altered mental status - loyola medicine · 2017. 7. 6. · altered mental status vanja c. douglas,...

Altered Mental StatusVanja C. Douglas, MD; S. Andrew Josephson, MD

ABSTRACTPurpose of Review: Altered mental status is a common reason for neurologicconsultation. Although it is often due to a systemic infection or metabolic derange-ment, a host of other etiologies can lead to irreversible brain injury if they are notpromptly identified and treated. A systematic approach to the patient is important,with an understanding of when to initiate a more advanced and potentially moreresource-intense diagnostic workup.Recent Findings: The last decade has seen advances in both the diagnosis andtreatment of altered mental status. A significant step forward in the diagnosis ofpatients with otherwise unexplained encephalitis has been the identification ofnumerous antibodies associated with paraneoplastic and nonparaneoplastic auto-immune encephalitis. The use of continuous electroencephalography has shown that asignificant proportion of otherwise unexplained altered mental status may be causedby nonconvulsive seizures. Several studies have demonstrated that proactive, multi-component interventions may be effective in preventing hospital-acquired delirium.The recent introduction of dexmedetomidinemay lead to decreased rates of delirium inthe intensive care unit if the results of clinical trials are borne out in practice.Summary: This article discusses causes of altered mental status, an initial approach toevaluating the patient, and elements of the advanced diagnostic workup. The articleconcludes with a general discussion of prevention and treatment.

Continuum Lifelong Learning Neurol 2011;17(5):967–983.

INTRODUCTIONAltered mental status is broadly definedas a change in cognitive function or levelof consciousness. It is a common reasonfor emergency department visits, hospi-talization, and neurology consultation.As many as 5% to 10% of emergencydepartment patients have altered men-tal status, with significantly higher ratesamong the elderly; over half of thesepatients are admitted to the hospital.1,2

Mortality rates for these patients arehigh, approaching 10% in some studies.2

Studies of delirium, which represents alarge subset of patients with alteredmental status, consistently report a prev-alence of 10% to 31% among elderlypatients who are hospitalized, with ratesapproaching 80% in the intensive careunit.3,4 At our hospital, approximately

15% of neurology consult requests arefor altered mental status.

The differential diagnosis for alteredmental status is broad and includes life-threatening yet treatable conditions;therefore, a systematic approach to thepatient is necessary. Most internal medi-cine hospitalists and emergency de-partment physicians are comfortableperforming the initial workup, and neu-rologists are usually consulted onlywhen a focal lesion is suspected orno immediate cause can be found. Thisarticle briefly discusses the initialapproach to the patient with alteredmental status and then delves into amore detailed discussion of the ad-vanced workup and less common diag-noses with which the neurologist shouldbe familiar.

Address correspondence toDr Vanja C. Douglas, UCSFDepartment of Neurology, Box0114, 505 Parnassus AvenueM798, San Francisco, CA 94143,[email protected] Disclosure:Dr Douglas has served aseditor-in-chief of TheNeurohospitalist and hasreceived personalcompensation for medicalrecord review and expertwitness testimony.Dr Josephson has receivedpersonal compensation foreditorial activities from Annalsof Neurology and JournalWatch Neurology.Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Douglas discusses the useof antipsychotics for thetreatment of agitated delirium.Dr Josephson reports nodisclosure.Copyright * 2011, AmericanAcademy of Neurology.All rights reserved.

967Continuum Lifelong Learning Neurol 2011;17(5):967–983 www.aan.com/continuum

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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DEFINITIONS ANDLOCALIZATIONIn their landmark monograph, Posnerand Plum describe consciousness ashaving two components: content andarousal.5 The content of consciousnessrefers to the higher-level cortical pro-cessing that allows for awareness of selfand environment and enables interac-tion with that environment. In the cur-rent conception of brain function, theseprocesses are understood to be carriedout by cortical regions and more wide-spread neuronal networks. For exam-ple, the ability to recognize both writtenand oral language, interpret its mean-ing, and produce speech is a part ofconsciousness usually served by regionsin the left temporal and frontal lobesand their connections. A focal lesion inone of these regions may lead to achange in the content of consciousnessbut will not affect arousal.

Arousal refers to the level of alertness.Pathologic states of arousal range fromcoma, a state of complete unresponsive-ness without eye opening, to drowsi-ness, in which a patient is arousable butneeds stimulation to stay awake, to hy-pervigilance, where patients are awakebut unable to focus their attention andare easily distracted by extraneous stim-uli. If such patients are able to commu-nicate, they almost universally have adeficit of attention and appear disori-ented and confused. Arousal is main-tained by various systems of neurons,most of which are located in the brain-stem, hypothalamus, basal forebrain,and thalamus and project diffuselythroughout the cortex.5 A lesion inter-rupting these projections in the brain-stem, bilateral thalami, or diffusely inboth hemispheres can lead to changesin level of arousal.

Altered mental status is a broadly in-clusive term used to describe a patientwith a change in either the content ofconsciousness or the level of arousal.

Encephalopathy is also a nonspecificterm, often used interchangeably withaltered mental status, which implies adiffuse process causing a change in thelevel of arousal. The termwill be used inthis manner throughout this article.Delirium is a more specific term, de-fined as an acute change in mentalstatus characterized by a deficit in at-tention and a fluctuating course witheither disorganized thinking or changein the level of arousal.6 Most changesin the content of consciousness, suchas aphasia or neglect, are readily dis-cernible upon examination, and suchpatients are usually easily triaged. Oc-casionally, however, a focal deficit maybe misclassified as delirium by an in-experienced clinician; conversely, delir-ium may rarely be caused by a focallesion. In addition, some processes maycause both focal deficits and delirium.Examples are basilar meningitis or alarge hematoma with mass effect lead-ing to hemiparesis and decreased re-sponsiveness. The neurologist’s task isto take a careful history and perform adetailed physical examination in orderto make these distinctions and direct anappropriate workup.

INITIAL APPROACH TOTHE PATIENTThe first step in the evaluation of apatient with altered mental status is toestablish the time course. Acute alteredmental status is a medical emergency. Apatent airway and intact circulation mustbe ensured, followed by measurementof vital signs and serum glucose. A fo-cused neurologic examination is imper-ative to rule out structural lesions, suchas a large stroke or hemorrhage, requir-ing emergent management. Naloxoneshould be administered if narcotic over-dose is suspected; thiamine and glucoseare also given routinely. Thiamineshould always be administered with orbefore glucose to avoid precipitation of

KEY POINTSh Altered mental status is

found in up to 10% ofemergency departmentpatients and is acommon reason forhospital admission.Patients with alteredmental status have ahigh mortality rate.

h Altered mental statusresults from a change ineither the content ofconsciousness or thelevel of arousal.

h Naloxone can beboth diagnostic andtherapeutic whenopiate overdose issuspected. Thiamineadministration shouldbe considered in allpatients with alteredmental status because itis benign and Wernickeencephalopathy isreversible iftreated promptly.

968 www.aan.com/continuum October 2011

Altered Mental Status


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Wernicke encephalopathy. Once thepatient is stabilized, further data gather-ing can be initiated (Table 1-1).

After the time course is established,the history should focus on determina-tion of baseline cognitive function andwhether any previous episodes of alteredmental status have occurred. Other im-portant elements of the history include

symptoms of infection such as fever,headache, stiff neck, cough, or dysuria;current medications and recent medica-tion changes; recreational drug and al-cohol use; and history of recent trauma.Specific attention should be paid tomedications known to cause delirium,such as those with anticholinergic prop-erties, benzodiazepines, and narcotics.7

TABLE 1-1 Basic Approach to Altered Mental Status

b Step 1 (All Patients)

Airway, breathing, and circulation; vital signs; blood glucose level

If glucose is low, administer thiamine and dextrose; consider naloxone inthe event of a possible opiate overdose

b Step 2 (All Patients)

History (special attention to baseline cognitive status, medications,symptoms of infection)

Physical examination (special attention to signs of infection; carefulneurologic examination to rule out a focal deficit)

Complete blood count, electrolyte panel including calcium, magnesium,and phosphorus

Liver and kidney function tests, including albumin

Urinalysis and culture, urine toxicology screen

Chest radiograph

ECG

b Step 3 (Guided by Findings on the Initial Evaluation)

Brain imaging with CT followed by MRI with diffusion and gadolinium ifthe cause remains unclear

Lumbar puncture (perform immediately after CT if meningitis is suspected;probably underused in patients presenting to medical care withaltered mental status; usually not necessary for hospital-acquiredencephalopathy unless the patient is immunocompromised or neurosurgical)

b Step 4 (Guided by Findings on the Initial Evaluation)

Serum ammonia, thyroid function tests, morning cortisol, vitamin B12,arterial blood gas

Sedimentation rate, autoimmune serologies including antinuclearantibodies, thyroperoxidase, and thyroglobulin antibodies

Blood cultures

Extended toxicology screen

EEG (perform sooner if high suspicion for status epilepticus)



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A history of comorbid conditions thatcould contribute to altered mental sta-tus (such as cirrhosis, chronic kidneydisease, chronic obstructive pulmonarydisease, epilepsy, psychiatric disease, orimmune compromise [including HIVinfection]) should be sought.

The general physical examinationshould focus on potential medical causesof alteredmental status. The head shouldbe examined for signs of trauma. Percus-sion and auscultation of the lungs mayreveal evidence of pneumonia or chronicobstructive pulmonary disease. Examina-tion of the heart and extremities mayshow signs of endocarditis or congestiveheart failure. Inspection of the skin candemonstrate signs of liver disease orneedle marks indicating injection drugabuse. The presence of asterixis maypoint toward metabolic encephalopathy.Signs of meningitis should be sought,including meningismus and the pete-chial rash associated with meningococ-cemia. However, the decision regardingwhether to pursue a lumbar punctureshould never rest solely on the presenceor absence of meningismus, becauseseveral studies suggest nuchal rigidity,Kernig sign, and Brudzinski sign areinsensitive.8Y10 Even jolt accentuation ofheadache (worsening of headache uponpassive head turning at 2 to 3 rotationsper second), touted as having a highsensitivity for meningitis in its originaldescription, was found to be very in-sensitive in a subsequent study.8,10

More critical for the neurologist is acareful search for a focal deficit. Patientswith psychosis are usually oriented andhave normal attention despite the pres-ence of delusions, hallucinations, anddisorganized thinking. Several strokesubtypes can present with changes inmental status ranging from abulia (inthalamic or orbital frontal infarcts) toagitation (in posterior cerebral arteryinfarcts and nondominant parietal lobeinfarcts) to Wernicke aphasia (which

can be initially mistaken for psychosisor delirium in left middle cerebral arteryinfarcts) to coma (with basilar arteryocclusion). The focal signs that usuallyaccompany such lesions may be over-looked by the non-neurologist. Focaldeficits accompanying altered mentalstatus may also be seen in lesions caus-ing mass effect or hydrocephalus orin those associated with meningitis. Incases where a focal deficit is found,brain imaging is mandatory. If a largevessel occlusion is suspected, vascularimaging with CT or magnetic resonanceangiography should also be performed.

The final part of the initial evaluationinvolves laboratory testing to rule outmetabolic derangements and commoninfections that lead to altered mentalstatus. This includes a complete bloodcount; measurement of electrolytes in-cluding calcium, magnesium, and phos-phorous; and tests of renal and liverfunction. Urine should be analyzed forinfection and drugs of abuse. An arterialblood gas may be helpful in revealinghypoxia or hypercarbia; a potential clueto the latter is an elevated bicarbon-ate concentration in the routine bloodchemistry suggesting chronic respira-tory acidosis. A chest x-ray may be help-ful if pneumonia is suspected. Becausemyocardial infarction can present withaltered mental status in the setting ofcardiogenic embolism or systemic hypo-tension, an ECG should be considered.

SUBSEQUENT EVALUATIONIf the cause of alteredmental status is notapparent after the initial workup, addi-tional testing may be necessary becauseof the large variety of treatable etiolo-gies (Table 1-2). However, an extensiveworkup for altered mental status is ex-pensive, can cause iatrogenic complica-tions, and may be unnecessary in somecases. Therefore, appropriate selectionof patients for further workup is critical.

KEY POINTSh The history should focus

on the time course,baseline cognitivefunction, medicationuse (includingover-the-counter drugsand herbals), alcoholand drug abuse,symptoms of infection,and recent trauma.

h A careful neurologicexamination is requiredin patients with alteredmental status to ruleout a focal deficit, thepresence of whichshould prompt urgentneuroimaging.

h The most significant riskfactors for delirium areadvanced age andpreexisting cognitivedysfunction.




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For patients with delirium with clearrisk factors and an obvious precipitant,workup beyond the initial approach de-scribed above may not be necessary.Delirium is theorized to occur in the set-ting of decreased cerebral reserve, result-

ing in diminished capacity to withstand avariety of insults that can trigger the acuteconfusional state. Advanced age and pre-existing cognitive dysfunction are themost consistently identified risk factorsfor delirium in prospective studies.12,13

TABLE 1-2 Commonly Cited Etiologies of Altered Mental Status

b Vascular

Ischemic strokea

Intracerebral or subarachnoidhemorrhage

b Infectious

Urinary tract infection

Pneumonia

Sepsis

Encephalitis

Meningitis

b Toxic

Intoxication and overdose

Withdrawal (alcohol, benzodiazepines,barbiturates, heroin)

Drugs (including prescription,over-the-counter,and herbal preparations)

b Traumatic

Concussion

Subdural hematoma

b Autoimmune

Neuropsychiatric lupus

Behçet syndrome

Vasculitis

Acute disseminatedencephalomyelitis

VGKC = voltage-gated potassium channel; LGI1 = leucine-rich glioma inactivated 1; AMPA = !-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = +-aminobutyric acid.aVascular lesions rarely lead to isolated delirium in the absence of other neurologic signs; rare exceptions include lesions of thethalamus and nondominant posterior parietal lobe.bA recent study implicates LGI1 as the antigen in limbic encephalitis previously attributed to VGKC antibodies. Because LGI1coprecipitates with VGKC, it is likely the commercial test for VGKC antibodies is actually detecting antibodies of LGI1.However, because direct testing for LGI1 antibodies is not yet available and because other disorders are associated with VGKCantibodies (eg, Morvan syndrome), it is still appropriate to order the commercial test for VGKC antibodies in patients with limbicencephalitis.11

Hashimoto encephalopathy(also called steroid-responsiveencephalopathy withautoimmune thyroiditis)

Autoimmune limbic encephalitis(antibodies against VGKCb, LGI1,NMDA receptors, AMPA receptors,GABAB receptors)

b Metabolic

Electrolytes

Hyponatremia/hypernatremia

Hypercalcemia

Hypermagnesemia

Hypophosphatemia

Endocrine

Hypothyroidism/hyperthyroidism

Hypocortisolism/hypercortisolism

Hypoglycemia/hyperglycemia

Hepatic encephalopathy

Uremic encephalopathy

Acute pancreatitis

Hypoxia and hypercarbia

Vitamin deficiencies

Thiamine

B12

Hypothermia/hyperthermia

Marchiafava-Bignami disease

Porphyria

b Iatrogenic (see Table 1-3)

b Neoplastic

Large brain tumors

Carcinomatous meningitis

Paraneoplastic limbicencephalitis (antibodiesagainst Ma2, Hu,CV2/CRMP5, Tr, VGKC,NMDA receptors,AMPA receptors)

b Seizure-Related

Postictal state

Nonconvulsive statusepilepticus

b Structural

Hydrocephalus

b Degenerative

Dementia with Lewy bodies

Prion disease

Other neurodegenerativedisorders usually are riskfactors for delirium butanother inciting causeis present

b Psychiatric DiseaseYRelated



Additional risk factors for delirium arelisted in Table 1-3. Although sometypes of neurodegenerative disease,such as Lewy body dementia, maycause delirium in and of themselves,most patients with dementia exhibitnormal levels of arousal and attentionuntil the very late stages of disease.Occasionally prion disease may pro-gress rapidly enough to present withencephalopathy. The insults that canprecipitate delirium include a wide rangeof pathologic conditions (Table 1-2),many of which may cause encephalop-athy in patients without risk factors,and iatrogenic insults that the patientwith sufficient cognitive reserve canusually withstand (Table 1-3). If a pa-tient without known underlying neuro-logic disease becomes delirious with arelatively innocuous insult such as aurinary tract infection, follow-up shouldbe arranged with neurology to screenfor an underlying process such as anincipient neurodegenerative disease.These patients have essentially failed a‘‘stress test for the brain,’’ and an under-lying disorder should be sought.

Delirium tends to improve steadilyonce the precipitant is removed ortreated; if a patient does not showgradual improvement, the diagnosisshould be revisited. In patients withouta clear precipitant, even if they havepredisposing risk factors for delirium,further workup may be warranted.Patients without risk factors for deliriumand those at high risk for intracranialinfection or neoplasm generally requirefurther workup as well. This is dis-cussed in more detail below.

NeuroimagingBrain imaging, at least with noncontrastCT, is mandatory in patients with alteredmental status who also have focal neuro-logic deficits or seizures. A head CT isalso recommended prior to performinga lumbar puncture.14 Other situations in

TABLE 1-3 DeliriumRisk Factors and Iatrogenic Precipitants

b Risk Factors

Age 9 70 years

Dementia or mild cognitive impairment

Vision impairment (usually less than 20/70 with correction)

Hearing impairment

Functional limitation

Alcohol abuse

Malnutrition (indicated by an albumin G 2 g/dL)

Dehydration (indicatedbyabloodureanitrogen/creatinine ratio9 18)

b Iatrogenic Precipitants

Use of restraints

Urinary catheters

Multiple procedures

Sleep deprivation

Untreated pain

Drugs

Anticholinergics

Benzodiazepines

Opiates

Antihistamines

Antiepileptics

Muscle relaxants

Dopamine agonists

Monoamine oxidase inhibitors

Levodopa

Steroids

Fluoroquinolone and cephalosporin antibiotics

Beta-blockers

Digitalis

Lithium

Calcineurin inhibitors7

Surgery

Thoracic (cardiac and noncardiac)

Vascular

Hip replacement




which the likelihood of intracranial pa-thology is high also mandate brainimaging. Examples include patients witha previous brain lesion, recent trauma,HIV, a history of organ transplantationor other immunocompromised state, ora history of cancer. Whether brain imag-ing should be routinely obtained inpatients with encephalopathy withoutfocal neurologic signs or the aforemen-tioned risk factors is more controversial.

Several attempts have been made tostudy the yield of brain imaging in pa-tients with altered mental status. Inemergency department patients with-out head trauma, altered mental statusis one of four clinical characteristics thatpredict an abnormal CT scan with highsensitivity (the others being headachewith vomiting, age greater than 60years, and focal neurologic deficits).15

In one study, 13% of 181 patients withaltered mental status had a clinicallysignificant finding on head CT.15 In amore recent study of 294 patients ad-mitted to an inpatient neurology servicewith acute confusion of unclear etiology,14% had a clinically significant finding

on either CT or MRI.16 Although mostpatients without focal neurologic deficitshad normal scans, half of those withfindings on brain imaging had no focalneurologic signs; these included pa-tients with ischemic stroke, encephalitis,and hydrocephalus. Conversely, in astudy of 106 consecutive CT scans per-formed in an emergency department foracute confusion in patients over age 70,all abnormal scans were in patients witheither focal neurologic findings or re-cent trauma.17 However, because MRIwas not used as a criterion standard inthis study, it is possible some intracra-nial lesions were missed.

Although strokes causing alteredmental status are almost always accom-panied by focal deficits, especially uponcareful neurologic examination, occa-sionally such localizing signs are absent(Case 1-1). Specific types of infarctionthat may cause such a scenario includethalamic infarctions in the paramedianterritory, nondominant parietal lobeinfarctions, and diffuse bihemisphericor watershed infarctions caused eitherby a proximal embolic source or a

KEY POINTSh In patients with

encephalopathy withouta focal deficit, brainimaging should still beobtained if the patienthas a history of trauma,HIV or anotherimmunocompromisedstate, cancer, or recentthoracic surgery oraortic catheterization.

h Thalamic andnondominant parietalstrokes, diffusebihemispheric emboli,and posterior reversibleencephalopathysyndrome are examplesof conditions that cancause encephalopathywithout focal neurologicdeficits and requirebrain imagingfor diagnosis.

Case 1-1A 55-year-old right-handed man was brought to the hospital with confusion.Two weeks ago, he experienced the sudden onset of fluctuatingdisorientation and forgetfulness. He also had exhibited strange behaviors suchas attempting to turn the television on with his cell phone. He underwent aright anterior temporal lobectomy 3 years ago formedically refractory epilepsybut still had one complex partial seizure per month. His last seizure was10 days prior to presentation. He had also experienced a steady decline inmemory and concentration associated with parkinsonism over the past 8years. His medications included carbamazepine, divalproex, levetiracetam,memantine, venlafaxine, quetiapine, and tamsulosin. On examination hewas awake but demonstrated psychomotor slowing, disorientation, andimpaired attention and short-term recall. His gait was wide based and mildlyunsteady, but otherwise his neurologic examination was normal.

Basic laboratory testing and urinalysis were normal. Carbamazepineand valproic acid levels were in the therapeutic range. CT of the brainshowed a remote lacunar infarct in the left internal capsule and the righttemporal resection cavity.

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diffuse cerebral vasculopathy.18,19 Exem-plifying the last-mentioned is a series ofeight patients with encephalopathy aftercoronary artery bypass grafting surgerywho received brain MRI, seven of whomhad multiple bilateral infarctions ondiffusion-weighted imaging.20 Three ofthese patients had no focal deficits whenexamined by a neurologist, and no alter-native explanation for their encephalop-athy could be found.

Posterior reversible encephalopathysyndrome (PRES) is another importantcause of altered mental status that maypresent without focal deficits and is diag-nosed by MRI. Patients usually presentwith diffuse encephalopathy, and most

also have seizures; hemiparesis or visualfield deficits occur in fewer than half ofpatients.21 The diagnosis is suspectedin the setting of eclampsia, hypertensiveemergency, or immunosuppression withcalcineurin inhibitors, although a numberof other medical conditions have beenassociated with PRES. Typical MRI find-ings include relatively symmetric, patchy,and confluent hyperintensities on T2-weighted images in the occipital andparietal white matter, although atypicalfeatures are common, including frontal,brainstem, and cortical involvement.22

In conclusion, if the cause of alteredmental status is not obvious after theinitial evaluation, brain imaging with at

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Comment. This patient presented to the hospital with a 2-week historyof delirium. He had no focal findings on neurologic examination, and hispreexisting cognitive dysfunction is a major risk factor for delirium. He istaking numerous medications known to cause delirium; however, norecent changes in dosage had been made. Thus, because no obviousprecipitant for delirium exists, a more extensive workup is warranted.

Because encephalitis can presentwith subacute delirium, a lumbar punctureshould be performed. Empiric treatment with acyclovir is reasonable until aherpes simplex virus PCR is negative. Serum ammonia can be checked, giventhe possibility of encephalopathy due to valproic acid. A vitamin B12 leveland thyroid function tests are also reasonable. Given the history of epilepsy,an extended EEG should be performed to rule out nonconvulsive statusepilepticus. Finally, an MRI can be diagnostic in cases of otherwiseunexplainedencephalopathy. Inthis case, additionallaboratory studieswere normal andthe EEG showedonly a right-sidedbreach rhythm withintermittenttemporal sharps butno seizures. An MRIshowed a subacuteinfarction in theleft anteromedialthalamus(Figure 1-1).

FIGURE 1-1 A, diffusion-weighted image. B, fluid-attenuatedinversion recovery sequence.




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least noncontrast CT is indicated. Whilethe yield of brain imaging in the ab-sence of trauma or a focal neurologicdeficit is likely low, especially in elderlypatients who are at higher risk for met-abolic encephalopathy, it is still possibleto find a clinically important lesion. MRImay be especially useful in such situa-tions. Case 1-2 is illustrative of thispoint.

Lumbar PunctureWhether to perform a lumbar puncturein a patient with altered mental statusdepends onwhether the change inmen-tal status developed before or during thehospitalization, because nosocomialmeningitis is very uncommon. In twoseries comprising 121 medical and sur-gical inpatients who underwent lum-bar puncture to rule out nosocomial

KEY POINTh Immunocompetent

patients without ahistory of neurosurgeryor head trauma whodevelop altered mentalstatus during theirhospitalization areunlikely to havemeningitis.

Case 1-2An 83-year-old right-handed woman presented to the emergency department with vertigo, numbness,and weakness. Her symptoms started 3 days ago with vertigo and numbness in the feet, followed bydysarthria and weakness that progressed to the point where she could no longer stand. She had beentaking metronidazole for the past month for a Clostridium difficile infection. In the emergencydepartment she was awake but slow to respond and diffusely weak; a CT scan showed diffuse atrophyand remote bilateral basal ganglia lacunar infarcts. Basic laboratory evaluation showed mild renaldysfunction with a blood urea nitrogen of 50 mg/dL and a creatinine of 1.5 mg/dL. Urinalysis suggesteda urinary tract infection. She was admitted to the hospital and started on cefazolin. Over the next24 hours she became progressively less responsive. A neurology consultation was obtained.

On neurologic examination, she sluggishly opened her eyes to painful stimuli but showed no othermotor response to central or peripheral pain and did not follow any commands. Brainstem reflexeswere intact. Tone and reflexes were normal, with the exception of absent ankle jerks, and plantarresponses were flexor.

Comment. This elderly patient was unresponsive with a nonfocal neurologic examination at thetime of consultation. She had a urinary tract infection and mild renal failure, which could lead toencephalopathy in an elderly patient. However, the history of vertigo, dysarthria, and bilateralweakness and numbness preceding the onset of unresponsiveness is suggestive of brainstemlocalization. The gradual progression of symptoms over days makes stroke unlikely, but progressivebasilar artery ischemia should be ruled out with an MRI and magnetic resonance angiography. A lumbarpuncture and EEG would also be reasonable if the patient does not improve with treatment of herurinary tract infection.

In this case, the MRI showed symmetricT2 prolongation in the bilateral dentatenuclei (Figure 1-2A), middle cerebellarpeduncles, dorsal pons, red nuclei(Figure 1-2B), splenium of the corpuscallosum, and bilateral centrum semiovale.A lumbar puncture was normal. Thesefindings have been described in Wernickeencephalopathy and with metronidazoletoxicity.23 The patient was treated withIV thiamine and her metronidazole wasdiscontinued; she showed gradual clinicalimprovement. This case illustrates theimportance of MRI in the workup of otherwiseunexplained delirium and the need to alwayscarefully review all of a patient’s medications.

FIGURE 1-2



meningitis, no cases were found.24,25

Thus, in the absence of additional fea-tures of CNS infection such as fever,headache, or neck stiffness, lumbarpuncture is of low yield in most pa-tients with hospital-acquired delirium.However, this conclusion should notbe generalized to patients with headtrauma, neurosurgical procedures ordevices, or HIV or other immunocom-promised states.

For patients who present to medicalattention with altered mental status,the threshold for performing a lum-bar puncture should be lower. Whilebacterial meningitis is unlikely inimmunocompetent patients with en-cephalopathy in the absence of feveror neck stiffness (95% of patients in apooled analysis had at least two of thethree cardinal manifestations of menin-gitis: encephalopathy, fever, and neckstiffness), lumbar puncture can diag-nose other causes of altered mentalstatus that may not cause fever as fre-quently, such as tuberculous or fungalmeningitis, aseptic meningitis, or carci-nomatous meningitis (Table 1-4).26 In-deed, the absence of fever may not besensitive enough to justify foregoinglumbar puncture. In a recent retrospec-tive study, Shah and colleagues found nosignificant difference between afebrileand febrile patients in the frequency ofCSF pleocytosis (18% and 24%, respec-tively) or meningitis/encephalitis (12%and 7%, respectively).27

In cases of meningitis, the CSF mayrarely be only mildly abnormal withinthe first 24 hours of illness.28 Therefore,a lumbar puncture should be repeatedif clinical suspicion remains high. TheCSF may also lack a pleocytosis in asmany as 10% of cases of encephalitis.29

Because early treatment significantlyreduces morbidity and mortality ofherpes simplex virus (HSV) encephali-tis, it is reasonable to have a low thresh-old to start acyclovir and test for HSV-1

TABLE 1-4 CSF Studies That May Be Helpful in the Workupof Unexplained Altered Mental Status

b All Patients

Redandwhitebloodcell countwithdifferential, protein,andglucose

Bacterial culture

PCR for HSV-1, HSV-2, and VZV

b When Encephalitis is Suspected11

Viral PCRs

HSV-1

HSV-2

VZV

Enterovirus

WNV

EBVa

IgG and IgM for WNVb, St. Louis encephalitisb, and EBV;additional viral serologies may be considered depending onseason, exposures, and geography

Bacterial PCRs

Tropheryma whippelii

Bartonella genus

Some rickettsiosesb

Venereal Disease Research Laboratory and Borrelia burgdorferiELISA and Western blotb

Acid-fast bacilli smear and culture,Mycobacterium tuberculosis PCRc

Fungal culture

Cryptococcus antigen, Histoplasma antigenb, Coccidioidesimmunodiffusion or complement fixationb

IgG index and oligoclonal bands

Testing for antibodies associated with paraneoplastic andautoimmune limbic encephalitis

b Patients With a History of Malignancy

Cytology and flow cytometry

b Patients Who Are Immunocompromised

PCR for cytomegalovirus, human herpesvirus 6, JC virus

Galactomannan if aspergillosis is suspected

HSV-1 = herpes simplex virus, type 1; HSV-2 = herpes simplex virus, type 2;VZV = varicella-zoster virus; WNV = West Nile virus; EBV = Epstein-Barrvirus; Ig = immunoglobulin.aCan be falsely positive because of blood contamination; should be performedwith serologic testing.bDepends on season, geographic location, and travel history.cDiagnostic yield is increased with samples of higher volume; tuberculosisPCR has low sensitivity.




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and HSV-2 DNA with PCR in patientswith altered mental status and fever,even in the absence of CSF abnormali-ties. The CSF PCR is 95% sensitivefor HSV when performed between 72hours and 10 days of illness onset; thetest should be repeated in cases wherethe clinical suspicion is high or the lum-bar puncture was performed early inthe course (Case 1-3).30

Special care must be taken to rule outinfection in immunocompromised pa-tients with altered mental status. Patientswith HIV are at risk for meningitis due to

Cryptococcus, tuberculosis, pyogenic bac-teria, syphilis, and cytomegalovirus (CMV)ventriculoencephalitis, especially whentheir CD4 count falls below 200 cells/mm3.31 Although toxoplasmosis and pri-mary CNS lymphoma usually presentwith focal deficits, multifocal diseasecan occasionally present with diffuseencephalopathy. In addition to commonbacterial and viral pathogens, organ andbone marrow transplant recipients areat high risk for CNS infection with lesscommon organisms, including CMV,varicella-zoster virus, human herpesvirus

KEY POINTh The CSF may lack a

pleocytosis in 10% ofcases of encephalitis.Clinicians should have alow threshold to startempiric treatment withacyclovir and test forherpes simplex viruswith CSF PCR in patientswith altered mentalstatus and fever orseizures.

Case 1-3A 59-year-old right-handed man was brought to the emergency department for altered mental status.Ten days ago he reported experiencing a headache and forgetfulness. On the morning of admission, hedeveloped nonsensical speech and an ambulance was called. He has a history of HIV with a CD4 countof 158 cells/mm3, and he is blind because of cytomegalovirus (CMV) retinitis. In the emergencydepartment he had a witnessed generalized seizure beginning with right gaze deviation. The seizurewas controlled with lorazepam, and a noncontrast head CT was normal. He was intubated for airwayprotection and admitted to the medical intensive care unit.

Comment. In patients with HIV with altered mental status and seizure, especially those with aCD4 count below 200 cells/mm3, a variety of infectious and noninfectious etiologies must beconsidered. Opportunistic infections of the CNS that predispose to seizures include toxoplasmosisand meningoencephalitis due to tuberculosis, syphilis, cryptococcus, or CMV. Of course, these patientsare also at risk for more common infections that are not limited to the immunocompromised host,such as bacterial meningitis, brain abscess, and herpes simplex virus (HSV) and varicella-zoster virusencephalitis. Noninfectious CNS diseases to be considered in patients with HIV include primary CNSlymphoma and cerebrovascular disease due to the accelerated atherosclerosis seen with proteaseinhibitors. Progressive multifocal leukoencephalopathy is less likely to present with seizures oraltered mental status and more likely to present with focal deficits.

In this case, a lumbar puncture revealed alymphocytic pleocytosis and elevated protein.Empiric therapy with antibiotics and acyclovirwas begun. An MRI showed T2 hyperintensitywith mild mass effect and enhancement in theleft medial temporal lobe (Figure 1-3). Cultureof CSF and PCR for HSV, varicella-zoster virus,andCMVwere negative, aswere the rapid plasmareagin and cryptococcal antigen. Antibiotics werediscontinued, but given the high suspicion forHSV encephalitis, acyclovir was continued. Arepeat HSV PCR on CSF drawn 3 days later waspositive. It is important to keep in mind that HSVPCR is only 95% sensitive; if clinical suspicion ishigh, patients should be treated empirically andthe test should be repeated on a fresh CSF sample.

FIGURE 1-3



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Adam Kapler

6, Aspergillus, and Nocardia. Diagnosisrelies on CSF PCR for viral organisms andoften direct culture for invasive fungaland atypical bacterial species. Someemerging data suggest that CSF galac-tomannan may be a sensitive markerfor CNS aspergillosis in patients whoare immunocompromised.32

Over the last decade it has becomeapparent that many cases of previ-ously undiagnosed encephalitis areassociated with antibodies to neuronalantigens. In some cases a putativeautoimmune etiology exists, and inother cases the illness is paraneoplas-tic. A recent population-based studyfrom England found 8% of cases ofencephalitis over a 2-year period wereassociated with antibodies to NMDAreceptors or what was formerly thoughtto be voltage-gated potassiumchannels.33

The MRI is often normal in such cases,but the CSF is usually inflammatory.34 Ina large series of paraneoplastic neuro-logic syndromes from a European regis-try, 93% had elevated CSF protein, whiteblood cell count, or oligoclonal bands.35

Importantly, in 10% of cases the onlyabnormality was the presence of oligo-clonal bands unique to the CSF. For thisreason, it may be helpful to checkimmunoglobulin G index and oligoclonalbands in patients with suspected ence-phalitis. If evidence of inflammationexists, further workup for an occult neo-plasm and antibody testing on serumand CSF may be warranted.

Neoplastic metastases to the subar-achnoid space resulting in carcino-matous meningitis often present withencephalopathy with or without con-comitant cranial neuropathies or radicu-lopathies. Cancers that most frequentlymetastasize to the leptomeninges in-clude breast, lung, melanoma, lym-phoma, and leukemia.36 While MRI maybe suggestive and even diagnostic insome cases, CSF cytology is often re-quired to make the diagnosis.

ElectroencephalographySeizures must be considered in patientswith unexplained encephalopathy. Sev-eral prospective studies have found anincidence of seizures in 10% to 19% ofsuch patients, with the higher ratesreflecting patients in the intensive careunit.37,38 Although repetitive motor ac-tivity, nystagmus, or gaze deviation mayincrease the likelihood of a positiveEEG, the absence of such findings doesnot rule out underlying nonconvulsiveelectrical activity, making EEG an essen-tialdiagnostic tool.39,40 Some studies sug-gest that 24 hours of recording tocapture seizure activity has a higher de-gree of sensitivity than a brief recording.37

Serum Laboratory StudiesSeveral endocrine abnormalities maycause altered mental status. Hyperthyr-oidism commonly leads to psychiatricsymptoms such as mania, depression,and anxiety, although abnormalities onneuropsychiatric testing, aside fromattentional deficits, are rarely encoun-tered.41 Severe thyrotoxicosis, however,may lead to delirium. Hypothyroidismcan cause significant cognitive dysfunctionor even stupor or coma when severe.42

Measurement of thyroid-stimulatinghormone and free thyroxine confirmsthe diagnosis. Cushing syndrome, dueto either endogenous or iatrogenic cor-tisol excess, may lead to psychosis ordelirium. Psychosis or delirium may alsobe the presenting feature of addisoniancrisis.43

Additional metabolic studies thatshould be undertaken in the patientwith encephalopathy include measure-ment of vitamin B12 and ammonia. De-ficiency of vitamin B12 has long beenassociated with both subacute cogni-tive decline and delirium. Hyperammo-nemia is associated with altered mentalstatus in several conditions in addi-tion to hepatic disease. For example, val-proic acid can lead to hyperammonemic

KEY POINTSh In a recent

population-based study,8% of encephalitiscases were associatedwith NMDA orvoltage-gatedpotassium channelantibodies.

h As many as 10% to19% of patientswith unexplainedencephalopathy arefound to have seizureson EEG. Often,extended periods ofrecording are requiredto capture seizures,and no clinical signsexist that reliably rulethem out.

h Endocrine andmetabolic disordersthat are less commoncauses of alteredmental status includehypothyroidism,hyperthyroidism,Cushing syndrome,Addison disease,vitamin B12 deficiency,and hyperammonemiaof various causes.




Adam Kapler

Adam Kapler

Adam Kapler

Adam Kapler

Adam Kapler

encephalopathy in both children andadults.44 Occasionally the serum ammo-nia may be normal but the CSF gluta-mine may be elevated.45 This can occurwith serum valproic acid levels in thetherapeutic range and is potentiated bythe coadministration of topiramate.Patients with cirrhosis are prone to hy-perammonemia andhepatic encephalop-athy due to acquired portal-systemicshunting, but congenital and acquiredportal-systemic shunts can also lead tothe same condition in patients withoutovert liver disease.46,47 Transrectal portalscintigraphy or angiographic studies ofthe portal circulation may be necessaryto demonstrate the shunt. Finally, veryrarely a urea cycle deficit may presentduring adulthood.

Occasionally, the presence of anoffending toxin or drug is not obviousfrom the initial history or the standardurine toxicology screen available in theemergency department. It is often help-ful to revisit the history with familymembers and friends to identify poten-tial ingestions. Over-the-counter andherbal medications should be reviewedthoroughly in addition to prescriptionmedications (Table 1-5). An extendedtoxicology screen may also be helpful.

In addition to paraneoplastic andautoimmune limbic encephalitis, severalother autoimmune diseasesmay presentwith encephalopathy, and serum auto-antibody testing may be diagnosticallyhelpful in such patients. Among thewide array of neurologic symptoms thatcan complicate systemic lupus erythe-matosus, acute confusional states andpsychosis are uncommon but well de-scribed, occurring in as many as 4% ofpatients with lupus in some series.48

Markers of disease activity such as com-plement levels, antinuclear antibodies,and double-stranded DNA should beelevated in active lupus; CSF analysis isuseful in working up other causes ofencephalopathy but is often normal in

active neuropsychiatric lupus.49 Auto-immune encephalitis has been reportedwith Sjogren syndrome but is veryrare.50 Other connective tissue diseasesmay cause altered mental status throughan ischemic mechanism due to eithervasculitis in most cases or thrombosis(arterial or venous) in antiphospholipidantibody syndrome.

Hashimoto encephalitis is a non-infectious, nonvasculitic encephalitisassociated with antithyroglobulin andantithyroperoxidase antibodies that us-ually responds to steroid treatment.Given the high incidence of antithyroidantibodies in the general population, itis unlikely they play a causative role inthis disorder; it is also unlikely their fre-quent occurrence in steroid-responsiveencephalopathy is incidental.51 Otherproposed names for this condition in-clude steroid-responsive encephalopathywith autoimmune thyroiditis and non-vasculitic autoimmune meningoencepha-litis; no single term has yet gained wideacceptance. Given the responsiveness ofthe condition to steroids, testing forantithyroid antibodies remains an impor-tant part of the workup for an otherwiseunexplained encephalopathy.

PREVENTION, TREATMENT,AND FOLLOW-UPTreatment of alteredmental status shouldfocus on the underlying cause. Specifictreatment for the conditions discussedhere is beyond the scope of this article. Incases of encephalopathy in which anunderlying cause cannot be determined,treatment is largely supportive. Potentiallyoffending medications should be dis-continued, bladder catheters shouldbe removed as soon as possible, andfamily members or sitters should beused in lieu of restraints to ensure pa-tient safety. Pharmacologic treatment ofalteredmental status should be avoided,given the potential for new medicationsto precipitate or worsen delirium. In

KEY POINTh Autoimmune causes

of altered mentalstatus include lupus,Sjogren syndrome,Hashimoto encephalitis,autoimmune limbicencephalitis, andvasculitis. Theseconditions are oftenresponsive tocorticosteroids.



Adam Kapler

TABLE 1-5 Commonly Prescribed Drugs Implicated as Causes of Altered Mental Statusa

b Drugs With Class Effect

Anticholinergics

Antiepileptics

Antihistamines (including H2 blockerssuch as cimetidine and famotidine)

Antipsychotics (via sedative effectsor neuroleptic malignant syndrome)

Benzodiazepines

Calcineurin inhibitors

Cephalosporins (especially in the settingof renal failure)

Dopamine agonists and levodopa

Fluoroquinolones

Monoamine oxidase inhibitors

Muscle relaxants (if centrally acting)

Opiates

Steroids

Tricyclic antidepressants

b Drugs Without Class Effect

Antiemetics

Promethazine

Antihypertensives

Clonidine

Nifedipine

Antidepressants

Bupropion

Mirtazapine

Paroxetine

Trazodone

Antifungal agents

Micafungin

Voriconazole

PosaconazoleaMany other medications have been reported to cause confusion, delirium, or encephalopathy with varying degrees of evidenceimplicating causality. In any patient with delirium, a careful review of all prescription and nonprescription medications is advised.

Reprinted from DRUGDEXA System. Thomson Reuters (Healthcare) Inc. www.thomsonreuters.com/products_services/healthcare/healthcare_products/a-z/drugdex_system. Accessed December 2010.

Antiparasitic agents

Mefloquine

Antiviral agents

Amantadine

Valacyclovir (especially in renal impairment)

Biological agents

Bevacizumab (due to hypertensive encephalopathy)

Interferon alpha

Chemotherapy agents

Asparaginase

Bicalutamide

Cytarabine

Decitabine

Fluorouracil

Ifosfamide

Irinotecan

Methotrexate

Nelarabine

Paclitaxel

Thalidomide

Mood stabilizers

Lithium

Sleep aids

Zolpidem

Eszopiclone

Others

Acetazolamide

Aspirin and aspirin-containing compounds (in overdoseand Reye syndrome)

Digoxin

Disulfiram

Dronabinol




cases in which sedative medications arerequired for patient safety, however,low doses of antipsychotics are consid-ered first-line agents, although they arenot approved by the US Food and DrugAdministration (FDA) for this indica-tion.52 Caveats to their use include theFDA black box warning regarding in-creased mortality among elderly pa-tients with dementia, their potential toprolong the overall length of an epi-sode of delirium while temporarilyrelieving symptoms, and their potentialfor profoundly sedating and extrapyra-midal effects in patients with Lewy bodydementia. Benzodiazepines should beavoided, except in cases of alcohol with-drawal, given their potential to exacer-bate symptoms of delirium. A recentCochrane Review found no studies sup-porting their use in nonYalcohol with-drawal delirium.53

In some patients, prevention of delir-ium may be possible by nonpharmaco-logic means. A 2007 Cochrane Reviewidentified only six prospective random-ized trials investigating prevention ofpostoperative delirium.54 Five of thesestudies examined pharmacologic in-terventions, including haloperidol,donepezil, diazepam, cytidine diphos-phocholine, and epidural versus halo-thane anesthesia; only haloperidolshowed promise in reducing the lengthand severity of delirium episodes, al-though the overall number was no dif-ferent between groups. The sixth studydemonstrated that a proactive geriatricsconsultation reduced the incidence ofpostoperative delirium from 50% to 32%among hip surgery patients. In a sepa-rate study not included in the CochraneReview, a multicomponent interven-tion using environmental and nursingstrategies reduced the incidence ofhospital-acquired delirium from 15% to9.9% in high-risk medical patients.55

Critically ill patients are at especiallyhigh risk for developing delirium.3 Not

only are they ill with conditions thatcan precipitate delirium and encepha-lopathy, in order to relieve the dis-comfort of mechanical ventilation theyare also exposed to various sedativemedications that are known causes ofdelirium. Recently a new selective !2agonist, dexmedetomidine, has shownpromise in reducing delirium whilemaintaining adequate sedation in crit-ically ill patients who are mechanicallyventilated. In three separate random-ized trials, dexmedetomidine outper-formed lorazepam, midazolam, andmorphine by reducing the prevalenceof delirium during intubation and re-ducing ventilator time from 5.6 to 3.7days compared with midazolam.56Y58

For patients with altered mentalstatus of any cause, follow-up with aneurologist is important because it oftentakes time for cognitive function tonormalize, if it does at all, and issuesregarding cognitive disability often needto be addressed. Patients with deliriumare also at high risk for developingdementia and should be reevaluatedin the outpatient setting.59 This will be-come especially important once pre-ventive and treatment strategies forneurodegenerative diseases are devel-oped, because delirium may becomeone way of identifying incipient cases ofmild cognitive impairment or dementia.

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