) and hyperventilated to a carbon dioxide par-tial pressure of 25 to 30 mm Hg. Mannitol, 20% solution,should be given at a dose of 1 g/kg intravenously over10 to 20 minutes.The patient should then undergo a CTscan (or magnetic resonance imaging [MRI]) as soon aspossible.As with bihemispheric causes of coma, abnormal


57

scans will fall into one of two categories: abnormal withoperable lesions (pontine infarct from basilar artery occlu-sion amenable to thrombolysis;Table 3-5 and Figure 3-9)and abnormal with nonoperable lesions (such as a large

Table 3-5 Brainstem Cause of Coma:CT Scan Abnormal with Operable Lesion


Ischemic Most often from cardiac Define source and treat infarct source or vertebrobasilar accordingly (local intra-

large artery disease (basilar arterial thrombolysis for occlusion) basilar occlusion, anti-

coagulation, antiplateletagent)

Consult cerebrovascular specialist and/or inter-ventional neuroradiolo-gist for possible intra-arterial thrombolysis

Abscess Bacterial, fungal, tuberculous, Define cause and treat parasitic accordingly

Consult neurosurgery for possible drainage andresection

Tumor Multiple types Consult neurosurgery for management

Corticosteroids for swelling

Hydrocephalus May have multiple causes Define causeConsult neurosurgery for ventriculostomy anddrainage



58

Figure 3-9 Pontine infarct.

Table 3-6 Brainstem Cause of Coma:CT Scan Abnormal with Nonoperable Lesion


Ischemic infarct Most often from cardiac Define source and source treat accordingly

(anticoagulation,antiplatelet agent)

Intracerebral Most often from Define cause and treat hemorrhage hypertension accordingly (correct

coagulopathy)Care is usually supportive

Head trauma Care is usually supportive


hypertensive hemorrhage; Table 3-6 and Figure 3-10).Identifying the CT scan appearance of brain herniation iscrucial in the evaluation of a comatose patient (see Figure3-7). If the CT scan or MRI does not disclose any abnor-mality, then a lumbar puncture should be performed toexclude meningitis and subarachnoid hemorrhage. It isimportant, however, in patients who are comatose with abrainstem-type coma and a normal CT scan, that basilarartery occlusion is not missed. This diagnosis, which istreatable with thrombolysis, must be definitively excludedwith vascular imaging (Table 3-7).


59

Figure 3-10 Pontine hemorrhage.

CONCLUSION

Coma is often mysterious, frightening, and catastrophic.Because the anatomy of consciousness is relativelystraightforward, the evaluation of coma should also be


60

Table 3-7 Brainstem Cause of Coma:CT Scan Normal


Early ischemic Most often from cardiac CT scan may be normal infarct source or vertebro- early. If possible basilar

basilar atherosclerotic occlusion must bedisease (basilar definitively excluded occlusion) with vascular study

(TCD, MRA, orangiogram)

Empirically, bolus with heparin if suspicion ishigh

Meningoencephalitis Bacterial, fungal, Define cause and treat tuberculous, viral, accordinglycarcinomatous,lymphomatous

Subarachnoid Most often from CT scan can be normal.hemorrhage aneurysm or trauma. Requires lumbar

CT scan may be puncture and CSF normal analysis for diagnosis

Consult neurosurgery for management

Diffuse axonal Most often from head Care is usually injury trauma supportive

CSF = cerebrospinal fluid; CT = computed tomography; MRA = mag-netic resonance angiography;TCD = median tissue culture dose.

straightforward. Consciousness comes from the cerebralcortex. Disruption of the cortex or the reticular activatingsystem ascending from the brainstem is necessary to pro-duce coma. With a brief neurologic examination, oneshould be able to differentiate between these two mainmechanisms of coma: bihemispheric disease or brainstemdisease. Brain imaging studies (CT scan or MRI) areneeded to define the exact cause within each category.Scans will be either abnormal with operable lesions,abnormal with nonoperable lesions, or normal. It isimportant to act quickly when stabilizing the patient,obtaining and acting on the scan, and continuing the eval-uation until the exact cause has been identified and treat-ment started.

RECOMMENDED READINGS

Fisher CM. The neurological examination of the comatosepatient.Acta Neurol Scand Suppl 1969;3–56.

Fisher CM. Acute brain herniation—a revised concept. SeminNeurol 1984;4:417–22.

Fisher CM. Brain herniation: a revision of classical concepts.Can J Neurol Sci 1995;22:83–91.

Plum F, Posner JB. Diagnosis of stupor and coma. 3rd ed.Philadelphia: F.A. Davis Company; 1980.


61

62

Status epilepticus is a medical emergency that must berecognized and treated quickly to prevent brain injury anddeath. Status epilepticus is the extreme end of a spectrumof seizure durations and frequencies, and cumulative neu-ronal damage develops with increasing duration or fre-quency of seizure activity.By definition,however, a seizurelasting longer than 30 minutes or two or more seizureswithin 30 minutes without the patient regaining con-sciousness between seizures constitutes status epilepticus.

Status epilepticus occurs most frequently in the veryyoung and old.The annual incidence of status epilepticusis about 50 cases per 100,000 per year, with one-third ofepisodes occurring in patients with known epilepsy inwhich withdrawal of antiepileptic medication or poorcompliance is the precipitating factor.Other causes includealcohol withdrawal, primary brain tumors, head injury,ischemic and hemorrhagic stroke, meningitis, encephalitis,and metabolic factors such as rapid and marked shifts inserum electrolyte concentrations.The following is a reviewof the clinical features of status epilepticus and a rationalapproach to this most feared type of seizure.

CLINICAL FEATURES

Generalized tonic-clonic status epilepticus is the mostcommon and potentially damaging form. A generalized

CHAPTER 4

APPROACH TO STATUS EPILEPTICUS

Michael De Georgia, MD, and John Andrefsky, MD

tonic-clonic seizure starts with a tonic contraction of thelimbs that lasts about 10 to 20 seconds (the tonic phase).The patient may violently arch the back and neck andscream as air is forced through the closed vocal cords.Thisis followed by repetitive relaxation of tone (the clonicphase). The clonic jerks gradually decrease in amplitudeand frequency over several minutes.Autonomic activity ishigh, and patients are usually hypertensive and tachycardic.Electroencephalography (EEG) demonstrates bilaterallysymmetric ictal discharges. Usually, a period of apnea thenbegins, ending with a deep inspiration and subsequentunconsciousness for minutes to hours (the postictal phase),followed by regaining of consciousness.

Patients in status epilepticus either continue to con-vulse or have intermittent seizures without regaining con-sciousness between seizures. After about 20 to 30 minutes,electromechanical dissociation may occur, that is, contin-uous electrographic sezuires with few clinical manifesta-tions except subtle lip or eyelid twitching (so-called non-convulsive status epilepticus). During this phase, systemicacidosis may result in reduced cardiac output, hypoten-sion, and reduced cerebral blood flow. Neuronal damageprobably results from glutamate-mediated excitotoxicityand the additive effects of impaired cerebral perfusion,hypoxemia, hyperthermia, and acidosis.

Distinguishing the patient who is postictal from theone who is in nonconvulsive status epilepticus can be dif-ficult clinically.The previous convulsive activity may nothave been witnessed,or only a brief seizure may have beenseen. Difficulty arises in the intensive care unit, wherepatients often have several reasons for altered conscious-

Approach to Status Epi lept icus

63

ness. A recent study showed that up to 10% of comatosepatients in an intensive care unit have nonconvulsive sta-tus epilepticus.When there is uncertainty, an EEG shouldbe done at the bedside.

Other forms of status epilepticus include absence sta-tus, focal motor status, and complex partial status. Thepatient with absence status may be confused or somnolent,with continuous or intermittent spike and slow-wave dis-charges on EEG.The patient with focal motor status hascontinuous jerking of certain muscle groups (epilepsiapartialis continua), whereas the patient with complex par-tial status often appears dazed and has automatisms (lipsmacking, repetitive hand movements).

APPROACH TO THE PATIENT WITH GENERALIZED TONIC-CLONIC STATUS EPILEPTICUS

General Management

Immediate intervention is crucial within the first minutesafter seizure onset.The first priority is airway managementbecause many patients develop airway obstruction or aspi-rate secretions (Figure 4–1). Airway obstruction can alsoworsen after antiepileptic medications are given (eg, ben-zodiazepines).The head should be positioned, the airwaysuctioned, and, if needed, an oral airway inserted. Oxygenshould be administered by nasal cannula or face mask.Endotracheal intubation and mechanical ventilationshould be done in patients without an adequate airwayand those with no spontaneous respiration or ineffectiverespiration (shallow breathing).Two large-bore peripheral


64


65

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intravenous lines should be inserted as soon as possible. Inpatients with tenuous venous access, a central venouscatheter should be inserted (the femoral vein is the quick-est and safest route).A medical history should be obtainedif possible. Blood should be withdrawn for a completeblood count and measurement of serum glucose, sodium,calcium, magnesium, blood urea nitrogen, anticonvulsantmedication levels, and a toxicology screen. Pulse oximetryor an arterial blood gas analysis should be done to ensureadequate oxygenation. If hypoglycemia is documented orsuspected, intravenous glucose (50 mL of 50% glucose)should be given (preceded by intravenous thiamine100 mg). All electrolyte abnormalities should be correctedcautiously, being careful not to “overcorrect.”For example,most patients with seizures develop metabolic acidosis.Bicarbonate should not be given, however, unless the pHis less than 7.0 because the risk of overcorrection and alka-losis may be greater than the risk of the acidosis itself.Patients should be adequately hydrated with normal salinebecause they often become dehydrated and there is a riskof rhabdomyolysis after vigorous muscle contraction.Patients with new-onset seizures should undergo com-puted tomographic scanning or magnetic resonance imag-ing. A cerebrospinal fluid analysis to exclude meningitis orencephalitis should be done if no cause of status has beenidentified.

Specific Treatment Plan

There are an infinite number of algorithms in the literaturefor treating status epilepticus. Sticking rigidly to one spe-


66

cific algorithm is less important than simply having a clearplan that one follows. Most patients with status epilepticuswill respond to therapy with a single antiepileptic drug.The longer seizures persist,however, the more difficult theyare to control.Benzodiazepines are the first line of therapy.There is little difference in the effectiveness of seizure con-trol between the benzodiazepines (lorazepam, diazepam,and midazolam). Lorazepam is started at a dose of0.1 mg/kg and a rate of 2 mg per minute until seizures stopor a total dose of 10 mg is reached. Diazepam is usuallystarted at a dose of 0.2 mg/kg at 4 mg per minute untilseizures stop or a total dose of 20 mg is reached.Lorazepamis more lipid soluble than diazepam and has a smaller dis-tribution phase, a slightly longer onset of action (2 to 3minutes instead of 1 to 2 minutes), and a longer duration,on average 6 hours compared with less than an hour withdiazepam (Table 4-1 and Figure 4-2).

Benzodiazepines should be followed immediatelywith phenytoin or fosphenytoin given as a 20 mg/kgloading dose to achieve a total level greater than 25 to30 mg/dL. The maximal rate of phenytoin delivery is50 mg/min (25 mg/min in elderly patients). Intravenousphenytoin is limited by complications such as infusion-sitereactions (phlebitis, tissue necrosis) and cardiovasculareffects (hypotension, cardiac arrhythmias). If significanthypotension develops, the infusion should be slowed orstopped.Fosphenytoin, a water-soluble prodrug of pheny-toin written as “phenytoin equivalents,” can be safelyadministered by rapid intravenous infusion (up to150 mg/min) or by intramuscular injection if there is novenous access.


67


68

Tabl

e 4

-1

Ant

iepi

lept

ic D

rugs

for

Sta

tus

Epil

epti

cus

Tim

eT

her

a-Load

-to

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ing

Ser

um

Sto

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um

Dose

IVH

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Sta

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leve

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rug

(mg/k

g)

Rat

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(min

)A

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)(L

/kg)

( �g/m

L)

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1 2

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8–24

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ot

(Ativ

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1–3

15–6

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2.6

0.5–

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69

Tabl

e 4

-1 (

Con

tinu

ed)

Tim

eT

her

a-Load

-to

Dura

-peu

tic

ing

Ser

um

Sto

ption

Pro

tein

Ser

um

Dose

IVH

alf-

Sta

tus

of

Bin

din

gV

Dle

vel

Dru

g(m

g/k

g)

Rat

elife

(min

)A

ctio

n(%

)(L

/kg)

( �g/m

L)

Fosp

heny

oin

20

150

mg/

10–1

5 h

10–3

0 12

–24

h90

–95

0.6–

0.7

10–2

0 (C

ereb

yx)

min

Phe

no-

20

100

53–

5–30

0.

5–10

h20

–45

0.5

10–4

0 ba

rbit

alm

g/m

in14

0 h

Pent

o-5–

100.

5–35

–10

–20

0.5–

35–5

51

20–5

0ba

rbit

al3

mg/

50 h

10 h

(Nem

buta

l)kg

/h

Pro

pofo

l2

5–10

40

–5–

10

Not

97

–99

60

Not

(D

ipri

van)

mg/

750

min

esta

blis

hed

esta

blis

hed

kg/h

IV =

int

rave

nous

;V

ol =

vol

ume

dose

.


70

15 m

inu

tes

5–10

min

ute

s

Adm

inis

ter

lora

zepa

m 0

.1 m

g/kg

IV

at a

rat

e of

2 m

g/m

in

(unt

il se

izur

es s

top

or m

axim

um 1

0 m

g).

If th

e pr

ecip

itatin

g ca

use

is n

ot k

now

n, p

atie

nts

shou

ld u

nder

go a

hea

d C

T;

if ba

cter

ial m

enin

gitis

is c

onsi

dere

d,

lum

bar

punc

ture

sho

uld

be p

erfo

rmed

.

Adm

inis

ter

phen

ytoi

n 20

mg/

kg IV

(ra

te m

g/m

in).

Blo

od p

ress

ure

shou

ld b

e cl

osel

y m

onito

red.

If hy

pote

nsio

n de

velo

ps, p

rovi

de b

olus

with

IV fl

uids

and

dec

reas

e th

e ra

te o

f inf

usio

n.

Figu

re 4

-2Th

e cl

onic

pha

se.

CT

= c

ompu

ted

tom

ogra

phy;

IV

= in

trav

enou

s.

One of the most common mistakes made in the treat-ment of status epilepticus is administering repeated dosesof benzodiazepines without treating the underlying pre-cipitating cause or starting a longer-acting antiepilepticdrug. Another common mistake is not giving enoughphenytoin or fosphenytoin.The usual loading dose of 1 gof phenytoin is usually insufficient for seizure control.

When seizure activity persists, another 5 to 10 mg/kgof phenytoin or fosphenytoin may be given.The next drugto use after that is controversial, and a neurologist, if notalready involved, should be consulted. Many recommendphenobarbital given as a loading dose of 10 to 20 mg/kgat a maximal rate of 100 mg/min to achieve a level of40 to 50 �g/mL. Phenobarbital is often used instead ofphenytoin in patients allergic to phenytoin and those withabnormal conduction patterns on electrocardiography.Several studies have shown intravenous midazolam, ashort-acting benzodiazepine commonly used for sedationin intensive care units, to be effective. Midazolam is givenas a loading dose of 0.15 mg/kg followed by an infusionof 0.05 to 4 mg/kg/h and is generally well tolerated.Recently, propofol, a very short-acting sedative agent, hasalso been shown to be effective. Propofol is given as abolus of 2 mg/kg followed by an infusion of 5 to10 mg/kg per hour (Figure 4-3).

Many centers proceed directly to pentobarbital, givenas a 5 to 10 mg/kg loading dose over an hour followed bya continuous infusion rate of 0.5 to 3 mg/kg per hour.Theinfusion rate should be adjusted to achieve a burst sup-pression pattern on bedside EEG (roughly aiming for 3 to10 bursts per minute).The main side effects of pentobar-


71


72

45 m

inu

tes

30 m

inu

tes

If se

izur

es c

ontin

ue, a

dmin

iste

r ad

ditio

nal

phen

ytoi

n 5−

10 m

g/kg

PE

IV.

Obt

ain

beds

de E

EG

.

If se

izur

es c

ontin

ue, i

ntub

ate

patie

nt(if

not

don

e al

read

y). M

ake

sure

that

ven

ous

acce

ss is

ade

quat

e an

d pl

ace

arte

rial l

ine.

Adm

inis

ter

phen

obar

bita

l 20

mg/

kg IV

(rat

e 10

0 m

g/m

in).

Blo

od p

ress

ure

shou

ld b

e cl

osel

y m

onito

red.

If hy

pote

nsio

n de

velo

ps, p

rovi

de b

olus

with

IV fl

uids

and

dec

reas

e th

e ra

te o

f inf

usio

n.

If h

ypot

ensi

on d

oes

not i

mpr

ove

with

fluid

cha

lleng

e, b

egin

vas

opre

ssor

drip

s(d

opam

ine

2−30

mg/

kg/m

in o

rph

enyl

ephr

ine

20−2

00 m

g/m

in)

Bed

side

EE

G s

houl

d be

hoo

ked

upan

d ru

nnin

g.

Figu

re 4

-3Th

e cl

onic

jerk

s gr

adua

lly d

ecre

ase.

EEG

= e

lect

roen

ceph

alog

ram

;IV

= in

trav

enou

s; P

E =

phe

nyto

in e

quiv

alen

ts.


73

60 m

inu

tes

If se

izur

es c

ontin

ue, a

dmin

iste

r pe

ntob

arbi

tal

5−15

mg/

kg lo

adin

g do

se fo

llow

ed b

yco

ntin

uous

infu

sion

rat

e 0.

5−3

mg/

kg p

er h

our.

Incr

ease

infu

sion

rat

e to

ach

ieve

burs

t sup

pres

sion

pat

tern

on

EE

G.

Mon

itor

bloo

d pr

essu

re c

ontin

uous

ly w

ithar

teria

l lin

e. T

reat

hyp

oten

sion

with

flui

ds,

vaso

pres

sor

agen

ts, o

r bo

th a

s in

dica

ted.

Mai

ntai

n pe

ntob

arbi

tal f

or 2

4 ho

urs,

then

decr

ease

dos

e gr

adua

lly, o

bser

ving

for

recu

rren

t sei

zure

s. If

nec

essa

ry, i

ncre

ase

dose

aga

in fo

r an

othe

r 24

hou

rs.

Fol

low

phe

nyto

in a

nd p

heno

barb

ital

leve

ls, m

aint

aini

ng th

em a

t hig

h ra

nge.

Con

tinue

eve

ry 1

2 to

24

hour

s to

wea

n pe

ntob

arbi

tal,

look

ing

for

unde

rlyin

g se

izur

e ac

tivity

.

Dur

ing

this

pha

se, m

etic

ulou

s in

tens

ive

care

man

agem

ent i

s re

quire

d in

clud

ing

mai

ntai

ning

hem

odyn

amic

sta

bilit

y an

dad

equa

te o

xyge

natio

n an

d ve

ntila

tion.

Pat

ient

s sh

ould

rec

eive

pro

phyl

axis

aga

inst

deep

ven

ous

thro

mbo

sis

and

gast

ric u

lcer

s.P

ulm

onar

y in

fect

ions

are

com

mon

: pat

ient

ssh

ould

be

suct

ione

d fr

eque

ntly

.

Figu

re 4

-4Th

e po

stic

tal p

hase

. EE

G =

ele

ctro

ence

phal

ogra

m.

bital are respiratory and myocardial depression.All patientsneed to be intubated and mechanically ventilated. Patientsshould have central venous access and, ideally, an arterialcatheter for continuous blood pressure monitoring.Intravascular volume should be maintained with intra-venous fluids. Vasopressor agents (dopamine or phenyl-ephrine) are almost always required in patients in burstsuppression with pentobarbital (Figure 4–4).

CONCLUSION

The clinical outcome of status epilepticus largely dependson the underlying cause of seizures. Prompt and appro-priate treatment, however, significantly reduces mortalityand morbidity. Therapeutic and diagnostic measures aredone simultaneously to stop the seizure as quickly as pos-sible. Most importantly, a predetermined specific treat-ment plan is needed.


DeLorenzo RJ, Pellock JM,Toen AR, Boggs JG. Epidemiologyof status epilepticus. J Clin Neurophysiol 1995;12:316–25.

Lowenstein DH, Alldredge BK. Status epilepticus at an urbanpublic hospital in the 1980s. Neurology 1993;43:483–8.

Meldrum B. Metabolic factors during prolonged seizures andtheir relation to nerve cell death. Adv Neurol 1983;34:261–75.

Meldrum B. Excitotoxicity and epileptic brain damage. EpilepsyRes 1991;10:55–61.

Parent JM, Lowenstein DH.Treatment of refractory generalizedstatus epilepticus with continuous infusion of midazolam.


74

Neurology 1994; 1837–40.Proposal for revised clinical and electroencephalographic classi-

fication of epileptic seizures: from the Commission on Clas-sification and Terminology of the International LeagueAgainst Epilepsy. Epilepsia 1981;22:498–501.

Treiman DM,Meyers PD,Walton NY,et al.A comparison of fourtreatments for generalized convulsive status epilepticus. NEngl J Med 1998;339:792–8.


75

76

Acute and rapidly progressive lesions of the spinal cordconstitute a medical emergency. Failure to recognize andrapidly treat lesions compressing the spinal cord oftenleads to permanent paralysis and, especially in the case ofcervical injuries, death.The signs and symptoms of cordcompression, whether by trauma, tumor, or abscess, con-sist of (1) pain localized to the area of cord involvement orin a root distribution related to the level of involvement,(2) limb weakness at and below the level of the lesion, (3)paresthesias in the distribution of a nerve root, and (4)bladder and bowel dysfunction.

CORD TRAUMA

The occurrence of cord trauma is often hidden becausecord trauma is only part of multiple injuries in 75 to 80%of cases. Persons with head injury and persons with mul-tiple trauma from motor vehicle accidents or falls fre-quently also sustain neck or other spine trauma, andunless precautions are made to prevent movement of thespine until it is clear that the spine is intact, further seri-ous cord damage may occur.1 Persons involved in motorvehicle accidents who are dazed or unconscious shouldhave their neck and spine immobilized if possible beforethey are moved, and immobilization should be main-tained until it is established that major spine injury has

CHAPTER 5

SPINAL CORD EMERGENCY CONDITIONS

Rober t M. Herndon, MD

not occurred. Over half of spine injuries are cervical, andbecause these are the most serious, special attention tothis region is important. Spine immobilization proceduresare taught to paramedics, and this has resulted in a verysignificant decrease in the number of cases in which fur-ther cord injury has been done following an accident.Most cervical fractures in the young and middle-aged arein the mid– to lower cervical spine; however, in thoseover 70 years who fall and fracture the cervical spine, themajority are high cervical or odontoid in location.2 Mostcervical fractures are visible on cervical radiographs, but,if in doubt, computed tomography (CT) will usuallyshow them. Magnetic resonance imaging (MRI) is goodfor showing cord damage but is relatively poor for show-ing damage to the vertebrae.3

High cervical cord and craniocervical junctioninjuries are particularly dangerous because they oftenresult in respiratory paralysis.Even small movements of theneck when facing a high cervical or odontoid fracture canlead to respiratory arrest. Remember that “C3, 4, and 5keep the diaphragm alive,” and, of course, the intercostalmuscles are supplied by the thoracic cord, so high cervicalcord injury leads not only to quadriplegia but also to res-piratory failure. Intubation and management of respiratorycollapse in patients with fractured spines must be in thehands of very experienced anesthesiologists and shouldnot be undertaken by the novice. It is possible to maintainrespiration with an Ambu bag until competent qualifiedpersonnel take over.

In lower cervical cord injury, proximal arm functionmay remain. Lesions in the thoracic or upper lumbar cord

Spinal Cord Emergency Condi t ions

77

lead to paralysis below the level of the lesion and rarelycause respiratory problems, although high thoracic lesionscan result in reduced pulmonary capacity owing to inter-costal muscle paralysis.

Hemisection of the cord leading to Brown-Séquard’ssyndrome (Figure 5-1) can occur with cord trauma owingto stab wounds or gunshot wounds and occasionallyowing to rotational fractures of the cervical spine. Thisresults in weakness or paralysis and loss of position andvibration ipsilateral to the lesion and loss of pinprick andtouch on the opposite side beginning two to three seg-ments below the level of injury.This is because the painfibers cross just anterior to the central canal one to threesegments above the point of entry to ascend in the ven-trolateral cord on the opposite side.

Anterior spinal artery occlusion is only rarely directlyrelated to trauma. It occurs more commonly owing tothrombosis of the great radicular artery of Adamkiewiczand may be seen following aortic surgery. This leads toinfarction of the anterior two-thirds of the spinal cordwith paraplegia and loss of pain and temperature sensationwith preservation of position and vibration below thelesion.

In cases of spinal cord injury, if the patient is con-scious, in most cases, a pinprick sensory level will providefairly accurate information regarding the level of theinjury. In some cases, particularly with inflammatory andchronic cord lesions, the sensory level may simply set alower limit on the area of involvement, but in trauma,local root involvement will usually indicate the level of thelesion quite accurately. If you find a sensory level, the


78


79

Figure 5-1 Example of Brown-Séquard’s syndrome from hemi-section of the left side of the spinal cord at about T9. Hatchmarks indicate an area of pain and temperature loss; cross-hatch indicates an area of upper motoneuron paralysis and pro-prioceptive loss.

lesion will be at or above that level. It is important to real-ize that the pain fibers cross to the other side just ventralto the central canal within about three segments fromtheir point of dorsal root entry. It is also important toremember that the vertebral level and the cord level arenot the same in the lower thoracic and lumbar regionsbecause the cord ends at about L2.Thus, lesions below thislevel compress the cauda equina, not the cord itself, andlesions at T12 and L1 will injure the lowermost segmentsof the lumbar cord.

Traumatic spinal injury is treatable, and with propermanagement, considerable improvement can be expected.Rapid stabilization of the neck or back with rapid surgicaldecompression when indicated will minimize the long-term disability. Currently the standard of care, Methyl-prednisolone, at a dose of 30 mg/kg as a bolus followed byan infusion at 4 mg/kg/h for 23 hours, has been recom-mended4 but is somewhat controversial.5

TUMORS AND METASTASES AFFECTING THE SPINALCORD

With the increasing longevity of patients with malignan-cies, the incidence of spread of tumor to involve vertebraeand the spinal canal has increased. Signs and symptoms ofspinal metastases are easy to miss in cancer patients withgeneralized weakness and diffuse pain.The occurrence ofnew spinal or neck pain in these patients, which persistseven while lying down, even if relieved by analgesics,deserves investigation. If the patient develops limb weak-ness, bowel or bladder incontinence, or paresthesias in a


80

nerve root distribution, it is an oncologic emergency.Depending on the level of the lesion, such patients canbecome paraplegic or quadriplegic extremely rapidly.Physical examination, plain films of the spine that willshow lytic or blastic lesions in vertebrae, and an MRIdirected to the spinal level found by clinical examinationor on the plain films will lead to definition of the lesion.If MRI is unavailable, CT will usually define the lesion.CT myelography and lumbar puncture should be avoidedbecause they can greatly aggravate the injury by removingthe protection provided by the cerebrospinal fluid pres-sure, which helps protect the cord from compression andspinal cord herniation (Table 5-1).6

In most cases, rapid institution of radiotherapy at thetime of discovery of the lesion will shrink the lesion andpreserve cord function. If the patient worsens after radia-tion therapy or the tumor is radioresistant, surgical decom-pression is indicated.This is urgent because failure of radi-ation to decompress the cord can lead to major permanentdeficits. Of those patients who are diagnosed and appro-priately treated while still ambulatory, 94% remain ambu-latory until terminally confined.

Primary extramedullary tumors involving the cordpresent with signs and symptoms essentially the same asthose with metastases, except the onset is usually much lessdramatic and may occur over many months or years. Painthat is unrelieved by lying down and radicular pain arevery common complaints.Table 5-2 lists the most com-mon primary extramedullary tumors affecting the cord.

It should be evident that a diagnosis or family historyof neurofibromatosis should provide a high index of sus-


81


82

picion for neurofibroma as the source when there is evi-dence of cord compression.

INTRAMEDULLARY CORD TUMORS

Primary intramedullary cord tumors often extend overmany segments. If the tumor is confined to a few seg-ments, the symptoms will usually be similar to those of

Table 5-1 Frequency of Metastatic TumorsCompressing the Spinal Cord

Tumor %

Carcinoma of the breast 25.5

Carcinoma of the lung 22.4

Lymphoma 7.8

Sarcoma 7.5

Carcinoma of the prostate 7.2

Hypernephroma 6.8

Carcinomas of the gastrointestinal tract 5.0

Multiple myeloma 4.4

Unknown primary 7.8

Miscellaneous 5.6

Adapted from Schutta H.6


83

extramedullary tumors except that they may be painless.The more common presentation is with a mixed sensoryloss. Pain may be a symptom if there is root entry zoneinvolvement, but many are painless. Intramedullary metas-tases to the spinal cord can occur but are rare.They pres-ent like primary intramedullary tumors but usuallyprogress more rapidly and are much rarer thanextramedullary metastases. Involvement of the pain fibersthat cross just anterior to the central canal will often givepain and temperature loss over several segments similar tothat seen in syringomyelia.As the tumor expands, the longmotor and sensory tracts may become involved, but thedorsal column sensory fibers from the sacral area are veryperipheral in the cord and are often spared.This so-called

Table 5-2 Most Common Primary ExtramedullaryTumors Affecting the Spinal Cord

Tumor %

Neurofibroma and schwannoma 29

Meningioma 26

Ependymoma 13

Miscellaneous 12

Astrocytoma 7

Metastatic and other 13

Adapted from Schutta H.6

sacral sparing is a good indication of an intramedullarycord lesion. Syringomyelia, which is a fluid-filled cavitygenerally found in the cervical cord, behaves in a mannervery similar to intramedullary tumors, with loss of painand temperature in the upper extremities, muscle wasting,usually in the intrinsic hand muscles, and reflex asymme-try and loss. Intramedullary metastases, usually from lungor breast carcinoma in advanced stages, behave like pri-mary intramedullary tumors except that they tend to growmuch faster.

The prognosis for most intramedullary cord tumors ispoor.They are generally not amenable to surgical therapyand usually are relatively resistant to radiation andchemotherapy. In the case of metastatic disease, they maybe relatively radiosensitive, but the majority of suchpatients have multiple metastases, and the survival rate ispoor. Nevertheless, radiation may preserve function longenough to be worthwhile in some cases.

INFLAMMATORY AND INFECTIOUS DISORDERS OF THESPINAL CORD

Transverse myelopathy (transverse myelitis) is an inflammatorydemyelinating condition of the spinal cord. It may be eitherpainful or painless and typically involves two to five cordsegments, although much longer regions of involvementcan occur.There are multiple etiologies.Many cases of mul-tiple sclerosis begin with a transverse myelitis. It also can beseen as a manifestation of a systemic disease, such as lupuserythematosus. It is marked by weakness and sensory lossbelow the level of the lesion, usually with a clear sensory


84

level to pinprick.The lesion may be partial or complete. Itis typically fairly symmetric and usually evolves over aperiod of a few hours to a few days, although, in rare cases,it can progress slowly for a week or two.Cerebrospinal fluidexamination may reveal an increase in white cells, predom-inantly lymphocytes, and there may be an increase in pro-tein or gammaglobulin G. Rarely, cord swelling will be sosevere that a cerebrospinal fluid block will occur and thecerebrospinal fluid protein will be very high. In such cases,cord necrosis from compromise of the blood supply sec-ondary to compression may be seen.An MRI of the spinewill show a high signal on T2-weighted images usuallyextending over several segments.Treatment with high-dosesteroids, such as 1 g of methylprednisolone daily for 3 to10 days, is warranted.Additionally, a search for underlyingsystemic disease is indicated.Transverse myelopathy is gen-erally seen in the second to fifth decades and is rare in chil-dren and older adults.

Epidural and paraspinal abscesses extending into theepidural space are rare but, if not recognized and treated,can cause cord compression or infarction and will oftenresult in paraplegia or quadriplegia.7,8 Paraspinal abscessesmay be acute or chronic.They are usually seen on a back-ground of chronic illness with impaired immunity or fol-lowing surgery, epidural anesthesia, or epidural catheterplacement for analgesia.9 Causes of impaired immunityinclude human immunodeficiency virus (HIV) infection,diabetes, chronic leukemias, lupus, and alcoholism.Epidural abscesses are more common in the thoracic andlumbar spine than in the cervical spine. They typicallypresent as severe localized spinal pain requiring narcotics


85

for pain control, and, initially, this may be the only indica-tion of the presence of an abscess.The source of infectionmay be an abscess elsewhere, including dental abscess,osteomyelitis, decubitus ulcer, or skin infection. Paraspinalabscesses can occur at any age.They are marked by backpain, fever, malaise, neck stiffness, and headache accompa-nied or followed by radicular pain.There is usually localtenderness over the spine. Neurologic signs are similar tothose seen with extradural tumors.The cerebrospinal fluidis cloudy and may be xanthochromic with increased whitecells, usually a mixture of polymorphonuclear leukocytesand lymphocytes, but the sugar content is normal. Theprotein may be elevated. CT or MRI will reveal thelesion, although the full extent of involvement is best seenon contrasted MRI.10 Prompt recognition and treatmentare essential if permanent paralysis, which can occurabruptly and without warning, is to be avoided.The mor-tality rate is about 30% in acute cases, but with promptrecognition and treatment before paraplegia has occurred,excellent recovery is possible. Surgical decompressionshould be carried out as soon as possible because neuro-logic deficits can occur very rapidly and may lead to per-manent deficits.

Chronic paraspinal abscess is usually due to tuberculosis,although cases of fungal paraspinal abscesses are rarelyreported.They typically begin with a dull ache in the backthat resembles the pain of disk disease.The pain graduallyincreases in intensity.The initial infection is often in thedisk space, which accounts for the pain. It spreads alongthe ligaments and often extends over two or three seg-ments. Diagnosis can be difficult, although the abscess will


86

usually show on a spinal MRI. Contrast enhancementoften provides additional information.10,11 If the abscess isuntreated, vertebral collapse with gibbus formation fre-quently occurs.Treatment is with antibiotics and surgicaldecompression.

REFERENCES

1. Anderson S, Biros MH, Reardon RF. Delayed diagnosis ofthoracolumbar fractures in multiple-trauma patients. AcadEmerg Med 1996;3:832–9.

2. Ryan MD, Henderson JJ.The epidemiology of fractures andfracture-dislocations of the cervical spine. Injury 1992;23:38–40.

3. Klein, GR,Vaccaro AR,Albert TJ, et al. Efficacy of magneticresonance imaging in the evaluation of posterior cervicalspine fractures. Spine 1999;24:771–4.

4. Bracken MB, Shepard MJ, Collins WF, et al.A randomized,controlled trial of methylprednisolone or naloxone in thetreatment of acute spinal-cord injury. N Engl J Med 1990;322:1405–11.

5. Hugenholtz H, Cass DE, Dvorak MF, et al. High-dosemethylprednisolone for acute closed spinal injury—only atreatment option. Can J Neurol Sci 2002;29:227–35.

6. Schutta H. Spinal tumors. In: Joynt RJ, Griggs RC, editors.Baker’s clinical neurology. Philadelphia: Lippincott Williamsand Wilkins; 1998. p. 1–750.

7. Schutta H. Diseases of the dura mater. In: Joynt RJ, GriggsRC, editors. Baker’s clinical neurology. Philadelphia: J. B.Lippincott Co.; 1994. p. 1–137.

8. Baker AS, Ojemann RG, Swartz MN, Richardson EP. Spinalepidural abscess. N Engl J Med 1975;293:463–8.


87

9. Wang LP, Hauerbert J, Schmidt JF. Incidence of spinalepidural abscess after epidural analgeisa. Anesthesiology1999;91:1928–36.

10. Sadato N, Numaguchi Y, Ragamonti D, et al. Spinal epiduralabscess with gadolinium enhanced MRI: serial follow-upstudies and clinical correlations. Neuroradiology 1994;36:44–8.

11. Fam AG, Rubenstein J.Another look at spinal tuberculosis.J Rheumatol 1993;20:1731–40.


88

Neuromuscular disorders may produce life-threateningweakness of the diaphragm (resulting in hypoventilation)or weakness of the oropharyngeal and upper airway mus-cles (leading to aspiration or obstruction). Patients withknown or previously undiscovered neurologic disease maypresent with respiratory failure as a logical sequel of achronic progressive neuromuscular condition such as amyo-trophic lateral sclerosis (ALS) or muscular dystrophy. Inaddition, patients with acute or subacute acquired disor-ders may present to the emergency department with res-piratory failure as an early or presenting manifestation(without an established diagnosis), as in the case of Guillain-Barré syndrome (GBS), botulism, and some patients withmyasthenia gravis (MG).

Ventilatory performance depends on three factors:inspiratory effort, expiratory effort, and airway patency.Mainly the chest wall muscles and the diaphragm driveinspiratory effort. The abdominal muscles are importantfor expiratory function, including cough. Poor expiratoryfunction is often overlooked as a feature of neuromuscu-lar weakness. A weak cough leads to a failure to clearsecretions, aspiration, mucus plugging, and pneumonia.Muscles of the upper airway, including those of themouth, tongue, palate, and larynx, largely maintain airwaypatency.These structures affect airway resistance and air-

89

CHAPTER 6

RESPIRATORY FAILURE DUE TONEUROMUSCULAR DISEASE

Rober t M. Pascuzzi, MD

flow and are critical for effective pulmonary function.Combined weakness of inspiratory and expiratory effortand of the upper airway muscles leads to a critical spiral ofdecreasing respiratory function.

GENERAL ISSUES REGARDING NEUROMUSCULARRESPIRATORY FAILURE

Respiratory Muscle Weakness and Fatigue

Respiratory muscle weakness and fatigue are frequentcontributors to ventilatory failure in the patient with neu-romuscular disease. Progressive muscle weakness andfatigue lead to low lung volume, hypoventilation, hyper-carbia, and, ultimately, hypoxemia. Life-threatening respi-ratory failure usually occurs when pulmonary functiondrops below 30% of predicted values.

Patient Evaluation

Symptoms of neuromuscular respiratory failure may bestraightforward, with patients complaining of subjectivedyspnea and “shortness of breath.” On the other hand, thepatient’s symptoms may be more nonspecific, such as rest-lessness, inability to sleep, and altered mental status (fromhypoxemia or hypercarbia).

Sleep is an important factor in patients with neuro-muscular respiratory insufficiency. Patients with dia-phragm weakness have better pulmonary function whenawake and sitting upright, ostensibly because gravity worksto enhance downward movement of the diaphragm dur-


90

ing inspiration.When lying flat, hypoventilation increasesin severity, leading to hypercarbia and hypoxemia. In addi-tion, if the patient has a degree of upper airway obstruc-tion or oropharyngeal weakness leading to aspiration, res-piratory status and pulmonary function are most severelycompromised during sleep. Therefore, patients withchronic or subacute respiratory failure may describe symp-toms consistent with nocturnal or sleep-associatedhypoventilation, including headaches on awakening(owing to high carbon dioxide partial pressure [PCO2]),daytime fatigue, and daytime sleepiness. Patients who havesignificant weakness of oropharyngeal muscles may com-plain chiefly of intermittent choking or difficulty clearingsecretions from the throat or may present with a history ofnew or recurrent aspiration pneumonia.

Examination

The experienced clinician will recognize the presence ofbifacial, tongue, and palatal weakness in patients withoropharyngeal weakness.The speech may be slurred and,when the palate is weak, may have a “nasal” quality—sounding like someone talking with a cleft palate. Dys-phonia (raspy voice) may present from an abrupt onset ofcough owing to weakness of the epiglottis. Look for theuse of accessory muscles and the presence of tachycardiaas other helpful signs to indicate respiratory insufficiency.

Assessing Diaphragm Function at the Bedside Askingthe patient to provide a vigorous sudden “sniff ” will givethe clinician a sense of diaphragm power.

Respirator y Fai lure due to Neuromuscular Disease

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Cough Asking the patient to take a huge breath andcough can lead to impressive and, at times, unexpectedinsight into the severity of a patient’s neuromuscular res-piratory function.A very weak cough should alert the cli-nician that the patient is at high risk for rapid respiratorydecompensation.

Observe for Paradoxical Abdominal Wall MovementNormally, with inspiration as the diaphragm contracts, theabdomen is forced down, leading to protrusion of thebelly. In severe diaphragm weakness, inspiration may bemore dependent on the intercostal and accessory muscles,in which case, the weak diaphragm muscle may be drawnup into the chest with inspiration, leading to a sunken orscaphoid appearance to the abdomen.The astute clinicianwill watch the abdominal wall movement with inspira-tion. If the movement is inward, then one should concludethat there is severe diaphragm muscle weakness.

Counting Test At the bedside, ask the patient to take ahuge breath and to begin to count aloud. Determine howhigh the patient can count in one breath. If the patient cancount to 10 in one breath, he or she has a forced vitalcapacity (FVC) of about 1,000 mL; if the patient cancount to 25, the FVC can be estimated to be about2,000 mL.

Spirometry FVC and peak inspiratory pressure are read-ily available measures in most medical facilities. Occasion-ally, patients will demonstrate stable or adequate functionby these tests, but during nighttime sleep, they will have


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more profound hypoventilation. Such patients may requirenighttime oximetry to detect serious hypoventilation.FVC is a readily obtainable measure of pulmonary func-tion that reflects clinically important respiratory muscleweakness.When the FVC falls below 15 to 20 mL/kg, res-piratory failure will follow. In an average-sized adult, 15 to20 mL/kg equals about 1,000 mL. Peak inspiratory forceless than 25 cm H2O is typically associated with precari-ous respiratory function and impending respiratory failure.In the acute setting, the FVC should be monitored at leastevery 4 hours and perhaps more often if the FVC dropsbelow 20 mL/kg.

Arterial Blood Gas

Arterial blood gas changes tend to occur relatively late inthe course of respiratory failure owing to neuromuscularweakness and therefore are not the optimal tool for mon-itoring the patient.Thus, arterial blood gas analysis is nota particularly good measure to follow in the patient withprogressive respiratory failure. Similarly, oxygen saturationfalls late only in neuromuscular respiratory failure and is aninsensitive measure in the acute setting.Every time you doan arterial blood gas analysis, you wake the patient up anddo a painful stick that stimulates respiration and gives afalsely elevated pulmonary function test, as reflected in theblood gases.

When Should You Intubate?

You should begin invasive/mechanical ventilation in thefollowing cases:


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1. In the patient with acute or subacute weakness, whenthe FVC is < 15 mL/kg (about 1,000 mL in the average-sized adult)

2. Poorly protected airway (oropharyngeal weakness): thepatient cannot handle oral secretions (choking); inter-mittent aspiration; upper airway obstruction

3. Significant hypoxemia4. If the patient just “looks bad” or appears to be strug-

gling to breathe, it is best to intubate. In general, it isbest to have a low threshold for hospitalization, forplacement in the intensive care unit (ICU), and for theuse of ventilatory support,whether it is noninvasive orendotracheal intubation with mechanical ventilation

5. The bottom line: when in doubt, intubate the patient!6. The top priority: when evaluating any patient with

respiratory failure, including those with neuromuscu-lar disorders, it is imperative to secure the patient’s res-piratory status as the top priority. Intubate the patient,protect the airway, and provide adequate supportivemechanical ventilation, and once the respiratory statusis secure, then focus on clarification of the underlyingdiagnosis and precipitating factors

Precipitating Factors

Neuromuscular patients often have acute precipitating fac-tors that lead to respiratory failure. Upper airway obstruc-tion and acute aspiration should be suspected in patientswith bulbar dysfunction (as is common in ALS and inMG). Bronchiolar mucus plugging and atelectasis com-monly develop in patients with poor diaphragm function


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and can lead to pneumonia. Patients with paralytic disor-ders are at increased risk of developing aspiration and arealso prone to deep vein thrombosis with pulmonaryemboli. Both scenarios are important to consider in theneuromuscular patient who has undergone acute respira-tory decline. Patients with MG may decompensate in thesetting of a superimposed infection or the use of a newmedication.Often identification and treatment of the pre-cipitating factor are crucial to a successful outcome.Addi-tionally, metabolic and electrolyte abnormalities, such ashypophosphatemia and hypokalemia, as well as hyper-glycemia,may exacerbate muscle weakness and precipitaterespiratory dysfunction.

CLINICAL PATTERNS OF NEUROMUSCULAR CONDITIONSTHAT MAY PRESENT WITH RESPIRATORY FAILURE

Myasthenia Gravis

MG is an autoimmune disorder of neuromuscular trans-mission in which there are autoantibodies that are directedagainst the nicotinic acetylcholine (ACh) receptor(AChR). AChR antibodies are detectable in the serum of80 to 90% of patients with MG.The prevalence of MG isabout 1 in 10,000 people.Women are affected about twiceas often as men. Symptoms may begin at virtually any age,with a peak in women in the second and third decades,whereas the peak in men occurs in the fifth and sixthdecades.

Autoimmune diseases such as rheumatoid arthritis,lupus, and pernicious anemia are present in about 5% of


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patients. Thyroid disease occurs in about 10%, often inassociation with antithyroid antibodies.About 10 to 15%of patients with MG have a thymoma, whereas thymiclymphoid hyperplasia with a proliferation of germinalcenters occurs in 50 to 70% of cases. In most patients, thecause of autoimmune MG is unknown.However, there arethree iatrogenic causes of autoimmune MG: D-penicil-lamine (used in the treatment of Wilson’s disease andrheumatoid arthritis), interferon-� therapy, and bone mar-row transplantation, which can, in some patients, be thecause of MG.

Clinical Features The hallmark of MG is fluctuating orfatigable weakness.The presenting symptoms are ocularin half of all patients (25% of patients initially presentwith diplopia, 25% with ptosis); within 1 month into thecourse of the illness, 80% of patients have some degreeof ocular involvement. Presenting symptoms are bulbar(dysarthria or dysphagia) in 10%, leg weakness in 10%,and generalized weakness in 10%. Respiratory failure isthe presenting symptom in 1% of cases. Patients usuallycomplain of symptoms from focal muscle dysfunctionsuch as diplopia, ptosis, dysarthria, dysphagia, inability towork with arms raised over the head, or disturbance ofgait. In contrast, patients with MG tend not to complainof “generalized weakness,” generalized fatigue, “sleepi-ness,” or muscle pain. In the classic patient, fluctuatingweakness is worse with exercise and improved with rest.Symptoms tend to progress later in the day. Many differ-ent factors can precipitate or aggravate weakness, such as


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physical stress, emotional stress, infection, or exposure tomedications that impair neuromuscular transmission.

Indications for Hospitalization Patients with severe MGcan deteriorate rapidly over a period of hours.Therefore,patients with dyspnea should be hospitalized immediatelyin a constant observation or ICU setting. Patients withmoderate or severe dysphagia,weight loss, and rapidly pro-gressive or severe weakness should be admitted urgently.This will allow close monitoring and early intervention inthe case of respiratory failure and will also expedite thediagnostic work-up and initiation of therapy.

Diagnostic Confirmation of MG The diagnosis is basedon a history of fluctuating weakness with corroboratingfindings on examination.There are several different waysto validate or confirm the diagnosis.

Edrophonium Test (Tensilon Test) To perform the test,one or two clearly clinically weak muscles must beselected for monitoring. Eyelid ptosis, dysconjugate gaze,and other cranial deficits provide the most reliable endpoints.The test should be administered in a clinical settingin which hypotension, syncope, or respiratory failure canbe managed because occasional patients decompensateduring the test. In patients with severe dyspnea, the testshould not be performed until the airway is secure. Anintravenous line should be placed.Atropine 0.4 mg shouldbe readily available in the event of bradycardia or extremegastrointestinal side effects. Edrophonium 10 mg (1 mL) is


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drawn up in a syringe, and 1 mg (0.1 mL) should be givenas a test dose while checking the patient’s heart rate forbradycardia (to ensure that the patient is not supersensitiveto the drug). If no adverse side effects occur after1 minute, another 3 mg is given. Many patients with MGwill show improved power within 30 to 60 seconds of giv-ing the initial 4 mg, at which point, the test can bestopped. If after 1 minute there is no improvement, anadditional 3 mg is injected; if there is still no response,1 minute later the final 3 mg is administered. If the patientdevelops muscarinic symptoms or signs at any time dur-ing the test (sweating, salivation, gastrointestinal symp-toms), one can assume that sufficient edrophonium hasbeen provided to see improvement in strength, and the testcan be stopped.When a placebo effect or examiner bias isof concern, the test should be performed in a double-blind, placebo-controlled fashion. The 1.0 mL controlsyringe may contain saline, 0.4 mg atropine, or 10 mgnicotinic acid.When improvement occurs, it typically lastsfor about 5 minutes and then quickly abates. Whenimprovement is clear-cut, then the test is positive. If theimprovement is borderline, it is best to consider the testnegative. In some patients, the edrophonium test should berepeated because the response may be inconsistent. Thesensitivity of the edrophonium test is estimated as 80 to90%. The specificity is difficult to determine becauseimprovement following intravenous edrophonium hasbeen reported in other neuromuscular diseases, includingLambert-Eaton syndrome, botulism, GBS, and motoneu-ron disease (including ALS), and in some patients withneoplasm or aneurysm affecting the cranial nerves.


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Caveat: Some patients with MG with severe bulbar orrespiratory weakness may decompensate during or imme-diately following the test.The test should be performed ina setting in which the patient’s respiratory status is secure.

Serologic Testing Overall, AChR binding antibodiesare present in about 80% of all myasthenic patients (50%of patients with pure ocular MG, 80% of those with mildgeneralized MG, 90% of patients with moderate to severegeneralized MG, and 70% of those in clinical remission).The level of AChR antibodies does not predict the sever-ity or clinical course of the patient.

Electrophysiologic Testing Using electromyography(EMG), repetitive stimulation testing of the limb musclesis widely available and has variable sensitivity dependingon the number and selection of muscles studied and vari-ous provocative maneuvers. In general, about 50% ofpatients with MG will have a decrement to repetitivestimulation. If there is weakness of the muscles undergo-ing study, the sensitivity is higher. A minority of patientswith pure ocular or slight generalized weakness have adecrement to repetitive stimulation.

Single-fiber electromyography (SFEMG) is a highlyspecialized technique, usually available in major academiccenters, with a sensitivity of about 90%.Abnormal single-fiber results are common in other neuromuscular diseases;therefore, the test must be used in the correct clinical con-text. The specificity of SFEMG is an important issue inthat mild abnormalities can clearly be present with a vari-ety of other diseases of the motor unit, including


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motoneuron disease, peripheral neuropathy, and myopathy.Disorders of neuromuscular transmission other than MGcan have substantial abnormalities on SFEMG. In con-trast,AChR antibodies are not present in patients withoutMG. In summary, the two highly sensitive laboratory stud-ies are SFEMG and receptor antibodies; nonetheless,neither test is 100% sensitive.

TreatmentFirst-Line Therapy: Cholinesterase Inhibitors Cholinesteraseinhibitors (CEIs) are generally safe and effective and rep-resent first-line therapy in all patients. Inhibition of acetyl-cholinesterase reduces the hydrolysis of ACh, increasingthe accumulation of ACh at the postsynaptic membrane.The CEIs used in MG bind reversibly (as opposed toorganophosphate CEIs,which bind irreversibly) to acetyl-cholinesterase.These drugs cross the blood-brain barrierpoorly and tend not to cause central nervous system sideeffects.Absorption from the gastrointestinal tract tends tobe inefficient and variable, with oral bioavailability ofabout 10%.Muscarinic autonomic side effects of gastroin-testinal cramping, diarrhea, salivation, lacrimation, anddiaphoresis may occur with any of the CEI preparations.Parenteral CEI can occasionally lead to bradycardia. Afeared potential complication of excessive CEI use isskeletal muscle weakness (“cholinergic weakness”).Patients receiving parenteral CEI are at the greatest risk ofcholinergic weakness. It is uncommon for patients receiv-ing oral CEI to develop significant cholinergic weaknesseven while experiencing muscarinic cholinergic sideeffects.


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Pyridostigmine (Mestinon) is the most widely usedCEI for long-term oral therapy. Onset of effect is within15 to 30 minutes of an oral dose, with peak effect within1 to 2 hours and wearing off gradually at 3 to 4 hourspostdose.The starting dose is 30 to 60 mg three to fourtimes per day depending on symptoms. Optimal benefitusually occurs with a dose of 60 mg every 4 hours. Mus-carinic cholinergic side effects are common with largerdoses.

Some patients require and tolerate over 1,000 mg perday, dosing as frequently as every 2 to 3 hours. Patientswith significant bulbar weakness will often time their doseabout 1 hour before meals to maximize chewing and swal-lowing. Of all of the CEI preparations, pyridostigmine hasthe fewest muscarinic side effects. Pyridostigmine may beused in a number of alternative forms to the 60 mg tablet.The syrup may be necessary for children or for patientswith difficulty swallowing pills. Sustained-release pyri-dostigmine 180 mg (Mestinon Timespan) is sometimespreferred for nighttime use. Unpredictable release andabsorption limit its use. Patients with severe dysphagia orthose undergoing surgical procedures may need parenteralCEI. Intravenous pyridostigmine should be given at aboutone-thirtieth of the oral dose. For patients with intolerablemuscarinic side effects at CEI doses required for optimalpower, a concomitant anticholinergic drug such asatropine sulfate (0.4–0.5 mg orally) or glycopyrrolate(Robinul 1 mg orally) on an as needed basis or with eachdose of CEI may be helpful. Patients with mild disease canoften be managed adequately with CEIs. However,patients with moderate, severe, or progressive disease will


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usually require more effective therapy. Cholinergic weak-ness (cholinergic crisis) is uncommon with oral drug usebut more likely when parenteral CEIs are used.

Corticosteroids For patients with severe MG, it is best tobegin with high-dose daily therapy of 60 to 80 mg/dorally. Early exacerbation occurs in about half of patients,usually within the first few days of therapy and typicallylasting 3 or 4 days. In 10% of patients, the exacerbation issevere, requiring mechanical ventilation or a feeding tube(thus the need to initiate therapy in the hospital). Overall,about 80% of patients show a favorable response to corti-costeroids (with 30% attaining remission and 50% markedimprovement). Mild to moderate improvement occurs in15%, and 5% have no response. Improvement begins asearly as 12 hours and as late as 60 days after beginningprednisone, but, usually, the patient begins to improvewithin the first week or two. Improvement is gradual,withmarked improvement occurring at a mean of 3 monthsand maximal improvement at a mean of 9 months. Ofthose patients with a favorable response, most maintaintheir improvement with gradual dosage reduction at a rateof 10 mg every 1 to 2 months. More rapid reduction isusually associated with a flare-up of myasthenic weakness.Although many patients can eventually be weaned off cor-ticosteroids and maintain their response, the majority can-not. Such patients usually require a minimum dose (5 to30 mg alternate day) to maintain their improvement.Complications of long-term high-dose prednisone ther-apy are substantial, including weight gain, swelling, hyper-


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tension, diabetes, osteoporosis, and cataracts, just to namea few.

Alternative immunosuppressive drug therapy is com-monly used in severe or refractory patients, but mostdrugs, including azathioprine,mycophenolate mofetil, andcyclosporine, require several months of therapy beforeclinical improvement is expected.

Plasma Exchange Plasma exchange (plasmapheresis) re-moves AChR antibodies and results in rapid clinicalimprovement. The standard course involves removal of2 to 3 L of plasma every other day or three times per weekuntil the patient improves (usually a total of five or sixexchanges). Improvement begins after the first fewexchanges and reaches its maximum within 2 to 3 weeks.The improvement is moderate to marked in nearly allpatients but usually wears off after 4 to 8 weeks owing tothe reaccumulation of pathogenic antibodies.

High-Dose Intravenous Immunoglobulin High-dose intra-venous immunoglobulin (IVIg) administration is associ-ated with rapid improvement in MG symptoms. Themechanism is unclear but may relate to down-regulationof AChR antibody production or to the effect of anti-idiotype antibodies. The usual protocol is 2 g/kg spreadout over 5 consecutive days (0.4 g/kg/d). Different IVIgpreparations are administered intravenously at differentrates (contact the pharmacy for guidelines).The majorityof patients with MG improve, usually within 1 week ofstarting IVIg.The degree of response is variable, and the


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duration of response is limited, like plasma exchange, toabout 4 to 8 weeks.

Drugs to Avoid in MG Avoid using botulinum toxin, D-peni-cillamine, interferon-�, chloroquine, quinine, quinidine,and procainamide. Aminoglycoside antibiotics should beavoided unless needed for a life-threatening infection.Neuromuscular blocking drugs such as pancuronium andvecuronium can produce marked and prolonged paralysisin patients with MG. Depolarizing drugs such as succinyl-choline can also have a prolonged effect and should beused by a skilled anesthesiologist who is well aware of thepatient’s MG. Iodinated intravenous contrast is occasion-ally associated with exacerbation of MG and should beavoided unless absolutely necessary.

Myasthenic Crisis Myasthenic crisis (Table 6-1) is a medicalemergency characterized by respiratory failure fromdiaphragm weakness or severe oropharyngeal weaknessleading to aspiration.Crisis can occur in the setting of sur-gery (postoperatively), with acute infection, or followingrapid withdrawal of corticosteroids (although somepatients have no precipitating factors). In some patients,the use of a new medication may precipitate crisis (Table6-2). Patients should be placed in an ICU setting and haveFVC and forced expiratory volume at 1 second checkedevery 2 hours. Changes in arterial blood gases occur rela-tively late in neuromuscular respiratory failure. Thereshould be a low threshold for intubation and mechanicalventilation. Criteria for intubation include a drop in theFVC below 15 mL/kg, severe aspiration from oropharyn-


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geal weakness, or labored breathing regardless of the meas-urements. If the diagnosis is not clear-cut, it is advisable tosecure the airway with intubation and stabilize ventilationand only then address the question of the underlying diag-


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Table 6-1 Acutely Deteriorating Myasthenic Patients

Myasthenic crisisRespiratory distressRespiratory arrestCyanosisIncreased pulse and blood pressureDiaphoresisPoor coughInability to handle oral secretionsDysphagiaWeaknessImproves with edrophonium

Cholinergic crisisAbdominal crampsDiarrheaNausea and vomitingExcessive secretionsMiosisFasciculationsDiaphoresisWeaknessWorse with edrophonium


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Table 6-2 Medications That May ExacerbateMyasthenia Gravis

Botulinum toxin

Chloroquine

Quinine

Quinidine

Procainamide

Aminoglycoside antibiotics

Ciprofloxacin

Recent high-dose corticosteroids (50% of MG patientshave an early exacerbation)

D-Penicillamine (causes MG)

Interferon-� (causes MG)

Neuromuscular blocking drugs (eg, pancuronium,vecuronium) can produce marked and prolongedparalysis in MG patients

Depolarizing drugs (succinylcholine) can also have aprolonged effect

Iodinated intravenous contrast is occasionally associatedwith exacerbation of MG

MG = myasthenia gravis.For a more extensive list and discussion of adverse drug effects onneuromuscular transmission, see the Myasthenia Gravis Foundation ofAmerica Web site (<www.myasthenia.org>).

www.myasthenia.org

nosis. If the patient has been taking CEIs, the drug shouldbe temporarily discontinued to rule out the possibility ofcholinergic crisis.

The development of respiratory failure in MG mayoccur suddenly or gradually for several reasons. Oropha-ryngeal or neck muscles may become weak, leading tocollapse of the airway.Vocal cord abductor muscles maybecome weak, leading to obstruction of the larynx and apresentation of stridor. Sustained coughing may weakenthe diaphragm muscles and thereby prevent the airwayfrom being cleared of secretions. When the diaphragm,intercostal, and abdominal muscles are sufficiently weak,inspiration may be critically reduced. Patients with MGare complex; bifacial weakness may limit their expressionof discomfort or distress. Patients with weakness of thediaphragm, abdominal, and intercostal muscles may appearto be taking rapid shallow breaths.The presence of para-doxical wall motion, in which an inspiration leads to amore scaphoid appearance of the abdomen (sunken asopposed to protrusion of the abdomen), should be a tell-tale sign of serious diaphragmatic weakness.

For the treatment of myasthenic crisis, the steps are asfollows:

1. Protect the airway with an endotracheal tube.2. Clear oropharyngeal pulmonary secretions with

suctioning.3. Use mechanical ventilation as needed to secure

respiration.4. Look for factors that may be identified as precipitants

of crisis.


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Screen for and correct any underlying medical prob-lems, such as systemic infection, metabolic problems (suchas diabetes), and thyroid disease (hypo- or hyperthyroidismcan exacerbate MG), and screen the patient’s medicationlist (see Table 6-2).

Cholinergic Crisis Cholinergic crisis is relatively uncom-mon compared with myasthenic crisis. It is particularlyunlikely in the patient taking oral CEIs.Thomas and col-leagues, in a retrospective review of 73 episodes of “crisis”from 1983 to 1984, found none in which cholinergic cri-sis was the culprit.1 However, with the use of parenteralCEIs, cholinergic weakness is, in fact, a real entity thatshould be considered and addressed.

Precipitating factors of acute or subacute weaknesswith respiratory failure in MG include infection, fever,aspiration, hyperthyroidism, and the adverse effects of avariety of medications (including prednisone).

Additional steps in management, in general, for thepatient in crisis are as follows:

1. It is reasonable to withhold CEIs for several days fol-lowing intubation and stabilization while potentialprecipitating factors are pursued.

2. Once the airway and ventilation are secure, it is appro-priate to treat the patients with one of a variety ofoptions, including high-dose corticosteroids, plasma-pheresis, and IVIg.

Recent Observations on the Role of Plasma Exchange and IVIg inSevere MG and Myasthenic Crisis Regarding treatment withhigh-dose IVIg compared with plasma exchange,Ronager


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and colleagues reported “clinical effect of high-dose intra-venous immunoglobulin compared to plasma exchange inpatients with moderate to severe myasthenia gravis,”2

comparing the two treatments in patients with moderateto severe MG. The study was a randomized, crossoverstudy.Twelve patients with generalized moderately severeMG were on immunosuppressive therapy for at least 3months, either azathioprine, prednisone, or both, with astable dose for 1 month prior to randomization. Onegroup of patients received IVIg 400 mg/kg/d for 5 con-secutive days and was then observed for 16 weeks. Thesecond group of patients was treated initially with plasmaexchange and later with IVIg.The patients were evaluatedusing a quantified myasthenia gravis clinical score(QMGS) and were evaluated at 1, 4, 8, and 16 weeks afterthe end of each treatment. Additional measures includedimmunoglobulin concentrations, titers of AChR antibod-ies, and, at baseline and 1 week after each treatment, repet-itive stimulation studies.

The Ronager study showed that 1 week after treat-ment, those who received plasma exchange had signifi-cantly improved QMGS, whereas such improvementcould not be shown 1 week after IVIg treatment.2 Fourweeks after treatment, there was significant improvementin QMGS in both the plasma exchange and IVIg groups;1 week and 4 weeks after treatment, no significant differ-ence between the two treatments was found. A highernumber of adverse events was noted during and after IVIgtreatment, but the adverse events were relatively minorand transient. Conversely, with plasma exchange, therewere fewer adverse events, but those that occurred


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included some that were judged to be more serious,including one patient with septicemia and another patientwith arterial bleeding.There were no significant changesin the EMG studies (repetitive stimulation).The authorsconcluded that both treatments have clinically significantbenefits in patients with chronic stable MG. In this limitedstudy, the authors felt that improvement was more rapidafter plasma exchange compared with IVIg but that theside effects observed with IVIg were more “benign” thanthose seen with plasma exchange.

Gajdos and colleagues reported on the clinical trial ofplasma exchange and high-dose IVIg in MG.3 Eighty-seven patients with exacerbation of MG were randomizedto one of two treatment groups. Group 1 received plasmaexchange (n = 4), three exchanges in total. The secondgroup received IVIg (n = 46), 0.4 g/kg/d for either 3 days(n = 23) or 5 days (n = 23).The primary end point wasthe myasthenic muscular score (MSS), with the change inscore from time of randomization to day 15.The resultsshowed that the MSS variation was similar in both theplasma exchange and IVIg patient groups, with animprovement in score of 18 points in the plasma exchangegroup and of 15.5 points in the IVIg group (p = .65).Thetwo different schedules of IVIg administration provided asimilar degree of improvement, but there was a trendtoward reduced improvement in the 5-day group com-pared with the 3-day group.

Regarding side effects, the plasma exchange group hadeight patients with side effects, whereas only one patientin the IVIg group had side effects.The authors concluded


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that although there was no difference in the efficacy ofboth treatments, the less frequent side effects in the IVIggroup suggest that this is an important therapy for treat-ment of myasthenic crisis.

Qureshi and colleagues reported a retrospective mul-ticenter chart review comparing the tolerance and efficacyof plasma exchange and IVIg in 54 episodes of myastheniccrisis.4The decision to treat with plasma exchange or IVIgwas at the discretion of the physician. In this retrospectivereview, the authors found that plasma exchange was some-what more effective than IVIg, as defined as the ability toextubate the patient at 2 weeks and the 1-month func-tional outcome.However, patients in the plasma exchangegroup had more adverse complications than those receiv-ing IVIg.The complications tended to be hemodynamicin the plasma exchange group.The authors concluded thatIVIg provided a good alternative treatment, particularly inpatients at risk of hemodynamic complications or in thosewho did not adequately respond to plasma exchange, andsuggested a formal, prospective, randomized trial.

Thomas and colleagues retrospectively reviewed therecords of 53 patients with 73 myasthenic crises at Colum-bia Presbyterian Medical Center from 1983 to 1994.1 Ageat the time of crisis was 20 to 82 years, with a median ageof 55 years.Women were more often affected than men ata ratio of 2:1, and the average interval from initial myas-thenic symptoms to initial episode of crisis was 8 months.Precipitating factors were headed by infection, typicallypneumonia or an upper respiratory infection, whichoccurred in 38%, whereas in 30% of patients, there was no


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clear-cut precipitating event. In 10% of patients, aspirationseemed to precipitate the myasthenic crisis. Twenty-fivepercent of patients were extubated by 7 days, 50% by13 days, and 75% by 1 month, with the longest duration ofintubation over 5 months.There were three independentpredictors of prolonged intubation over 5 months, includ-ing a preintubation serum bicarbonate level ≥ 30 mg/dL, apeak FVC on day 1 to 6 of postintubation at < 25 mL/kg,and age over 50 years. None of those with no risk factors,21% of those with one risk factor, 46% of those with tworisk factors, and 88% of those with three risk factorsremained intubated longer than 2 weeks.Complications inthis series of prolonged intubation were atelectasis, ane-mia, Clostridium difficile gastrointestinal infection, and con-gestive heart failure.Three episodes were fatal, for an over-all mortality rate of 4% (3 deaths in 73 crises). Four otherpatients died following extubation.All deaths were appar-ently related to multiple medical complications. Of thosewho survived, half were functionally dependent at homeor in a facility at the time of discharge. The authorsemphasized that not only are immunotherapies importantin addressing myasthenic crisis, but the prevention andmanagement of multiple medical complications are cen-tral to optimal outcome for myasthenic crisis. Theseauthors defined crisis as respiratory failure requiringmechanical ventilation.

Berrouschot and colleagues recently reported ontherapy of myasthenic crisis, reviewing their experiencewith the causes, course, and outcome of 63 myastheniccrises treated by their group over a 26-year period


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(1970–1995), with an interest in the effect of the follow-ing different therapeutic modalities:myridostigmine intra-venous, pyridostigmine plus prednisolone, and plasmaexchange.5 Of 235 patients with MG treated at the Uni-versity of Leipzig, the following observations were made.Forty-four patients experienced myasthenic crisis, for atotal of 63 presentations.The average annual incidence ofmyasthenic crisis over this time period in these patientswas 2.5%, a figure that was fairly consistent throughoutthe 26-year monitoring period. The 44 patients with crisisincluded 26 women and 18 men, with a mean age of43 years. Twenty-five patients had a single crisis,14 patients had two episodes, 4 patients had threeepisodes, and 1 patient had four episodes.The precipitat-ing factors included myasthenic weakness alone in 32%,respiratory infection in 27%, post-thymectomy in 17%,start of corticosteroid therapy in 5%, overdose of cholin-ergic drugs in 3%, underdose of cholinergic drugs in 2%,emotional stress in 2%, and no specific cause in 12%.Theaverage time from onset of MG to the occurrence of cri-sis was a mean of 37 months,with a broad range. Fourteen(22%) crises preceded thymectomy,whereas 46% followedthymectomy, and 20% occurred in patients who never hadthymectomy. Precrisis treatment included pyridostigminein 33%; pyridostigmine plus azathioprine in 25%; pyri-dostigmine, azathioprine, and prednisolone in 16%; pyri-dostigmine and prednisolone in 11%; and neostigmine in2%. In 8 patients (13%), crisis was the first manifestationof MG.The evolution of crisis was 1 to 3 days from onsetof deterioration to requiring mechanical ventilation in


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68%, 4 to 7 days in 22%, and 14 to 21 days in 10%. Pre-crisis treatment included increasing medication dosage in40%,plasma exchange in 1 patient, and an unchanged reg-imen in 58% of patients.The mean duration of mechani-cal ventilation was 9 days, with a range of 2 to 51 days.

With regard to treatment of crisis, 24 patients receivedpyridostigmine as a continuous intravenous infusion, from1 to 2 mg/h. Eighteen patients received pyridostigmine at1 to 2 mg/h continuous intravenous infusion, along with100 mg of prednisolone over 5 days, with a subsequentdecrease in dosage.Two patients were given azathioprine,and one received IVIg. Twenty-one patients receivedplasma exchange every 2 days.A variety of other immuno-suppressive drugs were administered in some of thesepatients as well.

Overall, the three treatment groups showed no signif-icant overall differences in the interval between the startof crisis and ventilation, and the outcome in the threegroups was similar. After 3 months, all but two patientsreached their precrisis status. Eight patients died duringcrisis (13%), with the causes being cardiac arrhythmia insix patients, cardiac arrest in five patients, defibrillation inone patient, and infection with pneumonia and sepsis afterlong-term ventilation in two patients. Autopsy was per-formed on seven of the eight patients, and four of themwere found to have malignant thymoma. One patient hadevidence of a viral myocarditis; otherwise, the heartautopsy was normal.The authors emphasized the impor-tance of general support for the patient in crisis with earlyintubation,mechanical ventilation, and treatment of infec-tion when present.


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Guillain-Barré Syndrome

GBS is usually a postinfectious illness.With the preven-tion of acute paralytic polio, GBS has become the mostcommon cause of acquired nontraumatic generalizedparalysis in adults. One of every 1,000 individuals willdevelop GBS at some point in their lifetime. GBS is clas-sically an acute inflammatory demyelinating polyneu-ropathy. Antecedent viral infection is identifiable in about66% of cases.Viral infection occurs 1 to 6 weeks prior toGBS. Documented viral infections have includedcytomegalovirus, Epstein-Barr virus, other herpesviruses,and human immunodeficiency virus. Other antecedentinfections include Campylobacter jejuni (severe diarrhea)and Mycoplasma. Some patients develop GBS in the set-ting of lymphoma, surgery, and vaccinations.

Clinical diagnostic critieria require progressive motorweakness in more than one limb and global hyporeflexiaor areflexia.Weakness usually progresses over several daysto 3 weeks in a relatively symmetric fashion. Althoughmotor signs predominate at the time of diagnosis, patho-logic and EMG evidence supports equivalent involvementof sensory and motor nerve fibers eventually. The cere-brospinal fluid classically exhibits elevated protein in theabsence of pleocytosis.Another diagnosis is likely if thereare > 50 white blood cells/mm3.The presence of a highwhite blood cell count in the cerebrospinal fluid shouldtrigger a search for sarcoidosis, human immunodeficiencyvirus, cytomegalovirus, and West Nile virus as an associ-ated or precipitating condition. EMG studies provide evi-dence of acquired demyelination in the form of conduc-


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tion block, multifocal and asymmetric slowing, or pro-longed distal motor latencies in warmed limbs.With sup-portive care, recovery is excellent in about 85% of patients.Usual recovery requires 4 to 6 months, but gradual furtherimprovement may occur over as long as 2 years.

Acute motor axonal neuropathy occurs in epidemicsduring the summer in China and is often associated withC. jejuni infection. Motor involvement with distal pre-dominance and sparing of cranial nerves is the usual pat-tern. Recovery is more guarded than in acute inflamma-tory demyelinating polyneuropathy because axonal loss isprominent.Acute motor sensory axonal neuropathy has apresentation similar to acute motor axonal neuropathyexcept that sensory involvement is also prominent.Recovery from acute motor sensory axonal neuropathy isoften incomplete. Miller Fisher syndrome consists of oph-thalmoplegia, ataxia, areflexia, facial weakness, and bulbarweakness.The clinical syndrome of Miller Fisher is asso-ciated with anti-GQ1b antibodies in 90% of patientsacutely.

The differential diagnosis of GBS includes several lesscommon but important conditions that are often over-looked or misdiagnosed (Table 6-3): tick paralysis; heavymetal poisoning, in particular arsenic and thalium; med-ication neurotoxicity from nitrofurantoin; solvent toxicity(hexane); thiamine deficiency; and acute intermittent por-phyria.All of these conditions should be considered in thepatient who presents with GBS.

Treatment Treatment of all of these conditions consistsof supportive medical care and, when necessary, IVIg or


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plasmapheresis. Supportive medical care may include man-agement in the ICU for adequate ventilation, airway pro-tection, and management of autonomic insufficiency.Early tracheostomy, enteral or parenteral feeding, subcuta-neous heparin, and passive range of motion help preventthe complications of prolonged, severe illness.The NorthAmerican Trial of Plasmapheresis (five treatments over 7 to10 days) demonstrated that the time to improve one clin-ical grade, time to independent walking, improvement at4 weeks, and outcome at 6 months were all improved inthe plasmapheresis group.6 A subsequent Dutch studydemonstrated an equivalent response between IVIg andplasmapheresis (Table 6-4).7


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Table 6-3 Guillain-Barré Syndrome “Look-alikes”

Tick paralysis

Heavy metal poisoning (in particular arsenic andthallium)

Medication neurotoxicity from nitrofurantoin

Solvent toxicity (hexane)

Thiamine deficiency

Acute intermittent porphyria


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Table 6-4 Summary of Guillain-Barré Syndrome

Acute/subacute “ascending paralysis”Legs then armsProximal = distal

Evolves over 1–3 wk (occasionally days)50% maximum by 1 wk80% maximum by 3 wk

Predominantly motor peripheral neuropathy

Symmetric loss of reflexes

About one-third have respiratory involvement

Recovery begins 2–4 wk after progression stopsBy 6 mo, 85% are ambulatoryRecurrence in 3%

Outcome2–5% mortalityHalf have some residual abnormality15% have significant handicap5% are severely disabled

LaboratoryElevated CSF protein; often takes 5–19 dNormal CSF cell count (cytoalbuminologic

dissociation), but 5–10% have up to 100 WBCs; in those patients, consider GBS associated with HIV,Lyme disease, sarcoidosis, CMV,West Nile virus

About 5% abnormal LFTsOccasional increased muscle enzymes (acute

denervation)

Continued


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Table 6-4 (Continued)

Severe or sudden cases: stool culture for Camplylobacter jejuni; many of these are associated with GM1

antibodies

Electrophysiology“Demyelinating neuropathy”

Very slow conduction velocitiesDispersed CMAPsConduction blockLook for prolonged F wavesNeedle examination with relatively little

fibrillationIn the first few days, the NCS may be normal or only

mildly abnormalNCS and EMG abnormalities “lag behind the clinical

examination”Severe reduction of CMAP amplitude predicts

outcome

ManagementFVC below 15 mL/kgFVC falls below 1 LPatient dyspneic or “looks bad”Err on the side of early intubationBedside “counting estimate”: 25 = 2 L, 10 = 1 L

Continued


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Immunotherapy of GBSCorticosteroids

Prospective trials show no benefitPE

Several large randomized trials show benefit (North American GBS study group, French,Swedish)6

GBS study group: total volume 200 mL/kg over 1–2 wk (4–5 exchanges of 3.5–4 L)7

No difference in complicationsTime to improve 1 clinical grade (come off vent,

walk) decreased by 50% in the PE group (19 vs 40 d)

Percentage of patients improved at 1 mo and average clinical grade 15–20% better in PE group

Time to independent walking decreased 40% in PE group (53 vs 85 d)

No benefit when PE started later than 2 wk after onset

10% “rebound” rate; may respond to repeat exchange

IVIg Dutch randomized trial showed 0.4 g/kg/d for

5 d as good as plasma exchange7

CMAP = compound muscle action potential; CMV = cytomegalo-virus; CSF = cerebrospinal fluid; EMG = electromyography; FVC =forced vital capacity; GBS = Guillain-Barré syndrome; GM = gangliosi-dosis; HIV = human immunodeficiency virus; IVIg = intravenousimmunoglobulin; LFT = liver function test; NCS = nerve conductionstudy; PE = plasma exchange;WBC = white blood cell.

Botulism

Consumption of sausage spoiled by Clostridium botulinumresulted in an outbreak of this paralytic illness in the 1700sin Germany, leading to the name “botulism,”derived fromthe Latin term for sausage, “botulus.” Botulinum toxinblocks ACh release at the presynaptic motor nerve termi-nal (and causes dysautonomia by blocking muscarinicautonomic cholinergic function as well).The intracellulartarget of botulinum toxin appears to be a protein of theACh vesicle membrane. The toxin is a zinc-dependentprotease that cleaves protein components of the neuroex-ocytosis apparatus.

Classic Botulism Classic botulism occurs after ingestionof food contaminated by botulinum toxin. Eight differenttoxins have been identified, but disease in humans iscaused by types A, B, and E.Type E is associated with con-taminated seafood.All types produce a similar clinical pic-ture, although type A may produce more severe andenduring symptoms. In all three types, the condition ispotentially fatal. Most cases result from ingestion of bot-tled or canned foods that have not been properly sterilizedduring preparation, especially home-canned foods.Today’stomatoes used in home canning may have a low acid con-tent compared with the tomatoes of the “good old days”and therefore may be more vulnerable to contamination.Foods cooked on an outdoor grill and then wrapped infoil for a day or two, creating an anaerobic environment,can lead to toxin production. Home-bottled oils shouldalso be considered; in the case of children, honey may bethe contaminated food.


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Clinical Features Clinical features begin 12 to 48 hoursafter ingestion of tainted food. Bulbar symptoms, includ-ing diplopia, ptosis, blurred vision, dysarthria, and dyspha-gia, occur initially and are followed by weakness in theupper limbs and then in the lower limbs. In contrast to thetypical patient with GBS, botulism is sometimes said toproduce an acute “descending paralysis.”Severe cases resultin respiratory failure, requiring mechanical ventilation.Botulism produces autonomic dysfunction, includingconstipation, ileus, dry mouth, and dilated pupils (some ofthese signs are seen in most but not all patients; normalpupils do not rule out the diagnosis of botulism).

Diagnosis The compound muscle action potentialamplitudes are typically low on motor nerve conductionstudies. Repetitive stimulation studies before and follow-ing exercise may show a decrement to low rates of repet-itive stimulation and postexercise facilitation of the com-pound muscle action potential amplitude. It is wise to sendboth stool and serum specimens to the laboratory fordetection of the toxin.The specimen is injected into theperitoneum of a mouse,whereas neutralized or inactivatedspecimen is injected in the control. If the mouse becomesparalyzed and dies, the diagnosis is secure.Toxin is foundin blood samples 30 to 40% of the time, whereas stoolsamples have a somewhat higher yield (thus the need tosend both samples).Newer polymerase chain reaction testsfor the organism have been used to screen for the bacte-ria in food.

Management Management involves placement of thepatient in the ICU and assiduous monitoring of pul-


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monary function every few hours. When the FVC fallsbelow 15 mL/kg or 1 L or if the patient appears to behaving respiratory difficulty, intubation and mechanicalventilation are necessary.There is a trivalent botulinumantitoxin, but its use is controversial, in part because ofadverse side effects that occur in about 20% of patients.There is some evidence that the antitoxin shortens thecourse of the illness, especially that associated withtype E. If one can make the diagnosis early, it may beworth using the antitoxin.

Clinical Course With aggressive support, the overallmortality remains about 5 to 10%,usually the result of res-piratory or septic complications. Other patients improveover a period of several weeks to several months. In thosewho survive, the eventual level of recovery is usually nearlycomplete. Several years after the illness, some patients havesubjective fatigue and autonomic symptoms, includingconstipation, impotence, and dry mouth.Clinical recoveryresults from brisk sprouting of new motor axons from thenerve terminal with reinnervation of denervated musclefibers.

Infant Botulism Infant botulism is probably the mostfrequent form of botulism.The infant ingests the spores ofC.botulinum,which lodge in the intestinal tract, germinatethere, and produce botulinum toxin in the gut. Honey hasoften been implicated as the contaminated food in infantdisease. In adults, the small amount of C. botulinum inhoney appears inadequate to colonize the gastrointestinaltract. The typical presentation is an infant between theages of 6 weeks and 6 months of age who exhibits gener-

alized weakness and constipation.The weakness may startin the cranial muscles and then descend, causing a weaksuck, a poor cry, and reduced spontaneous movement.Thecranial muscles are weak, with poor extraocular move-ments, reduced gag reflex, and drooling. Finding C. botu-linum in feces validates the diagnosis.The toxin is usuallynot detectable in the serum.EMG studies can point to thediagnosis in 80 to 90% of cases. Infantile botulism canrange from mild to severe. Management centers on obser-vation and general support (including respiratory stabil-ity).The recovery is usually excellent and runs a course ofseveral weeks to several months.

Wound Botulism Wound botulism occurs when toxin isproduced from C. botulinum infection of a wound. Thesymptoms are similar to those of classic botulism exceptthat the onset may be delayed for up to 2 weeks after con-tamination of the wound. The diagnosis is supported byEMG studies, demonstration of toxin in the patient’sblood, or finding the organism in the patient’s wound.Wounds that lead to botulism include direct trauma, sur-gical wounds, and wounds associated with drug use (suchas intravenous and intranasal cocaine).

Acute Weakness in the Critically Ill Intensive CarePatient

Prolonged paralysis from neuromuscular blockers mayoccur on occasion in patients without neuromuscularjunction disease. Factors that may influence the durationof neuromuscular blockade include dosage and duration of


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therapy, concurrent drug use (including muscle relaxants,corticosteroids, magnesium, and cimetidine), severity ofunderlying disease, electrolyte abnormalities, and renalinsufficiency (which may lead to high drug concentra-tions). Patients with metabolic acidosis, high serummagnesium levels, renal failure, and high blood levels of3-desacetyl-vecuronium appear more likely to experienceprolonged paralysis. Prolonged neuromuscular blockadecan be severe enough to produce neurogenic muscle atro-phy. Corticosteroids may potentiate the effects of musclerelaxants (see “Acute Quadriplegic Myopathy”).Prolongedweakness in intensive care patients can result from a mul-titude of causes, some leading to peripheral neuropathy,myopathy, junctional disturbance, or a combinationthereof. In many patients, multiple concomitant factorscontribute to prolonged paralysis.

Acute Quadriplegic Myopathy (Critical Illness Myopathy)Patients on corticosteroids seem prone to development ofacute and prolonged generalized weakness when exposedto neuromuscular blocking drugs (with days to weeks ofweakness persisting after the neuromuscular blocker isstopped). This condition seems particularly common inpatients treated for status asthmaticus.Creatine kinase maybe normal or markedly elevated. The nerve conductionstudies are usually normal, but the EMG needle examina-tion can show some myopathic features and some neuro-genic changes. Muscles may be electrically inexcitable,even with direct electrical stimulation. Muscle biopsyshows severe necrotizing myopathy, acute type II fiberatrophy, and selective degeneration of myosin filaments


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(on electron microscopy). Weakness typically developsover days, and muscle atrophy is often present.Weakness issymmetric, involving limbs proximal more than distal,often with respiratory compromise. Cranial muscles arerelatively spared. Even when patients have severe weak-ness, recovery can be excellent, although it may take sev-eral weeks to several months.

Critical Illness Neuropathy Acute quadriplegic myopa-thy is differentiated from critical illness neuropathy in thatthe latter is truly an axonal sensory/motor peripheral neu-ropathy.The sensory involvement can be established clin-ically or by nerve conduction studies. Both groups ofpatients are usually in the ICU with multisystem disease,severe generalized weakness, and difficulty weaning fromthe ventilator.

Inflammatory Myopathies

Diagnosis There are three common forms of myositis:polymyositis, dermatomyositis, and inclusion body myosi-tis (they each account for roughly one-third of subacuteor chronic myositis). Viral myositis is typically transientand lasts a week or two, and by the time the tests arearranged, the patient’s symptoms have resolved.Except forskin lesions, polymyositis and dermatomyositis are similarin their clinical presentation: proximal weakness in theneck flexors/extensors and shoulders/hips.These patientsdo not tell us, “Doctor, I’m weak”; rather, they complainof loss of a specific function: “I’m having trouble rising

from a chair, going up or down stairs.” Most patients withmyositis have little or no pain!

Examination The examination shows symmetric proxi-mal weakness, normal sensation, preserved reflexes, andnot much cranial weakness except for dysphagia, whichmay be seen in about 25% of patients.Although uncom-mon, patients with acute severe myositis may havediaphragm involvement and respiratory failure. The skinlesions in dermatomyositis include the following:

• Heliotrope rash (violet rash on the eyelids, named afterthe heliotrope plant).The plant has pretty blue, violet, orpink flowers and the fragrance of vanilla. The flowersface the sunlight in the morning and follow the sunacross the sky as the day progresses—hence the nameheliotrope.

• Red scaly lesions on the knuckles, elbows, and knees• Butterfly rash on the face• Rash on the sun-exposed regions of the head/neck/trunk• Periungual edema

Systemic manifestations of dermato- and polymyositiscan include fatigue,weight loss, arthralgias, and fever.Car-diac involvement can lead to arrhythmia, heart block, orcongestive failure. Interstitial lung fibrosis can lead to avariety of respiratory problems. Dysphagia and other gas-trointestinal motility abnormalities may occur.

Laboratory Findings Laboratory findings in dermato-myositis/polymyositis include elevated creatine kinase in


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90% of patients. EMG is abnormal in 90%, indicating thepresence of a myopathy; fibrillation suggests an “activecomponent” and may help distinguish inclusion bodymyositis and help select the muscle to biopsy. Musclebiopsy should distinguish the three common forms ofinflammatory myopathy (and help diagnose the uncom-mon forms as well):

• Polymyositis: muscle fiber necrosis, cellular infiltration• Dermatomyositis: vasculopathy, vasculitis, perifascicular

atrophy• Inclusion body myositis: inflammation and rimmed vac-

uoles on hematoxylin and eosin stain and oil red Ostain; electronic microscopy (EM) shows filamentousinclusions

Issues in Respiratory Involvement with ALS

Because most patients with ALS die from complications ofrespiratory failure, the clinician should anticipate the signsand symptoms of hypoventilation. Whether the goal isprolonged survival, maximal comfort, or both, the man-agement of respiratory failure in the patient with ALSshould be a high priority. Often the earliest signs of respi-ratory weakness are those associated with disturbed sleep.Daytime spirometry and blood gases may appear stable, butat night, the patient may experience severe hypoventila-tion. In general, the PCO2 will not begin to rise until theFVC falls below 50% of predicted. Early on, the bloodgases may show mild hypoxia and hypocapnea as patientshyperventilate to maintain oxygenation. As respiratory


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function deteriorates, the patient develops carbon dioxideretention from hypoventilation, and the serum bicarbon-ate levels become elevated as compensation for the respi-ratory acidosis. Significant hypercapnia typically developswhen the FVC is ≤ 30% of predicted, at which point, thepatient is at major risk of acute respiratory decompensation.

As the FVC falls to 50 to 60%, the patient with ALSbegins to develop symptoms of hypoventilation, and theuse of noninvasive positive pressure ventilation (bilevelpositive airway pressure) should be pursued to improvesymptoms (quality of life) and prolong survival.

PITFALL SCENARIOS

1. A patient is admitted for GBS with associated dyspnea.The patient’s blood gases are “normal”; therefore, thepatient is “stable” and is admitted to a ward bed forobservation. Four hours later, the patient has a respira-tory arrest and dies. Comment: In patients with neu-romuscular respiratory failure, the blood gas changesoccur relatively late. Do not be fooled, especially withpatients with GBS and MG.

2. A patient with ALS has chronic dyspnea owing todiaphragm weakness. In an effort to provide maximumcomfort, she is given supplemental oxygen. Over thenext hour, the patient appears much more comfortableand less short of breath.Two hours later, she appearsmore peaceful and is finally able to go to sleep. Severalhours later, she has a respiratory arrest and dies. Com-ment: The problem here is that the patient withchronic hypoventilation may have a chronic elevation


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of PCO2, leading to “hypoxic drive” of respiration.Thesupplemental oxygen raises the oxygen partial pres-sure, and the patient loses the hypoxic drive.Therefore,the patient further hypoventilates, leading to increas-ing levels of carbon dioxide.The patient appears morecomfortable, in part because of the sedating effects ofhypercapnia. Such sedation becomes increasingly pro-found, and over the next few hours, the patient followsa vicious cycle of increased sedation leading toreduced ventilation, which, in turn, raises the PCO2

even further, producing increasing sedation and, ulti-mately, a respiratory arrest.The solution is to use non-invasive ventilation (such as bilevel positive airwaypressure) prior to adding the supplemental oxygen.Also, starting with lower concentrations of supple-mental oxygen may be prudent.

3. A patient hospitalized for myasthenia has an FVCmeasurement of 400 mL.The nurse calls, asking you ifthe patient should be intubated.The patient insists heis stable and not short of breath.Comment: Always seethe patient and assess the situation firsthand.The FVCmay be wrong. It is often difficult to seal patients withfacial muscle weakness tightly around the mouthpiece,allowing air to escape when measuring the FVC.

REFERENCES

1. Thomas CE, Mayer SA, Gunger Y, et al. Myasthenia crisis.Clinical features, mortality complications and risk factorsfor prolonged intubation. Neurology 1997;48:1253–60.


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2. Ronager J, Raunborg M, Hermansen I, et al. Clinical effectof high-dose intravenous immunoglobulin treatment versusplasma exchange in patients with moderate to severe myas-thenia gravis.Artif Organs 2001;25:967–73.

3. Gajdos P, Chevert S, Clair B, et al. Clinical trial of plasmaexchange and high-dose intravenous immunoglobulin inMG.Ann Neurol 1997;41:789–96.

4. Qureshi AI, Choudry MA, Akbar MS, et al. Plasmaexchange vs. IVIg treatment of myasthenic crisis.Neurology1999;52:629–32.

5. Berrouschot J, Baumann I, Kalischewski P, et al.Therapy ofmyasthenic crisis. Crit Care Med 1997;25:1228–35.

6. GBS Study Group. Plasmapheresis and acute GBS. Neurol-ogy 1985;35:1096–104.

7. Dutch GBS Study Group.A randomized trial comparing IVgamma globulin and plasma exchange in acute GBS.N EnglJ Med 1992;326:1123–9.


Chalola JA. Pearls and pitfalls in the intensive care managementof Guillain-Barré syndrome. Semin Neurol 2001;21:399–405.

Cherington M. Botulism. Muscle Nerve 1998;10:27–31.Hund E. Critical illness polyneuropathy. Curr Opin Neurol

2001;14:649–53.Keesey JC. Crisis in myasthenia gravis: an historical perspective.

Muscle Nerve 2002;26:1–3.Kissel JT. Misunderstanding, misperceptions, and mistakes in the

management of the myopathies. Semin Neurol 2002;22:41–51.

Lacomis D, Campellone JV. Critical illness neuromyopathies.Adv Neurol 2002;88:325–35.


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Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscularweakness in the intensive care unit: a study of ninety-twopatients. Muscle Nerve 1998;21:610–7.

Lacomis D, Zochodne DW, Bird SJ. Critical illness myopathy.Muscle Nerve 2000;23:1785–8.

Lindenbaum Y, Kissel JT, Mendell JR.Treatment approaches forGuillain-Barré syndrome and chronic inflammatory demyeli-nating polyradiculoneuropathy. Neurol Clin 2001;19:187–204.

Pascuzzi RM. Pearls and pitfalls in the diagnosis and manage-ment of neuromuscular junction disorders. Semin Neurol2001;21:425–40.

Pascuzzi RM.ALS, motor neuron disease, and related disorders:a personal approach to diagnosis and management. SeminNeurol 2002;22:75–87.

Watling SM, Dasta JR. Prolonged paralysis in intensive care unitpatients after the use of neuromuscular blocking agents: areview of the literature. Crit Care Med 1994;22:884–93.


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Mr. J. K. is a 57-year-old man with a history of hyper-tension, coronary artery disease, and cigarette smoking.On the day of admission,he was in his usual state of healthand was out working in the fields on his tractor. He camein for lunch and was talking to his wife at the kitchentable.As he was getting ready to go back out, he suddenlybegan to slur his speech and could not get up out of thechair.His wife called their son,who practically carried Mr.K to the car, and they took him to the emergency depart-ment. He arrived at the emergency department approxi-mately 1 hour after the onset of symptoms. The triagenurse suspected a stroke, and he was evaluated urgently.

On examination in the emergency department, hisvital signs were stable (blood pressure 158/72 mm Hg,pulse 110 bpm and irregular, respiratory rate 16 breathsper minute, temperature 99°F). His general examinationwas notable for the following: no carotid bruits, equalradial and dorsalis pedal pulses, and an irregularly irregu-lar heart rate without murmur. His neurologic examina-tion was notable for an expressive aphasia, right homony-mous visual field deficit, a left gaze preference, right facialweakness, moderate right hemiparesis, and right hemisen-sory loss. Quantification of his examination using theNational Institutes of Health (NIH) Stroke Scale resultedin a score of 16, which indicates a large stroke.An emer-

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CHAPTER 7

ISCHEMIC STROKE

Patrick S. Reynolds, MD, and Terrence W. Bruner, MD, MBA

gent head computed tomographic (CT) scan was obtainedand was unremarkable (Figure 7-1). Electrocardiography(ECG) showed atrial fibrillation with no ST segmentchanges. Laboratory workup showed a normal metabolicprofile, including a blood sugar of 104 mg/dL; prothrom-bin time (PT) and partial thromboplastin time (PTT) werenormal, the complete blood count was normal, and theplatelet count was normal. Serum creatine phosphokinaseand troponin levels were not elevated.The patient had hadno recent surgical procedures and had no history of gas-trointestinal or genitourinary bleeding or trauma. Thepatient was felt to be a good candidate for thrombolytictherapy and met all laboratory and blood pressure param-eters for the stroke thrombolytic protocol.The risks andbenefits of thrombolytic therapy were discussed with thepatient’s wife and son, and informed consent was obtained


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Figure 7-1 Initial head computed tomographic scan in the emer-gency department approximately 1 hour, 45 minutes after thepatient’s stroke.

for administration of intravenous tissue plasminogen acti-vator (t-PA).

Intravenous t-PA was administered per protocol, withthe bolus begun 2:15 minutes after symptom onset. Hewas admitted to the acute stroke unit using the post–t-PAprotocol. His blood pressure remained stable on treatmentwith his usual blood pressure medications. Twenty-fourhours after the t-PA infusion, he was neurologically muchimproved.He was speaking fluently but continued to havesome naming and paraphasic errors. He could repeat. Hisgaze preference and homonymous hemianopia hadresolved.His facial droop and hemiparesis had dramaticallyimproved. His NIH Stroke Scale score had improved from16 to 6. He was participating well in physical, occupa-tional, and speech therapy, and he had passed his swallow-ing evaluation and could eat safely without increased riskof aspiration pneumonia. Approximately 24 hours afterthe t-PA infusion was completed, a follow-up brain CTscan was performed to evaluate the size of the residualinfarct and to look for intracranial hemorrhage.The CTscan (Figure 7-2) showed a moderate-sized residual infarctbut no hemorrhage.The patient was ruled out for myocar-dial infarction with serial cardiac enzyme testing.The pre-sumptive cause of his stroke was cardioembolism owing toatrial fibrillation; however, a further etiologic workup wasnevertheless necessary. A transthoracic echocardiogramwas performed to assess his ventricular performance andto determine if there had been any decreased cardiac func-tion since his last echocardiogram. This echocardiogramshowed mild left ventricular hypertrophy with an ejectionfraction of 55% and no segmental wall motion abnormal-

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ities.The left atrium was dilated, but no thrombus was seenon this examination.A carotid duplex sonogram was per-formed and showed mild, nonstenotic, atheroscleroticplaque in the patient’s internal carotid arteries bilaterally.

After the follow-up CT scan showed no hemorrhageand only a small residual infarct, the patient was started onintravenous heparin and warfarin for long-term anticoag-ulation. When his international normalized ratio (INR)was therapeutic (> 2.0), the heparin was discontinued, andthe patient was discharged home with outpatient therapy.For control of his blood pressure, he was continued on a�-blocker, an angiotensin-converting enzyme (ACE)inhibitor, and a thiazide diuretic. He was continued on hisstatin medication (3-hydroxy-3-methylglutaryl coenzymeA inhibitor [“statin”]) for cholesterol therapy and wasencouraged to stop smoking.


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Figure 7-2 Follow-up head computed tomographic scan approxi-mately 30 hours after stroke.

The patient returned in follow-up to the stroke clinic3 months after discharge. He was once again working as afarmer. His deficits had almost completely resolved, withthe only residual findings on examination being a verymild right facial weakness and minimal clumsiness of hisright hand. He had managed to quit smoking and wascompliant with his medications.

DEFINITION

Stroke is a sudden, nonconvulsive, focal neurologic deficitcaused by a disorder of blood vessels—a vascular event.

• Ischemic stroke (or infarction) is the death of neuronsand glia caused by lack of blood flow owing to an arteryblockage or inadequate perfusion.

• Hemorrhagic stroke is bleeding into the brainparenchyma owing to a ruptured blood vessel. Sub-arachnoid hemorrhage is bleeding into the subarach-noid space.

The diagnosis of stroke remains a diagnostic challengeas there are many potential nonvascular causes of acuteneurologic deficits, making good history and physicalexamination skills paramount in the evaluation of neuro-logically impaired patients. Some conditions that canmimic stroke are shown in Table 7-1.

EPIDEMIOLOGY INTRODUCTION

Stroke is the third leading cause of death in the UnitedStates and the leading cause of long-term disability. The

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American Heart Association (AHA) and the NationalStroke Association estimate that there are approximately700,000 new strokes each year and that approximatelyone-third of patients with new strokes will die. Thisequates to approximately one stroke every minute in theUnited States and one stroke death every 3 minutes.Theprevalence of stroke in the general population is 500 to700 in 100,000. The incidence increases with age from200 in 100,000 around age 60 to 3,000 in 100,000 afterage 85.There are estimated to be approximately 4 millionstroke survivors in the United States.


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Table 7-1 Conditions That May Mimic Stroke

Condition %

Infections 20

Seizure 17

Metabolic 13

Benign positional vertigo 6

Cardiac 5

Syncope 5

Other 19

Adapted from Libman RB et al.36

BACKGROUND

Ischemic stroke (infarction) accounts for 80 to 85% ofstrokes in the United States, and 15 to 20% of strokes arehemorrhagic: intraparenchymal or subarachnoid hemor-rhage.A transient ischemic attack (TIA) is a focal neuro-logic deficit caused by a temporary interruption of bloodsupply without permanent damage to brain tissue.By def-inition, a TIA is defined as a neurologic deficit lasting lessthan 24 hours.This definition is outdated, and with mod-ern imaging methods, we know that many patients withclinical deficits lasting only a few hours will have imagingevidence of permanent damage to their brain.The usualduration of a TIA is from 5 to 20 minutes, and most attackslast less than 1 hour.TIAs should be considered analogousto unstable angina in heart disease and mandate urgentevaluation and treatment. Ten percent of patients whohave a TIA will have a stroke within 3 months, but half ofthose (5%) will have a stroke within 48 hours of the TIA.The 5-year risk of stroke after a TIA is at least 30%.6

Risk Factors and Causes

A risk factor is a condition (disease, genetics, gender, age)that increases the likelihood of developing a diseaseprocess in the future. The cause of an ischemic stroke iswhat actually causes poor blood flow or blockage of theartery, leading to brain cell death. A risk factor is not thesame as a cause, and a risk factor such as hypertension can,in fact, predispose a patient to multiple causes ofstroke.1,2,7–12

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Causes of Ischemic Stroke

• Atherosclerosis: hardening (lipid buildup) of large vesselscausing distal thromboembolism or hypoperfusion

• Cardioembolism: blood clots originating in the heartand embolizing to brain arteries

• Small vessel disease: thickening of small intracranialarteries owing to hypertension, diabetes, smoking,atherosclerosis

• Hypercoagulable states: congenital or acquired abnor-malities leading to excessive or inappropriate bloodclotting

• Nonatherosclerotic vasculopathies: dissections (tearingof the inner layer of an artery, usually owing to trauma),vasculitis, fibromuscular dysplasia, collagen vasculardisorders

• Hypoperfusion (usually owing to relative hypotension):inadequate blood flow to a brain region

Nonmodifiable Risk Factors

• Age: the most important nonmodifiable risk factor. Pastthe age of 55, the risk of stroke doubles with each suc-ceeding decade

• Gender: men are at greater risk of stroke than women,but women have their strokes at an older age

• Race: the incidence of stroke in blacks is more thandouble that in whites, and the incidence is also higherin Hispanic Americans

• Family history: especially important if first-degree rela-tives have strokes at a young age


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Modifiable Risk Factors

• Prior stroke or TIA: knowing the cause allowsantithrombotic therapy for prevention of recurrentstrokes and allows aggressive treatment of all other riskfactors

• Hypertension: the most important risk factor for bothischemic and hemorrhagic stroke. Hypertension causesendothelial damage to both large and small vessels

• Heart disease: leading to embolism of clots from theheart to the brain• Atrial fibrillation: causes stasis of blood in the fibril-

lating atrium, leading to the formation of clots,whichmay then embolize

• Ischemic or nonischemic cardiomyopathies: causesevere left ventricular dysfunction,which leads to sta-sis of blood in the ventricle and the formation ofclots, which can then embolize

• Mechanical heart valves: lead to embolism• Cigarette smoking: accelerates atherosclerosis owing to

endothelial damage, free radical formation, heavyalcohol use: greater than two drinks per day increasesrisk of hemorrhagic stroke

• Hyperlipidemia: directly related to atherosclerosis• Heavy alcohol use: especially related to hemorrhagic

stroke• Asymptomatic carotid stenosis: may lead to throm-

boembolism in the future• Diabetes: probably functions by accelerating atheroscle-

rosis in large vessels by endothelial damage and con-tributes to lipohyalinosis in small vessels

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• Sympathomimetic drug use (both legal and illegal):induces hypertension, may induce a vasculitis, acceler-ates atherosclerosis through endothelial damage, andmay induce a hypercoagulable state

NEUROANATOMY

Anatomic Division

The brain can be divided into three major anatomic areas:the cerebrum, the cerebellum, and the brainstem. Thecerebrum can be further divided into the overlying cor-tex (“computer, processing center”) and connecting sub-cortical areas (“wiring”) and the two sides, or hemi-spheres, of the cerebrum. Each hemisphere controlsmovement and sensation from the other side of the body.

• Left cortex: in most people, the left hemisphere is dom-inant, meaning that the language center is in the lefthemisphere

• Right cortex: the right hemisphere recognizes and paysattention to the left environment and is more responsi-ble for spatial relations and artistic endeavors

• Subcortical areas: consist of the white matter (bundles ofaxons and nerves that connect the neurons), basal gan-glia (gray matter that modulates movement), and thethalami (gray matter that serves as a sensory relay centerand motor switchboard)

• Cerebellum: coordination center to control timing ofmotor movements. The cerebellar vermis controlstruncal balance and the cerebellar hemispheres con-


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trol appendicular (arms and legs) coordination andbalance

• Brainstem: connects and relays all information from thebrain to the spinal cord and to the rest of the body, allin a cross-sectional area little bigger than a quarter

Arterial Territory

• Middle cerebral artery: supplies most of the ipsilateralhemispheres and much of the deep white matter andbasal ganglia through small, penetrating arteries

• Anterior cerebral artery: supplies most of the medialportion of the hemispheres and a portion of the basalganglia and anterior thalamus

• Posterior cerebral artery: supplies the occipital cortex,large portions of the thalamus, and some of the tempo-ral lobe

• Basilar artery: supplies the pons, midbrain, parts of thecerebellum, and the posterior cerebral arteries

• Vertebral artery: supplies the medulla and the inferiorcerebellum

STROKE SYNDROME

The part of the brain affected by a stroke can be localizedbased on the patient’s signs and symptoms. All strokepatients have a sudden onset of a cluster of symptoms.Thepatient should be assessed for stroke risk factors, both bya history and physical examination and by laboratorymarkers.

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Stroke Signs by Brain Region Damaged

• Left hemisphere (dominant)• Cortical involvement: aphasia, right visual field

deficit, left gaze preference• Cortical and/or subcortical involvement: right hemi-

paresis, right hemisensory loss• Right hemisphere (nondominant)

• Cortical involvement: neglect (hemi-inattention), leftvisual field deficit, right gaze preference

• Cortical and/or subcortical involvement: left hemi-paresis, left hemisensory loss

• Cerebellum: truncal or gait ataxia, limb ataxia, vertigo• Brainstem: the hallmark is “crossed” findings (signs on

both sides of the body, usually cranial nerve findings onone side and motor/sensory findings on the other sideof the body• Hemiparesis or quadriparesis• Sensory loss on one or both sides• Diplopia, gaze palsies, nystagmus• Altered consciousness• Vertigo, hiccups, hoarseness, nausea, vomiting

Stroke Syndromes by Arterial Territory

• Left middle cerebral artery stroke• Language disturbance (aphasia)• Right visual field deficit• Left gaze preference• Right hemiparesis (arm weaker than leg)• Right hemisensory loss


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• Right middle cerebral artery stroke• Left-sided inattention (neglect syndrome)• Aprosody (abnormalities involving the emotional

content of speech)• Left visual field deficit• Right gaze preference• Left hemiparesis (the arm weaker than the leg)• Left hemisensory loss

• Posterior cerebral artery stroke• Contralateral homonymous visual field deficit• Contralateral sensory loss if thalamus involved• Memory loss if temporal lobe involved

• Basilar artery stroke: brainstem findings localizing to thepons or midbrain and possibly cerebellar findings

• Vertebral artery stroke: brainstem findings localizing tothe medulla and usually cerebellar findings

• Classic small vessel stroke syndromes (lacunar syn-dromes)• Pure motor stroke (usually localizes to internal cap-

sule or ventral pons)• Contralateral hemiparesis with equal weakness of

the face/arm/leg• No sensory or cortical findings

• Pure sensory stroke (localizes to the thalamus)• Contralateral sensory loss to all modalities• No motor or cortical findings

• Clumsy hand—dysarthria syndrome (usually localizesto the subcortical white matter or pons)• Mild, usually distal upper extremity weakness• Severe dysarthria, but language function is intact• No sensory loss or other cortical findings

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• Sensorimotor stroke (usually localizes to the subcor-tical white matter)• Contralateral hemiparesis• Contralateral hemisensory loss• No aphasia or neglect

PRIMARY PREVENTION OF STROKE

The goal is to prevent a first-ever stroke.13

• Hypertension is the most important treatable risk factor.Even a modest reduction in blood pressure has impor-tant effects on stroke prevention.8

• Identification of heart disease to prevent myocardialinfarction.Anticoagulation in patients with atrial fibril-lation dramatically reduces the risk of ischemic stroke.However, in many states, fewer than half of patients withknown atrial fibrillation and without bleeding con-traindications are placed on anticoagulation with war-farin.This is a public health problem, which needs bet-ter education of physicians.9

• Drug therapy with ACE inhibitors in at-risk patients(patients with heart disease or diabetes) can reduce therisk of first-time stroke.This effect is independent of theantihypertensive effect of these drugs, and this beneficialeffect is seen in patients without hypertension.12

• Treatment of hypercholesterolemia in at-risk patients(with known heart disease) with 3-hydroxy-3-methyl-glutaryl coenzyme A inhibitors (“statins”) reduces therisk of first-ever stroke.11


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• Carotid endarterectomy for patients with high-grade,asymptomatic internal carotid artery stenosis can pre-vent stroke in carefully selected patients who are oper-ated on by surgeons skilled in the procedure and whohave low complication rates.7

• Lifestyle changes: patients must be educated to be activeparticipants in their own health care. They should beencouraged and taught about the following importantlifestyle changes10:• Smoking cessation• Prudent diet, exercise, and weight loss• Stopping excessive alcohol use and sympathomimetic

drug use• Public education is needed regarding stroke signs and

symptoms and the fact that stroke is a treatable emer-gency.Teach the public to call 911 and to go to theemergency department for treatment of the acutestroke.

EMERGENCY ISCHEMIC STROKE CARE

Rapid identification and treatment of stroke patients areessential to minimize complications and enhance recov-ery. Ischemic stroke patients who present to the emer-gency department within 3 hours of their symptom onsetshould be evaluated for potential therapy with t-PA, athrombolytic drug that has been shown to enhancerecovery from stroke. Patients who receive intravenoust-PA according to strict guidelines have an approximately30 to 50% increase in their chance of having an excellentrecovery from their stroke, with a 6% risk of severe

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intracranial hemorrhage as a potential side effect, butappropriate administration of t-PA does not increasemortality (Figure 7-3).

Rationale for Thrombolytic Therapy

In the first few hours after a stroke, there is a central area(core infarction) of dead neurons and a surrounding zone(ischemic penumbra) of ischemic, nonfunctioning(stunned) neurons, which are still viable if the blood sup-ply can be re-established.A patient’s symptoms are due tothe combined effects of the core of ischemic damage plusthe dysfunction of the penumbra tissue. The amount ofsalvageable penumbra tissue cannot be determined byclinical examination or as yet by neuroimaging. Theamount of time that penumbra neurons can remain viableis also not known, but intravenous t-PA has been shownto be effective only when given within 3 hours of stroke.Direct intra-arterial delivery of lytic therapy to the mid-dle cerebral artery can extend that time window to6 hours with reperfusion and improved clinical outcome.

The presumed method of action of t-PA is to causelysis of an acute thrombus occluding an artery, therebyallowing reperfusion.This reperfusion allows the ischemicneurons to recover function.Thrombolytic therapy causesa significant risk of intracranial hemorrhage, however, andthere are strict clinical criteria that must be met to allowtreatment with thrombolytic therapy to be as safe aspossible. The most important parameters are accurateidentification of the time of symptom onset and not giv-ing t-PA to patients with a blood pressure greater than


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185/110 mm Hg, which increases the risk of intracranialhemorrhage. Patients with other potential risks for bleed-ing also should not receive thrombolytic therapy (Figure7-4).14–18


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Figure 7-4 Ischemic penumbra. The penumbra is the ischemicarea around the infarcted core. Courtesy of Dr. David Lee Gordon,Center for Research in Medical Education, University of MiamiSchool of Medicine.

Practical Emergency Stroke Care

Acute stroke is a treatable medical emergency.The Amer-ican Heart Association has identified a “Chain of Survival”to promote thrombolytic therapy for stroke: The 7 D’s:Stroke Chain of Survival and Recovery (from ACLSProvider Manual, copyright 2001, American HeartAssociation)19:

• Detection of the onset of stroke signs and symptoms• Dispatch through activation of the emergency medical

service (EMS) system and prompt EMS response• Delivery of the victim to the receiving hospital while

providing appropriate prehospital assessment and careand prearrival notification

• Door (emergency department triage)• Data (emergency department evaluation, including a

CT scan) • Decision about potential therapies• Drug therapy

There are three other “D’s” that should also bethought of as part of emergency care and should be con-sidered as well even when the patient is initially beingevaluated:

• Defeat the medical complications of stroke.• Determine the cause of the stroke (etiologic evalua-

tion—the patient’s type of stroke and risk factors shouldindicate to the physician the most likely cause of thestroke to allow initial workup to be directed at thosecauses).

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• Deter the next stroke (initiate appropriate secondaryprevention after the cause of the stroke has beendetermined).

Sample Checklist for Administration of recombinanttissue plasminogen activator (r t-PA) for Acute StrokeThrombolysis (Table 7-2)

Eligibility Criteria• Clinical diagnosis of acute ischemic stroke with onset

determined to be within 3 hours of administration ofbolus of rt-PA

• Age 18 years or older• A noncontrast CT scan must be obtained prior to t-PA

administration

Warnings• An increased risk of intracranial hemorrhage in very

large strokes (NIH Stroke Scale > 22)• An increased risk of intracranial hemorrhage if the CT

scan shows major early signs of infarct

Administration of t-PA• 0.9 mg/kg with a maximum total dose of 90 mg• 10% of total dose administered as a bolus over 1 minute

with the remaining 90% of the dose administered ascontinuous infusion over the next 60 minutes

Follow-up• Close monitoring of vital signs and neurologic exami-

nation


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Table 7-2

History No Yes*1. Only minor or rapidly improving

stroke symptoms ❑ ❑2. Clinical presentation worrisome for SAH ❑ ❑3. Active systemic bleeding ❑ ❑4. Major surgery or trauma in last 14 d ❑ ❑5. Head trauma, intracranial surgery, or

prior stroke in the last 3 mo ❑ ❑6. Gastrointestinal or urinary tract

hemorrhage in last 21 d ❑ ❑7. Recent arterial puncture at non-

compressible site ❑ ❑8. Recent lumbar puncture ❑ ❑9. History suggestive of possible seizure

at onset or after stroke ❑ ❑10. History of AVM or aneurysm ❑ ❑11. Any history of intracranial hemorrhage ❑ ❑12. Post-MI pericarditis ❑ ❑

Laboratory1. Intracranial hemorrhage or SAH on

CT scan ❑ ❑2. Blood pressure > 185/110 mm Hg

on repeated measurements or requires aggressive treatment to maintain these limits ❑ ❑

3. Abnormal blood sugar (< 50 or > 400 mg/dL) ❑ ❑

4. Platelet count < 100,000 ❑ ❑5. Elevated apt ❑ ❑6. INR > 1.5 ❑ ❑

*Any check in the “Yes” column makes the patient ineligible for tissueplasminogen activator therapy. Adapted from Report of the QualityStandards Subcommittee of the American Academy of Neurology.20

apt = activated partial thromboplastin time; AVM = arteriovenousmalformation; CT = computed tomography; INR = internationalnormalized ratio; MI = myocardial infarction; SAH = subarachnoidhemorrhage.

• Maintain blood pressure < 185/110 mm Hg• No anticoagulant or antiplatelet therapy for the first

24 hours• Avoid invasive lines and procedures if possible in the first

24 hours

EMERGENCY STROKE CARE

The goal of acute stroke care, whether or not the patientis a candidate for an acute intervention such as intravenoust-PA therapy, is to maximize the chance of recovery of thepenumbra, prevent medical complications, determine thecause of stroke, initiate appropriate secondary preventionbased on the mechanism of stroke, and enhance functionalrecovery through rehabilitation.

Four Things to Avoid in Emergency Stroke Care(The 4 Don’ts!)

• Avoid hypotension. Most stroke patients have an ele-vated blood pressure at the time of the stroke, usuallyowing to poorly controlled or unrecognized hyperten-sion prior to the stroke, as well as a physiologic responseto the stroke itself. Hypertension in the setting of anacute infarct may be beneficial by increasing perfusionpressure to the ischemic penumbra and, in general,should not be aggressively treated in the setting of acutestroke.Exceptions would be in patients with concurrentillnesses such as acute myocardial infarctions or aorticdissections or in patients who received thrombolytictherapy and whose blood pressure must be lowered to


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below 185/110 mm Hg. Acute blood pressure therapyshould, in general, be aimed at maintaining mean arte-rial pressure in the range of 120 to 130 mm Hg. Long-term control of blood pressure should be obtained overa period of several weeks. Short-acting nifedipineshould never be used in stroke patients because it causeslarge, acute drops in blood pressure that can potentiallyworsen the stroke.

• Avoid giving glucose. Hyperglycemia is associated withworsened outcome in stroke patients; therefore, it is bestto avoid giving glucose-containing solutions. Glucoseshould be given only if the patient has documentedhypoglycemia.

• Avoid hyperthermia.An elevated body temperature hasbeen shown to be associated with worse stroke out-comes. Fevers should be aggressively treated withantipyretics, and the cause of the fever should be deter-mined and directly treated.

• Avoid aspiration pneumonia.Aspiration pneumonia is amajor cause of morbidity and mortality in strokepatients. Most stroke patients (not just patients withbrainstem strokes) potentially have weak oropharyngealmuscles and/or poor or absent gag response.Aspirationprecautions include maintaining the head of the bed at30° or higher at all times and to avoid all oral intake,including medications, until the patient’s ability to swal-low safely can be fully evaluated. If there is any doubt,then a nasogastric tube should be placed for nutritionand medication until a formal swallowing evaluationcan be performed.

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Some Do’s! in Emergency Stroke Care

• Begin aspirin therapy after a CT scan has ruled outhemorrhage and if the patient is not a candidate forthrombolysis. If the patient receives thrombolytic ther-apy with t-PA, then all anticoagulant and antithrom-botic medications must be withheld and not adminis-tered for the first 24 hours.

• Therapy with aspirin within 48 hours of stroke onsethas been shown to be beneficial to decrease the rate ofrecurrence.

• Initiate deep vein thrombosis prophylaxis if the patienthas impaired mobility.

• Avoid hypotonic intravenous solutions, which couldworsen brain edema.

• Prioritize early mobilization and discontinue invasiveintravenous lines and Foley catheters as soon as possible

• Initiate physical, occupational, and speech therapy assoon as possible if clinically indicated.

Role of Heparin

In general, there is usually NO indication for intravenousheparin in acute ischemic stroke. Heparin has never beenshown to be beneficial and carries the risks of systemicand intracranial bleeding as well as the risk of heparin-induced thrombocytopenia. Subcutaneous heparin is ben-eficial for deep vein thrombosis prophylaxis. There aresome accepted uses of intravenous heparin24:

• Crescendo TIA: more than one TIA in 24 hours or sev-eral TIAs in the last few days


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• Stroke in evolution: progression of a patient’s clinicalstroke deficits thought to be from more ischemic dam-age to the brain owing to an increase in the size of thethrombus and worsened perfusion to that area of thebrain

• Stroke owing to arterial dissection• Stroke owing to intracranial venous thrombosis

ETIOLOGIC EVALUATION/SECONDARY PREVENTION

Laboratory Evaluation

The laboratory evaluation of the stroke patient should bedesigned to confirm the clinical syndrome identified onexamination, determine the cause of the stroke, and iden-tify all potential stroke risk factors. Such a comprehensiveworkup allows determination of appropriate antithrom-botic therapy for secondary prevention and maximumtreatment for risk factor modification:

• Etiologic evaluation encompasses imaging of the brainto confirm the type of stroke syndrome and evaluationof the heart, blood vessels, and blood components toidentify the cause of the stroke. In general, laboratorytests should be done in a sequence going from nonin-vasive to invasive testing until the cause is determined.

• Brain imaging consists of an emergent CT scan withoutcontrast in the emergency department to rule out hem-orrhage. Follow-up scanning is done by either CTwithout contrast or the far more sensitive magnetic res-onance imaging to visualize the actual ischemic lesion.

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• Blood vessel imaging can be done by duplex ultra-sonography to evaluate the extracranial carotid and ver-tebral arteries, by transcranial Doppler ultrasonographyto evaluate the intracranial vessels, and by magnetic res-onance angiography or CT angiography, which canevaluate both extra- and intracranial vessels. Conven-tional angiography can be performed to definitivelyimage the vasculature if the noninvasive studies do notprovide an answer.

• Cardiac evaluation consists of ECG and rhythm strip,cardiac telemetry to monitor for arrhythmias, especiallyatrial fibrillation, and echocardiography, which can beeither transthoracic or the more invasive but more sen-sitive transesophageal echocardiography.

• Blood workup consists of analysis of coagulation times(PT, activated PTT), hemoglobin and hematocrit, andplatelet count.Hypercoagulation profiles (including butnot limited to protein C and S levels, antiphospholipidprotein antibody titers, antithrombin III levels, and fac-tor V Leiden mutation) should be performed in youngerstroke patients or in patients with no clearly identified,more common cause. Young patients should also bescreened for illicit drug use, especially sympathomimeticdrugs—most importantly, cocaine.

• Risk factor evaluation consists of identifying and search-ing for the following modifiable risk factors:• Hypertension• Hyperlipidemia• Diabetes• Tobacco use


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• Excessive alcohol use• Illicit drug use• Hyperhomocysteinemia• Heart disease, especially atrial fibrillation or car-

diomyopathies

Secondary Prevention

Secondary prevention must be initiated early.Appropriatesecondary prevention is based on identification of thecause of stroke and identification of all modifiable riskfactors and potential surgical intervention.

• Aggressively treat all identified risk factors (hyperten-sion, diabetes, hyperlipidemia, hyperhomocysteinemia,heart disease, hypercoagulable states) and encouragechanges in lifestyle and behavior, especially regardingmedication compliance, diet and exercise, smoking andillicit drug cessation, and moderation of alcohol intake.

• Initiate antithrombotic therapy for secondary preven-tion based on an identified cause.Antithrombotic ther-apy is intended to decrease clot formation, which is theend result that causes arterial blockage in most ischemicstrokes.Antiplatelet therapy with aspirin has been shownto decrease stroke recurrence by approximately 25%.Ticlopidine, clopidogrel, and combination therapy withaspirin plus extended-release dipyridamole have all beenshown to be somewhat more effective at preventingrecurrent strokes than aspirin, but at a much higherprice. Antiplatelet therapy is generally thought to bemost effective in high-flow states in which platelet

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aggregation is thought to be the initiating event forthrombus formation.Anticoagulation with warfarin hasbeen shown to dramatically decrease cardioembolicstrokes owing to atrial fibrillation and mechanical valvesand in post–myocardial infarction cardiomyopathy.War-farin is thought to be more effective than antiplatelettherapy in low-flow states in which activation of clot-ting factors is thought to be the more important mech-anism of initial clot formation.23,25–33

• Carotid endarterectomy has been shown to be effectivefor stroke prevention in patients symptomatic withstroke or TIA in the setting of an internal carotid artery(ICA) stenosis of 50 to 99%.The benefit increases withincreasing severity of stenosis.The benefit is much lesswith stenoses in the 50 to 69% range, especially so indiabetic women in that stenosis range because surgicalcomplications almost cancel out benefits in that sub-group of patients.

• A large clinical trial has shown that carcinoembryonicantigen (CEA) for asymptomatic patients with ICAstenosis of 60 to 99% reduces stroke rate, but the risk-benefit ratio is much narrower than in symptomaticpatients.

Sample Secondary Prevention Guidelines Based onCause

• Atherosclerosis• Symptomatic ICA stenosis 70 to 99% = CEA fol-

lowed by aspirin therapy


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• Symptomatic ICA stenosis 50 to 99% = probableCEA but requires heightened risk-benefit assessmentand aspirin after CEA

• Extracranial carotid disease but less than 50% stenosis= antiplatelet therapy

• Intracranial disease: antiplatelet therapy unless possi-ble very high-grade intracranial stenosis

• Cardioembolic source: warfarin, usually with a target-INR of 2.0 to 3.0.• Lacunar syndrome: antiplatelet therapy• Hypercoagulable state: warfarin, INR 2.0 to 3.0• Nonatherosclerotic vasculopathy: therapy dependent

on cause• Dissection: warfarin for 6 months then antiplatelet

therapy• Vasculitis: immune-modulating therapy with

steroids, azathioprine, cyclophosphamide• Hypoperfusion: treat anemia, increase blood pressure• Treat hypertension aggressively after the acute stage of

the stroke.ACE inhibitors are neuroprotective in addi-tion to their antihypertensive effects. Considerationshould be made for treatment of stroke patients withACE inhibitors even in the setting of normal bloodpressure.

• Aggressive treatment of hyperlipidemia should be con-sidered, especially using “statin” medications, whichlikely reduce the incidence of recurrent stroke.

• Patients with hyperhomocysteinemia should probablybe treated with folic acid.

All risk factors should be aggressively screened for andtreated!

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CONCLUSION

• Stroke is a brain attack.• Stroke is not an accident.• Stroke is a treatable, preventable disease.

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31. Albers GW, Amarenco P, Easton JD, et al. Antithromboticand thrombolytic therapy for ischemic stroke. Chest 2001;119:300S–20S.

32. Yusuf S, Zhao F, Mehta SR, et al.The Clopidogrel in Unsta-ble Angina to Prevent Recurrent Events Trial Investigators.Effects of clopidogrel in addition to aspirin in patients withacute coronary syndromes without ST-segment elevation.N Engl J Med 2001;345:494–502.

33. Mohr JP,Thompson JL, Lazar RM, et al. A comparison ofwarfarin and aspirin for the prevention of recurrentischemic stroke. N Engl J Med 2001;345:1444–51.

34. North American Symptomatic Carotid EndarterectomyTrial Collaborators. Beneficial effect of carotid endarterec-tomy in symptomatic patients with high-grade carotidstenosis. N Engl J Med 1991;325:445–53.

35. Barnett H, Taylor D, Eliasziw M, et al. Benefit of carotidendarterectomy in patients with symptomatic moderate orsevere stenosis. N Engl J Med 1998;339:1415–25.

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36. Libman RB, Wirkowski EA, Rao TH. Conditions thatmimic stroke in the emergency department. Implicationsfor acute stroke trials.Arch Neurol 1995;52:1119–22.


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CASE

A 22-year-old man with a diagnosis of schizophreniahad been treated with risperidone and benztropine mesy-late. Because of an exacerbation of his psychosis withresultant paranoid delusions, he was admitted to the hos-pital. He demonstrated severe agitation and aggressivebehavior,which resulted in his antipsychotic therapy beingchanged from risperidone to parenteral haloperidol.Threedays later, he was noted to be intermittently slightly lessalert. On examination, there was significant axial andappendicular rigidity. He had a heart rate of 112 bpm anda temperature of 103°F. Laboratory evaluation revealed awhite blood count of 13,200 without a left shift. Theserum creatine kinase level was 3,140 U/L. Chest radiog-raphy and urinalysis were normal. A diagnosis of neurolep-tic malignant syndrome (NMS) was made.Haloperidol wasdiscontinued, and benztropine mesylate was tapered anddiscontinued over 3 days.Dantrolene was started in an ini-tial daily dosage of 75 mg. He was placed under a coolingblanket and hydrated with intravenous fluids. After 24hours of therapy, there was only mild improvement in therigidity and fever and no change in his level of alertness.The daily dosage of dantrolene was increased to 150 mg.On the third day, dantrolene was increased to 200 mg, andbromocriptine 2.5 mg three times daily was begun andthen titrated up to 5 mg three times daily on the fourth

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CHAPTER 8

NEUROLEPTIC MALIGNANT SYNDROME

Rober t L. Rodnitzky, MD

day.The rigidity began to improve, and the body temper-ature normalized. Liver function tests were monitoredwhile on dantrolene therapy.After 8 days of therapy, therewas no further rigidity, mental alertness was normal, andblood pressure and pulse rate were normal and stable.Dantrolene therapy was continued orally for the next 7days, and bromocriptine was continued for the next 5 days,with a subsequent 3-day taper to zero.Creatine kinase lev-els gradually normalized over the first 7 days of therapy.

DEMOGRAPHICS

NMS is a rare but potentially lethal complication of ther-apy with dopamine receptor blocking agents (DRBAs). Itcan also occur in patients with Parkinson’s disease afterrapid withdrawal of dopaminergic medications. Thereported incidence rate in patients receiving typical neu-roleptic drugs has varied widely, but in one of the largestand most recent studies, an incidence of 0.15% wasreported.1 This represented a significant decline in thereported incidence of 1.4% at the same medical center adecade earlier.2 The authors suggested that this nearly 10-fold decline in incidence reflected both better recognitionof risk factors and preemptive early recognition and treat-ment of the syndrome. In addition, declining use of depotagents and the use of lower overall dosages of neurolepticdrugs may have contributed to the declining incidence.3

CAUSATIVE AGENTS AND RISK FACTORS

NMS is most commonly associated with the use of typicalneuroleptics, such as haloperidol and fluphenazine. The


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atypical antipsychotic agents, including clozapine,4 olanza-pine,5 risperidone,6 and quetiapine,7 have all been reportedto cause NMS. However, there is a lower incidence inpatients receiving these atypical agents, and at least in thecase of clozapine, a milder syndrome with less predominantfever and elevation of creatine kinase may result.4 It isimportant to remember that antiemetic DRBAs such asmetoclopramide and prochlorperazine can also result inNMS. NMS can also occur in patients with Parkinson’s dis-ease after rapid withdrawal or reduction of dopaminergicdrugs8 or, rarely, during a daily wearing-off episode at theend of a levodopa interdose interval. NMS has beenreported to occur after therapy with a variety of drugs thatdo not have significant dopamine blocking action, such astricyclics, selective serotonin inhibitors, benzodiazepines,methylphenidate, and carbamazepine. Such cases are infre-quent, and in some reports, the clinical presentation is veryatypical or indistinguishable from serotonin syndrome.When caused by administration of neuroleptics, the onsetof the syndrome is usually within 1 month after the initi-ation or increase in dosage of the offending agent, althoughas many as 16% of cases develop within the first day oftherapy and 30% appear within 2 days.9 The incidence rateis highest in young males and in patients who are agitated,dehydrated, or hyponatremic or who have received a large,rapidly administered dosage of the offending DBRA.10–12

Elevation of serum levels of creatine kinase during non-NMS psychotic episodes has been found to increase therisk of NMS in the future.13 The syndrome can occur inchildren and in adults. A recent review of the literatureidentified 4 cases below the age of 6 years, 6 cases between

Neurolept ic Mal ignant Syndrome

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the ages of 6 and 10 years, and 22 cases between the agesof 11 and 14 years.14 The relatively low number of casereports in childhood may reflect the more limited use ofDRBAs in this age group.

CLINICAL FEATURES

The cardinal clinical manifestations of NMS are similarirrespective of its causation (Figure 8–1).The symptoma-tology consists of fever,muscular rigidity, autonomic insta-bility, and confusion or alteration in consciousness.15 Theautonomic disturbance may consist of any combination ofsymptoms, including tachypnea, tachycardia, labile bloodpressure, diaphoresis, and urinary retention. The moststriking movement disorder is rigidity,which is often axialand sometimes results in an opisthotonic posture. In areview of 52 cases of NMS, other movement disordersthat were moderately common included dystonia, chorea,and a parkinsonian appearance.16 Buccofacial dyskinesias,oculogyric crises, and blepharospasm can be noted but aremuch less frequent. In children, dystonia is more likely tobe the predominant extrapyramidal feature.14 Other neu-rologic signs that are occasionally reported in these casesinclude sialorrhea, dysphagia, flexor or extensor posturing,muscle stretch reflex abnormalities, and Babinski’s signs.Areview of over 300 cases of NMS found that changes ineither mental status or rigidity were the initial manifesta-tion in 82% of cases and were much more likely to beobserved before the onset of hyperthermia and autonomicdysfunction.17 In the same series, 70% of the cases fol-lowed a sequence of presentation consisting of mental sta-tus changes, rigidity, hyperthermia, and autonomic dys-


170

function. Fever is typically at least 38°C and often higher.Creatine kinase levels are usually above 2,000 IU/L andoften in the range of 15,000 to 20,000 IU/L.

Diagnostic confusion is possible because milder formsof the syndrome may exist without all of the cardinal fea-tures of the illness. Cases that are otherwise typical exceptfor absence of fever have been reported.18 In somepatients, even in those who ultimately die of the syn-drome, classic features such as muscle rigidity may not bepresent.19 Accordingly, it has been suggested that onlythree of the four classic features of the illness, fever, rigid-ity, altered consciousness, and autonomic instability, needto be present within a period of 1 day to consider thediagnosis of NMS.20 Another potential source of diagnos-tic confusion in NMS is the fact that some neuroleptics,particularly those characterized as atypical, can result inadverse effects that overlap with the symptoms of NMSand are inappropriately attributed to NMS.21 Lastly, itmust be kept in mind that there are other syndromesthat can result in hyperthermia, including malignanthyperthermia, anticholinergic poisoning, reactions tosympathomimetics, and infection, particularly meningi-tis.22 The recent increase in the use of 3,4-methylene-dioxymethamphetamine (Ecstasy) among adolescentsand young adults at drug-inspired dance gatheringsknown as “raves” has introduced an important differen-tial diagnosis consideration for NMS.23 Exposure to thisstreet drug, especially after dehydration resulting fromvigorous dancing, can result in a syndrome of hyperther-mia, autonomic instability, and elevated creatine kinaseresembling NMS.24


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It is sometimes difficult to distinguish NMS from theserotonin syndrome because these two conditions haveseveral clinical features in common, such as hyperthermiaand alteration in consciousness. Useful features for differ-entiating the two conditions include the predominance ofshivering, myoclonus, and gastrointestinal symptoms suchas diarrhea and nausea in serotonin syndrome as opposedto prominent rigidity, marked elevation of creatine kinase,and more prominent autonomic disturbances in NMS.

TREATMENT AND PROGNOSIS

The treatment of NMS should be considered emergent,especially in cases in which all of the clinical criteria arefulfilled. In these cases, serious morbidity and,occasionally,mortality are possible. Serious morbidity can occur,including cardiac failure and cerebellar degeneration.Themost common complications affecting the prognosis arerespiratory disturbances and renal failure, the latter ofwhich is associated with disseminated intravascular coag-ulation and rhabdomyolysis.

The first therapeutic measure that must be taken totreat NMS is discontinuance of the offending neurolepticor other causative drug, or, in the case of patients withParkinson’s disease, replacing the recently withdrawndopaminergic drug. In addition, drugs that inhibit heatdissipation, such as anticholinergic agents, should be dis-continued, preferably by tapering to avoid rebound phe-nomena. Supportive measures such as hydration and low-ering of fever should be started early. Occasionally,respiratory support is needed because of severe rigidity of


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respiratory musculature. Arrhythmias and blood pressureabnormalities must be treated.

The most commonly used specific medical therapiesfor NMS include bromocriptine and dantrolene followedby amantadine. Although the use of one or all of thesetherapies enjoys widespread acceptance, there are no rig-orous objective studies to support their efficacy in NMS.This is in large part due to the absence of prospectiveblinded placebo- or comparator-controlled studies of thecondition. Most large studies of therapy in NMS are ret-rospective case report analyses culled from the literature.One of the largest of these retrospective reviews evaluated734 cases of NMS and concluded that therapy with eitherbromocriptine, dantrolene, or amantadine resulted in alower mortality rate than supportive therapy alone.25 Incontrast, a smaller nonblinded, nonrandomized prospec-tive study of 20 consecutive patients concluded thatpatients receiving bromocriptine or dantrolene actuallyendured a longer duration of symptoms than those receiv-ing supportive therapy alone.26 The possibility of bias inselecting specific therapies in all of these reported casestudies is so great as to cast significant doubt on the rec-ommendations that they generate.

The treatment recommendations that follow hererepresent a view that, even in the absence of scientificconfirmation, has been elevated to the status of commonpractice.Bromocriptine therapy can begin at 2.5 mg every6 hours. If there is no response after 24 hours, the dosagecan be doubled and then be titrated further upwardaccording to clinical need to a dosage of 50 mg/d.Dantro-lene can be similarly titrated using dosages in the range of


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1 to 10 mg/kg/d in divided dosages. In most cases, dosagestoward the lower end of this range will be required, espe-cially as initial therapy.27

The question arises as to when to use these drugs andwhich of them to begin first.The earlier therapy is begun,the greater the likelihood of altering the course of NMS.Circumstances that would suggest the use of bromocrip-tine first include the presence of a severe alteration in thelevel of consciousness and preserved ability to receivemedication by mouth or nasogastric tube (there is no par-enteral dosage form of bromocriptine). Findings that sug-gest that dantrolene should be chosen as the initial ther-apy are severe muscle rigidity, marked hyperthermia, andan inability to safely administer medication orally or bytube (dantrolene can be administered intravenously).These recommendations are largely based on the notionthat bromocriptine will be most effective for symptomsrelated to central nervous system dysfunction, whereasdantrolene is more likely to improve rigidity and symp-toms that result from it, such as hyperthermia. In thisregard, it should be noted that it is possible that dantrolenemay have some central effects as well.28 If the clinicalcircumstances do not clearly favor one of these twodrugs over the other, bromocriptine is the preferred initialtreatment.

Whichever therapy is started initially, the other med-ication may need to be added if there is no apparentimprovement by 36 to 48 hours. Even after resolution ofsymptoms, treatment should be continued for 7 to 10 daysand for twice that duration if depot neuroleptics had beenadministered. Several second-line therapies are also avail-


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able.Amantadine was found to improve NMS mortality ina large meta-analysis,25 and there are case reports ofremarkable improvement after administration of carba-mazepine.29 Apomorphine, a rapidly acting dopamine ago-nist that can be administered subcutaneously, shows prom-ise of providing a more rapid and complete response thanbromocriptine, which must be administered orally.30

Plasma exchange has been reported to be effective in asingle case in which the procedure was used for removinga long-acting protein-bound neuroleptic drug from theperipheral circulation.31 Electroconvulsive (ECT) treat-ment should be considered in patients with an inadequateresponse to medical therapy. It may also be indicated inpatients whose psychosis has seriously worsened owing tothe required withdrawal of neuroleptics.32 It must be keptin mind that the autonomic dysfunction associated withNMS might increase the risk of serious cardiovascularproblems during ECT.

Recovery typically occurs over a 1- to 2-weekperiod, the longer resolution occurring in those patientswho received long-acting depot neuroleptics. Rechal-lenge with neuroleptics after recovery results in recur-rence of NMS in less than 15% of cases and is less likelyto occur if more than 2 weeks pass before the rechallengeand an atypical neuroleptic agent is used.33 During re-introduction, careful monitoring should be undertakenfor premonitory signs of NMS, such as an elevation ofcreatine kinase or the white blood count, signs of auto-nomic instability, or any alteration in the level of con-sciousness. In cases in which a transition from a typicalneuroleptic to an atypical antipsychotic agent is executed


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to prevent the primary occurrence of NMS or its reap-pearance, the risk of the syndrome may be increased ifthere is an overlap period during which both agents arebeing administered.34

The prognosis for rapid and complete recovery isimproved by early recognition and early intervention,including discontinuance of the offending drug and earlyinitiation of therapy. Untreated, the syndrome usuallyreaches peak severity within 3 days.With treatment, fever,rigidity, creatine kinase levels, and autonomic dysfunctionusually improve within 1 to 3 days, and full resolution canbe expected within 1 to 2 weeks or slightly longer if depotneuroleptics were used.29 Among those who recover fromthe acute hyperthermia, persistent symptoms such as aresidual catatonic state can be seen in a small percentageof cases.31 In a small percentage of patients, there is a fataloutcome. Patients with severe rhabdomyolysis, myoglo-binuria, and renal failure are most likely to succumb.25

Although mortality from NMS was reported to be as highas 76% in the 1960s,35 more recent studies suggest thatwith earlier recognition and better treatment, it is now inthe range of 5 to 8%.

REFERENCES

1. Keck PE Jr, Pope HG Jr, McElroy SL. Declining frequencyof neuroleptic malignant syndrome in a hospital population.Am J Psychiatry 1991;148:880–2.

2. Pope HG Jr, Keck PE Jr, McElroy SL. Frequency and pres-entation of neuroleptic malignant syndrome in a large psy-chiatric hospital.Am J Psychiatry 1986;143:1227–33.


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3. Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignantsyndrome in 12 or 9,792 Chinese inpatients exposed toneuroleptics: a prospective study. Am J Psychiatry 1990;147:1149–55.

4. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Cloza-pine-associated neuroleptic malignant syndrome: two newcases and a review of the literature. Ann Pharmacother1999;33:623–30.

5. Filice GA, McDougall BC, Ercan-Fang N, Billington CJ.Neuroleptic malignant syndrome associated with olanzap-ine.Ann Pharmacother 1998;32:1158–9.

6. Bajjoka I, Patel T, O’Sullivan T. Risperidone-induced neu-roleptic malignant syndrome. Ann Emerg Med 1997;30:698–700.

7. Stanley AK, Hunter J. Possible neuroleptic malignant syn-drome with quetiapine. Br J Psychiatry 2000;176:497.

8. Keyser DL, Rodnitzky RL. Neuroleptic malignant syn-drome in Parkinson’s disease after withdrawal or alterationof dopaminergic therapy.Arch Intern Med 1991;14:794–6.

9. Caroff SN, Mann SC. Neuroleptic malignant syndrome.Psychopharmacol Bull 1988;24:24–9.

10. Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control studyof neuroleptic malignant syndrome. Am J Psychiatry1997;154:1156–8.

11. Naganuma H, Fujii I. Incidence and risk factors in neu-roleptic malignant syndrome.Acta Psychiatr Scand 1994;90:424–6.

12. Elizalde-Sciavolino C, Racco A, Proscia-Lieto T, Kleiner M.Severe hyponatremia, neuroleptic malignant syndrome,rhabdomyolysis and acute renal failure. Mt Sinai J Med1998;65:284–8.

13. Hermesh H, Manor I, Shiloh R,et al. High serum creatininekinase level: possible risk factor for neuroleptic malignantsyndrome. J Clin Psychopharmacol 2002;22:252–6.


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14. Silva RR, Munoz DM,Alpert M, et al. Neuroleptic malig-nant syndrome in children and adolescents. J Am AcadChild Adolesc Psychiatry 1999; 38:187–194.

15. Rodnitzky RL, Keyser DL. Neurologic complications ofdrugs.Tardive dyskinesias, neuroleptic malignant syndrome,and cocaine-related syndromes. Psychiatr Clin North Am1992;15:491–510.

16. Kurlan R, Hamill R, Shoulson I. Neuroleptic malignantsyndrome. Clin Neuropharmacol 1984;7:109–20.

17. Velamoor VR, Norman RM, Caroff SN, et al. Progressionof symptoms in neuroleptic malignant syndrome. J NervMent Dis 1994;182: 168–73.

18. Peiris DT, Kuruppuarachchi K, Weerasena LP, et al. Neu-roleptic malignant syndrome without fever: a report ofthree cases. J Neurol Neurosurg Psychiatry 2000;69:277–8.

19. Wong MMC. Neuroleptic malignant syndrome: two caseswithout muscle rigidity. Aust N Z J Psychiatry 1996;30:415–8.

20. Sachdev P. The diagnosis of neuroleptic malignant syn-drome revisited.Aust N Z J Psychiatry 1996;30:875–6.

21. Hasan S, Buckley P. Novel antipsychotics and the neurolep-tic malignant syndrome: a review and critique. Am J Psy-chiatry 1998;155:1113–6.

22. Chan TC, Evans SD, Clark RF. Drug-induced hyperther-mia. Crit Care Clin 1997;13:785–808.

23. Arria A,Yacoubian G, Fost E, Wish E. Ecstasy use amongclub rave attendees.Arch Pediatr Adolesc Med 2002;156:.

24. Demirkiran M, Jankovic J,Dean JM. Ecstasy intoxication: anoverlap between serotonin syndrome and neurolepticmalignant syndrome. Clin Neuropharmacol 1996;19:157–64.

25. Sakkas D, Davis JM, Hua J, Wang Z. Pharmacotherapy ofneuroleptic malignant syndrome. Psychiatr Ann 1991;21:157–64.


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26. Rosebush PI, Stewart T, Mazurek MF. The treatment ofneuroleptic malignant syndrome. Are dantrolene andbromocriptine useful adjuncts to supportive care? Br J Psy-chiatry 1991;159:709–12.

27. Tsutsumi Y,Yamamoto K, et al.The treatment of neurolep-tic malignant syndrome using dantrolene sodium. Psychia-try Clin Neurosci 1998;52: 433–8.

28. Tanii H, Taniguchi N, Tsujio I, et al. Dantrolene sodiumreverses the increase in cAMP response element and TPAresponsive element DNA-binding activity in the rabbitbrain following haloperidol administration and heat stress.Psychiatry Clin Neurosci 1997;51:415–9.

29. Rosenberg MR, Green M. Neuroleptic malignant syn-drome: review of response to therapy. Arch Intern Med1989;149:1927–31.

30. Wang HC, Hsieh Y. Treatment of neuroleptic malignantsyndrome with subcutaneous apomorphine monotherapy.Mov Disord 2001;16:765–67.

31. Caroff SN, Mann SC, Keck PE Jr, Francis A. Residual cata-tonic state following neuroleptic malignant syndrome.J Clin Psychopharmacol 2000;20:257–9.

32. Trollor JN, Sachdev PS.Electroconvulsive treatment of neu-roleptic malignant syndrome: a review and report of cases.Aust N Z J Psychiatry 1999; 33:650.

33. Rosebush PI, Stewart TD, Gelenberg AJ.Twenty neurolep-tic rechallenges after neuroleptic malignant syndrome in15 patients. J Clin Psychiatry 1989;50:295–8.

34. Reeves RR, Mack JE, Torres RA. Neuroleptic malignantsyndrome during a change from haloperidol to risperidone.Ann Pharmacother 2001; 35:698–701.

35. Kellam AMP. The neuroleptic malignant syndrome, so-called: a survey of the world literature. Br J Psychiatry1987;150:752–9.


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CHAPTER 9

ENCEPHALITIS

Karen L. Roos, MD

Encephalitis is an acute infection of brain parenchymacharacterized clinically by fever, headache, and an alteredlevel of consciousness.There may also be focal or multifo-cal neurologic deficits and focal or generalized seizureactivity. Herpes simplex virus 1 (HSV-1) and the arthropod-borne viruses are the major etiologic agents of viralencephalitis in immunocompetent individuals.

CASE

A 60-year-old gentleman presents with a 3-week historyof fever, left hemicranial headache, and dysphasia. Hisdaughter had taken him to the emergency department ontwo occasions during the last 3 weeks. During each visit,he had cerebrospinal fluid (CSF) analysis, which demon-strated a lymphocytic pleocytosis with a normal glucoseconcentration and a slightly increased protein concentra-tion. The daughter was told that her father had viralmeningitis and would recover without antimicrobial ther-apy. She brings him for neurologic consultation becausehis difficulty with finding words is getting worse.

DISCUSSION

The clinical presentation of HSV-1 encephalitis includesfever, hemicranial or generalized headache, confusion, and

behavioral abnormalities.These complaints may be associ-ated with focal seizure activity or focal neurologic deficitssuch as a disturbance of language or hemiparesis. Symp-toms often take 2 to 3 weeks to reach maximal severity.The diagnosis of HSV-1 encephalitis is made by neu-roimaging, electroencephalography (EEG), and examina-tion of the CSF.Magnetic resonance imaging (MRI) is theneuroimaging procedure of choice (Figure 9-1).There is

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Figure 9-1 The characteristic abnormality on magnetic reso-nance imaging of herpes simplex virus 1 encephalitis is a highsignal intensity lesion on T2-weighted and fluid-attenuated inver-sion recovery (FLAIR) images in the medial and inferior tempo-ral lobes extending up into the insula.

a distinctive EEG pattern in HSV encephalitis consistingof periodic, stereotyped, sharp- and slow-wave complexesthat occur at regular intervals of 2 to 3 seconds and areexpressed maximally over the involved temporal lobe.These discharges may be either unilateral or bilateral andare seen in two-thirds of pathologically proven cases ofHSV encephalitis, typically between the second and thefifteenth day of the illness.Examination of the CSF revealsan increased opening pressure, a lymphocytic pleocytosisof 5 to 500 cells/mm3, red blood cells and/or xan-thochromia reflecting the hemorrhagic necrotic nature ofthe encephalitis, a mild to moderate elevation of the pro-tein concentration, and a normal or slightly decreased glu-cose concentration. CSF viral cultures for HSV-1 arealmost always negative.The availability of the polymerasechain reaction (PCR) for the detection of viral deoxyri-bonucleic acid (DNA) in CSF has increased the ability tomake a diagnosis of HSV encephalitis. It generally takesfrom 1 to 4 days to obtain the results of PCR assay forHSV DNA. Red blood cells in the CSF will inhibit thePCR reaction; therefore, bloody CSF should never be sentfor PCR to detect viral DNA. HSV DNA in CSF pre-cedes the appearance of HSV antibodies by several days(Figure 9-2). CSF and serum samples should be obtainedto determine if there is intrathecal synthesis of antibodiesagainst HSV.Antibodies to HSV do not appear in the CSFuntil approximately 8 to 12 days after the onset of diseaseand increase significantly during the first 2 to 4 weeks ofinfection. A serum-to-CSF antibody ratio of ≤ 20:1 isconsidered diagnostic of HSV infection. Brain biopsy isgenerally reserved for those patients who fail to respond to


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acyclovir therapy and in whom MRI does not reveal anarea of increased signal intensity on T2-weighted andfluid-attenuated inversion recovery (FLAIR) images in theorbitofrontal and temporal areas, and/or the CSF PCR is

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Encephalitis

Fever, headache, and an altered level of consciousness ± focal neurologic deficits ± seizure activity

Acyclovir plus ceftriaxone, cefotaxime, or cefepime plusvancomycin plus doxycycline (tick season)

MRI EEGSpinal fluid (CSF) analysis

Cell count with differentialGlucose and protein concentrationGram's stain and bacterial culturePCR (HSV-1 and HSV-2)Herpes simplex virus antibodiesIgM antibody titersViral culture

Serum for herpes simplex virus antibodiesSerum IgM antibody titersAcute convalescent sera for IgG antibody titers

Figure 9-2 CSF = cerebrospinal fluid; EEG = electroencephalog-raphy; HSV = herpes simplex virus; Ig = immunoglobulin; MRI =magnetic resonance imaging; PCR = polymerase chain reaction.

negative for HSV DNA and there is no evidence ofintrathecal synthesis of HSV antibodies.

The empiric therapy of encephalitis in an immuno-competent patient should include intravenous acyclovir(child: 30 mg/kg/d every 8-hour dosing interval); adult:30 mg/kg/d every 8-hour dosing interval); a third- orfourth-generation cephalosporin, either ceftriaxone(child: 100 mg/kg/d every 12-hour dosing interval; adult:4 g/d every 12-hour dosing interval), cefotaxime (child:200–300 mg/kg/d every 4- to 6-hour dosing interval;adult: 12 g/d every 4-hour dosing interval), or cefepime(4–6 g/d every 12-hour dosing interval); and vancomycin(child: 60 mg/kg/d every 6-hour dosing interval; adult: 2g/d every 6-hour dosing interval). Acyclovir is used forHSV-1 encephalitis, and the combination of a third- orfourth-generation cephalosporin and vancomycin is usedfor Streptococcus pneumoniae and Neisseria meningitidis, themost common causative organisms of community-acquired bacterial meningitis in children and adults andthe leading disease in the differential diagnosis ofencephalitis. In areas of the United States in which RockyMountain spotted fever is endemic, during tick season,doxycycline 100 mg twice daily is added to the empiricregimen.When HSV-1 is identified as the etiologic agentof the encephalitis, antimicrobial therapy is modified tointravenous acyclovir in a dose of 10 mg/kg every 8 hoursfor 3 weeks. Acyclovir-resistant strains of HSV-1 are rarebut increasing; therefore, the patient with clinical charac-teristics typical of HSV-1 who is not responding to acy-clovir should be treated with foscarnet (60 mg/kg every 8hours) in addition to acyclovir.


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The possibility that an arthropod-borne virus(arbovirus) is the etiologic agent of encephalitis should beconsidered in all cases of encephalitis occurring in latesummer and fall.The geographic area in which the patientlives or where the patient has visited is important in iden-tifying the arboviral etiologic agent of encephalitis (Table9-1).The arboviruses are inoculated into the host subcu-taneously by a mosquito bite and then undergo local repli-cation at the skin site. A viremia follows, and if there is alarge enough inoculum of virus, invasion and infection ofthe central nervous system occur. Infection of the centralnervous system by an arbovirus may be asymptomatic, amild febrile illness with headache, an aseptic meningitis, oran encephalitis.The onset of encephalitis symptoms is oftenpreceded by an influenza-like prodrome of malaise, myal-gias, and fever.This is followed by symptoms of headache,nausea, vomiting, confusion, disorientation, and, occasion-ally, convulsions. Progressive deterioration in the level ofconsciousness may occur from lethargy to stupor to coma.

Based on criteria established by the Centers for Dis-ease Control and Prevention,1 a confirmed case of arbovi-ral encephalitis is defined as a febrile illness withencephalitis during a period when arboviral transmissionis likely to occur plus at least one of the following: (1) afourfold or greater rise in viral antibody titer betweenacute and convalescent sera; (2) viral isolation from tissue,blood, or CSF; or (3) specific immunoglobulin M (IgM)antibody in CSF.A presumptive case is defined as a com-patible illness plus either a stable elevated antibody titer toan arbovirus (≥ 320 by hemagglutination inhibition, ≥ 128by complement fixation, ≥ 256 by immunofluorescent

Encephal i t is

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Table 9-1 Geographic Distribution of Arboviruses

Virus Geographic Area

La Crosse virus Midwestern United States (Indiana,Wisconsin,Minnesota, Illinois, Iowa)

St. Louis encephalitis Central and southeasternvirus United States, western and

eastern Canada

Japanese encephalitis China, southeast Asia, north-virus east India, Napal, and

Sri Lanka

West Nile virus Northeastern and midwesternUnited States and Florida

Eastern equine East and Gulf coast of theencephalitis virus United States, Minnesota,

Texas

Western equine States west of the Mississippiencephalitis virus River

Venezuelan encephalitis Venezuela,Texas, and Mexicovirus

Colorado tick fever virus Colorado, Utah, Montana,Wyoming, Idaho,California, South Dakota,Nevada, New Mexico

Powassan virus Canada (Powassan, Ontario) and New York

Encephal i t is

189

assay, or ≥ 160 by plaque reduction neutralization test) ora specific IgM antibody in serum by enzyme immunoassay.Treatment of arbovirus encephalitis is primarily support-ive care with management of the neurologic complica-tions of seizures and increased intracranial pressure. Riba-virin is a synthetic nucleoside analogue that has beendemonstrated in vitro to inhibit the replication of LaCrosse virus.

The differential diagnosis of a rash and encephalitisincludes the following: (1) enteroviral encephalitis, (2)meningococcemia, (3) West Nile virus encephalitis, and (4)Rocky Mountain spotted fever. Empiric therapy shouldinclude a combination of penicillin G for meningococ-cemia and doxycycline for Rocky Mountain spotted feverwhile awaiting the results of diagnostic studies.The rash ofRocky Mountain spotted fever is initially a diffuse ery-thematous maculopapular rash that has an appearance sim-ilar to that of the rash of meningococcemia. It progressesto a petechial rash, then to a purpuric rash, and, ifuntreated, to skin necrosis or gangrene.The rash of RockyMountain spotted fever typically begins on the wrists andankles, spreads distally and proximally within a matter of afew hours, and involves the palms and soles. Diagnosis ismade by direct immunofluorescence or immunoperoxi-dase staining of skin biopsies for detection of the bacteriaRickettsia rickettsii. Serologic diagnosis requires a fourfoldrise in antibody titer between acute and convalescent sera.Rocky Mountain spotted fever is treated with doxycycline100 mg twice daily.Doxycycline is used for a minimum of5 to 7 days and until the patient has been afebrile for≥ 2 days.

REFERENCE

1. United States of America.Arboviral disease. MMWR MorbMortal Wkly Rep 1995;44:641–4.


190

191

Fever, headache, and stiff neck are the classic triad ofsymptoms and signs of bacterial meningitis. Nausea, vom-iting, photophobia, and lethargy are also common com-plaints. The level of consciousness may deteriorate fromlethargy to stupor to coma while the patient is being eval-uated in the emergency department. Seizure activityoccurs in approximately 40% of patients with bacterialmeningitis and typically occurs at either the onset orwithin the first few days of the illness.

A stiff neck, or meningismus, is the pathognomonicsign of meningeal irritation.Meningismus is present whenthe neck resists passive flexion.Brudzinski’s sign is positivewhen passive flexion of the neck results in spontaneousflexion of the hips and knees.

The most common causative organisms of community-acquired bacterial meningitis are Streptococcus pneumoniaeand Neisseria meningitidis. Pneumonia may precede thesymptoms of pneumonococcal meningitis in an adult.Meningococcal meningitis may be accompanied by a rash,which begins as a diffuse erythematous maculopapularrash that resembles a viral exanthem. The lesions ofmeningococcemia rapidly become petechial.The rash ofmeningococcemia begins on the trunk and lower extrem-ities. Petechiae may also be found in the mucous mem-branes and conjunctiva and,occasionally, on the palms andsoles.

CHAPTER 10

BACTERIAL MENINGITIS

Karen L. Roos, MD

LABORATORY DIAGNOSIS

Examination of the cerebrospinal fluid (CSF) is the goldstandard for the diagnosis of bacterial meningitis.The clas-sic CSF abnormalities in bacterial meningitis are as fol-lows: (1) increased opening pressure, (2) a pleocytosis ofpolymorphonuclear leukocytes (10 to 10,000 cells/mm3),(3) a decreased glucose concentration (< 45 mg/dLand/or CSF-to-serum glucose ratio of < 0.31), and (4) anincreased protein concentration. Opening pressure shouldbe measured in the lateral recumbent position because thesitting position does not allow for accurate measurementof CSF pressure.The normal range of opening pressure forinfants and children up to 6 years of age is 10 to 120 mmH2O and for children and adults is 10 to 200 mm H2O,and pressures of 200 to 250 mm H2O are indeterminate. Inuninfected CSF in children and adults, the normal whiteblood cell (WBC) count ranges from 0 to 5 mononuclearcells (lymphocytes and monocytes)/mm3. In normal unin-fected CSF in children and adults, there should be nopolymorphonuclear leukocytes; however, with the use ofa cytocentrifuge, an occasional polymorphonuclear leuko-cyte may be seen. If the total WBC count is < 5 mm3, thepresence of a single polymorphonuclear leukocyte may beconsidered normal. The upper limit of normal value forCSF total WBC count is 22/mm3 in full-term neonates,30/mm3 in infants 0 to 8 weeks, and 5/mm3 in those olderthan 8 weeks of age. In normal uninfected CSF in new-borns, 60% of the cells are polymorphonuclear leukocytesand 40% are mononucleated cells.A normal CSF glucoseconcentration is between 45 and 80 mg/dL when the


192

blood glucose concentration is between 70 and120 mg/dL.Values below 45 mg/dL are abnormal, and aCSF glucose concentration of 0 mg/dL is not unusual inbacterial meningitis. Use of the CSF-to-serum glucoseratio corrects for hyperglycemia that may mask adecreased CSF glucose concentration. The CSF glucoseconcentration is low when the CSF-to-serum glucoseratio is < 0.5. A CSF-to-serum glucose ratio ≤ 0.31 ishighly predictive of bacterial meningitis. It takes approxi-mately 4 hours for the CSF glucose concentration to reachequilibrium with the blood glucose concentration afterthe administration of glucose; therefore, an ampule of D50(50 mL of 50% glucose) prior to lumbar puncture, ascommonly occurs en route to or in the emergencydepartment, is unlikely to significantly alter the CSFglucose concentration unless more than a few hourshave passed between glucose administration and lumbarpuncture.

Gram’s stain is positive in 70 to 90% of untreatedcases of bacterial meningitis. The latex particle aggluti-nation test for the detection of bacterial antigens ofS. pneumoniae, N. meningitidis, Haemophilus influenzae typeb (Hib), group B streptococcus, and Escherichia coli K1strains in the CSF is very useful for making a rapid diag-nosis of bacterial meningitis and for making a diagnosisof bacterial meningitis in those patients who have beenpretreated with oral or parenteral antibiotics in whomGram’s stain and CSF culture are negative. It is importantto emphasize, however, that a negative latex particleagglutination test for bacterial antigens does not rule outbacterial meningitis.The limulus amebocyte lysate assay

Bacter ial Meningi t is

193

is a rapid diagnostic test for the detection of gram-negative endotoxin in CSF and thus for making a diag-nosis of gram-negative bacterial meningitis.To date, CSFpolymerase chain reaction (PCR) tests are not as usefulin the diagnosis of bacterial meningitis as they are in thediagnosis of viral central nervous sytem infections. APCR assay is available for all of the common meningealpathogens, but it often takes several days to obtain a PCRresult, and by then Gram’s stain and/or culture haveidentified the etiologic organism.

The necessity of obtaining either a cranial magneticresonance image (MRI) or computed tomographic (CT)scan prior to lumbar puncture has been debated for years.If the neurologic examination demonstrates no focaldeficits, the level of consciousness is normal, and there isno evidence of papilledema, it is safe to perform lumbarpuncture without imaging the brain first. If the patient isbeing treated with antibiotics, there is no risk in delayinglumbar puncture until after neuroimaging is performed.Lumbar puncture should be performed with a 22- or 25-gauge needle, and a minimum amount of CSF should beremoved for analysis.Approximately 6 mL is sufficient toobtain cell count, glucose and protein concentrations,Gram’s stain and culture, and latex agglutination.An addi-tional 1 mL of CSF can be sent to the PCR laboratory forviral deoxyribonucleic acid (DNA) analysis.

Blood cultures should always be sent before or at thetime of initiation of antimicrobial therapy in patients withsuspected bacterial meningitis.Antibiotic therapy for sev-eral hours prior to lumbar puncture will not significantlyalter the CSF WBC count or glucose concentration, so


194

that the possibility of bacterial meningitis is not suspected,and it is not likely to sterilize the CSF, so that the organ-ism cannot be identified on Gram’s stain or grown in cul-ture.The CSF WBC count increases after the initiation ofantimicrobial therapy, and the glucose concentrationremains low for several days. Gram’s stain and bacterialculture should be negative 24 hours after the initiation ofantimicrobial therapy if the organism is sensitive to theantibiotic, but the etiologic organism can often still beidentified by the latex agglutination technique, and it isexpected that perfection of the PCR technique to detectbacterial DNA in CSF will also contribute to the diagno-sis of bacterial meningitis in patients being treated withantimicrobial therapy at the time of or prior to lumbarpuncture.

MRI is preferred over CT because of its superiority indemonstrating areas of cerebral edema and ischemia.Themeninges will diffusely enhance after the administration ofgadolinium. This is a nonspecific abnormality, however,and it occurs with any process in which there is anincrease in the permeability of the blood-brain barrier.

Raised intracranial pressure is an expected complica-tion of bacterial meningitis and is the major cause ofobtundation and coma in this disease. Raised intracranialpressure may lead to cerebral herniation.The incidence ofcerebral herniation caused by lumbar puncture in patientswith acute bacterial meningitis is not known. Most of thearticles written on this topic were written in the erabefore CT and MRI were available to demonstrate focalinfectious mass lesions or cerebral venous sinus thrombo-sis. The risk of cerebral herniation from acute bacterial


195

meningitis independent of lumbar puncture is approxi-mately 6 to 8%.When the possibility of increased intracra-nial pressure exists because of a decreased level of con-sciousness, lumbar puncture should either be delayed untilthe increased intracranial pressure can be treated or per-formed with a 22-gauge needle 30 to 60 minutes after1 g/kg of mannitol has been administered intravenously toreduce brain swelling.The patient can also undergo intu-bation and hyperventilation in addition to being treatedwith mannitol to decrease intracranial pressure prior tolumbar puncture. If lumbar puncture is delayed whileincreased intracranial pressure is treated, empiric antimi-crobial therapy should be given.

EMPIRIC THERAPY

Empiric antimicrobial therapy is initiated when bacterialmeningitis is suspected, before a diagnostic evaluation ispursued. Empiric therapy should be based on the possibil-ity that penicillin- and cephalosporin-resistant pneumo-cocci are the causative organisms of the meningitis andinclude a third- or fourth-generation cephalosporin,either ceftriaxone (pediatric dose: 100 mg/kg/d in a 12-hour dosing interval; adult dose: 2 g every 12 hours), cefo-taxime (pediatric dose: 300 mg/kg/d in a 4- to 6-hourdosing interval; adult dose: 3 g every 4 hours), or cefepime(adult dose: 2 g every 12 hours) plus vancomycin (pedi-atric dose: 40 to 60 mg/kg/d in a 6- or 12-hour dosinginterval; adult dose: 500 mg every 6 hours or 1 g every 12hours).Ampicillin plus gentamicin should be added to theempiric regimen for coverage of Listeria monocytogenes in


196


197

individuals with impaired cell-mediated immunity owingto a chronic illness, organ transplantation, pregnancy,acquired immune deficiency syndrome (AIDS),malignan-cies, or immunosuppressive therapy if they have not beenon trimethoprim-sulfamethoxazole prophylactic therapy.Empiric therapy of neonatal bacterial meningitis shouldinclude a combination of ampicillin plus cefotaxime orampicillin plus gentamicin to cover Streptococcus agalactiae,E. coli, L. monocytogenes, and Klebsiella pneumoniae. Acy-clovir (10 mg/kg every 8 hours) is added to the empiricregimen for treatment of bacterial meningitis in infants,children, and adults because viral meningoencephalitis,specifically herpes simplex virus encephalitis, is the lead-ing disease in the differential diagnosis.

ORGANISM-SPECIFIC THERAPY

Once the results of bacterial culture and antimicrobial sus-ceptibility tests are known, antimicrobial therapy can bemodified accordingly (Table 10–1).

Meningococcal Meningitis

Penicillin G or ampicillin can be used for meningococcalmeningitis. All CSF isolates of N. meningitidis should betested for penicillin and ampicillin susceptibility. If antimi-crobial susceptibility testing demonstrates that the isolateis a relatively penicillin-resistant strain of meningococciand in areas with a high prevalence of meningococci withdecreased susceptibility to penicillin, cefotaxime or ceftri-


198

Tabl

e 1

0-1

Ant

imic

robi

al T

hera

py o

f B

acte

rial

Men

ingi

tis

Antibio

tic

Tota

l D

aily

Dose

O

rgan

ism

(Dosi

ng I

nte

rval

)A

dve

rse

Effec

ts

Stre

ptoc

occu

s pn

eum

onia

eC

eftr

iaxo

neE

osin

ophi

liaA

dult

dose

:4 g

/d (

q12h

)B

iliar

y ps

eudo

lithi

asis

Chi

ld d

ose:

200

mg/

kg/d

(q1

2h)

or Cef

otax

ime

Nau

sea,

vom

itin

gA

dult

dose

:12

g/d

(q4h

)D

iarr

hea

Chi

ld d

ose:

200–

300

mg/

kg/d

(q4

h)or C

efep

ime

Adu

lt do

se:4

g/d

(q1

2h)

plus

Van

com

ycin

Red

man

syn

drom

eA

dult

dose

:2 g

/d (

q6 o

r q1

2h)

Leuk

open

iaC

hild

dos

e:40

–60

mg/

kg/d

(q6

–12h

)E

osin

ophi

lia

Con

tinu

ed


199

Tabl

e 1

0-1

(C

onti

nued

)

Nei

sser

ia m

enin

gitid

isPe

nici

llin

GR

ash

Adu

lt do

se:2

0–24

mill

ion

U/d

(q4

h)C

hild

dos

e:0.

2 m

illio

n U

/kg

(q4h

)or A

mpi

cilli

nM

acul

opap

ular

ras

hA

dult

dose

:12

g/d

(q4h

)N

ause

a,di

arrh

eaC

hild

dos

e:20

0–30

0 m

g/kg

/d (

q4h)

Stap

hylo

cocc

i

Met

hici

llin

sens

itiv

eN

afci

llin

Ras

hA

dult

dose

:12

g/d

(q4h

)N

eutr

open

iaC

hild

dos

e:15

0–20

0 m

g/kg

/d (

q4h)

Met

hici

llin

resi

stan

tV

anco

myc

inA

dult

dose

:2 g

/d (

q6 o

r q1

2h)

Leuk

open

iaC

hild

dos

e:40

–60

mg/

kg/d

(q6

–12h

)E

osin

ophi

lia

Con

tinu

ed


200

Tabl

e 1

0-1

(C

onti

nued

)

Gra

m-n

egat

ive

baci

lli

Nau

sea,

vom

itin

g,(w

ith

the

exce

ptio

n of

di

arrh

eaP

seud

omon

as a

erug

inos

a)C

efot

axim

e or

cef

tria

xone

Eos

inop

hilia

Bili

ary

pseu

dolit

hias

is

Pse

udom

onas

aer

ugin

osa

Cel

fazi

dine

Tra

nsie

nt

in li

ver

Adu

lt do

se:8

g/d

(q8

h)fu

ncti

on t

ests

Chi

ld d

ose:

150–

200

mg/

kg/d

(q8

h)

List

eria

mon

ocyt

ogen

esA

mpi

cilli

nM

acul

opap

ular

ras

hA

dult

dose

:12

g/d

(q4h

)N

ause

a,di

arrh

eaC

hild

dos

e:20

0–30

0 m

g/kg

/d (

q4h)

±G

enta

mic

inN

ephr

o- a

nd

Adu

lt do

se:6

mg/

kg/d

(q8

h)ve

stib

ulot

oxic

ity

Chi

ld d

ose:

6 m

g/kg

/d (

q8h)

Stre

ptoc

occu

s ag

alac

tiae

Peni

cilli

n G

Ras

h

axone should be used. A 7-day course of intravenousantibiotic therapy is adequate for most uncomplicatedcases of meningococcal meningitis.The index case and allclose contacts should receive chemoprophylaxis with a2-day regimen of rifampin (600 mg every 12 hours for2 days in adults and 10 mg/kg every 12 hours for 2 daysin children older than 1 year of age). Rifampin should notbe used in pregnant women. Adults can alternatively betreated with one dose of ciprofloxacin (750 mg) orazithromycin (500 mg).Close contacts are defined as thoseindividuals who have had contact with oropharyngealsecretions either through kissing or through sharing toys,beverages, or cigarettes.

The Advisory Committee on Immunization Practicesrecommends that college freshmen be vaccinated againstmeningococcal meningitis with a tetravalent (MenA, C,W-135,Y) meningococcal polysaccharide vaccine.1 MenCpolysaccharide vaccine would also be effective. In the pastfew years, there has been an increasing incidence ofmeningococcal infection outbreaks on college campuses.Most of these have been caused by serogroup C N. menin-gitidis, which is potentially vaccine preventable. During anoutbreak of meningococcal disease, individuals who havenot been previously vaccinated should be treated withchemoprophylaxis. Up to 33% of secondary cases ofmeningococcal disease develop within 2 to 5 days of pres-entation of the index case.Vaccination is not a substitutefor chemoprophylaxis to prevent secondary diseasebecause there is an insufficient amount of time for theoptimum effect of vaccination, which requires approxi-mately 1 to 2 weeks for good antibody production.


201

Pneumococcal Meningitis

Antimicrobial therapy of pneumococcal meningitis is ini-tiated with a third- or fourth-generation cephalosporinand vancomycin.All CSF isolates of S. pneumoniae shouldbe tested for sensitivity to penicillin and third- and fourth-generation cephalosporins. Once the results of antimicro-bial susceptibility tests are known, therapy can be modifiedaccordingly.Vancomycin is initially by parenteral adminis-tration, but consideration should be given to using intra-ventricular vancomycin in patients who do not respond toparenteral vancomycin. Cefepime is a broad-spectrumfourth-generation cephalosporin with in vitro activitysimilar to that of cefotaxime or ceftriaxone againstS. pneumoniae and N. meningitidis. In clinical trials,cefepime has been demonstrated to be equivalent to cefo-taxime in the treatment of pneumococcal and meningo-coccal meningitis. Meropenem is a carbapenem antibioticstructurally related to imipenem but reportedly with lessseizure proclivity than imipenem. Meropenem showsgood activity against penicillin-resistant pneumococci invitro, but the number of patients enrolled in clinical trialsof meropenem in bacterial meningitis has not been suffi-cient to date to assess its efficacy against penicillin-resistantpneumococci or its epileptogenic potential. For pneumo-coccal meningitis, a repeat lumbar puncture should beperformed 24 to 36 hours after the initiation of antimi-crobial therapy to document eradication of the pathogen.A 2-week course of intravenous antimicrobial therapy isrecommended for pneumococcal meningitis.


202

Gram-Negative Bacillary Meningitis

Gram-negative bacilli (Actinetobacter calcoaceticus, E. coli,Klebsiella species, Pseudomonas aeruginosa, and Enterobacterspecies) cause meningitis in older adults, neurosurgicalpatients, alcoholics, and adults with underlying diseases,such as cancer, diabetes, congestive heart failure, chronicpulmonary disease, and hepatic or renal disease.The third-generation cephalosporins, cefotaxime, ceftriaxone, andceftazidime, are equally efficacious for the treatment ofgram-negative bacillary meningitis, with the exception ofP. aeruginosa. Ceftazidime is the drug of choice forP. aeruginosa meningitis. A 3-week course of intravenousantibiotic therapy is recommended for meningitis due togram-negative bacilli.

Staphylococcal Meningitis

Staphylococcus aureus and coagulase-negative staphylococciare the predominant organisms causing meningitis as acomplication of neurosurgical procedures, particularlyshunting procedures for hydrocephalus, and as a compli-cation of lumbar puncture for the administration ofintrathecal chemotherapy. Meningitis due to S. aureus orcoagulase-negative staphylococci is treated with nafcillinor oxacillin.Vancomycin is the drug of choice for methicillin-resistant staphylococci and for patients allergic to peni-cillin.The CSF should be monitored during therapy, andif it continues to yield viable organisms after 48 hours ofparenteral therapy, then either intrathecal or intraventric-ular vancomycin can be added.


203

Streptococcus agalactiae Meningitis

S. agalactiae or group B streptococcus is a leading cause ofbacterial meningitis and sepsis in neonates and is increas-ingly seen in two groups of adults: puerperal women andpatients with serious underlying diseases. Meningitis dueto this organism is treated with penicillin G.

Listeria monocytogenes Meningitis

L. monocytogenes is a causative organism of meningitis inindividuals with impaired cell-mediated immunity fromAIDS, organ transplantation, pregnancy, malignancy,chronic illness, or immunosuppressive therapy.The routineuse of trimethoprim-sulfamethoxazole as a prophylacticagent to prevent Pneumocystis carinii pneumonia alsoreduces the risk of L. monocytogenes infection and thereforehas had the added benefit of decreasing the incidence ofL.monocytogenes meningitis in immunosuppressed individ-uals. Present recommendations are that meningitis due toL. monocytogenes be treated with a combination of ampi-cillin and gentamicin.

Haemophilus influenzae Meningitis

Prior to the routine use of the Hib conjugate vaccine,Hibwas the most common causative organism of bacterialmeningitis in children.The incidence of Hib invasive dis-ease among children 4 years of age and younger hasdeclined 98% since the introduction of the Hib conjugatevaccine. Hib remains a causative organism of bacterialmeningitis in older adults, immunocompromised patients,and patients with chronic lung disease, splenectomy,


204

leukemia, and sickle cell disease. Meningitis owing to thisorganism is treated with a third-generation cephalosporin,either ceftriaxone or cefotaxime.

PATHOGENETIC MECHANISMS OF BRAIN DAMAGEOWING TO MENINGITIS AND THE RATIONALE FORCORTICOSTEROID USE

The critical event in the pathogenesis of bacteria menin-gitis is the inflammatory reaction in the subarachnoidspace to the invading meningeal pathogen. It is not thepathogen itself that causes the neurologic complications.In bacterial meningitis, brain damage progresses long afterthe CSF has been sterilized by antibiotic therapy.The lysisof bacteria with the release of bacterial cell wall compo-nents in the subarachnoid space is the initial step in theinduction of the inflammatory process and the formationof a purulent exudate in the subarachnoid space. Compo-nents of bacterial cell walls, such as lipopolysaccharidemolecules (endotoxins), cell wall components of gram-negative bacteria, and teichoic acid and peptidoglycan, cellwall components of pneumococcus, induce meningealinflammation by stimulating the production of inflamma-tory cytokines and chemokines by microglia, astrocytes,monocytes, microvascular endothelial cells, and whiteblood cells in the CSF space. A number of pathophysio-logic consequences result from the presence of the inflam-matory cytokines in CSF, including an increased perme-ability of the blood-brain barrier that allows for theleakage of serum proteins and other molecules into theCSF, resulting in the formation of a purulent exudate in


205

the subarachnoid space. The purulent exudate obstructsthe flow of CSF through the ventricular system anddiminishes the resorptive capacity of the arachnoidgranulations in the dural sinuses, leading to obstructiveand communicating hydrocephalus. The inflammatorycytokines recruit polymorphonuclear leukocytes from thebloodstream that degranulate and release toxic metabolitesthat contribute to cytotoxic edema, cell injury, and death.Dexamethasone exerts its beneficial effect by inhibitingthe synthesis of the inflammatory cytokines and bydecreasing CSF outflow resistance and stabilizing theblood-brain barrier.

A meta-analysis of randomized, concurrently con-trolled trials of dexamethasone therapy in childhood bac-terial meningitis published from 1988 to 1996 confirmedbenefit for Hib meningitis if begun with or before antibi-otics and suggested benefit for pneumococcal meningitisin children.The American Academy of Pediatrics recom-mends the consideration of dexamethasone for bacterialmeningitis in infants and children 2 months of age andolder.2 The recommended dose is 0.6 mg/kg/d in fourdivided doses (0.15 mg/kg/dose) given intravenously forthe first 4 days of antibiotic therapy. Dexamethasoneshould be begun before or with the first dose of antibiotic.There are presently ongoing clinical trials of dexametha-sone therapy in adults with bacterial meningitis. Scientistsworking in the area of the molecular basis of neurologicinjury in bacterial meningitis are in favor of the use ofdexamethasone because of its beneficial effect in inhibit-ing the synthesis of the inflammatory cytokines.

Figure 10-1 shows the management of the patient


206


207

No

ra

shP

ete

chia

l or

pu

rpu

ric

rash

Blo

od

cu

lture

s, C

BC

Blo

od

cu

lture

s, C

BC

Dex

am

eth

aso

ne

(se

e t

ext)

Pe

nic

illin

G o

r a

mp

icill

in

Ce

ftri

axo

ne,

ce

fota

xim

e, o

rce

fep

ime

plu

s va

nco

myc

ina

nd

acy

clov

ir(d

ose

s o

f a

ntib

iotic

s in

Ta

ble

10

-1).

Fo

r n

eo

na

tes,

eld

erl

y,p

reg

na

nt

wo

me

n,

or

imm

un

osu

pp

ress

ed

,a

dd

am

pic

illin

Bio

psy

ski

n r

ash

Pat

ien

t w

ith

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dac

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fev

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tiff

nec

k, a

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ed le

vel o

f co

nsc

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s

Hea

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can

Figu

re 1

0-1

Rec

omm

ende

d m

anag

emen

t of

the

pat

ient

with

head

ache

, fe

ver,

stiff

nec

k, a

nd a

n al

tere

dle

vel o

f co

nsci

ousn

ess.

CB

C =

com

plet

e bl

ood

coun

t; C

T =

com

pute

d to

mog

raph

ic;

HS

V =

her

pes

sim

plex

vir

us;

PCR

= p

olym

eras

e ch

ain

reac

tion

; TB

= t

uber

culo

sis.


208

Sig

ns

of

incr

ea

sed

intr

acr

an

ial p

ress

ure

:d

ecr

ea

sin

g le

vel o

f co

nsc

iou

sne

ss,

po

orl

y re

act

ive

pu

pils

, p

ap

ille

de

ma

No

sig

ns

of

incr

ea

sed

intr

acr

an

ial p

ress

ure

To r

ed

uce

intr

acr

an

ial p

ress

ure

:m

an

nito

l, hy

pe

rve

ntil

atio

n

Ana

lysi

s of

cer

ebro

spin

al fl

uid

cell

coun

t, ch

emis

trie

s, G

ram

’s s

tain

and

bac

teria

l cul

ture

,la

tex

aggl

utin

atio

n, fu

ngal

sm

ear

and

cultu

re, c

rypt

ococ

cal a

ntig

en, P

CR

for

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V D

eoxy

ribon

ucle

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cid,

TB

sm

ear

or P

CR

and

cul

ture

Cau

sativ

e or

gani

sm id

entif

ied

Mod

ify a

ntim

icro

bial

ther

apy

(Tab

le 1

0-1)

If m

enin

goco

ccus

, med

icat

e in

dex

case

and

all

clos

e co

ntac

ts w

ith c

hem

opro

phyl

axis

Figu

re 1

0-1

Con

tinu

ed.

with headache, fever, stiff neck, and an altered level of con-sciousness and summarizes the above. In the figure, analy-sis of the CSF includes fungal smear and culture, crypto-coccal antigen and tuberculosis smear, or PCR andculture.This information is included for the sake of com-pleteness.

Fungal meningitis and tuberculous meningitis have amuch more insidious clinical presentation than bacterialmeningitis, typically presenting with low-grade fever andheadache of several weeks duration. In developed coun-tries, meningitis due to fungi or Mycobacterium tuberculosisis not typically a neurologic emergency.

REFERENCES

1. Harrison LH. Preventing meningococcal infection in col-lege students. Clin Infect Dis 2000;30:648–51.

2. Committee on Infectious Diseases. Dexamethasone therapyfor bacterial meningitis in infants and children. Pediatrics1990;86:130–3.


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CASE 1

A 54-year-old man with hypertension for 9 years com-plained of a sudden occipital headache and began tovomit.When he stood up to walk, he fell to the floor. Inthe emergency department, his blood pressure was160/120 mm Hg. He was alert and coherent.There wereno cranial nerve deficits, and he moved all limbs on com-mand. Sensation was intact in the limbs, and all reflexeswere normal. He was admitted to the hospital for controlof his blood pressure. Four hours later, he becameobtunded and slightly confused.A computed tomographic(CT) scan (Figure 11-1) showed a large hemorrhage in theright cerebellar hemisphere. The fourth ventricle wasnearly obliterated, and the midbrain was compressed.Dilatation of the lateral ventricle and temporal horns indi-cated acute hydrocephalus (Figure 11-2).After immediateevacuation of the hematoma, the patient quicklyimproved.

CASE 2

A 68-year-old woman complained of dizziness. A mildheadache and nausea followed.She required limited supportto walk. CT scanning revealed a 2.0 cm hematoma in the

CHAPTER 11

CEREBELLAR HEMORRHAGE ANDINFARCTION

John B. Selhorst, MD

anterior cerebellar vermis (Figure 11-3). Over the ensuingweek, the headache and nausea remitted.After several moreweeks, the patient was able to walk again unaided.

CASE 3

A 63-year-old truck driver developed transient, severe ver-tigo.The spinning sensation recurred 20 minutes later. ACT scan in an emergency department was normal.He washospitalized overnight for observation.The next morning,he was found in a stuporous state.He was transferred to anacute stroke unit within the hour. He arrived in coma.Pupils were small and reacted poorly to light. Eye move-

Cerebel lar Hemorrhage and Infarct ion

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Figure 11-1 Computed tomographic scan shows a large rightcerebellar hematoma that nearly obliterates the fourth ventricle(A) and compresses the dorsolateral midbrain (B) (Case 1).

A B

ments were absent with rotation of the head or caloricstimulation with ice water. Decerebrate posturingoccurred with pressure on the nail beds.A repeat CT scanshowed obliteration of the fourth ventricle and dilated lat-eral ventricles, including the temporal horns.An immedi-ate ventriculoperitoneal shunt was placed.Within the day,he was arousable and able to move each limb. Ten dayslater, he was independently ambulatory. His only neuro-logic deficit was an inability to perform a tandem walk.Twelve years later, he remained in good health.


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Figure 11-2 Computed tomographic scan through the lower cere-bral hemispheres discloses the enlarged comma shape ofdilated temporal horns (A) and expanded third and lateral ven-tricles (B) (Case 1).

A B

INTRODUCTION

Hemorrhage into the deep parenchyma of the cerebellumtypically occurs in older hypertensive males.The situationpresents several clinical challenges.The first involves diag-nosis, and the second deals with proper management.Thefollowing discussion outlines the requirements for timelyrecognition and discriminate treatment. Infarction of thecerebellum is a similar condition that differs by its slower,subacute evolution and softer mass effect.


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Figure 11- 3 Computed tomographic scan shows a 2.0 cmhematoma in the anterior vermis (A) that impinges on the upperfour th ventricle but does not result in obstruction of cere-brospinal fluid or expand the temporal horns (B) (Case 2).

A B

PATHOGENESIS

In patients with hypertension, cerebellar hemorrhagelikely results from rupture of a small microaneurysm on adeep, penetrating arteriole. Hematomas are less oftencaused by vascular malformations and coagulopathies.Theclinical picture varies by the size and location of the cere-bellar mass. A small hematoma, usually less than 3.0 cm,1

causes symptoms and signs that are limited to the cerebel-lum. Larger hematomas directly compress the underlyingbrainstem and obstruct the fourth ventricle or aqueduct.Secondary compression of the brainstem and hydro-cephalus are the chief causes of progressive neurologicdeterioration.2 This progression is often due to swellingaround the hematoma that occurs over several days orobstructed cerebrospinal fluid drainage and resultinghydrocephalus. Hydrocephalus reportedly occurs in two-thirds of patients and, by increasing intracranial pressure, isanother cause of progression.1

Cerebellar infarction results from obstruction of thesuperior, anteroinferior, or posteroinferior cerebellar arter-ies. If only the distal portion of a cerebellar artery isinvolved, infarction occurs only in the ipsilateral cerebel-lar hemisphere. If the occlusion is more proximal, near theorigin from the basilar artery, ischemia of the lateral brain-stem also occurs. Subsequent swelling of the cerebellarhemisphere varies in degree and occurs over several daysto 1 week. Because the mass consists of soft necrotic tis-sue, compression of the underlying brainstem is less severethan from a hematoma, but obstruction of the fourth ven-


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tricle can result in acute, noncommunicating hydro-cephalus with disastrous consequences (Case 3).

DIAGNOSIS

The acute expansion of a hematoma transmits pressure topain fibers in the dura, producing a headache that isreferred to the occiput.The increased tissue pressure stim-ulates the area postrema in the lower floor of the fourthventricle and accounts for acute nausea and vomiting.Because the hematoma is usually deep within the cere-bellar parenchyma, fibers from the vermis for control ofthe lower limbs are commonly affected.Vestibular controlof antigravity muscles in the trunk is also compromised bycompression of vestibulocerebellar pathways. The acutetruncal ataxia results in the inability to walk and, some-times, the inability to sit up without assistance.3 Thus, thetriad of headache, vomiting, and gait instability is consid-ered diagnostic of an acute cerebellar mass.

Complaints of dizziness also are common. Limb ataxiais present in hematomas in the lateral cerebellar hemi-sphere.As in Case 1, the preservation of consciousness andabsence of hemiparesis and cranial nerve signs deceivemany physicians and prevent them from recognizing thiscondition as a potential acute emergency. This pitfall isavoided by seeking an explanation for why every emer-gency department patient cannot walk. Failure to walkwithout assistance mandates that a CT scan is obtained todetect the high density of a hemorrhage or the hypoden-sity of infarction or impingement on the fourth ventricle


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(Figure 11-4). If the CT scan is normal, magnetic reso-nance imaging may be necessary to show an infarction.

Gaze paresis, loss of the corneal reflex, impairedoculovestibular responses, and altered levels of conscious-ness signal compression of the pons by the overlyinghematoma.2 A systolic pressure greater than 200 mm Hgat admission is also an indication of impending neurologicdeterioration.4 In patients with cerebellar infarction, addi-tional cranial nerve and long tract signs at presentation areindicative of ischemia from an occluded circumferentialartery.Their subsequent appearance is a sign of secondarycompression from edema. Progressive decline in the levelsof consciousness, quadriparesis, and decerebrate posturingare features of severe brainstem compression or obstructivehydrocephalus. Signs of progressive neurologic deteriora-tion develop quite rapidly or more slowly over days and upto 1 week.

MANAGEMENT

Early diagnosis is critical. Preservation of consciousnessoften corresponds to a favorable outcome.5 Once comadevelops, however, mortality escalates and may exceed80%. Consequently, immediate surgical intervention hasbeen advocated for all cerebellar hematomas. Clinicalscrutiny, however, shows that a more discriminatingapproach is justified (see Figure 11-4). Hematomas thataffect only gait and station often reabsorb, without a seri-ous functional consequence.These patients require med-ical support.Brainstem signs on presentation are, however,an indication for immediate evacuation of a cerebellar

hematoma. Obstructive hydrocephalus is suggested bysigns of increased intracranial pressure. It occurs at presen-tation or is delayed. Scanning shows expansion of the lat-eral ventricles, especially the temporal horns (Figure 11-2). Immediate decompression is accomplished by aventriculostomy. Improvement is more likely in patientswith hemorrhages less than 3.0 cm in which increasedintracranial pressure is the major pathologic process. Sub-stantial recoveries are reported,6 sometimes in less than 1hour (Case 2).7 The potential rapid benefit, avoidance ofgeneral anesthesia, and obviated postoperative complica-tions justify this approach. Failure to rapidly improveshould be followed by surgical intervention, which isneeded in over half of these patients.8 In patients withlarger masses, there is concern for upward herniation ofthe anterior cerebellar vermis, especially when the mid-brain is already dorsally compressed. In such patients,direct surgical intervention is advised, as with patientswith early brainstem signs. Importantly, and in contrast toother intracerebral hemorrhages, surgical relief hasprospects for a substantial recovery.

In patients with cerebellar infarction, simultaneouscranial nerve and long tract signs are due to lateral cir-cumferential artery ischemia from a more proximallyobstructed cerebellar artery. Early on, symptomatic com-pression from a soft cerebellar infarct is less likely. Manypatients require no more than medical support. However,in some patients, hydrocephalus develops rapidly, some-times in the first 3 days, or more insidiously over thecourse of 7 to 10 days. Alterations in the mental status,declines in the level of alertness, long tract motor signs,


218

and decerebrate posturing indicate acute hydrocephalus.Blockade of cerebrospinal fluid egress and dilation of thelateral ventricles is quickly confirmed by CT. An imme-diate ventriculostomy is potentially curative (Figure 11-4).Concern for upward herniation of the cerebellum is lowbecause of the lack of substantial pressure within theinfarcted mass.

REFERENCES

1. Little JR,Tubrian ED, Ethier R. Cerebellar hemorrhage inadults. J Neurosurg 1978;48:575–9.

2. St Louis EK,Wijdicks EFM, Hongzhe L. Predicting neuro-logic deterioration in patients with cerebellar hematomas.Neurology 1998;51:1364–9.

3. Heros RC. Cerebellar hemorrhage and infarction. Stroke1982;13:106–9.

4. Chin D, Carney P.Acute cerebellar hemorrhage with brain-stem compression in contrast with benign cerebellar hem-orrhage. Surg Neurol 1983;19:406–9.

5. Theodore WH, Striar J, Burger A. Nonsurgical treatment ofcerebellar hematoma. Mt Sinai J Med 1979;46:328–32.

6. Wijdicks EFM, Maus TP, Peipgras DG. Cerebellar swellingand massive brain stem distortion: spontaneous resolutiondocumented by MRI. J Neurol Neurosurg Psychiatry 1998;65:400–1.

7. Seelig JM, Selhorst JB, Young HR, Lipper M. Ventricu-lostomy for hydrocephalus in cerebellar hemorrhage. Neu-rology 1981;31:1537–40

8. Mathew P,Teasdale G, Bannan A, Oluoch-Olunya D. Neu-rosurgical management of cerebellar haematoma and infarct.J Neurol Neurosurg Psychiatry 1995;59:287–92.


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CASE 1

A 63-year-old alcoholic man underwent a radical neckdissection for carcinoma of the tongue. Afterward, dys-phagia restricted his diet to semisolids. Six months later, hebecame irritable and lethargic. Eye movements wereimpaired (Figure 12-1).One day after receiving 100 mg ofintravenous thiamine, he was fully alert and more coher-ent and had a full range of eye movements (Figure 12-2).

CHAPTER 12

WERNICKE’S ENCEPHALOPATHYJohn B. Selhorst, MD

Figure 12-1 (A) Right gaze was moderately paretic and (B) leftgaze was severely impaired. Abduction was more affected thanadduction. (C) Upgaze was preserved, but convergence occurredwith (D) downgaze.

A B

C D

Figure 12-2 Eye movements were completely restored 24 hoursafter admission of intravenous thiamine to the patient in Figure12-1.

A B

C D

CASE 2

A 21-year-old woman developed recurrent vomiting inthe second trimester of her first pregnancy. At 7 monthsgestation, she became confused. Gaze-evoked nystagmuswas observed in all directions of gaze. Magnetic resonanceimaging (MRI) illustrated diffuse hyperintensity observedaround the third ventricle (Figure 12-3).

CASE 3

A morbidly obese, 31-year-old woman underwent a gastricstapling procedure. Two months later, she became disori-ented and complained of diplopia. She required support towalk.The remaining neurologic examination was normal.

INTRODUCTION

As depicted in these cases, the triad of confusion, gaitinstability, and impaired ocular motility is diagnostic of

Wernicke’s Encephalopathy

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Figure 12-3 Fluid-attenuated inversion recovery imaging showshigh intensities (A) in the mammillary bodies, (B) in the peri-aqueductal area, and (C) in the medial thalami.

A B C

Wernicke’s encephalopathy (WE). Sometimes, however,the full-blown picture is not present or the typical signs areindistinct.Because the timely administration of thiamine iscrucial, this review presents the protean manifestations ofthiamine deficiency and the underlying conditions inwhich it occurs.A more comprehensive discussion is foundin the landmark monograph by Victor and colleagues.1

NEUROPATHOLOGY

Unique pathologic findings in Carl Wernicke’s seminal1881 report were punctate hemorrhages in the gray mat-ter surrounding the third ventricle and the floor of thefourth ventricle.1,2 These discrete hemorrhages, however,are found in only 10% of autopsy examinations. Atrophyof the mammillary bodies is the most common (75–85%)macroscopic finding. Dilation of the third ventricle andaqueduct is less distinctive but is often observed. Micro-scopic findings are (1) necrosis of neurons and their axons,(2) proliferation of microglia and astrocytes, (3) endothe-lial swelling in capillaries, and (4) petechial hemorrhages.These histologic changes occur along the anatomic mid-line, that is, the periventricular gray matter of the hypo-thalamus, thalamus, periaqueductal area of the midbrain,floor of the fourth ventricle, and cerebellum. With theonset of thiamine deficiency, experimental studies indicatethat glucose use declines in these regions and is followedby an increase in glucose turnover. Reversible reductionsin thiamine-dependent �-ketoglutarate dehydrogenase arefound in the cerebellum of thiamine-deficient rats and areproposed to account for neuronal degeneration.3


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PATHOGENESIS

For 50 years, the biochemical defect associated with WEwas unknown.The first clue to its pathogenesis arose fromthe production of typical neuropathologic changes of WEin rats fed diets lacking vitamin B1. Shortly thereafter, thesechanges were also observed in athiaminotic pigeons. Sub-sequently, an inactivator of thiamine, thiaminase, found inraw fish, was shown to be responsible for Chastek paraly-sis, a disorder of silver foxes with a neuropathology resem-bling WE in man. An inactivator of thiamine kinase,pyrithiamine, was later used in rats to block the activationof thiamine from its active form, thiamine pyrophosphate(TPP), and to reproduce the neuropathologic findings ofWE.The first report of the reversal of the signs and symp-toms of WE was in 1937, when B vitamins were given toa woman suffering from hyperemesis gravidarum. By1941, Jolliffe and associates conclusively demonstrated thatthiamine was the beneficial B vitamin for treating WE.4,5

Thiamine is required as a coenzyme at three interme-diate points in carbohydrate metabolism: pyruvate dehy-drogenase in the glycolytic pathway, transketolase inthe hexose monophosphate shunt, and dehydrogenase of�-ketoglutaric acid in the citric acid cycle. Reductions inTPP-dependent enzymes have been found in autopsyspecimens of the cerebellar vermis.The precise mechanismleading to cellular degeneration, however, is uncertain. Ina study of pyrithiamine-treated rats, a decline in pyruvateactivation and an accumulation in lactic acid occurred inthe hypothalamus, thalamus, and midbrain after neurologicsigns appeared.6 NMDA receptor–mediated excitotoxicity


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has also been proposed but not substantiated in thelaboratory.6

EPIDEMIOLOGY

A number of large, systematic autopsy studies have showna low but regular rate of WE. Histopathologic changeswere found in 1.7% of 1,600 consecutive autopsies inNew York, 3.4% of 4,000 sequential pathologic examina-tions in Brooklyn, 2.2% of 3,548 necropsies in Cleveland,1.7% of 2,891 pathologic examinations in Western Aus-tralia,2 and 0.8% of 8,735 autopsies in Norway. Except forthe latter report, these studies may be biased by samplinga population with a high incidence of alcoholism or mal-nutrition.

It is well recognized that WE most often occurs inalcoholics suffering from malnutrition. Consequently,WEis more common in men than in women. Presumably,alcohol displaces food in the diet but provides calories thatrequire thiamine for their metabolism. Liver disease in thealcoholic possibly impairs the storage and activation ofthiamine. Additionally, impaired thiamine absorption inthe intestine is reported in alcoholics, but this claim hasbeen challenged.7

Victor and colleagues obtained a definitive history ofalcoholism in 175 (71%) of 245 patients with WE.1 InHarper’s study, 88% of 51 patients were known alcoholics.2

Many other reports confirm that a majority of patientswith WE are chronic alcoholics, but they also show thatWE occurs in a varied minority of nonalcoholic patients(Table 12-1). Neoplasms and gastrointestinal diseases are


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particularly common in this group. More recently,WE hasbeen identified in patients infected with the acquiredimmune deficiency syndrome (AIDS) virus. A host ofiatrogenic causes have also been reported, including anincreasing number of patients developing WE after gastricbypass surgery.8–10

CLINICAL MANIFESTATIONS

Although the triad of confusion, gait ataxia, and oculo-motor deficits is diagnostic, all three features occur in asmall minority of patients.11 Components of the triadoccur singularly or in combination with one another.Confusion is by far the most prevalent sign (Figure 12-4)and results from defective retention of recent events andtheir temporal sequences. Commonly, the altered mentalstatus also includes disorientation, apathy, and poor con-centration. The gait consists of a reeling, wide-basedstance, and short, unstable steps. Maintaining the stance, ifit is at all possible, requires support. Involvement of thevestibular system in addition to the cerebellum accountsfor the imbalance. If an intention tremor is present, it isfound in the lower limbs.

The ocular signs are the least frequent of the diagnos-tic triad. Their distinctive occurrence, however, providesthe principal means of confirming the diagnosis.Typically,they are bilateral, but they are often asymmetric (see Fig-ure 12-1). Ocular weakness is partial or complete. Hori-zontal disturbances generally precede vertical ones.A con-stellation of eye signs is described: (1) gaze-evoked,downbeat, or upbeat nystagmus; (2) impaired abduction;


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Table 12-1 Illnesses Associated with Wernicke’sEncephalopathy

NeoplasmsGastrointestinal cancerHematogenous tumorsLymphoma

Gastrointestinal diseasesPyloric stenosisRadiation proctitisRecurrent vomitingProtracted constipation

Iatrogenic causesTotal parenteral nutritionProlonged intravenous feedingsHigh-glucose loadsGastric surgery for obesityHemodialysis and uremia

Drug complicationsDigitalisDirueticsTolazamideQuinine

Hyperemesis gravidarum Acquired immunodeficiency syndrome (AIDS)Psychiatric disorders

Anorexia nervosaSchizophrenia

DementiaNeonatal illnessStarvation

Prisoners of warHunger strikersObesity treatment


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(3) ptosis, usually mild; (4) bilateral internuclear ophthal-moplegia; (5) conjugate gaze deficits; (6) impairedoculovestibular responses; and (7) complete ophthalmo-plegia. In the largest clinical study, nystagmus occurred in85% of 232 patients (Figure 12-4).1 Abduction paresis,found in 54% of patients, was the second most commonocular abnormality. Isolated palsies of the oculomotor ortrochlear nerves were not encountered. Conjugate gazepalsy, present in 44% of patients, was the third most com-mon ocular disorder. Similar oculomotor signs have beeninduced experimentally in monkeys fed thiamine-deficient diets.12 In severe stages of deficiency, nystagmusprogressed to complete ophthalmoplegia. Dilation of thepupils and impaired pupillary light reflexes were alsoobserved. Interestingly, Victor and associates reportedasymmetric pupils or impaired pupillary light reaction in19% of patients but stressed that marked dilation or con-striction of a pupil was never an initial manifestation ofWE.1 Mild to severe ptosis occurred in thiamine-depleted

Figure 12-4 Clinical Signs in Wernicke’s Encephalopathy. Symp-tom frequency. Adapted from Harper CG et al.11


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monkeys, but when present in humans, it is often a minorfeature of the oculomotor disturbance.

It cannot be overemphasized that dependence on theclassic triad of signs to make a diagnosis of WE neglects thediverse presentations established by neuropathologicexamination. The absence of the classic triad is perhapsespecially true in the nonalcoholic patient. Therefore,attention to the less distinctive features of WE is impor-tant. Careful recording of symptoms occurring with thedevelopment of WE in prisoners of war suggests that aninsidious affectation of the mental state, such as apathy,lethargy, and confusion, is the earliest manifestation ofWE.13 Nausea and vomiting are often present as well.Infrequently, hypothermia may complicate recognition of

Figure 12-5 Common Eye Signs in Wernicke’s Encephalopathy.Adapted from Harper CG et al.11

WE; it is perhaps due to involvement of the preoptic-anterior hypothalamus. Hypotension, independent ofhypovolemia, is also encountered on occasion. In the alco-holic or malnourished patient, such symptoms should raisesuspicion and prompt treatment.

The relationship between WE and Korsakoff ’s psy-chosis (KP) and polyneuropathy is important to under-stand. In 1887, Korsakoff described a syndrome in alco-holics that was characterized by both an amnesic state andpolyneuropathy.1 Later, he observed the same conditionamong nonalcoholic patients. The mental alteration inthese patients is remarkable for the disproportionateimpairment of recent memory as opposed to other cogni-tive functions. The patients also lack concentration andinsight into their memory loss.There is disorientation andconfusion for a sequence of events.Temporal relationshipsare composed from fragments of memory scattered overtime. Confabulation results and consists of real but con-fused facts as opposed to purely imagined and unrealevents.The prognosis for recovery from KP is limited.

NEUROIMAGING

Changes found by computed tomography are not distinc-tive and are too infrequent to corroborate a diagnosis ofWE. MRI, however, mirrors the neuropathologic lesionsfound in the midline of the brainstem. In the acute phaseof WE, high intensities occur in the thalamus and peri-aqueductal area.14 Pathologic study suggests that thesechanges are caused by a spongy degeneration of the neu-ropil.15 These high intensities remit or decrease at later


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stages when the mammillary bodies and midbraintegmentum atrophy and the third ventricle widens.16

Symmetric contrast enhancement also occurs in the acutestages of WE in the mammillary bodies, thalamus, peri-aqueductal areas, and tegmentum of the pons17; this break-down in the blood-brain barrier is reversed with thiaminetherapy.18 Fluid-attenuated inversion recovery (FLAIR)imaging shows high-intensity changes in the walls of thethird ventricle and aqueduct of Sylvius (see Figure 12-3).FLAIR studies are perhaps a more sensitive study thanroutine MRI. These findings were found in 8 of 15patients (53%) in one series, indicating that MRI is usefulto confirm the disease but not to exclude it.19

LABORATORY STUDIES

Serum thiamine levels are not recommended because theyare often within the normal range in deficiency states.1

However, over 80% of whole-blood thiamine is found inred blood cells and reflects tissue concentrations through-out the body.A reliable measure of thiamine stores is theerythrocyte transketolase level (ETK) or the effect of itsactivation by TPP, the TPP effect. Low values indicate adeficiency in available thiamine.These assays are reliable20

but should not delay institution of treatment. Morerecently, high-performance liquid chromatography hasmore directly determined concentrations of erthrocytethiamine monophosphate and diphosphate.21 These assaysare reported as being as sensitive as ETK assays, as well asmore stable, easier to standardize, and less affected by fac-tors influencing enzymatic activity.


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TREATMENT

Patients with WE have a mortality rate of 17% in the first3 weeks and 26% over 3 years.1 Therefore, haste in recog-nizing and treating the disease is essential.The amount ofthiamine required is reflected in laboratory studies thatshow that 0.3 to 0.6 mg of thiamine is needed for themetabolism of each 1,000 calories. The commonlyaccepted minimum daily allowance of thiamine is 1.2 to1.7 mg. Symptoms of WE that developed in British pris-oners of war subsisting only on a diet of polished ricewere reversed by 2.0 to 4.0 mg/d of thiamine.13

Thiamine, 50 mg intravenous and 50 mg intramuscu-larly, should be given immediately whenever the diagno-sis of WE is considered (Figure 12-6). Concerns aboutanaphylactoid reactions with intravenous administrationhave not been borne out. Intravenous administrationshould be continued daily until the ocular, ataxic, andmental disturbances remit. Daily supplements of oral50 mg should be provided afterward to avoid a recurrenceof WE.Because some patients have not responded to stan-dard dosages, larger amounts, for example, 500 mg, havebeen recommended.11

In patients with ophthalmoplegia, the diagnosis is con-firmed by reversal of the ocular motility deficit within4 hours to 2 days. Gait ataxia and confusion resolve moreslowly. Full remission of the mental state depends on itsseverity and duration at onset of treatment.

Administration of magnesium is possibly an importantadjunct to proper therapy.22 Magnesium is a cofactor inmany of the glycolytic reactions requiring TPP. Magne-


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sium deficiency is known to develop in alcoholics, themalnourished, and patients having vigorous diuresis.Ver-tical gaze nystagmus and downbeat nystagmus are reportedin patients with severe hypomagnesemia.23 It is likely thatthiamine deficiency and magnesium deficiency com-monly coexist. In one patient with WE, transketolase lev-els did not rise until magnesium was added 24 hours afterthiamine was begun.24 For prompt therapeutic responses,magnesium levels should be measured and magnesiumadministered, if renal function permits, to those patientsreceiving thiamine for suspected WE.

PREVENTION

Prophylactic treatment depends on an understanding ofthe development of thiamine-deficient states. A depleted


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1. Acutely

Confusion

and/or

Ataxia

and/or

Ocular deficits

50 mg B-1, i.v.+

50 mg B-1, p.o.+

MgSO4, if needed

50 mg B-1, p.o.preventively

50 mg B-1, i.v.or p.o.

500 mg B-1, p.o.

resolution

no resolution

2. Prophylactically

Alcoholics

Undernourished

Figure 12-6 Treatment algorithim for Wernicke’s encephalopa-thy. IV = intravenously; MgSO4 = magnesium sulfate; PO = bymouth.

state is possible within 18 days after beginning a diettotally devoid of the vitamin. Prisoners of war in 1941developed WE in 6 to 8 weeks, but their diet was notcompletely lacking in thiamine.13

The necessity for prevention of WE and KP cannot beoveremphasized.

Thiamine should be provided presumptively to allalcoholics and patients with debilitating diseases (Figure12-6). The importance of thiamine supplementation inmany third world populations should also be apparent.Furthermore, the benefit of routine thiamine administra-tion in the undernourished is highlighted by reports of ahigh glucose load depleting the last available stores of thi-amine and precipitating WE. Finally, patients with debili-tating conditions are often vitamin deficient beforebecoming acutely ill.Therefore,when presenting with anyacute illness, any emaciated patient, alcoholic or nonalco-holic, who develops an altered mental status or other signsof WE should immediately receive 100 mg of thiamine.

REFERENCES

1. Victor M, Adams RS, Collins GH.The Wernicke-Korsakoffsyndrome and related neurologic disorders due to alcoholismand malnutrition. 2nd ed. Philadelphia: FA Davis; 1989.

2. Harper C.Wernicke encephalopathy: a more common dis-ease than realized. A neuropathologic study of 51 cases. JNeurol Neurosurg Psychiatry 1979;42:226–31.

3. Butterworth RF. Pathophysiology of cerebellar dysfunctionin the Wernicke-Korsakoff syndrome. Can J Neurol Sci1993;20 Suppl 3:123–6.


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4. Joliffe N,Wortis H, Fein MD.The Wernicke syndrome.ArchNeurol Psychiatry 1941; 46:569–97.

5. Wagner HP,Weir JF. Ocular lesion associated with postop-erative and gestational nutritional deficiency. Am J Oph-thalmol 1937;20:253–7.

6. Todd KG, Butterworth RF. Evaluation of the role ofNMDA-mediated excitotoxicity in the selective neuronalloss in experimental Wernicke encephalopathy. Exp Neu-rol 1998;149:130-8.

7. Breen KJ, Buttigieg R, Oddifdis S, Lourensz C, et al.Jejunal uptake of thiamin hydrochloride in man: influenceof alcoholism and alcohol. Am J Clin Nutr 1985;42:121–6.

8. Rosenberg S, Lopez MBS, Tsanaelis AM. Neuropathy ofacquired immunodeficiency syndrome (AIDS). Analysis of22 Brazilian cases. J Neurol Sci 1986;76:187–90.

9. Doraiswamy PM, Massey EW, Enright K, et al.Wernicke-Korsakoff syndrome caused by psychogenic food refusal:MR findings.AJNR Am J Neuroradiol 1994;15:594–6.

10. Shimomura T, Mori E, Hirono N, et al. Development ofWernicke-Korsakoff syndrome after long intervals follow-ing gastrectomy.Arch Neurol 1998;55:1242–5.

11. Harper CG, Giles M, Finaly-Jones R. Clinical signs in Wer-nicke-Korsakoff ’s complex: a retrospective analysis of 131cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry1986;49:341–5.

12. Cogan DG, Witt ED, Goldman-Rakic PS. Ocular signs inthiamine-deficient monkeys and in Wernicke’s disease inhumans.Arch Ophthalmol 1985;103:1212–20.

13. DeWardena HE, Lennox B. Cerebral beriberi (Wernicke’sencephalopathy). Lancet 1947;i:11–17.

14. Gallucci M, Bozzao A, Splendiani A, et al. Wernickeencephalopathy: MR findings in five patients. AJR Am JRoentgenol 1990;155:1309–14.


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15. Suzuki S, Ichijo M, Fujii H, et al. Acute Wernicke’sencephalopathy: comparison of magnetic resonance imagesand autopsy findings. Intern Med 1996;35:831–4.

16. Yokote K, Miyagi K, Kuzuhara S, et al. Wernickeencephalopathy: follow-up by CT and MR. J Comput AssistTomogr 1991;15:835–8.

17. Shogry ME, Curnes JT. Mammillary body enhancement onMR as the only sign of acute Wernicke encephalopathy.AJNR Am J Neuroradiol 1994;15:172–4.

18. Schroth G, Wichmann W,Valavanis A. Blood-brain-barrierdisruption in acute Wernicke encephalopathy: MR find-ings. J Comput Assist Tomogr 1991;15:1059–61.

19. Antunez E, Estruch R, Cardenal C, et al. Usefulness of CTand MR imaging in the diagnosis of acute Wernicke’sencephalopathy. AJR Am J Roentgenol 1998;171:1131–7.

20. Nordentoft M, Timm S, Hasselbaich E, et al. Thiaminepyrophosphate effect and erythrocyte transketolase activityduring severe alcohol withdrawal syndrome.Acta PsychiatrScand 1993;88:80–4.

21. Tallaksen CM, Bell H, Bohmer T. Thiamin and thiaminphosphate ester deficiency assesed by high performance liq-uid chromatography in four clinical cases of Wernickeencephalopathy.Alcohol Clin Exp Res 1993;17:712–6.

22. McLean J, Manchip S.Wernicke’s encephalopathy inducedby magnesium depletion. Lancet 1999;353:1766.

23. Saul RF, Selhorst JB. Downbeat nystagmus with magnesiumdepletion.Arch Neurol 1981;38:650–2.

24. Traviesa DC. Magnesium deficiency: a possible cause of thi-amine refractoriness in Wernicke-Korsakoff encephalopa-thy. J Neurol Neurosurg Psychiatry 1974;37:959–62.


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The goal of this chapter is to familiarize the clinicianwith the neurologic examination and to provide somehelpful tips in obtaining or interpreting data from theexamination. It is not intended as a thorough review of alldetails of a complete and comprehensive neurologicexamination. We have tried to direct some of our com-ments to the specific conditions discussed in more detailin the other chapters of this book. Guidelines for a com-prehensive neurologic examination and an examinationon a patient with an altered level of consciousness havebeen proposed by the American Academy of Neurology(AAN) and are outlined in Tables 13-1 and 13-2.

GENERAL EXAMINATION

A general physical examination certainly complements aneurologic examination when evaluating patients withneurologic diseases.

Head and Neck Examination

In patients with altered levels of consciousness, it isimportant to inspect and palpate the patient’s head forsigns of trauma, including looking for blood behind theear (Battle’s sign) and around the eyes (raccoon eyes).Thenose should be inspected for blood or cerebrospinal fluid

CHAPTER 13

TIPS ON THE NEUROLOGIC EXAMINATION

James D. Fleck, MD, and José Biller, MD

Tips on the Neurologic Examinat ion

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Table 13-1 Guidelines for a ComprehensiveNeurologic Examination

1. Mental statusa. Level of alertnessb. Language function

i. Fluencyii. Comprehensioniii. Repetitioniv. Naming

c. Memory (short and long term)d. Calculatione. Visuospatial processingf. Abstract reasoning

2. Cranial nervesa. Vision

i. Visual fieldsii. Visual acuityiii. Funduscopic examination

b. Pupillary light reflexc. Eye movementsd. Facial sensatione. Facial strength—muscles of facial expressionf. Hearingg. Palatal movementh. Speechi. Neck movements

i. Head rotationii. Shoulder elevation

j. Tongue movements3. Motor function

a. Gaiti. Casualii. On toesiii. On heels

Continued


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iv. Tandemb. Coordination

i. Fine finger movementsii. Rapid alternating movementsiii. Finger to noseiv. Heel to shin

c. Involuntary movementsd. Pronator drifte. Tone (resistance to passive manipulation)f. Bulkg. Strength

i. Shoulder abductionii. Elbow flexion and extensioniii. Wrist flexion and extensioniv. Finger flexion, extension, and abductionv. Hip flexion and extensionvi Knee flexion and extensionvii. Ankle dorsiflexion and plantar flexion

4. Reflexesa. Muscle stretch reflexes

i. Bicepsii. Tricepsiii. Brachioradialisiv. Patellarv. Achilles

b. Plantar responses 5. Sensation

a. Light touchb. Pain or temperaturec. Proprioceptiond. Vibration

Adapted from http://aan.com/students/clerkship/neurology_clerkship.pdf (accessed Dec 10, 2003).


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Table 13-2 Guidelines for the NeurologicExamination in Patients with Altered Levels of

Consciousness

1. Mental statusa. Level of arousalb. Response to auditory stimuli (including voice)c. Response to visual stimulid. Response to noxious stimuli applied centrally

and to each limb

2. Cranial nervesa. Response to visual threatb. Pupillary light reflexc. Oculocephalic (doll’s eyes) reflexd. Vestibulo-ocular (caloric testing) reflexe. Corneal reflexf. Gag reflex

3. Motor functiona. Voluntary movementsb. Reflex withdrawalc. Spontaneous and involuntary movementsd. Tone (resistance to passive manipulation)

4. Reflexesa. Muscle stretch reflexesb. Plantar responses

5. Sensation (to noxious stimulation)

Adapted from http://aan.com/students/clerkship/neurology_clerkship.pdf (accessed Dec 10, 2003).


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drainage. Otoscopy should be done to look for bloodbehind the eardrum. Auscultation for bruits should bedone as part of the general cardiovascular examination.Astethoscope bell can be placed along the anterior borderof the sternocleidomastoid (SCM) muscle in the regionof the upper border of the thyroid cartilage to listen forcervical carotid artery bruits and along the posterior bor-der of the SCM muscle to listen for vertebral arterybruits.The bell can also be gently placed over closed eyesto listen for ocular bruits. Auscultation of the mastoidprocesses, and temporal, frontal, or parietal head regionsmay be helpful in certain circumstances. Irritation of thesubarachnoid space, by infection or blood, can lead tonuchal rigidity, a resistance to active and passive neckflexion. No neck manipulations should be done until acervical spinal cord lesion or fracture or dislocation ofcervical vertebrae has been ruled out with appropriateradiologic tests. Brudzinski’s neck sign is noted if passiveflexion of the head is followed by flexion of both thighsand legs. Kernig’s sign can also be used to test formeningeal irritation. The hip and knee are flexed, andthen the knee/leg is slowly and gently passively extend-ed, looking for pain and resistance to leg extension. Inpatients with suspected giant cell arteritis, the superficialtemporal arteries should be palpated for tenderness orinduration. The temporal areas and scalp should be pal-pated for tenderness.

Chest/Respiration

For patients with neuromuscular respiratory difficulties,there are some bedside tests of function. The simplest

method is to ask the patient to count aloud on a singledeep breath. If the patient can count to 10, the forcedvital capacity (FVC) is approximately 1 L. If the patientcan count to 25, the FVC is approximately 2 L. Otherrespiratory patterns may be helpful in localizing lesions inpatients who are comatose.These are briefly discussed inthe section on examining the comatose patient.

Cardiovascular

An irregularly irregular pulse may be indicative of atrialfibrillation, multifocal atrial tachycardia, premature atrialcontractions, or premature ventricular contractions.

Abdomen

In encephalopathic patients, hepatomegaly and spleno-megaly may be signs of hepatic disease with portal hyper-tension. Massive splenomegaly may be seen in malaria.Abdominal striae may be a sign of Cushing’s syndrome.

Extremities/Spine

In patients with spinal cord or spinal column trauma, thespine, especially the cervical spine, should be immobilizeduntil appropriate radiologic studies are done. In patientswith potential spinal cord lesions, the spinous processes atthe appropriate level may be tender to palpation.

Skin

Observation of the skin may be helpful. Skin temperatureand color may help lead to a diagnosis. One should


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inspect the skin for ticks, needle marks, or characteristicrashes. Characteristic rashes may give away the diagnosisin infectious diseases such as Rocky Mountain spottedfever or meningococcal meningitis. Livedo reticularismay be seen in younger patients with ischemic strokeowing to hypercoagulable states such as antiphospholipidantibody syndrome. Kaposi’s sarcoma may be seen inhuman immunodeficiency virus (HIV)-positive patients.

A COMPREHENSIVE NEUROLOGIC EXAMINATION

Guidelines for a comprehensive neurologic examinationhave been published by the AAN and are noted in Table13-1. The major sections of the neurologic examinationinclude mental status, cranial nerves (CNs), motor func-tion, reflexes, and sensation.We discuss these individuallyand provide some helpful hints on interpreting observa-tions made during the examination.

Much information regarding a patient’s mental statuswill be noted while obtaining the history. The patient’slevel of alertness is noted when speaking with the patient.Asking patients simple orientation questions such as theirname, the date, and their location will quickly give youinformation on their sensorium. Having them recite themonths or spell words backward can test their attentionspan. The fluency of speech and ability to comprehendspoken language are noted when the patient answersquestions. Asking patients to name objects, repeat aphrase, read, and write will complete a quick screen oflanguage function. Asking patients to remember threeobjects can test short-term memory. Simple calculations


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can be done on a piece of paper.Visuospatial processingcan be tested by asking patients to reproduce drawnobjects, such as interlocking pentagons, or perhaps todraw the face of a clock. Asking patients to interpret themeaning of proverbs can test abstract reasoning.

Testing CN function is most easily done by remem-bering and testing them in numeric order.The olfactorynerve (CN I) is not often tested in a routine neurologicexamination. However, having patients identify a com-mon smell such as coffee or wintergreen with each nos-tril separately is a reasonable first test. A noxious or irri-tating odor, such as ammonia, should not be used to testolfaction as these odors also activate the fibers of thetrigeminal nerve (CN V).

The optic nerve (CN II) plays a major role in visionand is the afferent limb of the pupillary reflex.Visual acu-ity is best tested using a distance chart but can be testedwith a pocket visual chart. When testing visual acuity,patients should wear their appropriate corrective lenses.Reading glasses should be worn if necessary for nearvision when using a pocket visual chart. Confrontationvisual fields should be done with the patient coveringone eye with a hand.A number of the examiner’s fingerscan be presented in each of the four quadrants of eacheye, and the patient is asked to state how many fingerswere presented.Visual field testing is often not done orforgotten by those not experienced in the neurologicexamination but often provides useful information. Forexample, a homonymous hemianopia may be the mostdramatic sign of an occipital lobe infarction. The pupil-lary light reflex is one of the most important parts of the

neurologic examination. Normally, both pupils willpromptly constrict when light is focused on either retina,giving both the direct and the consensual response. Thealternating light test is the standard clinical technique tolook for a relative afferent pupillary defect (RAPD).Swinging the light from eye to eye will elicit a briskerreaction to light in the unaffected eye and a less briskreaction or dilatation of the pupil in the affected eye. AnRAPD is a sensitive indicator of a unilateral injury to theafferent pupillary pathway, typically large retinal lesions,or damage to the optic nerve, which is most common.For example, an ischemic optic neuropathy associatedwith giant cell arteritis may give an RAPD. A fundus-copic examination is extremely important in establishingthe appearance of the optic disk, retina, and macula.Ideally, the fundus should be viewed after pharmacologicmydriasis to ensure the best view. Papilledema, or aswollen optic disk, is often a sign of increased intracranialpressure and makes funduscopy one of the most impor-tant parts of the examination of patients with headaches.Papilledema can be seen in conditions that globallyincrease intracranial pressure such as meningitis, sub-arachnoid hemorrhage, or intracranial mass lesions.A pal-lid swollen disk is often seen in giant cell arteritis.Cholesterol emboli (Hollenhorst plaque) may be indica-tive of ulcerating atheromatous plaque in the ipsilateralcarotid artery.

The oculomotor nerve (CN III), trochlear nerve(CN IV), and abducens nerve (CN VI) innervate themuscles that move the eyes or extraocular muscles. Theabducens nerve innervates the lateral rectus muscle. The


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trochlear nerve innervates the superior oblique muscle.The oculomotor nerve innervates the rest of the extraoc-ular muscles, which include the medial rectus, inferiorrectus, superior rectus, and inferior oblique muscles.Theoculomotor nerve also innervates the muscles that con-strict the pupil and the levator palpebrae superioris,which helps elevate the eyelid. The patient should beasked to follow an object that tests all directions of move-ment of both eyes. In a complete CN III palsy, there isptosis or drooping of the eyelid and dilatation of thepupil, and the eye is deviated laterally and a bit down-ward.

The trigeminal nerve (CN V) innervates the musclesof mastication or chewing and is responsible for facialsensation. The three main branches of the trigeminalnerve, the ophthalmic branch, maxillary branch, andmandibular branch, provide sensation for the forehead,cheek, and chin, respectively. Facial sensation can be test-ed in much the same way as sensation in other parts ofthe body is tested.This is outlined below.

The facial nerve (CN VII) innervates the muscles offacial expression. The most easily tested facial musclesinclude the frontalis, which wrinkles the forehead; theorbicularis oculi, which close the eye tightly; and thebuccinator, which helps one smile. The distribution offacial weakness will help localize lesions. A lesion of thefacial nucleus, the facial nerve fascicles within the brain-stem, or the facial nerve itself can lead to a lower motorneuron type of facial weakness in which all ipsilateralfacial muscles will be equally weak. If the corticobulbarfibers are affected, producing an upper motor neuron


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lesion, then the lower face will be much more affectedthan the upper face as the neurons guiding upper facialmuscles receive bilateral innervation. For example, theentire ipsilateral face will be weak in a typical idiopathicfacial nerve palsy or Bell’s palsy. In a patient with a hemi-spheric infarction, typically the smile is much weakerthan forehead wrinkling, and, in fact, the frontalis func-tion may be normal.

The vestibulocochlear nerve (CN VIII) is essentiallytwo fiber systems that participate in hearing (cochlearnerve) and balance, equilibrium, and orientation in space(vestibular nerve). Hearing can be tested in several ways.The ability of the patient to hear two fingers rustledtogether, hear whispered words, or detect the sound of avibrating tuning fork can be tested.

The glossopharyngeal nerve (CN IX) and the vagusnerve (CN X) can be quickly tested by asking the patientto raise the soft palate. In a unilateral lesion, the uvuladeviates to the opposite side and the ipsilateral soft palatewill not elevate. The gag reflex is discussed below.Dysarthria, or difficulty with articulation of speech owingto disturbances of muscular control, can be seen in bothcentral and peripheral nervous system disorders andtherefore can be seen in many lesions of the nervoussystem.

The spinal accessory nerve (CN XI) innervates theSCM muscles and the rostral or proximal parts of thetrapezii muscles. It can be tested by having the patientshrug the shoulders (trapezii) and attempt to return thehead to the midline position against resistance after it hasbeen turned to the right and left. It is best to actually pal-


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pate the SCM muscle being tested so that activation isfelt. It is important to realize that the left SCM helps turnthe head to the right and the right SCM helps turn thehead to the left.The hypoglossal nerve (CN XII) inner-vates the tongue musculature. The tongue should beobserved for atrophy and fasciculations as a clue to lowermotor neuron lesions. The patient is then asked to pro-trude the tongue. If there is a unilateral weakness, thenthe tongue will protrude toward the side of the lesion.

Examination of motor function is the next step in theneurologic examination. Although the testing of poweror strength is important in examining the motor system,there are certainly other techniques that should not bemissed. Inspection of overall and individual muscle bulklooking for atrophy or hypertrophy may be helpful informulating a diagnosis.Testing of muscle tone, or resist-ance to passive manipulation, is also important and maybe normal, decreased, or abnormally increased. Musclesbeing tested for tone should be relaxed.The most com-mon forms of increased muscle tone are spasticity andrigidity. Neuroleptic malignant syndrome is associatedwith severe generalized muscle rigidity. The patientshould be observed for involuntary hyperkinetic move-ments such as tremor, chorea, myoclonus, hemiballismus,athetosis, and dystonia. The testing of muscle power orstrength is the most used part of the examination of themotor system and is the part most familiar to all physi-cians. Although a multitude of muscles can be tested forpower, the main movements tested in the routine neuro-logic examination include shoulder abduction, elbowflexion and extension, wrist flexion and extension, finger


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flexion, extension, and abduction, hip flexion and exten-sion, knee flexion and extension, and ankle dorsiflexionand plantar flexion. Muscle power can be rated on a5-point scale, as listed in Table 13-3. A subtler test ofupper extremity power is asking patients to hold theirarms and hands outstretched in front of them, with eyesclosed. If there is mild weakness, there may be slowpronation of the hand, slight flexion of the wrist andelbow, and downward drift of the arm. The testing ofpatients with suspected hysteria or malingering may showgive-away weakness. The muscle being tested may notsustain contraction and may give way abruptly rather thangradually.There may also be inconsistency in the amountof power exerted for the individual muscle groups.Coordination is the smooth execution of motor move-ments. Although cerebellar lesions often cause incoordi-nation or ataxia, it can also be seen in lesions of thepyramidal system, extrapyramidal system, and sensory sys-tem.The most common methods of detecting incoordi-

Table 13-3 Grading of Muscle Power

0 No contraction

1 Flicker or trace of contraction

2 Active movement with gravity eliminated

3 Active movement against gravity

4 Active movement against gravity and resistance

5 Normal power


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nation are the finger-to-nose test in the upper extremi-ties and the heel-to-shin test in the lower extremities.Rapid alternating movements can also be done to testcoordination and dexterity. Having the patient tap on thethigh with the palm and dorsum of the hand alternatelyor tap the toes on the ground can test for impairment ofrapid alternating movements. The testing of musclestretch reflexes is also an important part of the motorexamination. The most commonly tested muscle stretchreflexes are the biceps, triceps, brachioradialis, patellar (orknee jerk), and Achilles (or ankle jerk). The part of thebody to be tested should be relaxed, and the best positionis usually intermediate between full extension and flex-ion. Muscle stretch reflexes can be graded on the scalepresented in Table 13-4. Often it is not the absolute num-ber assigned to the reflex but the degree of symmetry orasymmetry noted.The most important superficial reflex isthe plantar response.With the patient supine and relaxed,the lateral sole of the foot is stimulated starting near theheel and moving toward the toes.The toes will flex in anormal plantar response. If the corticospinal tract is inter-rupted or diseased, the great toe will dorsiflex and theother toes will often fan out.This great toe extension toplantar stimulation is the Babinski sign. When muscleweakness is noted, the most fundamental question to beanswered by the examination is whether a lower motorneuron or upper motor neuron lesion is present. Chronicupper motor neuron lesions (those affecting the corti-cospinal tract) classically show weakness, increasedtone/spasticity, hyperreflexia, and a Babinski’s sign in theappropriate distribution based on the anatomic location


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of the lesion. Chronic lower motor neuron lesions classi-cally show weakness, decreased tone, hypo- or areflexia,and flexor or neutral plantar response again in the appro-priate distribution based on the anatomic location of thelesion.

The sensory examination is the most subjective partof the neurologic examination because it relies on theresponses of the patient and not on the examiner’s obser-vations. It is often also the most tedious and time-consuming part of the examination. At times, it seemsunreliable and confusing. However, much informationcan be gained by an appropriate sensory examination.The most common modalities tested are light touch, painor temperature sensation, proprioception, and vibration.Light touch can be tested with a cotton swab or a gentletouch with the examiner’s finger. Pain sensation can betested with a sharp object, such as a safety pin. It is impor-tant to use sharp objects only once and dispose of them

Table 13-4 Grading of Muscle Stretch Reflexes

0+ Absent

1+ Present but diminished

2+ Normal

3+ Increased but not necessarily to a pathologic degree

4+ Markedly hyperactive, often with associated clonus

appropriately because of the possibility of transmittingpathogens, especially viruses, between patients.Temperature sensation can be tested using the cool endof a tuning fork and comparing it to the examiner’swarmer finger. Vibration is tested with a tuning fork.Proprioception is tested by moving an isolated toe or fin-ger up or down, often by only a few millimeters, and ask-ing the patient in which direction the digit was moved. Itis important to hold the digit on the lateral portions orsides and not the top or bottom as the patient may sensethe pressure direction and correctly state the direction ofmovement based on the pressure sensation and not a trueawareness of the joint position. Certainly, not everysquare inch of the skin is examined completely in everyexamination as this would be impractical. However, adetailed examination of the appropriate anatomy shouldbe done in any patient with a complaint of sensorychanges such as numbness, pain, or tingling. It is impor-tant to test the main sensory modalities as they take dif-ferent anatomic paths within the central nervous system,especially the spinal cord. Pain and temperature sensationsare carried by the spinothalamic tracts, and vibration andproprioception are carried in the dorsal columns of thespinal cord. In testing sensation of all types, the mostaccurate results are obtained by proceeding from the areaof less sensation to the area of more or normal sensation.The pattern of sensory loss often guides in localizing alesion within the nervous system, and some specific pat-terns are noteworthy. For example, in hemispheric braininfarcts, the pattern is typically one of loss of all modali-ties of sensation on the contralateral face, body, and


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extremities. In peripheral neuropathies, the sensorychanges are most often distal in the extremities, with thelegs often being more affected than arms. With lesionscompressing the spinal cord, there is most often loss ofsensation distal to the lesion. Some noteworthy anatomiclandmarks include the nipple level, which is at the T4sensory level, and the umbilicus, which is at the T10 sen-sory level. Sensory loss may occur in the perianal andgenital areas, a “saddle distribution,” due to lesions of thecauda equina or conus medullaris.

Examination of gait should be done in every personcapable of walking. In fact, if given only one part of theexamination with which to make a diagnosis, most neu-rologists would choose the station and gait examination.An integration of most parts of the nervous system isnecessary to walk normally. Patients should be observedwalking with as little assistance as necessary to keep themsafe. If possible, they should be asked to walk on theirheels and toes. Tandem walking, or walking along astraight line with one foot directly in front of the other,should be attempted in all patients who are not at signif-icant risk of falling. Certainly, some gait patterns can giveaway a diagnosis. Easy examples are the hemiparetic gaitof a patient who has had a stroke, the shuffling gait of apatient with parkinsonism, or the ataxic gait of a patientwith cerebellar disease.

EXAMINATION OF THE PATIENT IN COMA OR ALTEREDLEVEL OF CONSCIOUSNESS

Guidelines for the examination of patients with alteredlevels of consciousness are presented in Table 13-2. In


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general, any part of the comprehensive neurologic exam-ination listed previously that can be performed should beperformed. However, many aspects of the comprehensiveneurologic examination cannot be performed in patientsunable to follow commands or follow a course of action.Other reflex testing is often done in comatose patientsthat is not routinely performed on alert patients. Theseare highlighted in this section.

A general physical examination should be performedin all patients with an altered level of consciousness andmay be helpful in arriving at a cause. Some examples arelisted above in the general examination section. Simplemethods such as smelling the patient’s breath may provehelpful in determining a cause, especially toxic ingestions.For example, a garlic breath odor may be seen in arsenicpoisoning, and cyanide poisoning may cause a bitteralmond odor. Ethanol ingestions can often be diagnosedby the characteristic breath odor.

As implied by their name, evaluation of vital signs isimportant in the examination of a comatose patient.Hypertension may be due to increased intracranial pres-sure or just be due to chronic primary hypertension.Hypotension may be due to hypovolemia, hemorrhagicshock, or myocardial depression. Hyperthermia can beseen in infections such as meningitis, encephalitis, or sep-sis. It can also be seen in disruption of autonomic path-ways, neuroleptic malignant syndrome, or a serotoninsyndrome. Hypothermia may be due to exposure (envi-ronmental), hypoglycemia, or hypothyroidism.Wernicke’sencephalopathy and sedative overdose can also lowerbody temperature. Respiratory patterns may also be help-


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ful in diagnosing the cause of the altered level of con-sciousness or the location of a lesion in the brain.Hyperventilation can be seen in metabolic acidosis, pul-monary edema, or primary respiratory alkalosis or fromcentral neurogenic hyperventilation. Hypoventilationmay be due to pulmonary insufficiency, central alveolarhypoventilation, or other causes. An abnormal breathingpattern may point to a lesion in a specific location with-in the brain. Cheyne-Stokes respiration or periodicbreathing is probably the most common pattern and istypically caused by bilateral cerebral hemisphere dysfunc-tion or dysfunction of the diencephalon. Central neuro-genic hyperventilation is seen in low midbrain or upperpontine lesions. Dysfunction or lesions of the midcaudalpons often cause apneustic breathing. Ataxic breathing iscaused by medullary lesions.

The patient’s state of consciousness is measured bytheir awareness and responsiveness to the environment.There are many levels or states of awareness, and theyhave been identified by many descriptors, such as stupor,lethargy, somnolence, confusion, and delirium.The defi-nitions for these states are a bit variable and are likely acontinuum from normal to coma. Coma is defined as astate of complete loss of consciousness or a state ofunarousable unresponsiveness. In practice, it is most help-ful to describe the patient’s response to stimuli. Theseinclude auditory stimuli such as a voice or loud clap, visu-al stimuli such as light or a threatening gesture, or nox-ious stimuli applied in central locations (eg, the sternum)and each limb. Responses such as arousal, eye opening, orgrimacing should be noted.


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Several CN reflexes can be done to test the integrityof the brainstem from the midbrain to the medulla.Thepupillary light reflex is relatively resistant to metabolicinsults and is one of the most important signs in distin-guishing structural from metabolic causes of coma.Again,the afferent limb of this reflex is some optic nerve fibersand the efferent limb is the oculomotor nerve (CN III).For example, a structural lesion compressing CN III willtypically cause an ipsilateral fixed and dilated pupil. Apontine lesion may cause pinpoint pupils that require amagnifying glass to see the preserved trace light reflex.Any eye movements present and their pattern should benoted. Roving conjugate spontaneous eye movementsimply that the nuclei responsible for ocular motility inthe midbrain and pons are communicating with eachother. Eye movements can be induced by the oculo-cephalic (doll’s eyes) and vestibulo-ocular (caloric testing)reflexes.The oculocephalic reflex is easier to accomplishbut is less of a stimulus to eye movements than thevestibulo-ocular reflex. In a comatose patient lying supinewho may be intubated, performing horizontal oculo-cephalics is easier, but vertical oculocephalics can also bedone. Before performing the oculocephalic reflex, onemust be sure that there are no abnormalities of the cervi-cal spine. The head is then quickly turned from side toside. If the brainstem is intact, then the eyes will move inthe direction opposite to the skull movement and staylooking forward.The corneal reflex is done by touchingthe lateral portion of the cornea with a nonabrasive stim-ulus such as a wisp of cotton. A positive corneal reflexoccurs when both eyes blink to the stimulus.The afferent


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limb of this reflex is the trigeminal nerve (CN V), where-as the efferent limb is the facial nerve (CN VII).The gagreflex is produced by stimulating the posterior tongue orpharynx and looking for elevation and constriction of thepharyngeal muscles, which often produces a cough, gag,or swallow.This reflex may be difficult to do in intubat-ed patients or in those with an altered level of conscious-ness. It can also lead to aspiration pneumonia. The gagreflex may be an overrated test, and, given its potential forcausing problems, it is often skipped in the evaluation ofcomatose patients.

In testing the motor function of a comatose patient,inspection of muscle bulk and testing of muscle toneshould not be forgotten. Obviously, the comatose patientcannot cooperate with formal testing of the power of allmuscle groups, but some information regarding motorfunction can be deduced from some simple maneuvers.Watching for voluntary movements may show an asym-metry between the two sides. Reflexive posturing, eitherdecerebrate or decorticate, may indicate fairly severebrain injury. Reflexive withdrawal of the extremities topainful stimulation such as nail-bed pressure may be theonly way to see movement of the extremities.Testing themuscle stretch reflexes and evaluating plantar responsesare necessary.Asterixis, which is commonly sought in theupper extremities, may be indicative of a variety of meta-bolic encephalopathies or focal brain lesions. Testing ofsensation is often extremely limited except for gross eval-uation of responses to pain.

Despite what appears to be a limited neurologicexamination in the comatose patient, quite a bit of useful


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information can be gained. Often a tentative diagnosiscan be made on the basis of the examination alone. Forexample, for a patient with intact brainstem reflexes,symmetric spontaneous and induced movements of theface and extremities, and symmetric reflexes, the mostlikely cause of their coma would be a metabolic derange-ment that is affecting the brain diffusely. If the patient iscomatose, with bilateral papilledema, a unilateral CN IIIpalsy with a fixed and dilated pupil, and no movement ofthe contralateral body, one must be suspicious of a massor structural lesion.


Biller J. Practical neurology. 2nd ed. Philadelphia: LippincottWilliams and Wilkins; 2002.

DeMyer WE. Technique of the neurologic examination—aprogrammed text. 4th ed. New York: McGraw-Hill; 1994.

Guarantors of Brain. Aids to the examination of the peripheralnervous system. London: Baillière Tindall; 1986.

Haerer AF. Dejong’s - the neurologic examination. 5th ed.Philadelphia: JB Lippincott; 1992.

Orient JM. Sapira’s art and science of bedside diagnosis. 2nd ed.Philadelphia: Lippincott Williams and Wilkins; 2000.


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258

AAbdomen

examination of, 241Abducens nerve, 244Abducens nerve palsy, 42Abduction paresis

with Wernicke’s encephalopathy, 227Abscess

with coma, 52t, 53t, 57tepidural, 85, 86paraspinal, 85, 86–87

Absence status epilepticus, 64ACE

for hypertension, 161for ischemic stroke, 136, 146

Acetylcholine receptor (AChR), 95, 99Acinetobacter calcoaceticus, 203Acquired immunodeficiency syndrome

(AIDS)with Wernicke’s encephalopathy, 226t

Acute intermittent porphyria, 116, 117tAcute quadriplegic myopathy, 125–126Acyclovir

for encephalitis, 186AIDS

with Wernicke’s encephalopathy, 226tAirway management

generalized tonic-clonic statusepilepticus, 64

Airway obstructionwith neuromuscular respiratory failure,

91, 94Alcoholism, 85

with stroke, 141, 147with Wernicke’s encephalopathy,

220–233ALS, 89

pitfalls, 129–130respiratory involvement in, 128–129

Amantadinefor neuroleptic malignant syndrome,

175Aminoglycosides

contraindicated in myasthenia gravis,104

Ampicillinfor bacterial meningitis, 196, 199tfor Listeria monocytogenes meningitis,

204

Amyotrophic lateral sclerosis (ALS), 89pitfalls, 129–130respiratory involvement in, 128–129

Anemia, 112Aneurysm

anterior cerebral artery, 3fanterior communicating artery, 5berry, 9, 11–13internal carotid-posterior

communicator, 5mycotic, 10posterior fossa, 5

Angiotensin-converting enzyme (ACE)for hypertension, 161for ischemic stroke, 136, 146

Anisocoria, 47Ankle jerk, 249Anorexia

with giant cell arteritis, 23Anterior cerebral artery, 5, 143

ruptured aneurysm, 3fAnterior communicating artery

aneurysm, 5Antiplatelet therapy

for lacunar syndrome, 161for stroke, 159

Antithrombotic therapyfor stroke, 159

Apathywith Wernicke’s encephalopathy, 228

Apneustic breathing, 44–45Apomorphine

for neuroleptic malignant syndrome,177

Appetitewith giant cell arteritis, 21

Arboviral encephalitisdefined, 187

Arboviruses, 187geographic distribution of, 188t

Areflexiawith Guillain-Barre syndrome, 115

Armoutstretched

drift of, 4Arm pain

abrupt onset of, 5Arsenic poisoning, 116, 253Arterial blood gases

INDEX

for comatose patient, 48neuromuscular respiratory failure, 93

Arteriovenous malformation, 11Arthropod-borne virus, 187Aspiration

with neuromuscular respiratory failure,94

Aspiration pneumoniawith stroke, 155

Aspirinfor atherosclerosis, 160for stroke, 156, 159

Asterixis, 256Ataxia, 45Ataxic breathing, 254Atelectasis, 112


Atherosclerosiswith stroke, 140, 160–161

Ativanfor generalized tonic-clonic status

epilepticus, 67, 68tAtrial fibrillation, 241

with stroke, 141, 146Atrial tachycardia, 241Atropine, 97

intoxicationdilated and fixed pupils with, 42

Auscultation, 240Autoimmune disease

with myasthenia gravis, 95Autonomic instability

with neuroleptic malignant syndrome,170

Azathioprinefor myasthenia gravis, 109, 113for vasculitis, 161

BBabinski’s sign, 46, 48, 170, 249Bacillary meningitis

gram-negativetreatment of, 203

Back painabrupt onset of, 5

Bacterial meningitis, 8, 191–209antimicrobial therapy of, 198t–200tbrain damage pathogenic mechanisms,

205–209CSF, 192–197CT, 194, 195empiric therapy for, 196–197

laboratory diagnosis of, 192–196management of, 207f–208fMRI, 194PCR, 194

Barbiturate intoxicationsmall pupils with, 42

Basilar artery, 143occlusion, 59stroke, 145

Basilar skull fracturein comatose patient, 38

Battle’s sign, 236in comatose patient, 38

Bell’s palsy, 246Benign positional vertigo

mimicking stroke, 138tBenzodiazepines

causing neuroleptic malignantsyndrome, 169

for generalized tonic-clonic statusepilepticus, 67, 71

overdoseflumazenil for, 38

Benztropine mesylate, 167Berry aneurysm

ruptured, 9, 11–13Biot’s breathing, 45Bitter almond odor

with cyanide poisoning, 253Bladder

loss of control with headaches, 5Blepharospasm


Blinking, 44Blood patch

for post-lumbar puncture headache, 8Blood pressure

labilewith neuroleptic malignant

syndrome, 170Blood vessel

CT angiography, 158transcranial Doppler ultrasonography,

158Blurred vision

with botulism, 122Botulinum toxin


Botulism, 89, 121–124classic, 121clinical course of, 123

Index

259

clinical features of, 122diagnosis of, 122infant, 123–124management of, 122–123

Braincentral herniation, 46CT, 157uncal herniation, 46–48

Brain herniation syndromes, 45–48, 47f,56

CT, 56MRI, 56

Brainstem, 35, 143indicators of function, 38–39, 40f–41fstroke signs in, 144

Brainstem diseasesigns of, 46–47

Breathgarlic

with arsenic poisoning, 253shortness of

with neuromuscular respiratoryfailure, 90

Breathingapneustic, 44–45Biot’s, 45

Bromocriptinefor neuroleptic malignant syndrome,

168, 175Bronchiolar mucus plugging


Brown-Sequard’s syndrome, 78, 79fBrudzinski’s sign, 4, 38, 240

with bacterial meningitis, 191Buccofacial dyskinesia


Butterfly rash, 127

CCaffeine sodium benzoate

for post-lumbar puncture headache, 8Caloric testing, 255Campylobacter jejuni

with Guillain-Barre syndrome, 115,116

Carbamazepinecausing neuroleptic malignant

syndrome, 169Cardiac telemetry

with stroke, 158Cardioembolism

with stroke, 140Cardiovascular system

examination of, 241Carotid endarterectomy

with ischemic stroke, 147for stroke, 160

Carotid stenosisasymptomatic

with stroke, 141Cefepime

for bacterial meningitis, 196, 198tfor encephalitis, 186for pneumococcal meningitis, 202

Cefotaximefor bacterial meningitis, 196, 198t, 200tfor encephalitis, 185for gram-negative bacillary meningitis,

203for Haemophilus influenzae

meningitis, 204for meningococcal meningitis, 197for pneumococcal meningitis, 202

Ceftazidimefor gram-negative bacillary meningitis,

203Ceftriaxone

for bacterial meningitis, 196, 198tfor encephalitis, 186for gram-negative bacillary meningitis,

203for Haemophilus influenzae

meningitis, 205for meningococcal meningitis, 197

CEIfor myasthenia gravis, 100–102

Celfazidinefor bacterial meningitis, 200t

Central neurogenic hyperventilation, 44Cerebellar hematoma

CT, 211f, 213fdiagnosis of, 215–217

Cerebellar hemorrhage, 11with hypertension, 213–214

Cerebellar hemorrhage and infarction,210–219

cases of, 210–213management algorithm, 216fmanagement of, 217–219

Cerebellum, 142–143stroke signs in, 144

Cerebral arteryanterior, 5, 143

ruptured aneurysm, 3f

Index

260

posterior, 143, 145Cerebral edema, 54f

with coma, 53tCerebral herniation

with bacterial meningitis, 195Cerebrospinal fluid (CSF)

bloodyexamination of, 10

rhinorrhea or otorrheain comatose patient, 38

CerebrumCT, 212f

Cerebyx. See Fosphenytoin (Cerebyx)Cervical carotid artery, 240Cervical fractures

with coma, 43CT, 77MRI, 77respiratory arrest, 77

Chestexamination of, 240–241

Cheyne-Stokes respiration, 44, 46, 254China

motor axonal neuropathy in, 116Chloroquine


Cholesterol emboli (Hollenhorst plaque),244

Cholinergic crisis, 105t, 108Cholinesterase inhibitors (CEI)

for myasthenia gravis, 100–102Chorea


Cigarette smokingwith ischemic stroke, 133, 147with stroke, 141

Cimetidineprolonged paralysis from, 125

Classic botulism, 121Clopidogrel

for stroke, 159Clostridium botulinum, 121, 123–124Clostridium difficile, 112Clozapine


Clumsy hand-dysarthria syndrome, 145CN reflex tests, 255Coagulation times

with stroke, 158Cocaine, 124

with stroke, 158Coccidioidal meningitides, 4Coitus

headaches during, 13College freshmen

meningococcal meningitis, 201Colorado tick fever virus

geographic distribution of, 188tComa, 32–61

bihemispheric cause ofabnormal CT with nonoperable

lesions, 53tabnormal CT with operable lesions,

52tvs. brainstem, 35t, 38–39normal CT, 54t–55t

brain herniation syndromes, 45–48brainstem causes of

abnormal CT with nonoperablelesions, 58t

abnormal CT with operable lesions,57t

normal CT, 60tcase study of, 32–33cervical fractures with, 43CT, 49defined, 33, 254diagnosis and treatment algorithm,

50f–51fexamination of, 252–257general medical evaluation of, 36–38,

37flumbar puncture, 49, 59management of, 48–59motor responses, 45neurologic examination, 38–39,

40f–41freversible causes of, 38

Communicating arteryanterior

aneurysm, 5Complex partial status epilepticus, 64Computed tomography (CT)

brain herniation syndromes, 56cerebellar hematoma, 211f, 213fcerebrum, 212fcervical fractures, 77coma, 49, 52t–58t, 60tepidural abscess, 86ischemic stroke, 134, 134f, 136, 136fprior to lumbar puncture for

headaches, 8spinal cord tumors, 81

Index

261

Confusionwith neuroleptic malignant syndrome,

170with Wernicke’s encephalopathy, 221,

228Congestive heart failure, 112Conjugate gaze deficits

with Wernicke’s encephalopathy, 227Consciousness

anatomy of, 33–34defined, 33grading levels of, 36loss of with headaches, 2, 5

Constipationwith botulism, 122with Wernicke’s encephalopathy, 226t

Contrast agentsintravenous

contraindicated in myastheniagravis, 104

Corneal reflex, 255Coronary artery disease

with ischemic stroke, 133Cortex

left, 142right, 142

Cortical diseasebilateral, 34cause of, 34

Corticosteroidsfor giant cell arteritis, 27for myasthenia gravis, 102–103prolonged paralysis from, 125

Coughfor diaphragm function assessment, 92

Cough/gag, 44Counting test

for diaphragm function assessment, 92Cranial nerves

assessment of, 237tC-reactive protein

for giant cell arteritis, 23, 28for headaches, 2

Creatine kinasewith neuroleptic malignant syndrome,

171Crescendo transient ischemic attack

(TIA), 156–157Critical illness

myopathy, 125–126neuropathy, 126

Cryptococcal meningitides, 4CSF

bloodyexamination of, 10

rhinorrhea or otorrheain comatose patient, 38

CT. See Computed tomography (CT)Cushing’s syndrome, 241Cyanide poisoning, 253Cyclophosphamide

for vasculitis, 161Cytomegalovirus

with Guillain-Barre syndrome, 115

DDantrolene

for neuroleptic malignant syndrome,167–168, 175

Decerebrate posturing, 45Decorticate posturing, 45Dementia

with Wernicke’s encephalopathy, 226tDermatomyositis, 126–128

laboratory findings, 128Descending paralysis, 122Dexamethasone

for bacterial meningitis, 206Dexterity, 249Diabetes mellitus, 26, 85

with stroke, 141Diaphoresis


Diaphragmassessment of

with neuromuscular respiratoryfailure, 91–93

Diarrheawith Guillain-Barre syndrome, 115

Diazepam (Valium)for generalized tonic-clonic status

epilepticus, 67, 68tDiet

with ischemic stroke, 147Diffuse axonal injury

with coma, 60tDigitalis toxicity

with Wernicke’s encephalopathy, 226tDilantin

for generalized tonic-clonic statusepilepticus, 67, 71

Dilated pupilswith botulism, 122

Dioxymethamphetamine, 171Diplopia

Index

262

with botulism, 122with giant cell arteritis, 22

Diprivanfor generalized tonic-clonic status

epilepticus, 69t, 71Dipyridamole

for stroke, 159Disturbed sleep

with amyotrophic lateral sclerosis,128–129

Diuretic toxicitywith Wernicke’s encephalopathy, 226t

Dizzinesswith cerebellar hematoma, 215

Doll’s eye maneuver, 43, 255Dopamine

for pentobarbital burst suppression, 74Dopamine receptor blocking agents

adverse effects of, 168Doxycycline

for Rocky Mountain spotted fever,186, 188, 189

D-penicillaminecontraindicated in myasthenia gravis,

104Drug intoxication

with coma, 38, 55tDry mouth

with botulism, 122Dysarthria, 246

with botulism, 122Dyskinesia

buccofacialwith neuroleptic malignant

syndrome, 170Dysphagia

with botulism, 122with neuroleptic malignant syndrome,

170Dysphonia


Dyspneawith myasthenia gravis, 97with neuromuscular respiratory failure,

90Dystonia


EEastern equine encephalitis virus

geographic distribution of, 188t

Ecchymosesin comatose patient, 38

Ecstasy, 171Edrophonium test (Tensilon test)

for myasthenia gravis, 97–99Elderly

with giant cell arteritis, 23Electrolyte disturbances

with coma, 55tEmbolic amaurosis fugax, 21Encephalitis, 66, 182–189

case of, 182Endotracheal intubation

of comatose patient, 36, 48for generalized tonic-clonic status

epilepticus, 64for neuromuscular respiratory failure,

93–94Enterobacter, 203Enteroviral encephalitis, 189Epidural abscess, 85

CSF, 86CT, 86MRI, 86

Epidural hemorrhagewith coma, 52t

Epilepsia partialis continua, 64Epilepsy, 62Epstein-Barr virus

with Guillain-Barre syndrome, 115Erythrocyte sedimentation rate (ESR)


Escherichia coli, 193, 197, 203ESR


Exercisewith ischemic stroke, 147with myasthenia gravis, 96–97

Extensor plantar response, 4Extramedullary spinal cord tumors, 81,

83tExtremities

examination of, 241Eye movements

in comatose patient, 42–45

FFacial nerve, 245–246Fever

with bacterial meningitis, 190with giant cell arteritis, 22

Index

263

Index

264

with headache, 2with neuroleptic malignant syndrome,

170, 171Flumazenil (Romazicon)

for benzodiazepine overdose, 38, 49Fluphenazine

causing neuroleptic malignantsyndrome, 168–169

Focal motor status epilepticus, 64Folic acid

for hyperhomocysteinemia, 161Fosphenytoin (Cerebyx)

for generalized tonic-clonic statusepilepticus, 67, 68t, 69t, 71

Frisén scale of papilledema, 13, 17t

GGag reflex, 246, 256Gait

examination of, 252instability

with Wernicke’s encephalopathy,221

Garlic breathwith arsenic poisoning, 253

Gastric surgerywith Wernicke’s encephalopathy, 226t

Gastrointestinal cancerwith Wernicke’s encephalopathy, 226t

Gaze-evoked nystagmuswith Wernicke’s encephalopathy, 221

Gaze paresiswith cerebral hematoma, 217

GCA. See Giant cell arteritis (GCA)Generalized tonic-clonic status

epilepticus, 62–63cerebral spinal fluid, 66clonic phase, 7sf, 70fmanagement of, 64–74, 65fpost-ictal phase, 73f

Gentamicinfor bacterial meningitis, 196, 200tfor Listeria monocytogenes meningitis,

196, 204Giant cell arteritis (GCA), 2, 20–30, 240

clinical diagnosis of, 22–23diagnostic algorithm for, 24f–25flaboratory diagnosis of, 23–26signs of, 22symptoms of, 20–21treatment of, 27–28typical case of, 28

Gram-negative bacillary meningitis

treatment of, 200t,203Gram-negative bacilli, 200tGrilled foods

botulism, 121Group B streptococcus, 193Guillain-Barre syndrome, 89, 115–120,

118t–120tdiagnosis of, 115–116differential diagnosis of, 116, 117tpitfalls, 129treatment of, 116–117

HHaemophilus influenzae, 193

meningitis, 204Haloperidol

causing neuroleptic malignantsyndrome, 168–169

Headachesabrupt onset of worst, 2, 13with bacterial meningitis, 191changes in, 1–2de novo in patient over 50, 2, 22–23as emergency, 1–17with fever, 2with giant cell arteritis, 21, 22with leg weakness, 5long-standing, 4with loss of bladder control, 5with loss of consciousness, 2, 5lumbar puncture for, 5–8with neuromuscular respiratory failure,

91new, 1–2with subarachnoid hemorrhage, 5,

9–13with third nerve palsy, 5

Head and neck examination, 236–242Head trauma

with coma, 55t, 58tpapilledema with, 13

Heart valvesmechanical

with stroke, 141Heavy metal poisoning, 116, 117tHeliotrope rash, 127Hematocrit

with stroke, 158Hematogenous tumors

with Wernicke’s encephalopathy, 226tHematoma

cerebellarCT, 211f, 213f

Index

265

diagnosis of, 215–217Hemisphere

large unilateral lesions of, 35left

stroke signs in, 144right

stroke signs in, 144Hemodialysis

with Wernicke’s encephalopathy, 226tHemodynamic stability

of comatose patient, 36Hemoglobin

with stroke, 158Hemorrhage

cerebellar, 11, 210–219with hypertension, 213–214

epiduralwith coma, 52t

intracerebralwith coma, 52t, 58t

pontine, 59fsubarachnoid, 2, 10

with coma, 52twith headaches, 5vs. traumatic puncture, 12t

subduralwith coma, 52t

Hemorrhagic strokedefined, 137

Hemotympanumin comatose patient, 38

Heparinfor ischemic stroke, 136for stroke, 156–157

Hepatomegaly, 241Herniation

risk factors for in lumbar puncture formeningitis, 9t

Herpes simplex virus 1 (HSV-1)encephalitis, 182–189

CSF, 182, 185fEEG, 183MRI, 183, 185fPCR, 183

Herpesviruseswith Guillain-Barre syndrome, 115

Hexane toxicity, 116, 117tHip pain

with giant cell arteritis, 21, 22HIV, 85, 242

with Guillain-Barre syndrome, 115Hollenhorst plaque, 244Home-canned foods

botulism, 121Honey

botulism, 121Hospitalization

myasthenia gravis, 97HSV-1. See Herpes simplex virus 1

(HSV-1) encephalitisHuman immunodeficiency virus (HIV),

85, 242with Guillain-Barre syndrome, 115

Hydrocephaluswith cerebellar hematoma, 213–214,

218with coma, 52t, 57t

Hypercarbiawith neuromuscular respiratory failure,

91Hypercholesterolemia

with ischemic stroke, 146Hypercoagulation

with stroke, 158Hyperemesis gravidarum

with Wernicke’s encephalopathy, 226tHyperglycemia

with stroke, 155Hyperhomocysteinemia

with stroke, 161Hyperlipidemia

with stroke, 141, 161Hypertension, 253

with cerebellar hemorrhage, 213–214with stroke, 133, 139, 141, 146, 161

Hyperthermia, 253with stroke, 155

Hyperventilation, 254central neurogenic, 44

Hypoglossal nerve, 247Hypoglycemia

in comatose patient, 38with generalized tonic-clonic status

epilepticus, 66Hypoglycorrhachia, 10Hypoperfusion

with stroke, 140, 161Hyporeflexia

with Guillain-Barre syndrome, 115Hypotension, 253

with stroke, 154with Wernicke’s encephalopathy, 229

Hypothermia, 253with Wernicke’s encephalopathy, 228

Hypotonic intravenous solutionscontraindicated in stroke, 156

Hypoventilation, 254with neuromuscular respiratory failure,

91Hypoxemia


Hypoxiawith coma, 55t

IIleus

with botulism, 122Illicit drug use

with stroke, 158Inclusion body myositis, 126–128

laboratory findings, 128Infant botulism, 123–124Infection, 26

mimicking stroke, 138tInflammatory myopathies, 126–128

diagnosis of, 126–127examination of, 127laboratory findings, 127–128

Intensive care patientacute weakness in, 124–125

Interferoncontraindicated in myasthenia gravis,

104Internal carotid-posterior communicator

aneurysm, 5Intracerebral hemorrhage

with coma, 52t, 58tIntracranial pressure

bacterial meningitis, 195Intramedullary spinal cord tumors, 82–84

prognosis of, 84Intravenous contrast agents


Intravenous feedingswith Wernicke’s encephalopathy, 226t

Intravenous immunoglobulin (IVIg)for Guillain-Barre syndrome, 117for myasthenia gravis, 103–104,

110–111Intubation. See Endotracheal intubationIrregular pulse, 241Ischemic infarct

with coma, 52t–54t, 57t, 58t, 60tIschemic penumbra, 150fIschemic stroke, 133–162, 242

causes of, 139–140conditions mimicking, 138t

CT, 134, 134f, 136, 136fdefined, 137ECG, 134emergency care of, 147–154epidemiology of, 137–138incidence of, 138neuroanatomy, 142–143risk factors for, 139–142thrombolytic therapy for, 134–135t-PA for, 135, 147–150, 149f, 152–154transthoracic echocardiogram, 135

IVIgfor Guillain-Barre syndrome, 117for myasthenia gravis, 103–104,

110–111

JJapanese encephalitis virus

geographic distribution of, 188t

KKaposi’s sarcoma, 242Kernig’s sign, 4, 38, 240Kernohan-Woltman phenomenon, 48Klebsiella pneumoniae, 197, 203Knee jerk, 249Korsakoff ’s psychosis, 229

LLabile blood pressure


La Crosse encephalitisribavirin, 189

La Crosse virusgeographic distribution of, 188t

Lacunar syndromewith stroke, 161

Latent strabismus, 42Left cortex, 142Left hemisphere

stroke signs in, 144Left middle cerebral artery stroke, 144Legs

abrupt onset of pain, 5weakness with headaches, 5

Lethargywith bacterial meningitis, 191with Wernicke’s encephalopathy, 228

Leukemia, 85Limb ataxia

with cerebellar hematoma, 215Listeria monocytogenes, 196, 197, 200t

Index

266

meningitis, 204Livedo reticularis, 242Lorazepam (Ativan)

for generalized tonic-clonic statusepilepticus, 67, 68t

Lumbar puncturecontraindications to, 10, 11tCT prior to, 8for headaches, 5–8in meningitis

risk factors for uncal and cerebellarherniation, 9t

needle placement, 6–7patient positioning, 5–6patient preparation for pressure

measurement, 7–8site preparation, 6

Lymphomawith Guillain-Barre syndrome, 115with Wernicke’s encephalopathy,

226t

MMagnesium

prolonged paralysis from, 125for Wernicke’s encephalopathy, 231

Malaisewith giant cell arteritis, 22

Malaria, 241Malignancy, 26Mannitol

for brain herniation, 56Mastoid processes, 240Mechanical heart valves

with stroke, 141Mechanical ventilation

for comatose patient, 48of comatose patient, 36for generalized tonic-clonic status

epilepticus, 64for neuromuscular respiratory failure,

93–94MenC polysaccharide vaccine, 201Meningeal irritation

signs of, 38Meningismus

with bacterial meningitis, 191Meningitides

coccidioidal, 4cryptococcal, 4

Meningitis, 4, 13, 66. See also Bacterialmeningitis

lumbar puncture in

risk factors for uncal and cerebellarherniation, 9t

meningococcal, 191, 242college freshmen, 201therapy of, 197–201

pneumococcal, 191treatment of, 202

staphylococcustreatment of, 203

Streptococcus agalactiaetreatment of, 204

Meningococcal meningitis, 191, 242college freshmen, 201therapy of, 197–201

Meningococcemia, 189Meningoencephalitis

with coma, 54t, 60tMental confusion

with giant cell arteritis, 21Mental status

assessment of, 237tMeropenem

for pneumococcal meningitis, 202Mestinon

for myasthenia gravis, 101, 113Metabolic acidosis

with generalized tonic-clonic statusepilepticus, 66

with prolonged paralysis, 125Metastases

affecting spinal cord, 80–823,4-methylene-dioxymethamphetamine

(Ecstasy), 171Methylphenidate


Methylprednisolonefor giant cell arteritis, 30for transverse myelitis, 85for traumatic spinal injury, 80

Midazolam (Versed)for generalized tonic-clonic status

epilepticus, 67, 68t, 71Middle cerebral artery, 143, 144Miller Fisher syndrome, 116Monocular visual loss

abrupt onset of, 2Motor axonal neuropathy

in China, 116Motor function

assessment of, 237t–238tMotor responses

coma, 45

Index

267

Motor vehicle accidents, 76Motor weakness

with Guillain-Barre syndrome, 115Mouth

drywith botulism, 122

MSS, 110Multiple sclerosis, 84Muscle power, 248

grading of, 248tMuscle relaxants

prolonged paralysis from, 125Muscle stretch reflex, 249

abnormalities with neurolepticmalignant syndrome, 170

grading of, 250tMuscular dystrophy, 89Muscular rigidity


Myasthenia gravis, 89–115, 95–100acutely deteriorating, 105tcholinesterase inhibitors, 100–102clinical features of, 96–97eletrophysiologic tests for, 99–100hospitalization, 97medications exacerbating, 104, 106tpitfalls, 130serologic tests for, 99treatment of, 100–114

Myasthenic crisis, 104–108, 105ttreatment of, 107–108

Myasthenic muscular score (MSS), 110Mycoplasma

with Guillain-Barre syndrome, 115Mycotic aneurysm

ruptured, 10Myridostigmine

for myasthenia gravis, 113

NNafcillin

for bacterial meningitis, 199tNaloxone (Narcan)

for narcotic overdose, 38, 49Narcan

for narcotic overdose, 38, 49Narcotic overdose

naloxone for, 38, 49National Institutes of Health Stroke Scale,

133Nausea

with bacterial meningitis, 191

Neckexamination of, 236–242pain

abrupt onset of, 5with giant cell arteritis, 21

stiff, 4with bacterial meningitis, 191

stiffness on forward bending, 38Neisseria meningitidis, 186, 191, 193, 197,

199t, 201, 202Nembutal

for generalized tonic-clonic statusepilepticus, 69t, 71

side effects of, 71–74Nerve fiber layer infarcts, 13Neurofibroma

of spinal cord, 82Neurofibromatosis, 81–82Neuroleptic malignant syndrome,

167–178, 247clinical features of, 170–174demographics of, 168ECT, 177etiology of, 168–170risk factors for, 168–170treatment algorithm for, 172f–173ftreatment of, 174–178

Neurologic examination, 236–257with altered levels of consciousness,

239tcomprehensive, 242–252guidelines for, 237t–238thead and neck examination, 236–242

Neuromuscular blockersprolonged paralysis from, 124–125

Neuromuscular diseaserespiratory failure due to, 89–130

Neuromuscular respiratory failure, 89–130clinical patterns of, 95–100examination, 91–93patient evaluation, 90–91precipitating factors, 94–95respiratory muscle weakness and

fatigue, 90New headaches, 1–2Night sweats

with giant cell arteritis, 22, 23with serotonin reuptake inhibitors, 22

Nitrofurantoin neurotoxicity, 116, 117tNonconvulsive status epilepticus, 63Nonsteroidal antiinflammatory drugs

erythrocyte sedimentation rate, 23Nose

Index

268

examination of, 236–237Nystagmus

gaze-evokedwith Wernicke’s encephalopathy,

221

OOcular motility

examination, 4impaired

with Wernicke’s encephalopathy,221

Oculocephalic reflex, 255Oculogyric crises


Oculomotor nerve, 244, 245palsy, 42

Oculovestibular reflex, 43Olanzapine


Ophthalmoplegiawith Wernicke’s encephalopathy, 227

Opiate intoxicationpinpoint pupils with, 42

Optic disksswelling of, 13

Optic nerveexamination of, 243swollen, 4

Optic neuritis, 13Optic neuropathy

with giant cell arteritis, 22, 29fOropharyngeal weakness


Osteoporosis, 28Otoscopy, 240Over 50

giant cell arteritis in, 21, 22headaches arising de novo, 2

Oxygenfor generalized tonic-clonic status

epilepticus, 64

PPain

arm, 5back, 5hip, 21, 22with intramedullary spinal cord

tumors, 83

leg, 5neck, 5, 21with paraspinal abscess, 86–87shoulder, 21testing of, 250

Pancuroniumcontraindicated in myasthenia gravis,

104Papilledema, 4, 244

Frisén scale of, 13, 17tgrade I, 15fgrade II, 15fgrade III, 16fgrade IV, 16fgrade V, 17fwith head trauma, 13recognition of, 13

Paradoxical abdominal wall movementfor diaphragm function assessment, 92

Paralysisdescending, 122

Paranoid delusions, 167Paraplegia, 85Paraspinal abscess, 85, 86–87Parinaud’s syndrome, 43Parkinson’s disease


Penicillaminecontraindicated in myasthenia gravis,

104Penicillin G

for bacterial meningitis, 199t, 200tfor meningococcal meningitis, 197for meningococcemia, 189

Pentobarbital (Nembutal)for generalized tonic-clonic status

epilepticus, 69t, 71side effects of, 71–74

Periungual edema, 127Pernicious anemia

with myasthenia gravis, 95Phenobarbital


Phenylephrinefor pentobarbital burst suppression, 74

Phenytoin (Dilantin)for generalized tonic-clonic status

epilepticus, 67, 71Photophobia

with bacterial meningitis, 191Pituitary apoplexy

Index

269

with subarachnoid hemorrhage, 10Plantar response, 249Plasma exchange

for myasthenia gravis, 103, 108–114Plasmapheresis

for Guillain-Barre syndrome, 117PMR, 20Pneumococcal meningitis, 191

treatment of, 202Pneumocystis carinii pneumonia, 204Pneumonia

aspirationwith stroke, 155

with bacterial meningitis, 191Pneumocystis carinii, 204

Poisoning, 117t, 166, 253thallium, 116

Polymyalgiawith giant cell arteritis, 21

Polymyalgia rheumatica (PMR), 20Polymyositis, 126–128

laboratory findings, 128Pontine hemorrhage, 59fPontine infarct, 58fPosterior cerebral artery, 143Posterior cerebral artery stroke, 145Posterior fossa

aneurysm in, 5Postictal

with coma, 55tvs. nonconvulsive status epilepticus,

63–64Post-lumbar puncture headache, 8Posturing, 45


Powassan virusgeographic distribution of, 188t

Prednisolonefor myasthenia gravis, 113

Prednisonefor giant cell arteritis, 27–28for myasthenia gravis, 109

Premature atrial contractions, 241Premature ventricular contractions, 241Procainamide


Proctitisradiation

with Wernicke’s encephalopathy,226t

Propofol (Diprivan)


Proprioceptiontesting of, 251

Pseudomonas aeruginosa, 200t, 203Ptosis, 245

with botulism, 122with Wernicke’s encephalopathy, 227

Pulseirregular, 241

Pulse oximetryfor comatose patient, 48

Pupillary light reflex, 243–244Pupils

in central brain herniation, 46constriction of, 4dilated, 245

with botulism, 122dilated and fixed

with atropine intoxication, 42examination of

in comatose patient, 39–42light reactivity, 39pinpoint

with opiate intoxication, 42size of, 39small

with barbiturate intoxication, 42unilateral constriction of, 4unilaterally enlarged

with brainstem disorder, 42Pure motor stroke, 145Pure sensory stroke, 145Pyloric stenosis

with Wernicke’s encephalopathy,226t

Pyridostigmine (Mestinon)for myasthenia gravis, 101, 113

Pyrithiamine, 223

QQuadriplegia, 85Quetiapine


Quinidinecontraindicated in myasthenia gravis,

104Quinine


toxicity with Wernicke’sencephalopathy, 226t

Index

270

RRaccoon eyes, 236

in comatose patient, 38Radiation proctitis

with Wernicke’s encephalopathy, 226tRadicular artery of Adamkiewicz

thrombosis of, 78RAPD, 244Rash

butterfly, 127differential diagnosis of, 189heliotrope, 127

Raspy voicewith neuromuscular respiratory failure,

91Raves, 171Reflexes

assessment of, 238tasymmetry of, 4

Reflexive posturing, 256Reflexive withdrawal, 256Relative afferent pupillary defect

(RAPD), 244Repetitive stimulation

for botulism, 122Respiratory arrest

cervical fractures, 77Respiratory failure. See also

Neuromuscular respiratory failurewith myasthenic crisis, 107

Respiratory muscleneuromuscular respiratory failure, 90

Restwith myasthenia gravis, 96–97

Reticular activating system, 33, 34f, 35Rhabdomyolysis

with generalized tonic-clonic statusepilepticus, 66

Rheumatoid arthritiswith myasthenia gravis, 95

Rhythm stripwith stroke, 158

Ribavirinfor La Crosse encephalitis, 189

Rickettsia rickettsii, 189Right cortex, 142Right hemisphere

stroke signs in, 144Right middle cerebral artery stroke, 145Rigidity, 247


Risperidone, 167


Rock Mountain spotted fever, 189, 242doxycycline for, 189

Romaziconfor benzodiazepine overdose, 38, 49

Romberg’s testing, 4

SSarcoidosis

with Guillain-Barre syndrome, 115Scalp, 240

erythematouswith giant cell arteritis, 22

tenderwith giant cell arteritis, 21, 22

Schizophrenia, 167Seizures, 62–74

mimicking stroke, 138tSelective serotonin inhibitors


Sensationassessment of, 238t

Sensorimotor stroke, 146Serotonin reuptake inhibitors

night sweats with, 22SFEMG

for myasthenia gravis, 99–100Shortness of breath


Shoulder painwith giant cell arteritis, 21, 22

Sialorrheawith neuroleptic malignant syndrome,

170Single-fiber electromyography (SFEMG)

for myasthenia gravis, 99–100Skin

examination of, 241–242Sleep

disturbedwith amyotrophic lateral sclerosis,

128–129with neuromuscular respiratory failure,

90–91Slurred speech

with ischemic stroke, 133Smoking

with ischemic stroke, 133, 147with stroke, 141

Somnolent patients

Index

271

grading consciousness in, 36Spastic hemiplegia, 45Spasticity, 247Speech

slurredwith ischemic stroke, 133

Spinal accessory nerve, 246Spinal cord

emergency conditions, 76–87infectious and inflammatory disorders

of, 84–87trauma, 76–80tumors, 80–82

CT, 81extramedullary, 81, 83tintramedullary, 82–84metastatic compressing, 82tMRI, 81radiotherapy, 81

Spine immobilization, 77examination of, 241

Spirometryfor diaphragm function assessment,

92–93Splenomegaly, 241St. Louis encephalitis virus

geographic distribution of, 188tStaphylococcus aureus, 203Staphylococcus meningitis

treatment of, 203Starvation

with Wernicke’s encephalopathy, 226tStatins

for hyperlipidemia, 161Status epilepticus, 56f, 62–74. See also

Generalized tonic-clonic statusepilepticus

absence, 64clinical features of, 62–64with coma, 55tcomplex partial, 64EEG, 63focal motor, 64incidence of, 62nonconvulsive, 63

Sternocleidomastoid muscle, 240Steroids

for vasculitis, 161Stiff neck, 4

with bacterial meningitis, 191Strabismus

latent, 42Streptococcus agalactiae, 197, 200t

meningitis, 203–204Streptococcus pneumoniae, 186, 191, 193,

198t, 202Stroke. See also Ischemic stroke

ECG, 158emergency care of, 154–157hemorrhagic

defined, 137laboratory evaluation, 157–158practical emergency care of, 151–154primary prevention of, 146–147pure motor, 145risk factors, 158–159secondary prevention of, 159–160sensorimotor, 146signs of

public education for, 147Stroke syndrome, 143–146Stupor

defined, 36Subarachnoid hemorrhage, 2, 10

with coma, 52t, 55t, 60twith headaches, 5, 9–13vs. traumatic puncture, 12t

Subcortical areas, 142Subdural hematoma, 53fSubdural hemorrhage

with coma, 52tSuccinylcholine, 104Sympathomimetic drugs

with stroke, 142Syncope

mimicking stroke, 138tSyringomyelia, 83, 84Systemic lupus erythematosus, 84, 85

with myasthenia gravis, 95

TTachycardia


Tachypneawith neuroleptic malignant syndrome,

170Temporal arteries, 240

biopsy for giant cell arteritis, 26–27biopsy for headaches, 2palpation of, 4

Temporal arteritis. See Giant cell arteritis(GCA)

Tensilon testfor myasthenia gravis, 97–99

Thallium poisoning, 116

Index

272

Thiamine, 223deficiency, 38, 116, 117tfor Wernicke’s encephalopathy, 231

Thiamine pyrophosphate (TPP), 223Thiazide diuretic

for ischemic stroke, 136Thigh pain

with giant cell arteritis, 21Third nerve palsy

with headaches, 5Thymic lymphoid hyperplasia

with myasthenia gravis, 96Thymoma

with myasthenia gravis, 96Thyroid disease

with myasthenia gravis, 96TIA, 139, 156–157

crescendo, 156–157with stroke, 141

Tick paralysis, 116, 117tTiclopidine

for stroke, 159Tissue plasminogen activity (t-PA)

for ischemic stroke, 135, 147–150, 149fadministration of, 152–154, 153t

Tolazamide toxicitywith Wernicke’s encephalopathy, 226t

Tomatoesbotulism, 121

Total parenteral nutritionwith Wernicke’s encephalopathy, 226t

t-PA. See Tissue plasminogen activity (t-PA)

TPP, 223Transient ischemic attack (TIA), 139

crescendo, 156–157with stroke, 141

Transverse myelitis, 84–85CSF, 85MRI, 85

Transverse myelopathy, 84–85Traumatic puncture

vs. subarachnoid hemorrhage, 12tTricyclic antidepressants


intoxicationdilated and fixed pupils with, 42

Trigeminal nerve, 245Trimethoprim-sulfamethoxazole

for bacterial meningitis, 197Trochlear nerve, 244Tuberculosis, 4

Tumorsaffecting spinal cord, 80–82with coma, 57t

UUnconsciousness

with cerebral hematoma, 217with neuroleptic malignant syndrome,

170Uremia

with Wernicke’s encephalopathy, 226tUrinary retention


VVaccine

MenC polysaccharide, 201Valium

for generalized tonic-clonic statusepilepticus, 67, 68t

Vancomycinfor bacterial meningitis, 198t, 199tfor encephalitis, 186for pneumococcal meningitis, 202for staphylococcus meningitis, 203

Vasculitiswith stroke, 161

Vecuroniumcontraindicated in myasthenia gravis,

104Venezuelan encephalitis virus

geographic distribution of, 188tVenous sinus thrombosis

with coma, 55tVentriculostomy

for cerebellar hematoma, 219Versed

for generalized tonic-clonic statusepilepticus, 67, 68t, 71

Vertebral artery, 143stroke, 145

Vertigobenign positional

mimicking stroke, 138tVestibulocochlear nerve, 246Vibration

testing of, 251Vision

blurredwith botulism, 122

Visual acuityexamination of, 243

Index

273

Visual fieldexamination of, 243

Visual losswith giant cell arteritis, 21, 22monocular

abrupt onset of, 2Voice

raspywith neuromuscular respiratory

failure, 91Vomiting

with bacterial meningitis, 191with Wernicke’s encephalopathy, 226t

WWall-eyed, 43Warfarin

for cardioembolism, 161for stroke, 160

Weight losswith giant cell arteritis, 21, 23with ischemic stroke, 147

Wernicke’s encephalopathy, 220–233,220f, 253

cases of, 220–221clinical manifestations of,

225–229clinical signs of, 227fepidemiology of, 224–225ETK, 230eye signs of, 228fFLAIR, 230illnesses associated with, 226tlaboratory studies, 230–231neuroimaging, 229–230neuropathology, 222pathogenesis of, 223–224prevention of, 233treatment algorithm for, 232ftreatment of, 231–232

West Nile encephalitis, 189West Nile virus

geographic distribution of, 188tWound botulism, 124

Index

274

basic neurologic life support

Documents

ba cter ial

magnetic resonance imaging

quality standards subcommittee

neuroleptic malignant syndrome

tenuous venous access

international normalized ratio

giant cell arteritis

west nile virus