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Learning Objectives for this file: 1. Demyelinating & degenerative diseases 2. Dementia 3. Basal ganglia lesions 4. Peripheral neuropathies & radiculopathies 5. Head Trauma

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DEMYELINATNG & DEGENERATIVE DISEASES: These conditions get progressively worse over time Multiple sclerosis: SEE ALSO CASE FILE FOR MORE ON THIS TOPIC • Pathology: Patchy demyelination (plaques), abnormal CSF – abnormal proteins. • Etiology:

o Cluster of genetic loci predisposing to MS (HLA class 2 region on chromosome 6, and also a locus on chromosome 1); these gene regions are also associated with increased incidence of auto-immune disease

o What is the trigger ? Auto-Immune ? Virus ? o MOST COMMON demyelinating disease

• Presentation & DX: o loss of focal neurologic function o Common presentation is amaurosis fugax (sudden painless loss of vision in one

eye) o Diagnosed on MRI Scan (patchy demyelination of CNS)

• McDonald Criteria for diagnosis require neuroimaging demonstration of dissemination of lesions in space (DIS) and time (DIT) (Polman, et al, 2011): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084507/?report=classic

• Therapy: Current therapies include interferons, plasmapheresis, cooling, cortisol

CT of MS with small, high-signal densities in peri-ventricular regions (see black arrow) representing plaques of demyelination.

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Amyotrophic Lateral Sclerosis (ALS) (LOU GEHRIG'S disease): • Etiologic theories:

o Over-accumulation of the neurotransmitter glutamate in the CNS, causing excito-toxicity of anterior horn cells in spinal cord

o These neurons then die that would normally innervate skeletal muscle and there is loss of lower motor neuron (LMN) function with muscle paresis

• Presentation: o Denervation atrophy with fasciculations – lower LMN lesion with muscle paresis o Increased reflex activity (autonomic hyper-reflexia) with spasticity o Spastic paraparesis (no sensory loss – all motor) o Eventually loses ability to speak, swallow and breathe o Finally needs intubation with mechanical ventilation

• See NIND info page: https://www.ninds.nih.gov/Disorders/All-Disorders/Amyotrophic-Lateral-Sclerosis-ALS-Information-Page

• Good overview article with in-depth information on genetics, presentation, natural history (Brown & Al-Chalabi, 2017): http://www.nejm.org/doi/full/10.1056/NEJMra1603471

• Newer treatments are now available o Riluzole (Rilutek) inhibits glutamate release presynaptically; may also also block

postsynaptic receptors o Edaravone (Radicava) is an antioxidant

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DEMENTIA SYNDROMES: progressive loss of memory and learning with associated behavioral and adaptive deterioration resulting in early death (neuro-endocrine failure). In DSM-5: under section “Neurocognitive Disorders” ALZHEIMER’S DEMENTIA (AD): (see image below) • most common type of dementia – over over 2/3 of all dementia cases in North Asia and

Europe are caused by AD • Previously, Alzheimer's disease (AD) was called a diagnosis of "exclusion" — after

everything else was ruled out, Alzheimer's was left. • MUST rule out potentially curable forms of dementia, and recognize other dementias (that

may require special interventions or have special medication concerns). Survival after diagnosis: much shorter than previously thought – median time after diagnosis to death is just over 3 years. B. THREE DOMAINS OF DISABILITY: the “ABCs” of dementia –> 1. Activity (Function) 2. Behavior 3. Cognition:

• memory & language • learning (new information) & problem solving • perception (abnormal perception = hallucinations) • abstract thinking (able to finish a "what if..." question) • judgment

C. WHAT ABOUT "NORMAL AGING"? there is some decline these domains —

Attention: • Selective attention mildly diminished, divided attention more so. • Example: Driving – can’t merge into traffic while yelling at your kids

Learning & Memory: • No change in recognition or immediate memory. • Very mild decline in learning (new information), retrieval, recall and working

memory. Intellect:

• Mild decline in nonverbal IQ testing • No change in verbal IQ

Language: • No change in naming, fluency, comprehension, calculation

Visuo-spatial abiity: • Very mild decline in perception • No change in spatial judgment and praxis (purposeful motor skills).

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Pathology: • Beta-amyloid plaque: is it a CAUSE of dementia or just FOUND in dementia?

o Amyloid precursor protein (APP) is clipped by gamma secretase enzyme and forms beta-amyloid; with the contribution of apo-E4 and free radicals, it becomes insoluble and deposits out side the cell.

o These deposits are postulated to poison neurons by allowing increased calcium entry into neurons, an also increasing glutamate neurotransmitter entry into cells (over-excitation similar to ALS disease)

• Neurofibrillary tangles: is it a CAUSE of dementia or just FOUND in dementia? o Called a "tauopathy" since tau protein is normally formed inside the neuron as

the crosspieces of micro-tubules that maintain the shape and "shipping" lines from soma down the axon; in AD, this protein collapses and twists into paired helical fragments.

o Caused by free radical damage? Genetics (tau polymorphism)? Comorbidity? These tangles are often called flames on histological slides of biopsied brain.

• Problems with neurons: o Dendritic pruning: loss of dendrites over time o Synaptic losses: cellular death neurons related to lack of stimulation from loss of

neuron-to-neuron synaptic neurotransmission o Lipid disorder of the CNS: presence of apo-lipo-protein based on genetics (APOE-

E2, -E3, -E4); these proteins may be what causes insolubility of beta-amyloid and collapse of tau into tangles.

o Glucose metabolism: decreased transport molecules GLUT3 & GLUT1 contribute to cell death. Additionally, there is a decrease in the mitochondrial enzymes needed for glucose metabolism.

o Loss of cholinergic neurons: deficiency in ACh in brain specific regions, with decreased synthesizing ChAT enzyme. Less ChAT means less ACh.

o Cells try to divide before they die: recent findings indicate that these cells have abnormal cell mitosis cycles even before the amyloid plaque shows up

• Reactive gliosis: more glial o More butylcholinesterase (BuChE) than acetylcholinesterase (AChE) due to

increased numbers of glial cells. o Reason – reaction to inflammation? Neuron death?

• Anatomical Brain Region Specificity: o Hippocampus: memory & learning, ancient cortex o Nucleus basalis of Meynert: neurons project to cortex (contain estrogen receptors) o Frontal regions: apotptosis (dying off) with increased COX-2 enzyme presence as

occurs in the inflammtory reaction o Free radical impact: possible protection in melatonin, diet (anti-oxidants), vitamins

E & C, selegiline, gingko biloba Current theories: • Beta-amyloid plaque poisons neurons? Tauopathy destroys neurons? • Excessive glutamate causes excito-toxicity of neurons in NMDA learning pathways? • Inflammatory states, excessive lipid deposition, exposure to toxins poisons neurons • Contributing factors include lifestyle (e.g., lack of physical activity, see

http://biomedgerontology.oxfordjournals.org/content/early/2016/07/15/gerona.glw130.abstract )

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Enzymatic Pathways & Receptor Activity for Acetylcholine: • Synthesis:

o ChAT (Choline Acetyl transferase enzyme) synthesizes acetylcholine (ACh) o ChAT activity is reduced in AD.

• Presynaptic receptors: o Are muscarinic (M2) autoreceptors governing release of ACh from neuron o These are reduced in AD.

• Degradation: o Two main enzymes, AChE (acetyl-cholinesterase) found in soluble form at the

synapse and in the insoluble form at the neuron membrane; and BuChE (butyl-cholinesterase) mainly from glial cells (increased in AD).

o ACh degraded to Choline & acetate (choline is "recycled" to synthesize more ACh). o As AD progresses, AChE levels actually drop and the major contribution to

degradation is from the reactive gliosis of increased glial cells producing increased BuChE.

Pathologic Histology in Alzheimer’s Disease: includes the presence of neurofibrillary tangles (loss of structural tau protein), flame hemorrhages, and beta-amyloid deposits. This represents the final changes of this progressive degenerative disease. The loss of cholinergic neurons results in lack of neuron trophic relationships and a spreading circle of neuron cell death as time goes by. Preservation of these neurons is the goal of current therapy, including the use of cholinesterase inhibitors (AChEIs) that inhibit the enzyme that degrades acetylcholine (ACh). The longer the ACh is able to stimulate the remaining neurons, there will hopefully be a prolonged lifespan of neurons that rely on ACh stimulation.

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Natural History of Disease: • Early signs: "lower" functions affected

o Memory loss affecting job skills or other useful activities o Difficulty performing familiar tasks o Problems with language

• Later signs: more "social" and "higher" functions affected o Disorientation regarding time or place o Impaired judgment

• Overview: o Insidious onset and progressive gradual worsening of dementia o Prominent difficulty with memory (especially retention and retrieval of new material o Onset after age 60 yo o No focal neurological signs or gait difficulties (early in course of disease) o Exclusion of other causes of dementia (systemic morbidities, intracranial

pathology) o 85% of those meeting clinical criteria for AD have histologic confirmation of AD

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Alzheimer's disease pathophysiology SUMMARY: • Most common dementia • Histologic findings include neurofibrillary tangles & beta-amyloid plaque • Functional changes in neurons include loss of dendritic function & loss of cholinergic

neurons o Acetylcholine theory:

Increased butylcholinesterase enzyme degrades ACh at abnormally high rate and this results in neuron death

Thus some treatments are aimed at increasing ACh in the brain with Cholinesterase inhibitors (ChEIs)

o NMDA & Glutamate theory: NMDA learning pathways Possibly excitatory glutamate excess that needs to be blocked Thus some treatments are designed to protect NMDA learning pathways

• Prevention strategies include management of cardiovascular risk factors, cognitive stimulation, physical activity, diet rich in antioxidants (fruits, veggies)

• The Lancet commission on dementias: http://www.thelancet.com/commissions/dementia2017 and full PDF http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)31363-6.pdf The Lancet Commissions (2017) Dementia prevention, intervention and care. http://dx.doi.org/10.1016/S0140-6736(17)31363-6

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OTHER DEMENTIAS: Lewy Body Dementias (LBD): • Atypical rapidly progressive with animate hallucinations and lethal response to neuroleptic

drugs • Protein deposits seen on histology • Phenothiazines can have lethal complications – must recognize diagnosis! • Include:

o Parkinson’s disease (PD) dementia (see more on PD below) o Lewy Body dementia

• See: http://www.lbda.org/category/3437/what-is-lbd.htm “Slow Virus” (prion diseases): • Usually younger victims of dementia – infectious etiologies such as prions • Examples:

o Creutzfeldt-Jakob o Bovine spongiform encephalopathy (Mad Cow)

• May be able to diagnose prions: https://www.nih.gov/news-events/news-releases/nih-italian-scientists-develop-nasal-test-human-prion-disease

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Vascular Dementia (VaD): (Previously called Multi-Infarct Dementia) • Sudden onset of dysfunction in one or more cognitive domains & stepwise deterioration • Focal neurologic signs – including weakness of an extremity, exaggeration of deep

tendon reflexes (DTRs), extensor plantar responses (Babinski), gait abnormalities. • Evidence of stroke risk factors and/or systemic vascular disease (abdominal aortic

aneurysm, carotid artery disease, peripheral vascular disease, claudication) • Evidence of previous stroke (CVA) • Presence of cardiovascular risk factors (hypertension, dyslipidemia, smoking, family

history) – the Hachinski Scale (currently, an easier to perform is the Modified Hachinski Score – a score >0 means contribution from vascular areas is likely)

• Subtypes of VaD: o Binswanger’s disease: a form of vascular dementia with hypertension, dementia,

a pseudobulbar state (difficulty chewing, swallowing and demonstrate slurred speech), a gait disorder often of Parkinsonian type, transient ischemic attack (TIA), and multiple strokes; may have a hypercoagulopathy condition

o CADASIL: (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of hereditary stroke disorder; associated with mutation of the “Notch 3” gene on chromosome 19. Part of the inherited metabolic disorders called the leukodystrophies. Presentation includes migraine headache, transient ischemic attacks (TIA), and potential development of VaD. Other presentation is pseudobulbar palsy (present with difficulty chewing, swallowing and demonstrate slurred speech)

White matter lesions on MRI in VaD (multi-infarct dementia)

Other causes of dementia presentation:

• mass lesions • untreated hydrocephalus • untreated hypothyroidism • chronic alcoholism • Pick's disease (pre-senile dementia) • tertiary syphilis • chronic meningitis • AIDS • depression manifesting as “pseudo-dementia”

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MILD COGNITIVE IMPAIRMENT (MCI): • Now thought to actually represent early AD (used to be thought of as a normal variant of

aging) • Some assessment tests may help predict progression to AD, see:

http://www.ncbi.nlm.nih.gov/pubmed/27299935 Progression of brain findings from normal to MCI to Alzheimer dementia: From: Petersen RC. Mild cognitive impairment. N Engl J Med, 9 June 2011;364:2227-34.

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BASAL GANGLIA CONDITIONS: PD & Huntington’s Chorea Parkinsonism (Parkinson’s disease, PD): • Familial cause of brain degeneration and coordination difficulties with rest tremor • Risk factors:

o exposure to toxins such as pesticides (inhalation allows access to the brain via the olfactory bulb)

o see: http://parkinson.org/Understanding-Parkinsons/Causes-and-Statistics/Environmental-Factors

• Early variant: develops earlier in life o May be genetic associated with the Parkin gene o See: https://ghr.nlm.nih.gov/gene/PARK2#conditions

• Findings: o progressive rigidity including Cogwheel rigidity o bradykinesia (slow movements & difficulty moving & initiating movements) o rest tremor (disappears when the individual USES their hands to do something) o postural instability with abnormal gait o soft speech o mask facies (face does not seem to show normal emotional expression) o associated with depression and development of dementia of Lewy Body type

• Pathophysiology: o Decreased dopamine in the basal ganglia (substantia nigra neurons that project

to caudate & putamen). o These are normally inhibitory (dopaminergic) neurons, so that there is an

imbalance of too much cholinergic and GABA influence; lack of dopamine causes disinhibition & the symptom profile.

o Dopamine is inhibitory, so you see constant baseline increased muscle activity, leading to rigidity, tremor.

o There are multiple other symptoms (postural, glandular) & dementia due to improper feedback/effects on the hypothalamus & neuro/endocrine systems

o NIND info page: https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page

• Video: o Parkinsonian gait: https://www.youtube.com/watch?v=j86omOwx0Hk

• Hope for the future? o Recent studies have shown that dopamine therapies may induce some stem cells

in the brain to differentiate into neurons o These are specific dopaminergic drugs that stimulate D3 receptors in the brain o Another approach is transplantation of these stem cells into the brain and then

stimulate them to become neurons o A newer therapy is deep brain stimulation (DBS) – this is an AMAZING video:

https://www.youtube.com/watch?v=MEBdXbZ5CDM

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Huntington’s chorea (Huntington’s disease, HD): genetic illness • Autosomal dominant abnormality in the HD gene

o The HD gene provides instructions for making a protein called huntingtin o A mutation in which a DNA segment, known as a CAG repeat, is abnormally

expanded within the HD gene o Normally, this segment is repeated 10 to 35 times within the gene; in Huntington’s

the gene is expanded to repeat 36 to more than 120 times with production of huntingtin protein that contains a long stretch of the amino acid glutamine.

o Ultimately leads to the death of neurons and an imbalance in the basal ganglia, with overactive dopaminergic pathways

o Symptoms start in adulthood • Symptoms

o progressive chorea & dementia o See video of “Huntington’s Dance” (Chorea):

https://www.youtube.com/watch?v=KP7DaxZy7FY • Treatment:

o some drug treatments are designed to antagonize dopamine to slow progression, but there is no cure

• Diagnostics: o Prenatal testing is available (amniocentesis or CVS) to test for the gene o genetic testing can also be done on prospective parents with HD in the family

(they can decide whether or not to have a baby) • NIND info page: https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-

Information-Page

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PERIPHERAL NEUROPATHY: • Affect nerves after they leave the spinal cord but before they reach effector organ. Presentation: • Motor (weakness and muscle atrophy, decreased reflexes) • Sensory (numbness, paresthesias) effects. Workup: • Electromyelogram and nerve conduction (EMG/NC) • Porphyria • B12 deficiency • protein analysis • DM neuropathy • Nephropathy associated • Toxic (heavy metal) • LP analysis

o e.g. in Guillain-Barre see elevated CSF protein Guillain-Barre Syndrome (GBS) – a Polyneuropathy: • Usually follows a viral or bacterial infection (e.g. an upper respiratory infection or

pneumonia) • Thought to be immunologic in response to the infection – involving both humoral

(immunoglobulin) and cellular (T cell) activity • There is ascending polyneuropathy

o Can be pure motor, pure sensory, or both motor & sensory o Starts symmetrically in the lower limbs and ASCENDS o Eventually, will be unable to breathe and needs mechanical ventilation o The sensory neuropathy can also include dysesthesias and be extremely painful o Lumbar puncture and nerve conduction studies are done o Eventually the syndrome resolves, although in some people, there are persistent

recurrent episodes of motor and sensory dysfunction • Recent review article: Yuki N, Hartung HP. Guillain-Barre Syndrome. N Engl J Med 14

June 2012; 366(24):2294-304. At: http://www.nejm.org/doi/full/10.1056/NEJMra1114525

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Diabetic peripheral neuropathy (DPN): • Elevated glucose levels cause changes in body proteins since the glucose attaches to

proteins by the glycosylation (glycation) reaction and results in “glycation end products” • The patient complains of sensory deficit and painful dysesthesias and there also may be

motor components with resultant muscle atrophy • This neuropathy is distal (e.g. lower limb) & symmetric • This is probably the most common neuropathy in the USA • Associated findings in the lower extremity may include Charcot foot (joint abnormality from

reduced blood flow) and diabetic ulcers (also from diminished blood flow to the skin)

Graphics from (with permission): Vinik, A.I. (2016) Diabetic Sensory and Motor Neuropathy. New England Journal of Medicine, 374(15), 1455-64. DOI: 10.1056/NEJMcp1503948

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RADICULOPATHIES: Occur due to damage of spinal roots. MORE NEXT PAGE… • Pathophysiology:

o Can be inflammatory, traumatic (avulsion), compressive (tumor, disc, spinal stenosis), arachnoiditis, infectious.

o Inflammation = radiculitis o Physiologic effects: Decreased tendon reflexes, denervation atrophy, fatigue,

fasciculations. o Similar effects due to plexus injuries.

• Presentation: o The symptoms follow the innervation pattern by dermatomal distribution

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Dermatome levels & radiculopathy: • Sensory input from the body corresponds to the level their sensory afferents (peripheral

neuron processes) where they enter the spinal cord as a spinal nerve • Radiculopathy: • You will see sensory symptoms in the body area that correspond to any destructive

processes in vertebrae or spinal cord • Example:

o osteophytes of osteoarthritis (DJD) on the vertebral bones may “pinch” a spinal nerve and you’ll feel pain corresponding to that body region

o example – L4 osteophyte causing pain in the medial calf (see dermatome chart) o example – L2 herniated spinal disc causing pain in the buttock and anterior thigh o If the clinical problem also involves the motor outflow, the symptoms will also

include loss of motor function – extremely bad prognostic sign if there is motor involvement

Website allows you to click on the nerve’s name and see it’s cutaneous distribution: http://www.neuroguide.com/nerveindex.html absolutely fantastic !!

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Electromyogram (EMG) and Nerve Conduction (NC) Study: • These tests are usually ordered together • Used to determine if there are diseases or damage to the peripheral nerves • Records electrical activity of nerves AND muscles • Surface EMG/NC:

o use electrodes like the kind used in EEG and EKG o only gives good information about surface muscles o not useful in diagnosis of neuropathy

• Needle EMG/NC: o involves placing needle electrodes in the skin and measuring electrical conduction o may be painful for some patients (warn them)

• Usually done for diagnosis of: o peripheral neuropathy (e.g. DM) o radiculopathy (e.g. spinal stenosis) o polyneuropathies (e.g. inflammatory demyelination, hypothyroidism)

• EMG/NC website: https://teleemg.com/

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HEAD TRAUMA – TRAUMATIC BRAIN INJURY (TBI): Pathophysiology: • Traumatic injury to the brain physical, intellectual, emotional, social and vocational

changes • Definition:

o any physiological disruption of brain function that is traumatically induced o involves loss of consciousness (LOC) o loss of memory before (retrograde amnesia) or subsequent to injury

(anterograde amnesia) o any altered mental state at the time of diagnosis – feeling dazed, disoriented,

confused o any focal neurologic deficits on clinical exam (these may be temporary or

permanent) Examples of types of head trauma: • DAI (DIFFUSE AXONAL INJURY) (brainstem contusion):

o From shaking type injury or trauma involving rotational stresses. Think of MVA, shaken baby

o Diffuse cortical & brainstem damage (shearing stresses, torn blood vessels, torn neurons and axons).

o Pediatric Exam: Check retina for hemorrhages, bones for metaphyseal corner fractures,

bone scan for old multiple fractures think child abuse o Leads to most surviving disabled o Findings:

Coma > 6 hours (axonal disruption) Persistent cognitive, psychologic, and sensory/motor deficits may persist,

depending on extent of trauma. Severe DAI used to be called brainstem contusion

• FOCAL INJURY (CONTUSIONS): o Blunt (closed) or open (penetrating) trauma o Cause of most deaths from head trauma.

• COUP INJURY: o Blow to frontal skull

• COUP & CONTRE-COUP INJURY: o Blow to occipital skull & brain strikes inner lining of irregular shaped frontal

bones on rebound, causing frontal damage also. o Injuries leading to focal brain injury (contusions) usually result from a blow or

penetrating foreign object (e.g. bullet).

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CLINICAL Categories of diffuse brain injury are: • MILD CONCUSSION – also called “Mild TBI (mTBI)”:

o Temporary axonal disturbance with amnesia and LOC o Controversy – many feel that to be diagnosed as TBI (concussion) there needs to

be LOC; others do not require this for the definition o Duration of clinical findings is RESTRICTED to memory loss lasting less than 24

hours, altered mental state or LOC lasting less than 30 minutes; Glasgow Coma Scale (GCS) with score of 13-15 at 30 minutes post-injury

• CLASSIC CEREBRAL CONCUSSION (moderate or severe TBI): o MODERATE: LOC from 20 minutes to 6 hours and GCS of 9-12 o SEVERE: LOC of more than 6 hours and GCS of 3-8

Symptoms Post-trauma: • Relate to area and type of damage including psychiatric, endocrine, seizure as well as

cognitive and sensory/motor deficits • Observe in ER x hours for resolution of abnormal neurologic findings, admit if

focal/lateralizing signs or signs of increased ICP develop • Any associated fracture radiology workup & neurosurgical consult (except maybe for

hairline skull without neurological symptoms) • Responsible caregiver check x 24 hrs Q 2-4 hours for ICP symptoms Long-term symptoms:

• In some individuals, long-term symptoms will exist for years or indefinitely • Usually in moderate/severe TBI (sTBI) but can also occur in mTBI • Newer diagnostics:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm517526.htm • No real predictive tests, although some experimental diagnostics may help in the

future: https://www.nih.gov/news-events/news-releases/key-protein-found-have-role-long-term-complications-traumatic-brain-injury

NIND info page: https://www.ninds.nih.gov/Disorders/All-Disorders/Traumatic-Brain-Injury-Information-Page DoD info page (a lot of recent research has been done by the military): http://www.defense.gov/News/Special-Reports/0315_tbi CPG for mild TBI (mTBI) (2012): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303645/ CDC TBI & concussion: https://www.cdc.gov/traumaticbraininjury/index.html From the DoD: http://www.healthquality.va.gov/guidelines/Rehab/mtbi/mTBICPGFullCPG50821816.pdf and fact sheet http://www.dcoe.mil/files/Fact_Sheet_Summarizing_VA_DoD_CPG_mTBI.pdf and recommendations for neuroimaging following mTBI: http://dvbic.dcoe.mil/files/resources/2013_Neuroimaging_Recs_CR_07_08_13_1350.pdf and progressive return to function after mTBI: http://dvbic.dcoe.mil/files/resources/2014_PRA_PCM_CR_A3_FINAL.pdf Newer diagnostics? FDA-approved computerized testing

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ASSESSING THE UNRESPONSIVE PATIENT OR PATIENT WITH HEAD TRAUMA: • Many instruments to assess neurologic functioning and also assign prognosis • Glasgow Coma Scale (see below) • There are others as well, such as the Four Score Coma scale and more Glasgow coma scale for adults • Total score is range of: 3-15 • Minor head injury: 13-15 • Moderate head injury: 9-12 • Severe head injury (coma): 3-8 • Vegetative state: 3 • Persistent vegetative state (lasts >1month) • Brain death – specific criteria (see below)

Modified Pediatric Glasgow Coma Scale for Children under age 5 yo: SCORE 2 to 5 YRS 0 TO 23 Mos.

5 Appropriate words or phrases Smiles or coos appropriately 4 Inappropriate words Cries and consolable 3 Persistent cries and/or screams Persistent inappropriate crying &/or screaming 2 Grunts Grunts or is agitated or restless 1 No response No response

Other Scales to assess coma:

• Modified Pediatric coma scale: http://ilemsc.org/PTHI/PGCS_Form.pdf • “Four-Score” coma scale: http://www.coma.ulg.ac.be/images/four_e.pdf • Review article on more coma scales: http://www.scielo.br/pdf/anp/v68n6/19.pdf

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“POSTURING” AS A CLUE TO PATHOLOGY: Seen with brain tumors as well as TBI • Decorticate posturing

o With death of cortex (flexion/adduction of upper limbs & extension with plantar flexion in lower limbs)

o UMN not inhibiting brainstem anti-gravity position. • Decerebrate posturing

o With lower brainstem injury + cerebral damage (all four extremities in rigid extension, & hyperpronation upper limbs and plantar flexion of feet)

o Wverstimulation of postural righting and vestibular reflexes. ALTERATIONS OF MUSCLE TONE AND MOVEMENT AS CLUES TO NEUROLOGIC PATHOLOGY: • Hypotonia (reduced overall muscle tone) • Hypertonia (and/or spasticity with hyper-reflexia & clonus, and/or rigidity) • Paralysis (diplegia, paraplegia, hemiplegia, quadriplegia) • Weakness (paresis) • Hyperkinesia (choreas) • Tardive dyskinesia (drugs that bind to dopamine receptors mimic the action of too much

dopamine with stereotypic movements) • Hypokinesia (akinesia, bradykinesia).

Decorticate posturing (top) Decerebrate posturing (middle) Mixed (bottom)

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NEUROLOGIC DEATH: • Cerebral Death:

o Irreversible coma from damage to cerebral hemispheres (but not brainstem or cerebellum).

o Lower functions (breathing, heart, temp, GI) are maintained. • Brain Death:

o Irreversible brain damage. o Coma, no spontaneous respiration (apnea), absent spinal/brainstem reflexes

and dilated/fixed pupils, flat EEG. o Brain usually is self-autolyzing o Often evaluating for the possibility of organ donation

Assessment of brain stem function to determine brain death:

• oculocephalic reflex – the normal reflex results in conjugate gaze (don’t do this if suspect cervical spine injury – the head needs to be moved from side to side)

o When turning the head to one side, the eyes turn to the other side to maintain the visual axis straight ahead

o This is a positive reflex and indicates an intact brainstem o If this reflex is LOST, then the eyes move along with the head and there is likely

brainstem damage o Other tests also may be used o See animation at:

http://library.med.utah.edu/kw/animations/hyperbrain/oculo_reflex/oculocephalic2.html (press the “play” button)

• Other brainstem reflexes: o Iris contraction o Consensual contralateral constriction of pupil o Ciliospinal reflex (pinch skin on back of neck -- pupil dilates) o Corneal reflex o Orbicularis oculi (eyelids close with retinal exposure to bright light) o Auditocephalogyric reflex (head/eyes turn towards loud sound) o Jaw reflex (pons) o Gag reflex (medulla).

• CPG on determination of brain death in infants & children: http://www.ncbi.nlm.nih.gov/pubmed/21849823 and http://pediatrics.aappublications.org/content/128/3/e720.full a

• Example – policy guide on determining brain death (NY State Dept. of Health): http://www.health.ny.gov/professionals/hospital_administrator/letters/2011/brain_death_guidelines.htm

• Example – brain death determination process at UC San Diego: http://surgery.ucsd.edu/som/surgery/divisions/trauma-burn/training/protocols/Documents/Brain_Death_Process.pdf

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“LOCKED-IN” SYNDROME (LIS): Presentation • Arousal level and cognitive function are intact with upper CN also preserved (CN I - VI) • Patient can look up & blink – that’s all they can do! • Locked-in syndrome (LIS) has been described as "paralyzed and voiceless" • May be confused with a "vegetative" state if not diagnosed correctly. • Usually, the reason for developing LIS is due to traumatic brain injury (TBI), but also may

be caused by various neurologic disorders (such as Guillain-Barre syndrome), ALS, or even vascular (blood vessel) disorders such as thrombosis (blood clot) in the basilar artery.

Pathology: • An interruption of the motor (movement) impulses sent from the brain cortex to the spinal

cord, so those impulses can't "make it out" to the body. • If patients can retain control over a few motor functions, usually those in the very upper

part of the body (such as eye blinking), then it is obvious they are not in a coma. • But not all can retain even this minor control of movement. • No medications, surgery or other treatments to "reconnect" the cortex with the spinal cord. Patient care: • The idea of living with almost full body paralysis, while having normal cognitive function

and awareness, sounds like a nightmare to most people. • Bias exists in that caregivers assume the individual wishes to die – but those with LIS

often self-report good quality of life (Bruno, et al., 2011): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191401/

• Advances in technology: o Years ago, someone had to stand at the bedside with an alphabet board and the

patient used eye blinks (one blink: yes, two blinks: no) to pick out letters to spell words.

o Now, eye-tracking can pick out letters on a screen using "brain-computer interface" (BCI) technology: http://www.bltt.org/software/dasher/ and http://www.npr.org/2014/10/26/359081510/electrode-cap-helped-locked-in-patient-get-his-thoughts-out and https://www.technologyreview.com/s/534206/a-brain-computer-interface-that-works-wirelessly/

For a review of such technology, see (Shih, Krusienski & Wolpaw, 2012): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497935/ Figure 2 of this article shows the technology behind BCI

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Example of brain-computer interface for LIS: From: Vansteensel, MJ, et al. (2016) Fully implanted brain-computer interface in a locked-in patient with ALS. N Engl J Med, 375(21), 2060-2066.

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UNRESPONSIVE WAKEFULNESS SYNDROME (“Vegetative” state): • This is NOT brain death • No life support needed

o Brainstem/spinal reflexes are intact (including chewing, pupils, swallowing, etc) o There are sleep/awake cycles. o No discrete motor response to stimuli, or intelligible speech.

• Usually results from trauma DO NOT USE the word “vegetable” – that is a derogatory term – a layperson misinterpretation of our clinical term “vegetative.” SPINAL CORD TRAUMA: • Fractures, hematomas and herniations • Can result in cord concussion (temporary) or cord contusion (temporary) as well as

compression, laceration, transections (complete/incomplete), hemorrhage, obstruction to blood flow & ischemia.

• Immediate sequelae includes edema, with worsened prognosis o In the past, high-dose IV methylprednisolone (corticosteroids) was used in the

attempt to reduce edema. However, this intervention was not found effective and in fact may be linked to higher rate of adverse events, so no longer recommended

o See: https://spinalcordresearchandadvocacy.wordpress.com/2013/03/21/congress-of-neurological-surgeons-recommends-against-use-of-steroids-in-acute-spinal-cord-injury/

Impairment scale for traumatic spinal cord injury From: Ropper AE & Ropper AH (2017) Acute spinal cord compression. N Engl J Med, 376(14), 1358-69. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMra1516539 (good overview article)

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SPINAL SHOCK & AUTONOMIC HYPER-REFLEXIA (DYSREFLEXIA): • After sudden (acute) destruction of pyramidal system (e.g. cord injury). • Complete absence of spinal cord functions below the level of the lesion & absence of

normal autonomic feedback. Findings: • Hyperactive reflexes and autonomic hyper-reflexia (abnormally increased intensity of ANS

reflexes – there is no input from the brain or anything above the lesion) • Cardiovascular responses of HTN, H/A, bradycardia, nausea can be life-threatening. • Unusual combination of bradycardia with HTN. Pathophysiology: • Autonomic Dysreflexia (also called autonomic hyperreflexia) is usually caused when a

painful stimulus occurs below the level of.spinal cord injury. • Peripheral sensory receptor stimulation (e.g. distended bladder) causes a reflex ANS

response without the normal coordinating and suppressive feedback control from the UMN and spinal cord reflexes.

• RECALL the Normal Reflex Arc: o Stimulus (bowel/bladder distension) sensory impulse via spinothalamic tract travels

to the CNS and causes reflex o Efferent corticospinal tract (SOMATIC) & lateral horn (AUTONOMIC) neurologic

outflow to complete the reflex arc and o Rinal effector action (bladder empties).

• Blocked Reflex Arc Causes Autonomic Hyperreflexia: o Some stimulus (e.g. full bladder) sends afferent signals via spinothalamic tract to

spinal cord, but sensory impulse cannot travel fully up the spinal cord to the CNS since the flow is blocked at the level of cord damage.

o Meanwhile, intact autonomic reflexes below the damage level send efferent sympathetic outflow (reflexive response to stimulus)

o Results in system-wide vasoconstriction with HTN, pallor, pilomotor spasm resulting from baroreceptor stimulation (CN IX afferent) and vagus CN X (parasympathetic) activation causing bradycardia.

• Lack of normal compensatory efferents: o Normally, additional autonomic response is sent down the cord to cause arterial

vasodilatation, flushing, sweating (sympathetic cholinergic, blockage of alpha receptors on blood vessels)

o BUT due to cord blockage, these additional compensatory efferent impulses never make it out to the effector organs.

• Final result: o <edical emergency with bradycardia (mediated by cranial nerve loop above the

spinal cord lesion), HTN (lower spinal reflex arc below the spinal cord lesion). o Normal negative feedback does NOT occur to stop either the bradycardia or the

HTN. o Treatment -- stop the reflex arc loops by ending the primary initiating stimulus (e.g.

empty the full bladder!) See next page…picture tells the whole story

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Follow the sequence of events from numbers 1, 2, 3, 4 on the picture

Possible reasons that trigger this response: • Bladder (most common): from overstretch or irritation of bladder wall

Urinary tract infection, Urinary retention Blocked catheter, Overfilled collection bag Non-compliance with intermittent catheterization program

• Bowel – over-distension or irritation: Constipation / impaction Distention during bowel program (digital stimulation) Hemorrhoids or anal fissures Infection or irritation (eg. appendicitis)

• Skin-related Disorders: Any direct irritant below the level of injury (e.g. prolonged pressure by object in shoe or chair, cut, bruise, abrasion), Pressure sores (decubitus ulcer), Ingrown toenails Burns (eg. - sunburn, burns from using hot water) Tight or restrictive clothing or pressure to skin from sitting on wrinkled clothing

• Sexual Activity/ stimulation and OB/GYN: Over stimulation (stimuli to the pelvic region which would ordinarily be painful if sensation were present) Menstrual cramps, Labor and delivery

• Other: Heterotopic ossification, Acute abdominal conditions (gastric ulcer, colitis, peritonitis), Skeletal fractures

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DISORDERS OF ACETYLCHOLINE AT THE NMJ: Lambert-Eaton myasthenic syndrome (LEMS): (disorder of ACh release) • Rare disorder • Presynaptic neuron condition – release of ACh is impaired • Symptoms:

o Proximal muscle weakness, depressed DTRs, post-tetanic potentiation, autonomic conditions

o Similar to myasthenis gravis o facilitation is strength improvement after exercise and is seen with this syndrome

• Pathology: o Autoimmune attack against the voltage gated calcium channels (VGCC) on the

presynaptic neuron so that less ACh is released; possibly due to “cross-linking” of calcium channels

o Since stored ACh is preserved, rapid repetitive stimulation can release enough ACH for muscle contraction

o Normally seen with cancer patients, especially small-cell lung cancer (SCLC) • Diagnosis:

o EMG, antibodies to VGCC • Course of illness: progressive weakness, and death from the underlying cancer • Pharmacologic correlations:

o Avoid neuromuscular blocking agents, aminoglycoside antibiotics, magnesium, iodinated IV contrast agents, calcium channel blockers

o Treatment includes acetylcholinesterase inhibitors (e.g. pyridostigmine/Mestinon); an orphan drug called DAP (3,4-diaminopyridine) that improves ACh release; immunosuppressants (e.g. corticosteroids, IVIG)

• Rare diseases info page: http://rarediseases.org/rare-diseases/lambert-eaton-myasthenic-syndrome/

• NIND info page: https://www.ninds.nih.gov/Disorders/All-Disorders/Lambert-Eaton-Myasthenic-Syndrome-Information-Page

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Pseudocholinesterase Deficiency: (disorder of cholinesterase enzyme – ENZYME disorder) • Cholinesterase enzymes consist of several enzymes that degrade ACh • In tissues (at the synapse) and circulating in plasma • Include butylcholinesterase, acetylcholinesterase • Pseudocholinesterase is an enzyme that has no known physiologic function, however • Pharmacologic correlate:

o Pseudocholinesterase hydrolyzes succinylcholine o 95% of an IV dose is hydrolyzed before reaching the NMJ; the effect on the NMJ is

from the remaining 5% (causing prolonged depolarization of the NMJ and flaccid paralysis of the skeletal muscle within one minute)

o Normally, the muscle returns to normal about 5 minutes later o Pseudocholinesterase deficiency can result in delayed return to normal by up to 8

hours • Pathology:

o Allelic inheritance of defective genes o Acquired causes – infections, burns, liver disease, cancer, malnutrition, uremia,

organophosphate pesticide poisoning o Also may be caused by drugs – acetylcholinesterase inhibitors, beta-blockers,

chlorpromazine, contraceptives, metoclopramide, MAOIs • Diagnosis: pseudocholinesterase enzyme assay • Treatment:

o Fresh frozen plasma (FFP) can be administered prophylactically, but raises risk of transfusion infection or complications

o Note that if the patient received FFP prior to surgery, it can “mask” a pseudocholinesterase deficiency syndrome

o Treatment includes mechanical ventilatory support until respiratory muscle paralysis resolves (succinylcholine just passively diffuses away from the NMJ)

o Another approach is to use cholinesterase inhibitors, but this may result in a transient improvement, followed by severe prolonged paralysis – so is considered a controversial approach

• There is an opposite syndrome where the patient doesn’t respond at all to succinylcholine – a genetic variant (C5 variant) with more than normal enzyme, and they are resistant to the effects of succinylcholine

• Cautions: adequate preop history, monitor electrical titanic stimulation under succinylcholine administration, monitor respiratory function to be sure of adequate spontaneous ventilations

• Other: these patients may be at increased risk of sudden cardiac death when using cocaine

• Followup: notify blood relatives to get pseudocholinesterase testing; wear Medic-Alert bracelet

• Genetics Home Reference Info Page: https://ghr.nlm.nih.gov/condition/pseudocholinesterase-deficiency

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Myasthenia Gravis: (disorder of AChR – acetylcholine RECEPTOR disorder)

• Rare disorder • It is not a “single” disease but exists in multiple subgroups with varying involvement of

organ systems • Good overview (Gilhus, 2016): http://www.nejm.org/doi/full/10.1056/NEJMra1602678

• Pathology: o Autoimmune attack against nicotinic ACh receptors (AChR) at the NMJ o Thus, autoantibodies are present against AChR o Many have thymus disorders as well o Male:female ratio is 2:3

• Symptoms & Complications:

o Progressively reduced muscle strength with repeated muscle use, then improvement after rest

o Symptoms start once number of AChR is 30% of normal o Complications include aspiration, pneumonia, and falls/fractures o Often only the bulbar (eye) muscles are affected (in 15% only ocular symptoms are

present) o Severe cases have slack facial muscles, neck weakness, absent gag reflex o If unable to clear bronchial secretions may also have wheezes/rhonchi o Cholinergic crisis can occur from excess medication o DTRs are preserved

• Neonatal Transitory Myasthenia Gravis: if born to a mother with MG

o Antibodies crossed over placenta; symptoms last for 1 - 10 weeks, treat supportively until abates (otherwise treatment is similar)

• Diagnosis:

o Edrophonium (Tensilon) test (monitor for bradycardia, heart block, asystole) o Ice-pack test (cooling muscles may restore muscle function)(e.g. place ice over

ptotic eyelids and ptosis resolves in 80% of cases) o AChR antibodies

Ice pack test (from NEJM 2016): http://www.nejm.org/doi/full/10.1056/NEJMicm1509523

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• Some drugs can cause exacerbations: o Antibiotics (macrolides, fluoroquinolones, aminoglycosides, tetracycline) o Anti-arrythmics (beta-blockers, calcium channel blockers, quinidine, lidocaine,

procainamide) o Other (lithium, diphenylhydantoin, chlorpromazine, muscle relaxants, levothyroxine,

ACTH, corticosteroids)

• Treatment and management: o Cholinesterase inhibitors (neostigmine, pyridostigmine, physotigmine) to keep more

ACh at the synapse Complication of cholinergic crisis with excess ACh effect – flaccid muscle

paralysis, bronchospasm, diaphoresis, cyanosis, respiratory failure and SLUDGE syndrome (salivation, lacrimation, urinary incontinence, diarrhea, GI upset, hypermotility/emesis)

o Airway and intubation: if airway management needed, test for gag reflex – if present, oral airway can be used If need to intubate, rapid sequence intubation must be modified – do not use

depolarizing paralytics like succinylcholine (unpredictable results), instead use a rapid-onset nondepolarizing drug (rocuronium/Remuron, vecuronium/Norcuron)

o Thymectomy (surgical removal of thymus gland), see: http://www.nejm.org/doi/full/10.1056/NEJMoa1602489

• NIND info page: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-

Sheets/Myasthenia-Gravis-Fact-Sheet • Rare diseases info page http://rarediseases.org/rare-diseases/myasthenia-gravis/