COMMON WORK-UPS

ALTERED MENTAL STATUS / DELIRIUM

Nick Szumski, MD. Reviewed by Joanna Jen, MD, PhD. 6/05 Ruben Guzman 5/10

This is probably the one of the most common consults here at UCLA.

Key historical points: Acuity (acute/subacute/chronic), onset (gradual/sudden/stepwise), progression (waxing and waning/fixed), associated features (hallucinations, hemiparesis, medication schedule), recent complaints (severe headache, stiff neck, chest pain). Why is patient in hospital? Any suggestion of cardiac, renal, or liver disease? Any recent surgery? Any new or change in medication?

Delirum risk factors: old age, underlying dementia, cardiac or orthopedic surgeries, ICU setting, decreased vision or hearing.

I. Commonly cited etiologies of delirium:

* Disease states:

- Vascular: SDH, stroke, ICH or SAH

- Infection: UTI, PNA, sepsis, encephalitis, meningitis

- Toxic: intoxication and overdose

Witdrawal (etoh, benzos, barbiturates, opiates)

- Trauma: concussion

- Autoimmune: SLE, Hashimoto’s encephalopathy, autoimmune limbic encephalitis, (abs against VGKC, NMDA, AMPA).

- Metabolic:

Electrolytes: hypo/hyperNa, Hypercalcemia, hypermagnesemia, hypophosphatemia.

Endocrine: hypo/hyperparathyroidism, hypo/hypercortisolism, hypo/hyperglycemia,

Hepatic encephalopathy

Uremic encephalopathy

Hypoxia and hypercarbia

Vitamin deficiencies: thiamine, B12

Malnutrition (albumin <2)

Dehydration: BUN/creatinine ration > 18

- Neoplastic:

Large brain tumors, carcinomatous meningitis

Paraneoplastic limbic encephalitis (abs vs Ma2, Hu, CV2/CRMPS, amphiphysin, VGKC, NMDA and AMPA receptors).

- Seizures: postictal state, nonconvulsive status epilepticus

- Structural: hydrocephalus

- Degenerative: dementia with Lewy bodies, other neurodegenerative

disorders usually are risk factors for delirium but another inciting cause is

present.

- Psychiatry disease: in older adults this is rarely the cause.

* Iatrogenic precipitants:

- Restraints

- Urinary catheters

- Multiple procedures

- Sleep deprivation

- Untreated pain

- Drugs: any drug with anticholinergic properties, benzodiazepines, opiates,

antihistamines, antiepileptics, muscle relaxants, dopamine agonists, MAOi,

levodopa, steroids, NSAIDS, fluoroquinolones, cephalosporins, beta-blockers,

digitalis, lithium, calcineurin inhibitors.

- Surgery: thoracic (cardiac and noncardiac), vascular, hip replacement.

Source: continuum 2010; 16(2)

II. Key physical exam points:

Vital signs: Fever? Tachypnea? Tachycardia? Hypotension?

Signs of trauma (especially if “found down”)?

Meningismus (Kernig’s/Brudzinski’s)

Rash (e.g. meningococcal or viral exanthema)?

Stigmata of heart failure (crackles)? Lung disease (clubbing)? Liver disease (caput, icterus/jaundice, asterixis)?

Papilledema and other signs of possible increased ICP (4^th/6^th nerve palsies)?

Abnormal movements (e.g. subtle hand/face twitching which may indicated non-convulsive status epilepticus)?

Focal findings on neurologic exam? (Don’t miss the “blown pupil”!)

Check alertness, orientation, attentiveness (try digit span or count backwards from 20 to 1)

o Lethargic – does not become fully alert, conversant but inattentive

o Stuporous – does not completely arouse to painful stimuli, little or no verbal response, may briefly obey commands when aroused by painful stimuli

o Comatose – no verbal or complet motor rexponses to any stimulus.

III. Basic approach to delirium:

Step 1 (all patients):

Assesment of airway, breathing and circulation; vital signs; blood glucose

level. If blood glucose low administer 100mg IM thiamine and then dextrose 1amp D50; consider

naloxone in the possibility of opiate overdose.

Step 2 (all patients)

- History (special attention to baseline cognitive status, medications,

symptoms of infection).

- Physical examination (special attention to signs of infection, careful

neurologic examination to rule out a focal deficit).

- CBC with diff, chem 10, Lytes including Ca, Mg, Phosp., LFTs including

albumin, UA and culture, blood cultures, urine toxicol screen, blood EtOH,

- CXR, ABG if indicated, EKG.

Step 3 (guided by findings on the initial evaluation).

- Brain imaging with MRI with diffusion and gad or CT

- Lumbar puncture (immediately after imaging if suspicion for meningitis).

Opening pressure, cell count with diff (tubes 1 and 4), glucose, protein,

viral/fungal /bacterial cultures. Consider VDRL, HSV-PCR, lyme ab, cocci

ab, AFB stain/culture, India inf prep base on clinical suspicion.

Step 4 (guided by findings on the initial evaluation).

- Serum ammonia, morning cortisol, thyroid function test, B12/folate, RPR

(reversible dementia labs, for chronic cases, consider checking MMA and

homocysteine).

- Sedimentation rate, autoimmune serologies, thyroperoxidase and

thyroglobulin abs.

- Extended toxicology screen: consider blood draw for medication levels:

phenobarbital, phenytoin, carbemazepine, valproic acid (does this patient

have epilepsy?); lithium, tricyclic antidepressants (does this patient have

access to psych medications?).

- EEG (perform sooner if high suspicion for convulsive or nonconvulsive

status epilepticus).

Source: continuum 2010; 16(2)

IV. Treatment:

·Treat the underlying cause if known (e.g. Abx, O₂, diuresis, AED’s, etc.)

·Good empirical ideas:

o Thiamine 100mg IM. Especially if patient history unknown, or includes EtOH use. Always give PRIOR to glucose to avoid precipitating Wernicke’s encephalopathy.

o 1 amp D50: Always give thiamine first.

o Consider Naloxone 1 amp (safe), flumazenil 0.2mg (repeat q 1 min up to 1mg – risk of precipitating benzo withdrawal seizures)

· If febrile, consider empiric CSF coverage: Rocephin, Vancomycin, ampicillin (Listeria), acyclovir as indicated. Don’t hold for LP if delayed.

· If signs of increased ICP, then scan before LP and consider mannitol (1-2g/kg bolus, 0.5-1g/kg q6h), Lasix, intubation -- hyperventilation (goal pCO₂ = 30)

· If medications must be used in the treatment of delirium antipsychotics are the drug of choice, just remember there is a FDA’s black box warning of increased mortality in elderly patients. Try to avoid the use of benzos for management of agitation since this may disinhibit more the pt in the setting of agitation and in the elderly.

· Recommended meds:

Haloperidol: 0.5 mg to 1 mg BID: can also be gien IM. PO dose may be repeated after 4 hrs and IM dose after 60 min.

Seroquel: 25 mg BID. Case series demonstrating safety and probable efficacy. Often used for pts with baseline extrapyramidal syndromes.

V.Things to keep in mind:

· Usual players: anoxia/hypoxia, renal/hepatic dysfunction, CNS infection, systemic infection, medication overdose or side effect, drugs of abuse, hypoglycemia, metabolic derangement, UTI, exacerbation of underlying dementia or psychiatric disorder, sundowning, sleep deprivation, sensory overload or deprivation.

· DO NOT miss these:

o Verbal paraphasias? Poor understanding? -- Rule out stroke/bleed causing Wernicke’s aphasia.

o Ophthalmoplegia of any kind? Ataxia? EtOH history? -- Rule out Wernicke’s encephalopathy (thiamine 100mg IM is ALWAYS a good empiric idea)

o Subtle twitching? History of seizures? -- Rule out non-convulsive status

ANTIBODIES – Paraneoplastic

Steve Sykes, MD

Anti-Hu (ANNA-1)

Sensory neuronopathy, limbic encephalitis (and encephalomyelitis), cerebellar degeneration, autonomic dysfunction

Small-cell lung, neuroblastoma, prostate

ANNA-3

Sensory neuronopathy, encephalomyelitis

lung

Anti-Yo (PCA-1)

Cerebellar degeneration (Targets Purkinje cells)

Ovarian, breast, lung

Anti-Ri

Ataxia, +/- opsoclonus-myoclonus

Breast, gynecologic, lung, bladder

Anti-Ma1

Brain stem encephalitis, cerebellar degeneration

Lung, other

Anti-Ma2

Limbic brain stem encephalitis

Testicular

Anti-MAG (myelin-associated glycoprotein)

Peripheral neuropathy

Waldenstrom’s macroglobulin-emia

Anti-Tr

Cerebellar degeneration

Hodgkin’s lymphoma

Anti-amphiphysin

Stiff person syndrome, encephalomyelitis

Breast, small cell lung

Anti-VGCC (voltage gated calcium channel)

Lambert-Eaton myasthenic syndrome

Small cell lung

Anti-retinal (anti-recoverin)

Retinopathy

Small cell lung, melanoma, gynecologic

Anti-CRMP5 (anti-CV2, collapsin response mediator protein-5)

Encephalomyelitis, cerebellar degeneration, chorea, sensory neuropathy

Small cell lung, thymoma

Anti-PCA-2

Encephalomyelitis, cerebellar degeneration, Lambert-Eaton syndrome

Small cell lung

Anti-mGluR1

Cerebellar degeneration

Hodgkin’s lymphoma

Anti-VGKC (voltage gated potassium channel)

Neuromyotonia (Isaac’s syndrome)

Thymoma, small cell lung

Sources: 1. Darnell, et al. Paraneoplastic syndromes involving the nervous system. NEJM, October 2003.

2. Geyer, et al. Neurology for the boards, 2002.

ANTIBODIES – Miscellaneous

Steve Sykes, MD. Updated by Sarah Kremen, MD.

Anti-GM1 (ganglioside)

GBS (Miller-Fisher variant),

multifocal motor neuropathy

Anti-GQ1b

GBS (Miller-Fisher variant→opthalmoplegia, ataxia)

Anti-Sulfatide

Axonal sensory neuropathy

Anti-Jo

Polymyositis

Anti-AChR, Anti-MuSK (muscle specific receptor tyrosine kinase)

Myasthenia gravis

Associated with thymoma

SSA (Ro), SSB (La)

Sjogren’s

Also seen in SLE

Anti-GAD

Stiff-person syndrome

May be seen with Type 1 DM

Anti-thyroglobulin, anti-thyroid peroxidase, anti-thyrotropin receptor

Hashimoto’s encephalitis

May be euthyroid despite presence of encephalitis and antibodies

Anti-gliadin

Cerebellar degeneration

Seen in celiac disease

Darnell, et al. Paraneoplastic syndromes involving the nervous system. NEJM, October 2003.

Geyer, et al. Neurology for the boards, 2002.

APHASIA

Dan Arndt, MD and Susan Shaw, MD. Reviewed by Mario Mendez, MD, 6/06 .

Perisylvian – Broca’s, Wernicke’s, Global

Wernicke’s: Fluent (regular speed) nonsensical syllables

Broca’s: Broken, Often w/ agramatism paraphasia

Extrasylvian – Watershed areas, Transcortical lesions

Transcortical Motor: Frontal, outside L peri-Sylvian region

Transcortical Sensory: Temporoparietal, outside L peri-Sylvian region

Repetition Aphasia: L peri-Sylvian regions

Mixed Transcortical Aphasia: Somewhere in circuit

Anomic Aphasia: Anywhere-L hemi, Ang or Supramarg Gyrus, Temp (Spec Category loss), also BA37, post-temporal

Repetition – Arcuate Fasiculus (Wernicke’s to Broca’s)

Fluency

Fluent

Words/min >100

Phrase length 5.8 words/phrase

Agrammatism Absent

Content Empty/Paraphrasic

Effort NL

Speech NL

Nonfluent

Words/min <50

Phrase length 1.2 words/phrase

Agrammatism Present/Telegraphic

High content words

Effortful/Hesitant

Speech Dysarthric/Dysprodia

Paraphasic Errors:

Semantic: similar meaning to intended word (ie. mother/wife)

Word Substitution: unrelated to intended word

Phonological (Literal): Sound structure <50% erroneous

Neologistic: Word >50% erroneous

Spoonerisms: syllable transposition btw words (‘bood goy’ for ‘good boy’)

Bi/Multilingual – different aphasia patterns. Parallel is most common.

Prosody/Aprosodia:

R hemi – Singing/Amusia (Tone deafness, Monotone, No recognition)

Basal Ganglia–Pledge of Allegiance, count to 10, curse words. Better rep.

Differential Diagnosis:

Aphemia (Frontal Operculum): – Post-language deficit in speech production. Nonfluent verbal output. NL read/writing/comprehension. Distinguish from Broca’s.

Thalamic: Sensory

Basal Ganglia (Subcortical): Stuttering/Difficulty initiating

SMA: Stuttering/Difficulty initiating.

Motor Praxis: Lip/tongue vs. motor mov’ts.

Primary Auditory Deafness (Superior to Wernicke’s in W.M.): NL Reading

Pure Word Deafness (Wernicke’s to Broca’s intact): Pre-language auditory deficit. Cannot understand meaning of words. NL read, write, comp. Distinguish from Wernicke’s.

Schizophrenia: word salad, consistent linguistic errors, has a theme (versus jargon aphasia, which has no fixed linguistic errors and no theme)

Prognosis: Recovery Variables

Age: younger age better recovery than older age

Lesion size

Gender: Female better than male (bilaterality of language)

Type of aphasia

Handedness: Left handed vs right-handed

BELL’S PALSY Susan Shaw, MD, updated by Brandon Hirota, M.D. 6/08

Syndrome

CN7 inflammation within the facial canal

Acute unilateral facial paralysis, equal involvement of upper and lower.

May have loss of taste in anterior 2/3 of tongue ipsilaterally.

Diagnosis

Diagnosis is clinical.

Differential Diagnosis:

cerebellopontine angle tumor – decreased hearing or efferent corneal reflex. Obtain MRI with gadolinium.

Ramsay Hunt – ear pain, vesicles in external auditory canal. Reactivation of latent VZV in geniculate ganglion on ipsilateral side.

Lyme disease – rash or tick bite. Swelling or erythema of face. Check Lyme titers, CSF for antibodies.

Middle ear infection

Sarcoidosis – consider especially if paralysis is bilateral.

Others: HIV, Sjogren’s, facial nerve tumor, iatrogenic

Treatment

(NEJM 2007; 357(16): 1598-607)

- Benefit seen with prednisolone tx started within 3 days of onset

- No benefit seen with acyclovir in combination with prednisolone

(Otol Neurotol. 2007; 28(3): 408-13)

– Benefit seen with valacyclovir in combination with prednisolone, tx started within 7 days of sx onset

(Uptodate.com)

- Rec prednisone 60-80mg/day x 1 week

- In severe cases, suggest prednisone 60-80mg/day in combination with valacyclovir 1000mg TID for 1 wk

COMA PROGNOSIS Nick Szumski, MD and Sarah Kremen, MD. Reviewed by Joanna Jen, MD, PhD, 6/06, Edited by Hermelinda Abcede, MD 5/09

“Levy criteria”

Helpful starting point, but old, limited data on specific populations – USE WITH CAUTION.

Link:

Glasgow Coma Scale:

Eye opening (1 – None; 2 – To pain; 3 – To voice; 4 – Spontaneous)

Best verbal (1 – None; 2 – Sounds; 3 – Inappropriate words; 4 – Disoriented; 5 – Oriented)

Best motor (1 – None; 2 – Extensor (decerebrate) posturing; 3 – Flexor (decorticate) posturing; 4 – Withdrawal; 5 – Localization; 6 – Obeys commands)

Not typically useful for our purposes in acute situations (helps neurosurgeons)

May provide prognostic information: After cardiac arrest, 48-hour GCS of 3-4/15 was found in one study to lead to 53/54 death/coma/PVS, 1/54 awakening with recovery.

EEG: The following patterns in a comatose patient typically portend a poor prognosis: burst suppression, diffuse low voltage, alpha coma, or electrocerebral inactivity, and in some cases, periodic lateralized epileptiform discharges (PLEDs). After a hypoxic-ischemic event and resuscitation, the EEG may change significantly within the first hours to several days. In general, a faster return to a normal pattern is a more positive sign for some recovery. EEG is susceptible to medication and hypothermia.

SSEP: Cortical median nerve potential (N20) absence provides >95% poor prognosis. If N20 is present, then ability tdetermine prognosis is less clear. SSEPs are not affected by medications but are affected by hypothermia.

See Koenig, et al. Neurol Clin 24 (2006) 89–106 for review of EEG/SSEP in prognosis after resuscitation.

Brain Death:

Before asking question, must have:

Proximate, known cause of state that is untreatable

Metabolic derangements as normalized as possible

Nsedative drugs on board

Core temperature >32 degrees C.

Demonstrated by:

Lack of responsiveness tall stimuli (spinal reflexic triple flexion may persist)

Nbrainstem reflexes (pupillary, corneal, oculocephalic/Doll’s eyes, vestibuloocular/cold calorics, jaw jerk, grimace, gag, cough). Triple reflex is allowed, but if patient is posturing, they are not braindead.

Apnea test (respiratory therapists are trained tdthis):

- ABG tconfirm pCO2 of 35-45; preoxygenate with 100% O2; disconnect from vent with blowby O2; monitor for 4-6 minutes for spontaneous breathing; redraw ABG tconfirm pCO2 >55 at end of test.

- Stop if arrhythmia, hypotension, desaturation.

- Two exams spaced 6-24 hours apart by separate MD’s. In the state of California, you need twlicensed physicians tdeclare brain death. There is nrequirement that one needs tbe a neurologist.

Confirmation by EEG, angiography, PET, SPECT, or Transcanial Dopplers may be considered in certain cases (for example, in cases where it may be difficult tverify loss of oculocephalics in pt with c-spine injury).

When documenting brain death, the following must be in the note: absence of: motor response tnoxious stimulation, pupillary light response, corneal, gag, oculo-vestibular reflex, absence of spontaneous breathing.

See AAN Guidelines, gto: http://www.aan.com/professionals/practice/guideline/index.cfm

CEREBROSPINAL FLUID STUDIES Sarah Kremen, MD. Reviewed by Callene Momtazee, MD, 6/06. Updated by Brandon Hirota, MD, 6/08 Always get: opening pressure, cell count/diff, protein, glucose

Normal values:

ICP: 60-195mm H2O. With increased ICP, may see Cushing’s triad: hypertension, bradycardia, respiratory slowing. Intracranial hypertension can cause cardiac arrhythmias, neurogenic pulmonary edema, and stress ulcers

Cells: 0-5, mononuclear; nPMNs; PMNs more indicative of bacterial infection, lymphocytic more indicative of TB (later), viral, GBS, Neoplasm; monocytic more indicative of viral, fungal, neurosyphilis. Fudge factor of 1WBC per 1000 RBC in a traumatic tap.

Protein: Normal 15-45. Elevated protein signifies breakdown of blood brain barrier. Protein levels increase caudally slab’s normal values for ventricular/cisterna magna will be inaccurate. May alssee elevation in Froin syndrome, diabetes, neonates. Fudge factor of 1mg/dL per 1000 RBC in a traumatic tap.

Glucose: Normal 45-80. (2/3 of serum glucose level). Higher values can be seen in newborns and hyperglycemia. Causes of low glucose: Acute purulent and syphillitic and acute/chronic TB, and fungal meningitis, mumps, HSV and VZV encephalitis can occasionally, carcinomatous meningitis, subarachnoid hemorrhage, CNS lupus, rheumatoid meningitis, chemical meningitis. --Will not be lowered in localized meningitis, encephalitis or abscess

CSF in Disease

Causes of xanthochromia: blood, jaundice, hypercarotenemia, rifampin, CSF protein > 150, malignant tumors. Oligoclonal bands: indication of inflammatory process in CNS, seen in MS, in 100% of SSPE, and any infection, vasculitis, tumors and carcinomatous meningitis, CNS lupus, Guillain Barre, neurosarcoid, adrenoleukodystrophy.

Myelin Basic Protein: one of the few proteins made exclusively in CNS by oligodendrocytes; thought tbe a marker of demyelination, but alselevated in stroke, anoxia, trauma, tumor, infections, Wernicke’s disease and leukodystrophies.

Traumatic tap vs SAH:

Traumatic: normal opening pressure, unequal blood in tubes (1>4), nxanthochromia; IgG synthesis and index can alsbe increased

SAH: increased opening pressure, equal blood in tubes (1=4), xanthrochromia if > 6 hours

Infection:

1. Cultures: bacterial, viral, fungal

2. Stains: gram, India Ink

3. Titers: Cocci, crypto, toxo, cystercercosis, VDRL, lyme, mycoplasma, West Nile, meningoencephalitis panel

4. PCRs include: AFB, HSV, VZV, CMV, EBV, HTLV, West Nile

5. Other: 14-3-3 for CJD, ACE for sarcoid

FIndings

MS: normal cell count and diff in 2/3 of pts, elevated protein in 40% of pts, oligoclonal bands (seen more often with exacerbation, seen in 83-94% of definite MS patients) and increased IgG synthesis (compare tserum IgG synth). Some alsget myelin basic protein.

Tumor: Need three high volume taps of 10cc each for cytology – then deliver the CSF specimen tthe cytology lab on A level and personally hand it tsomeone. Don’t send CSF for cytology on weekend because needs tbe fresh for analysis.

Neurosyphilis: positive VDRL plus pleocytosis. (npleocytosis, not current infection)

GBS: elevated protein, and up t50 lymphocytes (albumino-cytologic dissociation)

Lymphoma: cytology, EBV pcr may be positive

Sources: CSF Lecture, Callene Momtazee, M.D., 2005.; Washington Manual Survival Guide, 2004.

DEMENTIA Susan Shaw, MD. Reviewed by Joanna Jen, MD, PhD, 6/05

I. In a practice guideline published by the American Academy of Neurology, the DSM-IIIR definition of dementia (identical tthe DSM-IV definition) was reported thave good tvery good reliability and was recommended for rotine use (Neurology 2001: 56(9) pp 1143-53):

impairment in short and long-term memory

associated with impairment in another cognitive sphere: abstraction, judgment, other higher cortical function or personality change

severe enough tinterfere significantly with work, usual social activities, or relationships with other people.

not in the setting of delirium or confusional state

A. Differential diagnosis

Rule out: delirium (waxing/waning cognition), depression, seizures, trauma (subdural).

Major dementia syndromes: Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, Parkinson’s disease with dementia. Others include progressive supranuclear palsy, alcohol-related, medication-related, AIDS dementia complex, normal pressure hydrocephalus, Wernicke-Korsakoff.

History: progressive cognitive decline, behavior changes. Obtain medication history, education level.

Exam: mini-mental state exam (MMSE), digit span, clock drawing, frontal executive function (e.g., animals in 1 minute –normal >12; F-words in 1 minute - normal >9; Luria sequences; pattern drawing; abstraction, judgment), praxis, neglect, frontal release signs.

Labs: B12, TSH. Consider RPR, CBC, chem 10, liver panel, HIV, thiamine level.

Imaging: noncontrast CT or MRI. Consider PET or SPECT scan.

Other: neuropsychiatric testing, depression screen. EEG or LP if indicated.

Treatment

Cholinterase inhibitors: donepezil, rivastigmine, galantamine, tacrine

Possibly disease-modifying agents: memantine, vitamin E

Non-pharmacologic: nutrition, exercise

Behavioral disturbances

- delusion, hallucinations -- atypical antipsychotic, consider olanzapine or quetiapine. Avoid: risperidone (parkinsonian side effects), haloperidol.

- depression -- SSRI, consider sertraline or citalopram. Avoid: TCAs (may worsen confusion), paroxetine (most anticholinergic), fluoxetine (most drug interactions).

- agitation -- evaluate for environmental or infectious cause. Trazodone or atypical antipsychotic.

- sleep disorders -- improve sleep hygiene. Avoid: diphenhydramine and long-acting benzodiazepines in elderly. Zolpidem (Ambien) has fewer side effects. Parkinson’s often has RLS or PLMS; dementia with Lewy bodies often has REM sleep behavior disorders.

FDA approved medications for AD: Donepezil, Galantamine, Rivastigmine

Mini-Mental State Exam

Rapid Progressive Dementia: Creutzfeldt-Jakob (CJD)

Pari Young, MD. 6/08

GtDr. Geschwind’s (UCSF) website: http://memory.ucsf.edu/Education/Disease/cjd.html and call his secretary at (415) 476-6880 or (415) 476-4800.

MRI: T1, T2, FLAIR, and most importantly Diffusion Weighted (DWI) sequences for detecting the abnormalities seen in this disease. FLAIR and particularly DWI best for detecting classic abn: cortex (cortical ribboning) and basal ganglia (specifically the caudate and putamen), and in some cases the medial and posterior thalamus. Imaging abn often bilateral, but may initially be unilateral.

EEG: May see slowing, or periodic sharp wave complexes. Seen in 75-85% of sporadic CJD cases. May not be seen until late in disease course.

CSF studies: 14-3-3, IgG studies, Oligoclonal Bands. Athena Diagnostics: total tau dementia panel #178 (p-tau, A-beta 14). MayLabs: neuron-specific enolase

Serum: Hashimoto’s labs: anti-tpo, anti-thyroglobulin, rheum work-up, ANA, ESR, HIV, Lyme. Athena diagnostics: paraneoplastic planel test # 369 ( voltage-gated K+ channel Ab and Anti-CV2 Ab can make the basal ganglia T2 hyperintense, but NOT ADC dark. CJD: basal ganglia is T2 hyperintense AND ADC dark. )

Familial CJD

There is a commercially available genetic test for the familial form of CJD:

Website: www.cjdsurveillance.com. PRP gene familial mutations- known ones can be tested. You need tsend 4 tubes of blood in K+EDTA tubes- overnight FedEx.

Tips on explaining the diagnosis tpatients:

GET ATTENDING BACK-UP TBREAK THE NEWS!

When Dr. Geschwind breaks the news he describes that in CJD, a normal protein in the human body changes its shape, becomes malformed, and initiates this disease of the brain’s grey matter (much like normal cells become cancerous). This abnormal protein then stimulates others like it tabnormally change shape, triggering a cascade and propagation of the disease. These misfolded normal proteins cause brain damage and CJD disease. The protein is called prion. He often does not mention “Mad Cow”, however if it is brought up, he describes that if this abnormally formed protein was somehow ingested, for instance through infected animal meat, it can trigger this same malformation of prion protein in the human brain causing the disease. Some people have a genetic defect in the gene for the (prion) protein itself that they were born with, that makes them “more susceptible” tabnormal protein transformation.

HEADACHE Susan Shaw, Andrew Charles, 6/05; Brandon Hirota, 6/08; Neal Rao, Mollie Johnston 6/10

Differential Diagnosis

Life-threatening Causes

SAH: Consider in patients with photosensitivity, meningismus, sudden onset of severe headache.

Bacterial Meningitis: fever, photosensitivity, meningismus, immunocompromised.

Herniation depressed level of consciousness, focal neurologic signs, papilledema, known neoplasms.

Venous thrombosis: focal neurologic signs, proptosis, papilledema, hypercoagulable states (OCPs, pregnancy).

Primary Headaches

Migraine: nausea, vomiting, photophobia, phonophobia, throbbing, worse with movement, moderate/severe pain.

Tension: generalized pain, frontal and occipital.

Cluster: periorbital pain; i/l tearing, nasal congestion, or conjunctival injection. Circadian, usually at night, in clusters of days tweeks.

Trigeminal neuralgia: sharp, intermittent shooting pains, usually V2 or V3 distribution.

Paroxysmal hemicrania. May have features similar tcluster, but much more common in women. Very responsive tIndomethacin

Secondary Headaches

Bleeds – SAH, ICH

Stroke/Sinus Thrombosis

Infectious – meningitis, sinusitis, post-herpetic neuralgia

Posttraumatic

Increased ICP – mass lesions (tumor, hemorrhage), malignant hypertension, pseudotumor cerebri

Decreased ICP – spontaneous, post-LP. Positional component.

Temporal arteritis – temporal artery tenderness, jaw claudication, older men

Drugs – caffeine withdrawal, nitrates, Aggrenox, opiates

Evaluation

Sick or not sick? Rule out life-threatening causes in anyone whlooks sick. But keep in mind migraine frequently looks sick.

Previous history of headache? -- think migraine.

Check for fever, level of consciousnes, papilledema, meningismus, focal neurologic signs.

Tests

When tget imaging?

- 1^st or worst HA

- new HA > 55 year old

- focal neurological signs

- history of malignancy or HIV

- Evidence of increased (mass/lesion) or decreased ICP (meningreal enhancement on MRI)

CT w/wcontrast, MRI w/ MRV if suspicion for venous thrombosis.

LP if suspicion for SAH or meningitis, even if CT is negative. CT is negative in 10-15% of SAH. LP is most sensitive for SAH 12 hours after onset of symptoms. Look for RBCs and xanthochromia.

Note: Must get CT prior tLP in patient with any of the following: a) depressed level of consciousness (even if from intoxication), b) focal neurologic signs, c) papilledema. Alsconsider CT first in AIDS patients.

ESR if suspect Temporal ateritis

Management

SAH, ICH or herniation: call neurosurgery stat.

Meningitis: LP, antibiotics; see Meningitis.

Venous thrombosis: anticoagulation, thrombolytics/interventional.

Trigeminal neuralgia: neurontin 200 mg BID, titrate up tefficacy. Or carbamazepine start 100-200 mg BID, maintenance 600-1200 mg. Others: oxcarbazepine, baclofen

Increased ICP: imaging, LP for opening pressure; see Increased ICP.

Decreased ICP: bed rest, caffeine intake. Epidural blood patch if conservative measure fail. If nknown reason for leakage, get CT myelography or CSF leak study.

Temporal Arteritis: start prednisone 100 mg qday, call ophthalmology for biopsy

Migraine

Abortive agents:

First try triptan(avoid if focal findings) plus antiemetic

Headache cocktail :

NSAID +triptan/ergot + antihistamine or dopamine/5HT antagonist

NSAIDS: toradol 60 mg IM or 30 mg IV

Triptans/ergots: Imitrex 6 mg subQ or DHE 1 mg IV (not both within 24 hours). Cardiac monitor for IV DHE.Can repeat imitrex or DHE after 1 hr, max 2 doses for either within 24 hours.

Antihistamines: Benadryl 25-50 mg IV may use phenergan IM 25-50mg for both antiemetic and antihistiminergic properties (IV can give purple glove syndrome)

Dopamine/5HT antagonists: compazine 10 mg IV or metoclopramide 10 mg IV, Zofran 4mg IM is very effective antiemetic and 5HT antagonist which counters migraine mechanism.

Last resort: Depacon 10-15 mg/kg/day divided qday-TID or

DHE 1 mg q8 IV

Can consider sending out on Medrol Dose pack for intractable headaches unresponsive tabove.

Very last resort is opiates: opiates condition chronic migraineurs tbe rewarded and sedated for being in pain and migraines cannot be long term with opiates, nmore than 2 doses/month max.

Think of alternate diagnosis (eg: early V1 HSV) if above fails

Prophylactic agents:

First line: Riboflavin 400mg/day, CoQ10 300-600mg/day, Mg 300-500mg/day, melatonin 5mg qhs, butterbur 75mg bid

topiramate 25-100 mg/day QHS or divided BI

propranolol 40-320 mg/day divided TID; other beta blockers less efficacious (metoprolol, atenolol)

amitriptyline start 10-25 mg QHS; nortriptyline start 10 mg QHS

valproic acid 125-750 mg TID

verapamil 80-160 mg divided TID

Namenda 10mg pbid (off label)

Cluster

Abortive agents:

FIRST CHOICE: Calan SR (verapamil) 180 mg qday + frovatriptan 2.5 mg 1 tablet qday for several days until Calan kicks in.

6-10 L/min 100% O2 by nonrebreather for nmore than 15 minutes

Imitrex 6 mg P/subQ or 20 mg intransal; or other triptan

D.H.E. 1 mg IV, not texceed 2 mg/dose or 6 mg/week

lidocaine 4% 1 cc intranasally

Prophylactic agents:

verapamil 120-360 mg/day divided TID/QID

prednisone 20-40 mg/day, efficacious only if start at beginning of cluster period

IDIOPATHIC INTRACRANIAL HYPERTENSION Christopher Giza, MD, 9/05. Adapted by Susan Shaw, MD.

Definition: Intracranial hypertension without structural lesion or CSF flow abnormality. AKA benign intracranial hypertension or pseudotumor cerebri.

Clinical:

Symptoms: headache (usually bilateral), visual loss, transient visual obscurations, pulsatile tinnnitus, diplopia, retro-orbital pain, rarely shoulder/arm pain.

Exam: VF defects, loss of contrast sensitivity, papilledema, uni- or bilateral CN6 palsy.

May be classified as either idiopathic or symptomatic.

- Idiopathic – proposed diagnostic criteria (Friedman & Jacobson, 2002)

1. Signs and symptoms due televated ICP or papilledema.

2. Elevated CSF pressure by LP in lateral decubitus position (>200 mm H₂0).

3. Normal CSF profile

4. Nstructural abnormality on neuroimaging

5. Nalternative etiology (including medication)

- Symptomatic etiologies: cerebral venous occlusion, radical neck dissection, hypoparathryoidism, hypervitaminosis A, lupus, renal disease, medication (tetracycline, minocycline, nalidixic acid, corticosteroids [withdrawal]).

DDx: Rule out structural lesion, rule out symptomatic etiologies

Chronic daily headache / transformed migraine, chronic meningitis (infectious or neoplastic), cerebral venous thrombosis, hypertension, gliomatosis cerebri, optic nerve head anomalies

Red flags that it’s not IIH: atypical demographics, CN palsies other than VI, altered mentation, focal neursigns, abnormal CSF profile, rapid/explosive onset of S/Sx, INO, vertical gaze disturbance

Diagnosis:

LP – lateral decubitus OP >250; >200 in kids; normal cell count & chemistry.

CT / MRI – normal; nstructural lesion identified. May see empty sella.

MRV – eval for venous thrombosis or venous sinus stenosis

Treatment

1.Weight loss

2.Acetazolamide – 250-1000mg bid. Others: methazolamide, topiramate.

3.Furosemide – if acetazolamide doesn’t work.

4.Corticosteroids – limited use for intractable cases / awaiting surgical intervention. May cause rebound headaches or worsening of symptoms.

5.Surgery – for rapid/progressive visual loss, severe papilledema, or medication-intractable cases - optic nerve sheath decompression/fenestration or CSF diversion via LP shunt.

Prognosis:

Predictors of visual loss – 1) recent wt gain, 2) high-grade or atrophic papilledema, 3) subretinal hemorrhage, 4) significant visual loss at presentation and 5) hypertension.

Nonpredictors of visual loss – 1) symptom duration, 2) transient visual obscurations, 3) diplopia, 4) headache severity, 5) LP opening pressure or 6) pregnancy.

Friedman & Jacobson, Neurol 2002, J Neuro-Ophthal 2005; Goetz, Textbook of Clin Neurol. 2^nd ed, 2003.

INCREASED INTRACRANIAL PRESSURE Christopher Giza, MD, Raman Sankar, MD. Adapted by Sarah Kremen, MD. Reviewed and revised by Paul Vespa, MD, 6/25/06

I. Normal ICP is typically 5-10 mm Hg. ICP > 20 mm Hg can result in harm, due therniation or global brain ischemia. . The classic rostral-caudal warning signs that this may be occurring include a dilated, nonreactive pupil on one side or bilaterally in a patient with an abnormal mental status and/or motor posturing. Broad DDX: Mass lesions (tumor, bleed), VP shunt malfunction, head trauma, hypoxia, pseudotumor cerebri, dural sinus thrombosis, chronic meningitis, hypervitaminosis A, Medications: tetracycline, steroids.

II. Evaluation

A. Symptoms: headache, lethargy, nausea, vomiting, blurry vision.

B. Physical exam: obtundation, abnormal posturing, parinaud’s sign, loss of venous pulsations on fundascopic exam, papilledema (later sign), blown pupil, gaze palsies (CNVI most sensitive tincreased ICP, and beware that bilateral CNVI palsy may mean globally increased ICP and not bilateral pontine lesions), focal neurological deficits, Cushing’s Triad (bradycardia, hypertension, irregular respirations).

C. Head CT (the most likely place tstart) tstart trule out tumor, hemorrhage, abcess, meningitis, acute hydrocephalus, evidence of trauma or anoxia (MRI is better for some of these things, such as meningitis). Look for midline shift, hydrocephalus, loss of basal cisterns, effacement of sulci.

D. consider MRI if visual loss, rule out mass lesion or infection, sinus thrombosis (add MRV)

III. Treatment:

1. Begin treatment presumptively before imaging study.

2. Intubate and hyperventilate (tpCO₂ approximately 30-35)

3. Tilt head of bed up t30 degrees.

4. Hypertonic saline – 3% saline through central line (can give 50 cc/hr via peripheral IV and usually rate does not exceed 100 cc/hr (goal Na 145-155, check Na levels q6h).

5. Mannitol (0.5 gram/kg – 1.0) iv bolus and repeat q3-6 hrs – Follow urine osmolality (UOsm >320 increases risk of renal failure). Follow osmotic gap and have it ngreater than 18-20. (In practice, following urine osms is not always done, and has not always been found tbe helpful.)

Osomotic gap: measured Osm-calculated Osm

Calculated osm = (Nax2) + BUN/2.8 + glucose/18

Side effects of mannitol: renal failure, pulmonary edema, hypotension, hyponatremia, seizures.

6. Call the neurICU team for assistance with intervention (ICP monitor, ventriculostomy, decompression/resection)

7. Dexamethasone for edema secondary ttumor/abscess, dose is usually 4-10 mg q 6. Not useful and not indicated for edema due tbrain trauma or hypoxia-ischemia. (cytotoxic versus vasogenic edema)

8. Maintain cerebral perfusion pressure CCP (MAP-ICP) >60-70mm Hg. Consider using vasopressors if necessary.

9. Order the Neuro-ICU ICP order set (has automated orders for elevated ICP)

At UCLA, call the neuro- ICU team (pager 94330) for help with patients that you think will need neuro-ICU care. If you are at WLAVA, call neurosurg resident on call if you think the patient will need a ventriculostomy or hemicraniectomy; the patient will be primarily managed by MICU. At OVMC, there is nin-house neurosurg team, scall MICU team or ER for assistance depending on where patient is located. All ventriculostomy or hemicraniectomy patients need tbe sent out tCounty or UCLA stat.

Sources: emedicine.com, 2005; On Call Neurology 2^nd Ed, 2001., Handout created by Dr. Christopher Giza and Dr. Raman Sankar, 2000 and 2002., Washington Manual Neurology Survival Guide, 2004.

MENINGITIS Po-Heng Tsai, MD, 6/07. Revised by Brandon Hirota, MD, 6/08

I. Syndrome of fever, headache, and meningismus (can alshave N/V, photophobia, and lethargy)

II. Epidemiology (most common causative organisms):

Neonates: group B strep and gram negative bacilli

Adults 15-50 years of age: S. pneumoniae and N. meningitides

Adults >50 years of age: S. pneumoniae and enteric gram negative bacilli but alsListeria monocytogenes and H. influenze

Post neurosurgical procedure: gram-negative bacilli and staphylococci except for shunts: coagulase-negative staph and S. aureus

Viruses: enteroviruses, arthropod-borne viruses, HSV, EBV, HIV, VZV

III. CSF profile of meningitis: Refer tCSF studies section.

IV.Diagnostics

-Indications for head CT prior tLP: focal neurological deficit, new-onset seizure, papilledema, abnormal level of consciousness, and immunocompromised state.

-Blood cultures should be drawn in addition tLP

-CSF workup:

Cultures: bacterial, viral, fungal

Stains: gram, India Ink

Titers: Cocci, crypto, toxo, cystercercosis, VDRL, lyme, mycoplasma, West Nile, meningoencephalitis panel

PCRs include: AFB, HSV, VZV, CMV, EBV, HTLV, West Nile

V. Empiric treatment of bacterial meningitis

1. If suspect bacterial meningitis and patient looks very sick, dnot hold antibiotics while waiting for CT and LP, unless you can get them w/in 1hr.

2. Consider ceftriaxone 2 g IV q12 or cefepime 2 g IV q8, vancomycin 1 g q12. Add ampicillin IV 3 g q6 if concern for Listeria (>50 years old or immunocompromised).

3. Penicillin allergic: chloramphenicol 12.5 mg/kg IV q6 or clindamycin 900 mg IV q8 or meropenem 1 g IV q8

4. Dexamethasone: 10mg IV q6 for 4 days starting before or with first dose of antibiotics.

5. Add acyclovir 10 mg/kg q8 hr empirically until CSF HSV returns negative.

6. Tick season: add doxycycline

Sources: emedicine.com, 2005; On Call Neurology 2^nd Ed, 2001, Infectious Disease, Continuum, 2006

MOVEMENT DISORDERS: HYPERKINETIC MOVEMENTS Nick Szumski, MD 7/05. Revised/reviewed by Yvette Bordelon, MD, 6/06

Describe what you see:

Body part(s) affected (e.g. focal, segmental, lateralized, generalized)

Amplitude

Frequency (e.g. constant, intermittent)

Conditions that bring it out (e.g. rest, posture, intention, action)

Triggers (e.g. stress, anxiety, movement (kinesigenic))

Supression (e.g. volitional or with sensory trick)

Associated findings

Tests (e.g. Archimedes’ spiral, penpoint hovering, handwriting)

Name it (or them – these may coexist):

Tremors – Rhythmic, oscillatory movement with alternating agonist/antagonist contraction.

Enhanced physiologic – 8-13 Hz, low amplitude – Tremulousness brought out by posture, stress, sympathetic stimulation: caffeine, pimping, random gunfire, etc.

Parkinsonian – 3-5 Hz, coarse, low-high amplitude – Resting tremor, reduced by action. Pill-rolling seen in hands; causes cogwheeling; chin tremor can be seen. Worse with stress, fatigue. Can often be brought out with distraction. Classic and asymmetric in idiopathic PD, but less often seen or symmetric in parkinson’s plus syndromes.

Essential – 8-12 Hz, low thigh amplitude – Postural (and action) tremor, reduced by rest, typically affecting upper extremities. Vocal and head tremor often seen along with it (think Katherine Hepburn in her later years). Worse with stress, fatigue. EtOH can help. Family history usually present.

“Rubral” – 2-5 Hz, high-amplitude – So-called wing-beating tremor or Holmes’ tremor, often associated with Wilson’s disease but actually much less specific than that. Actually, probably related tcerebellar outflow interruption in vicinity of red nucleus, not damage tthe nucleus itself.

Orthostatic – 13-18 Hz tremor of legs that appears a few seconds after standing Rare, possibly a variant of ET.

Palatal (aka palatal myoclonus) -- 60-100 Hz – Often associated with audible clicking, lesions of the triangle of Guillain and Mollaret (trivia point for later)

Chorea – Greek for “dance”. Fast, jerky, irregular, unsustained, involuntary movements that flow from one muscle group tanother. Discrete or confluent.

§ e.g. Huntington’s, Syndenham’s, Wilson’s, neuroleptic-induced, neuroacanthocytosis, vascular, PANK2 deficiency, DRPLA, chorea gravidarum

§ Parakinesia – Incorporation of an involuntary movement inta pseudo-voluntary movements (e.g. crossing legs, gesturing – Michael J. Fox has made a career of this)

§ Motor impersistence – Finding often associated with chorea (esp Huntington’s), cannot maintain an action with chorea. Can’t keep tongue protruded or grip (“milkmaid’s grip”).

Athetosis – Greek for “changeable”. Slow, continuous, purposeless movements. Slower and affects distal musculature compared tchorea. Can form pattern (e.g. extension-pronation vs. flexion-supination of arm).

Ballism – Uncontrolled, wild flinging of a limb; large-amplitude chorea.

§ e.g. damage tsubthalamic nucleus, bilateral seen in nonketotic hyperosmolar coma

§ interestingly, responds tHaldol

Dystonia –Uncontrolled agonist-antagonist co-contraction resulting in abnormal postures.

§ Primary (e.g. idiopathic dystonia or dystonia musculorum deformans (DYT1)), or secondary (Huntington’s, Wilson’s, neuroleptic-induced, PNK2 deficiency, kernicterus)

§ Focal (Torticollis, spasmodic dysphonia, blepharospasm, writer’s cramp), segmental (Meige syndrome), or generalized (DYT-1)

§ Acute reaction: e.g. oculogyric crisis (typical and atypical neuroleptics, metoclopramide, prochlorperzine, , etc.) treated with Benadryl

Myoclonus – Very fast, shock-like jerk. Myoclonic seizure describes ictal event of fitting same definition with electrocerebral correlate. Very broad differential.

Tic – Stereotyped, suppressible but irresistible action performed tavoid uncomfortable feeling.Simple vocal (e.g. sniff, grunt), simple motor (e.g. eye blink), complex vocal (e.g. utterances, corprolalia is rare despite movies), complex motor (e.g. reaching up and touching nose).

OTHER:

Tardive dyskinesias -- Can appear as any combination of the hyperkinetic movements described above except tremor. Occurs as consequence of using dopamine receptor blocking agents. Often orobuccal, with tongue/lip protrusion.

Akathisia – Greek for “unable tsit still”. Inner feeling of restlessness causing inability tsit still, leading tvariety of shifting movements that are somewhat voluntary. Tardive form may accompany dyskinesias.

Myokymia – Irregular fibrillations of facial muscle fibers, with spontaneous motor unit activity at ~30-70 Hz.

Asterixis – Very fast, brief loss of tone; like negative myoclonus.

Stereotypy – Stereotyped, but without ultimately irresistible nature. Seen in patients with schizophrenia, developmental delay, autism.

American Academy of Neurology (2004) Continuum: Movement Disorders, Vol. 10, Number 3, June 2004.

Goetz, CG (2003) Textbook of Clinical Neurology, 2^nd ed. Saunders, pp. 193, 286-297.

Victor, M & Ropper, AH. (2001) Adams and Victor’s Principles of Neurology, 7^th ed. McGraw-Hill, pp. 77-120

PARKINSON’S DISEASE

Po-Heng Tsai, MD. Updated by Andrew Dorsch, MD, 6/08

I. Symptoms

1. Motor: tremor, bradykinesia, rigidity, postural instability

2. Other: autonomic dysfunction (constipation, orthostasis), depression, sleep disturbance, cognitive impairment

II. Review of Systems M.S.C.A.D. (adapted from Nick Szumski, M.D.)

Motor: falls/near falls, freezing episodes, dysphagia

Sleep: quality/amount, restedness, fatigue, daytime somnolence, sleep attacks, nocturia, vivid dreams

Cognitive: hallucinations/illusions, compulsive behaviors (esp on dopamine agonists!)

Autonomic: orthostasis/lightheadedness, constipation, frequency/urgency

Depression: depression screen

III. Management of motor symptoms

A.If there is nsignificant functional impairment (e.g. difficulty with writing, turning in bed, buttoning, talking, shakiness, and slowness in ADL), can monitor and provide group support, exercise and nutrition counseling.

B.If there is functional impairment and the patient is > 75 yrs and/or with cognitive decline, consider levodopa/carbidopa (Sinemet) therapy. Start with ½ tab of 25/100 BID-TID and titrate it up t1 tab TID-QID. A total of 75 t100 mg/day of carbidopa is required treduce potential side effects (nausea, orthostatic dizziness, sedation, confusion, and hallucinations). Sinemet should be separated from meals tprevent competition of absorption by neutral aminacids (Half hr prior tmeal or 2hr post).

C.If the patient is younger and without cognitive decline, consider starting a dopamine agonist. Premipexole (Mirapex): start at 0.125mg TID and titrate up weekly as tolerated t0.5 – 1.5mg TID. Ropinirole (Requip): start 0.25mg TID and titrate up slowly as tolerated t2-5mg TID. Watch out for sedation, nausea, peripheral edema, paranoia compulsive behavior, and hallucinations

D. If tremor is a predominate feature, consider amantadine (100mg daily t100mg BID) or anticholinergics.

E. Motor fluctuations develop (e.g. dyskinesia, wearing-off) after years of treatment with levodopa. May consider: 1)amantadine for peak-dose dyskinesia, 2) entacapone (peripheral COMT inhibitor) with each dose of Sinemet, 3) Stalev(combination pill of carbidopa, levodopa, and entacapone), 4) MAO-B inhibitor (selegiline, rasagiline) or adding a dopamine agonist.

IV. Other information

1. Parkinson’s patients admitted tthe hospital are often very ill. It is very important that they receive their medications at their outpatient schedule (check the MAR and remind the nurse) tprevent worsening of their condition.

2. Patients will rarely admit tcompulsive behaviors, often due ta lack of insight. Very clear and explicit questions are needed telicit their presence (ie. excess shopping, gambling, pornography)

Sources: Dr. Bronstein’s handout and PADRECC pocket guide for Parkinson’s Disease

MULTIPLE SCLEROSIS Sarah Kremen, MD. Reviewed by Barbara Giesser, MD, 6/05. Updated by Edward Barton, MD and Brandon Hirota, MD, 6/08

The 2005 Revisions tthe McDonald Diagnostic Criteria for MS

CLINICAL PRESENTATION ADDITIONAL DATA NEEDED FOR MS

DIAGNOSIS

2005 Revised McDonald Diagnostic Criteria for MS

What is a Positive MRI?

3 out of 4 of the following:

? 1 Gd-enhancing brain or cord lesion or 9 T2 hyperintense brain and/or cord lesions if there is nGd-enhancing lesion

? 1 or more brain infratentorial or cord lesion

? 1 or more juxtacortical lesion

? 3 or more periventricular lesions

Note: Individual cord lesions can contribute along with individual brain lesions treach required number of T2 lesions

What Provides MRI Evidence of Dissemination in Time?

? A Gd-enhancing lesion detected in a scan done at least 3 months after onset of initial clinical event at a site different from the initial event or

? A new T2 lesion detected in a scan done at any time compared ta reference scan done at least 30 days after initial clinical event

What is Positive CSF?

Oligoclonal IgG bands in CSF (and not serum) or elevated IgG index

What is Positive VEP?

Delayed but well-preserved wave form

Initial MS lab workup:

? MRI brain w/wo, and sagittal FLAIR, often add C spine

? CSF: cell ct, prot, glu, IgG synth rate and index, oligoclonal bands, MBP

? MS mimic w/u: ESR, ANA, Lyme, ACE, RF, RPR, HIV, HTLV 1/2, B12, vasculitis labs (if indicated)

Disease Modifying Drugs:

? Interferon B 1-alpha Avonex: 30mcg IM/wk, Rebif: 44mcg SC 3x/wk

? Interferon B 1-beta (Betaseron): 0.25mg SC QOD

? Copaxone: 20mg SC qday

? Fingolimod (Gilenya) 0.5 mg /day

1. Polman et al. Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions tthe “McDonald” Criteria.

Ann Neurol. (2005) 58:840-846.

2. Barkhof et al. Comparison of MR imaging criteria at first presentation tpredict conversion tclinically definite MS. Brain (1997) 120:2059-2069.

3. Tintoré et al. Isolated demyelinating syndromes: comparison of different imaging criteria tpredict conversion tclinically definite MS. Am J Radiology (2000) 21:702-706.

http://www.nationalmssociety.org/pdf/forpros/dx_tipsheet.pdf, accessed 5-27-06

TRANSVERSE MYELITIS:

Differential and lab work up based on clinical suspicion for the following:

infectious myelitis

systemic autoimmune disease (SLE, antiphospholipid, Sjogren's, systemic sclerosis, neurosarcoidosis, Bechet's)

paraneoplastic

primary demyelinating (MS or NMO)

Imaging: typically, the entire spinal cord should be imaged sthat false negative results that may be caused by misleading localizing signs, such as a thoracic sensory level caused by a cervical lesion, can be avoided.

Flow chart and lab recs: Elliot M. Frohman, M.D., Ph.D., and Dean M. Wingerchuk, M.D. N Engl J Med 2010; 363:564-572August 5, 2010. http://www.nejm.org/toc/nejm/363/6/

MULTIPLE SCLEROSIS EXACERBATION

This is a common call from the ER, as well as from outpatients. MS exacerbations (alstermed relapses) can result from a new white matter lesion or lesions, or may be unmasking of old deficits by a known precipitant, most commonly infection, such as UTI (pseudoexacerbation). In addition, some women with MS may alsexperience an increase in symptoms premenstrually. Goal is ttry tdifferentiate between a new lesion and pseudoexacerbation.

I. Evaluation: Obtain a history, with particular focus on:

Date and method of diagnosis of MS

Disease subtype if known

Baseline function (can they walk unassisted or require a walker, dthey work, how is their bowel and bladder function, etc)

Current symptoms and time of symptom onset (time course for MS attack is usually over several days, not hours; and symptoms should last >24 hours; time between attacks are defined as 30 days apart, excluding pseudoexacerbations).

Common triggers

“typical” exacerbations and number of exacerbations in the last year

Response tsteroids and date of last treatment

History of previous treatments, including responses and failures

Last bowel movement, bowel regimen

History of bladder dysfunction or bladder infections

Any recent illnesses?

Has there been an increase ambient temperature or exposure tincreased humidity?

Been stressed recently?

Perimenstrual?

-Da physical exam, with particular attention to:

Visual acuity, color saturation, APD, pale optic disc, pain with eye movement, INO

Motor exam – look for weakness, spasticity

Coordination – dysdiadokinesia, intention tremor (end tremor on finger-to-nose)

Gait and mobility

Long tract signs, such as upgoing toes

II. Management

Remember - Usually the symptoms will improve if the underlying cause is treated.

If the patient seems tbe fairly sick or incapacitated, admit them.

If a pseudoexacerbation from infection, treat the infection. The patient’s symptoms should improve.

Regardless of your suspicion for etiology of the patient’s symptoms, you can treat the symptoms, whether that be pain, spasticity.

If you suspect exacerbation from an underlying new lesion, you can start steroids. This generally consists of a regimen of methylprednisolone 1 gm IV q day for 3-5 days, followed sometimes by a prednisone taper starting at 40 or 60mg pq day, over 11 t14 days; or prescribed Medrol dose pack.

If you are unsure if this is a true exacerbation, you can always order an MRI of the brain with and without gadolinium, and if warranted, the appropriate MRI spine series, tlook for new MS plaques. While persons with exacerbations are more likely tdemonstrate gad enhancement on a scan, they could in fact be having an exacerbation and not show enhancement( or vice versa); the presence of enhancement would be more likely tpredict response tsteroids.

There is nrush on admission night tstart IV steroids if you are unsure of true exacerbation. It is okay tadmit and decide on a management and treatment plan the next day with the attending and the chief resident. Treat the symptoms in the meantime.

Sources: Current Therapy in Neurologic Disease, 6^th edition, 2002; The Washington Manual Neurology Survival Guide, 2004.

NEUROMUSCULAR EMERGENCIES Sarah Kremen, MD, Suman Kalanithi, MD, and Pari Young, MD

Patients with neuromuscular diseases such as myasthenia gravis or Guillian-Barré (GBS) can quickly decompensate and need intubation. You should have a low threshold tsend these patients tthe ICU, even if just for observation. In addition, patients with GBS can develop autonomic instability, with labile BPs, neurogenic pulmonary edema, bradycardia or tachycardia, another reason tkeep a close watch and send tthe unit.

How tmonitor these patients:

on presentation, immediately check a forced vital capacity (FVC) and negative inspiratory force (NIF)

Check FVC and NIF q 2-6 hours, depending on patient’s respiratory values, other vital signs are, and how the patients look

FVC and NIF have been shown tbe a more reliable way tfollow patient’s respiratory status than checking O2 saturation, or ABG

GBS patients should alsbe put on telemetry tmonitor their pulse and BP, as should any myasthenic patient whis in distress

Good bedside tests in myasthenia:

- Neck flexion/extension: correlates with respiratory ability

- Sustained upward gaze, counting numbers in one breath (slow steady pace): can use ttrack patient’s progress

Criteria for sending a patient tthe ICU:

reduction of the FVC t20ml/kg

labile BP, pulse or other cardiopulmonary instability

Common criteria for intubation:

reduction of FVC t15ml/kg (approximately 1L in a 70 kg person) or rapid decline

NIF <-20 cm H2O

PO2 < 70 mm Hg on room air

PCO2 > 50mm Hg associated with acidosis (pH<7.35)

Positive expiratory force < 40 cm H2O

Tidal volume < 5ml/kg

Severe dysphagia with inability tprotect the airway, or stridor

The key is tintubate early! These patients can look good one minute and then suddenly gdownhill fast, and elective intubation is always better than emergency intubation.

Sources: The Washington Manual Neurology Survival Guide, 2004; On Call Neurology 2^nd Ed, 2001.

Management of Myasthenic Crisis

1. Eliminate triggers: infection, culprit drugs (aminoglycosides, other antibiotics, steroids, antiarrhythmics, beta-blockers, succinylcholine, increased doses of cholinesterase inhibitors), metabolic derangements

2. Plasmapheresis: typically 5 exchanges. Produces rapid but transient improvement (lasts weeks). Potential side effects include hypotension, paresthesias, coagulopathies, electrolyte derangements, removal of protein-bound drugs. May be preferable tIVIG in severe exacerbation.

3. IVIG: 2 g/kg, usually over twtfive days. Improvement alstransient. Screen for selective IgA deficiency before initiation by drawing serum IgA level. Use after plasmapheresis if performing both. Potential side effects include F/C/N/V, HA, CHF, ARF/ATN, thrombotic events, hemolysis, anaphylaxis.

4. Steroids: e.g. prednisone 1 mg/kg/day IV. Commonly causes initial exacerbation of weakness. Maximal improvement after weeks. Often added after plasmapheresis/IVIG has already been initiated.

5. Cholinesterase inhibitors: may wish thold initially as can cause increased weakness and increased secretions.

6. If needed, Pyridostigmine can be given IV. Conversion: 1/30 of oral dose. Caution for cholinergic crisis with pyridostigmine >120mg PQ3Hrs

7. PT/OT consult

Management of Acute GBS

1. Plasmapheresis/IVIG as above (equivalent effect)

2. Steroids generally not indicated

3. Compression hose/pharmacotherapy if hypotensive

4. Gabapentin/carbamazepine for neuropathic pain

5. PT/OT consult

MEDICATIONS THAT EXACERBATE MYASTHENIA

Anesthetic agents

Chloroprocaine

Diazepam

Ether

Halothane Ketamine Lidocaine

Neuromuscular blocking agents Propanidid Procaine

Antibiotics

Aminoglycosides

Amikaicin

Gentamicin

Kanamycin

Neomycin

Netilmicin

Paromomycin

Spectinomycin

Streptomycin

Tobramycin

Fluoroquinolones

Ciprofloxacin

Levofloxacin

Norfloxacin

Others

Ampicillin

Clarithromycin

Clindamycin

Cloistin

Erythromycin

Lincomycin

Quinine

Telithromycin

Tetracyclines

Anticonvulsants

Gabapentin

Phenytoin

Trimethadione

Antipsychotics

Chlorpromazine

Lithium

Phenothiazines

Anti-rheum drugs

Chloroquine

Penicillamine

Cards Meds

Beta blockers

Bretylium

Procainamide

Propafenone

Quinidine

Calcium channel blockers

Corticosteroids

Neuromuscular blockers/Muscle relaxants

Botulinum toxin

Magnesium sulfate

Methocarbamol

Ophthalmologic meds

Betaxolol

Echothiphate

Timolol

Tropicamide

Proparacaine

Others

Anticholinergics

Carnitine

Cholinesterase inhibitoers

Deferoxamine

Diuretics

Emetine

Interferon-alpha

Iodinated contrast agents

Narcotics

OCPs

Oxytocin

Antiretroviral protease inhibitors

Thyroxine

A Neuroanatomical Approach tAcute Flaccid Paralysis

1. Muscle (acute myopathies):

- Inflammatory myopathy (polymyositis, dermatomyositis)

- Rhabdomyolysis (extreme exertion, drugs, viral myositis, crush injury etc.)

- Acute alcoholic necrotizing myopathy

- Periodic paralyses (hypokalemic, hyperkalemic)

- Metabolic derangements (hypophosphatemia, hypokalemia, hypermagnesemia)

- Thyroid or steroid myopathy

2. Neuromuscular Junction:

- Myasthenia Gravis

- Botulism

- Tick paralysis

- Other biotoxins (tetradotoxin, ciguatoxin)

- Organophosphate toxicity (can alscause neuropathy)

- Lambert-Eaton Myasthenic Syndrome (LEMS)

3. Nerve (acute neuropathies):

- Diphtheria

- Porphyria

- Drugs & Toxins (arsenic, thallium, lead, gold, chemotherapy - cisplatin / vincristine)

- Vasculitis (incl. lupus, polyarteritis)

- Paraneoplastic and Paraproteinemias

- Multifocal motor neuropathy

4. Nerve Roots (acute polyradiculopathies):

- Guillain-Barre Syndrome

- Lyme disease

- Sarcoidosis

- HIV

- other viruses (CMV, VZV, West Nile)

- Cauda equina syndrome (lumbar disc, tumor, etc.)

- Plexus lesions (brachial plexitis, lumbosacral plexopathy)

5. Anterior Horn Cell (motor neuron diseases):

- Amyotrophic lateral sclerosis (ALS) - with UMN findings

- Poliomyelitis

- Kennedy's disease (spinobulbar atrophy / androgen receptor gene)

- other spinomuscular atrophies (inherited)

- Anterior spinal artery syndrome (with grey matter infarction)

6. Spinal Cord (corticospinal tract diseases):

- Inflammatory (Transverse myelitis)

- Subacute combined degeneration (B12 deficiency)

- Spinal cord infarction

- other myelopathies (spondylosis, epidural abscess or hematoma)

7. Brain

- Pontine lesions (eg. central pontine myelinolysis, basis pontis infarct or bleed)

References

Neurological Medicine Pocketbook © 2003-2004 UWNeurology Residents

NEURO-ONCOLOGY Sarah Kremen, MD, Jeremy Rudnick, MD, Nick Szumski, MD. Reviewed by Albert Lai, MD, PhD. Revised by David Piccioni MD, PhD and Timothy Cloughesy, MD 6/08

Adults: 70% occur supratentorially. Occurrence in order of decreasing frequency: metastases (100k/ year), glioma (13k/year), meningioma (17%), schwannoma (5%). The twmost common brain tumors in adults are mets >>> gliomas. Most common brain mets in adults are: lung, breast, melanoma; then renal, colorectal, lymphoma. Hemorrhagic mets: melanoma, choriocarcinoma, renal; less commonly thyroid, lung.

Children: 70% occur infratentorially. Occurrence in order of decreasing frequency: pilocytic astrocytoma and medulloblastoma > ependymoma.

Most common brain mets in kids: neuroblastoma, sarcoma, germ cell tumors.

Differential diagnosis of a mass lesion: tumor, infection, demyelinating, infarction, hemorrhage. Consider biopsy in unclear cases – only tissue can give an answer and direct proper therapy in some cases.

Gasser Hathout’s Tumor Lecture (2005-6) – Transcribed by Nick Szumski

The most important step is tknow that location and age of the patient are more important in getting the diagnosis than the appearance of the tumor. So, when looking at a mass, ask yourself:

1) is the mass intra or extra axial; anterior or posterior fossa; skull base?

2) What is the age of the patient?

3) Generate list of possibilities given the information from 1) and 2)

4) Then look at the tumor appearance

12 Primary Brain Tumor Categories:

1) Glioma (astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma)

2) Neuronal (neurocytoma, DNET, gangliocytoma, ganglioglioma [mixed])

3) PNET (medulloblastoma, pineoblastoma, neuroblastoma, retinoblastoma)

4) Epidermal inclusion (e.g. craniopharyngioma)

5) Skull base (chordomas, etc.)

6) Lymphoma

7) Germ cell (germinoma, teratoma, choriocarcinoma, embryonal cell, endoermal sinus tumor)

8) Pituitary

9) Pineal

10) Meningioma

11) Schwannoma (CN VIII >> CN X, VII, V >> all others)

12) Hemangioblastoma

Astrocytomas [WHGrade : Name (histology) – Features]

I : Pilocytic astrocytoma (pilocytic) – Childhood; local, excisable growth, often cystic; enchance.

II : Low-grade glioma (fibrillary) – Invades white matter, 1/3 dnot enhance.

III : Anaplastic astrocytoma (fibrillary) – Higher grade, enhances, mitoses.

IV : GBM (fibrillary) – Highest grade, enhances; “pseudopalisading around central necrosis” on path and/or endothelial proliferation.

Child – Posterior fossa

Pilocytic astrocytoma (1/3) – Cerebellar hemisphere (95%) – usually cystic + solid enhancing portion.

Medulloblastoma (1/3) – Midline (4^th ventricle) – rounded, pushes stuff out of way, fairly homogenous, can unusually be posterior t4^th ventricle.

Ependymoma (1/6) – Midline (4^th ventricle) – Soft, tends ttake shape of ventricle, with inferior point, growth through foramina; heterogeneous; “perivascular pseudorosettes” on path.

Brainstem glioma (1/6) – Brainstem – ~1/2 fibrillary, ~1/2 pilocytic.

Child – Pineal region (in order – difficult tdifferentiate on MRI, but vast difference on path)

1. Germinoma (10-20:1 M>>F in this region; dense on CT, enhances on MRI)

2. Pineocytoma

3. Pineoblastoma

4. Teratoma (look for fat – bright on both T1/T2)

5. Other germ cell (b-HCG: germinoma or chorio; AFP: endodermal sinus; both: embryonal cell)

6. Astrocytoma

Child – Perisellar region (in order)

1. Craniopharyngioma – Far and away most likely; cystic 95% of time, often proteinaceous

2. Hypothalamus/chiasm glioma – Pilocytic enhances / low-grade fibrillary does not enhance

3. Germinoma – Dense on CT, enhancing; M = F in this region

Adult – Perisellar region (in order)

1. Pituitary adenoma – Must have big sella -- “snowman”; can’t see any residual pituitary tissue.

2. Meningioma – Dural tail, enhances.

3. Giant carotid aneurysm

4. Craniopharyngioma – Cystic, fluid-fluid level may be present.

Adult - Supratentorial

Astrocytoma – Hyperintense on T2

Lymphoma – Isointense on T2, ncentral necrosis, often periventricular with subependymal enhancement (one variant is only subependymal; DDx would include CMV if HIV+).

General tip: Masses seen in the 3^rd ventricle RARELY arise from 3^rd ventricle. Use pineal or perisellar differential instead as appropriate.

Glioblastoma Treatment:

Standard therapy: concurrent XRT and temadar daily for 6 weeks with PCP prophylaxis, then pulsed temadar, 1^st 5 days of every 28 day cycle. Watch for ANC nadir at day 21.

Most common treatment for recurrence: Avastin (anti-VEGF). Given q2 weeks. Side effects include hypertension, stroke, and PRES. HTN treated empirically, usually with ACE as first line. After stroke, stop Avastin, and treat as usual. May anticoagulate if necessary.

Initial Meningioma Management:

Follow with imaging at 3, 6, 12 months tsee if lesion is growing, then follow clinically if stable.

AED for seizures as needed.

Management of Common Tumor Complications

1) Seizure – AEDs can be tapered one week post-operatively.

Primary Prophylaxis: AAN practice parameter: nindication for prophylactic AEDs routinely in brain tumor patients. Use clinical judgement if a tumor is invading cortex.

After first seizure: Use non-enzyme inducing AEDs tavoid interactions with chemotherapy. Keppra and/or depakote most effective in recent meta-analysis. Alsconsider: lamotrigine, zonisamide, topiramate, gabapentin.

However, if a patient presents in status, then load on fosphenytoin, and treat status per protocol.

2) Increased ICP– Cause: vasogenic edema. Sx: headache, nausea, vomiting. Load decadron 10mg IV, then 4mg QID. Double dose every 48h until maximal response. May dose bid. There is not much efficacy in doses higher than 40mg daily.

Steroid side-effects: insomnia, acne, increased appetite, lipomatosis (including in the epidural space with cord compression), memory loss, thrush, myopathy, psychosis or irritability, osteoporosis, avascular necrosis, glaucoma,

opportunistic infections (long term), hyperglycemia.

For long term steroid use, watch ALC < 600 and consider bactrim DS MWF for PCP prophylaxis, and bisphosphonates for osteoporosis.

Don’t forget tput every pt on PPI and sliding scale insulin with glucose checks when starting steroids.

Emergency Treatment of Impending Cerebral Herniation
Therapy	Dosage	Onset-Duration
Hyperventilation	Lower pCO2 t25-30mmHg	Seconds tminutes
Osmotherapy (second line)	Mannitol 0.5-2 g/kg IV over 15 min, with 25g IV boosters as needed	Minutes tHours (may augment with lasix as below)
Corticosteroids (first line)	Decadron 40-100mg IV push, then 40-100mg total every 24 hours depending on sx	Hours tDays (may augment with IV lasix 40-120mg x1)

The response tsteroids is proportional tcontrast enhancement of tumor and amount of surrounding edema on imaging.

3) Venous Thromboembolism– Cancer patients are hypercoagulable and at risk for DVT and VTE.

Primary prevention: compression stockings, pneumatic boots, and subcutaneous heparin or lovenox.

Secondary prevention: Enoxaparin, dalteparin, fondaparinux are superior twarfarin and heparin in cancer patients.

IVC filters are reserved for those in which anticoagulation is contraindicated: recent craniotomy, frequent falls, poor compliance, and prolonged thrombocytopenia secondary tchemotherapy.

NEURO-OPHTHALMOLOGY Sarah Youssof, MD. Reviewed by Anthony Arnold, MD 6/07

Diplopia

Ddx:

Mechanical (orbital fracture)

Extraocular muscle disorder (thyroid disease, orbital myositis)

NM junction disorder (MG)

CN 3, 4, 6 peripheral nerve or central nuclei

Supranuclear oculomotor pathway (INO, skew deviation)

Toxins/meds (alcohol, AEDs)

*Note: Complete oculomotor nerve palsy sparing pupil is usually NOT due taneurysm

#Note: Subtle 6^th nerve palsy: slight lag in abduction of affected eye when testing bilateral horizontal saccades; cover-uncover test usually positive in primary gaze, though worse while affected eye looks laterally

Horner’s syndrome

I. Decending (1^st order neuron located in hypothalamus): -- lateral brainstem -- cervical cord -- thoracic cord levels T1, T2 -- synapse on 2^nd order neuron

- Possible lesion: lateral brainstem, spinal cord (e.g. infarct, cord trauma)

II. Preganglionic (2^nd order neuron located in intermediolateral cell column): -- ventral roots T1,T2 -- white rami -- paravertebral sympathetic chain -- ascend tsynapse on 3^rd order neuron

- Possible lesion location: first and second thoracic roots and sympathetic chain (e.g. apical lung tumor, trauma, tumor)

III. Postganglionic (3^rd order neuron located in superior cervical ganglion): -- carotid plexus along walls of ICA -- pupillary dilator muscle

- Possible lesion location: carotid plexus, cavernous sinus, orbit (most postganglionic neuron lesions are usually benign and idiopathic but concerning pathology may include carotid dissection, cavernous sinus thrombosis, infection, aneurysm or neoplasm, orbital infection or neoplasm)

Work-up: (not needed if congenital onset < 4 weeks)

MRI brain, MRI and MRA neck, CT chest

Drops used for dilated ophthexams:

1) Mydriacyl 1% (generic: Tropicamide), 1-2 drops per eye.

2) Neo-Synephrine 2.5% (Phenylephrine) 1 drop per eye. Contraindication: Narrow angle glaucoma (check with anterior chamber depth assessment prior)

From Blumenfeld, Neuroanatomy Through Clinical Cases.

PERIPHERAL NEUROLOGY: BRACHIAL PLEXUS

Figures compiled by Aimee Pierce, MD, and PTsai, MD

Source: UpToDate

PERIPHERAL NEUROLOGY: LUMBOSACRAL PLEXUS

Aids tthe Examination of the Peripheral Nervous System, 4th edition, page 37.

PERIPHERAL NEUROLOGY: DERMATOMES American Spinal Injury Association (ASIA) Dermatome Map

KEY REFLEXES AND THEIR NERVE ROOTS Compiled by Aimee Pierce, MD, and PTsai, MD Root Motor Action Sensation Reflex Trigeminal (V3) Mastication Chin Jaw Jerk C5 Shoulder abduction, elbow flexion Lateral arm Biceps C6 Wrist extension, elbow flexion Lateral forearm, thumb, index finger Brachioradialis C7 Elbow extension Middle finger Triceps L4 Hip flexion, knee extension Medial shin Patellar S1 Foot plantar flexion Lateral foot and sole Achilles From Blumenfeld: Neuroanatomy through Clinical Cases, p. 318.

PERIPHERAL NEUROLOGY: PERIPHERAL NEUROPATHY

Dan Arndt, MD and Susan Shaw, MD. Reviewed by Perry Shieh, MD 6/07

Workup: Labs, EMG/NCS, +/-MRI-Spine

Diff Dx: UMN lesion, radiculopathy, NMJ, myopathy, motor neuron disease (see Plexopathy Vs Radiculopathy Vs Neuropathy)

History:

Look for:

Rapid progression Purely demyelinating

Multifocal distribution Abnormal lab tests

If above negative, can probably stop as >60% neuropathies are cryptogenic.

Rapid progression:

Pure Sensory with ataxia: α-Hu

Amyloid: Nerve Bx

Vasculitis: Nerve Bx and labs below

Multifocal distribution:

R/Vasculitis

Can check ACE

Nerve Bx

Constitutional Sx’s: vasculitis, paraneoplastic, lymphoproliferative disorder

Labs

Screening labs:

HbA1c

RPR

B12/Folate (+/-MMA/Homocyst)

TSH (actually causes myopathy and not neuropathy)

SPEP/IFE

Order if clinically indicated:

Fasting glucose, 3hr GTT,

HIV

ESR, ANA, Rheumatoid factor

Hep C, cryoglobulins

UPEP

Lyme

Paraneoplastic (α-Hu)

Urine for heavy metals

GALOP

HTLV-1

CMT,

α-GM1/MAG/Sulfatide,

Vasculitis: Cryo, RF, HepC, ANA, ESR, ANCA, SSA/B

Sensorimotor neuropathy panel: (=$1215) Co-SGPG ELISA, α-Sulfatide IgG/M, α-MAG ELISA, α-Hu Ab, Co-GM1 IgG/M/A, Co-GM1 AsialIgM, Co-GD1b, Co-GSC 1gM

Etiologies

Vitamins: ? ↑/↓ E ?↓B ? Beriberi ?↓B3 ? ↑B6 ? Pellagra (D, D, D)

Treatable: DM, thyroid, B12 deficiency, syphilis, vasculitis, demyelinating

Assoc w/ other findings:

SPEP/IFE: Amyloid, Multiple myeloma, Waldenstrom’s, POEMS

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, Skin changes)

Paraneoplastic: α-Hu - Sensory Neuronopathy

Toxic Neuropathies

Porphyria: Urine/Stool Porphyrins, Delta-ALA, Motor p Meals

Hereditary: young age, +FH, musculoskel deform (pes cavus), pain uncommon

Charcot-Marie-Tooth: (Most common):

1. NCS/EMG tdetermine axonal vs demyelin, then genetic testing.

2. If demyelin, send in order: 1. PMP-22 dup/del, 2. MPZ, 3. Connexin-32

Price: PMP22 dup/del ($545), PMP seq ($545), CMT panel ($4495)

Demyelinating: CMT 1 = 78% of all AD neuropathies

CMT 1a: Order “PMP-22 dup/del” (“PMP-22” sequences the entire gene)

CMT 1b: MPZ (Myelin Protein Zero)

Axonal: CMT 2 – 22% of all AD neuropathies

Mixed Ax-Dem: X-linked CMT. Connexin-32

Phenotype similar tCMT 1a. Males more affected than females.

Autosomal recessive: Spinal muscular atrophy

X-linked: Bulbospinal Musc Atrophy

HSAN

Demyelinating: (rule out cold skin temp on NCS -- False +)

AIDP: 60% 4limbs by presentation

? Miller-Fisher Variant: opthalmoplegia, ataxia, areflexia

CIDP:

- Slowly progressive, symmetric proximal & distal weakness, sensory sx’s

- Progression over > 2mos

- Relapsing/remitting in 50%

- Generally idiopathic

-- Rx: Corticosteroids, IVIG, Plasmapharesis → 66-95%

- 2nd Line: Imuran, Cytoxan, Cyclosporine

- R/Concurrent Illness: HIV, Transplant, Paraprotein, POEMs, Hep C, IBD, CTD, Thyroid, DM, MS, Nephrotic Syndrome

- SPEP/IFE on EVERY pt → 10-20% w/ M-protein, but generally IgG or A MGUS. If IgM reconsider dx, as pt may have DADS

DADS: (Distal Acquired Demyelinating Syndrome → distal limbs)

[Katz et al. Neurology 2000. 54: 615-620]

-Sensory >> Motor Sx’s

-May c/Gait unsteadiness, tremor

+ M-Protein (IgM Kappa) on SPEP-- DADS-M. Very very poor response tRx (only 30% with subjective sensory improvement)

- Absent M Prot or IgM -- DADS-I (Idiopathic). Intermediate response tplasma exchange

MMN: Multifocal Motor Neuropathy → Asymm Limb weakness → Usually P.N. distribution

- Begins w/ distal UE

- Weak muscles show little atrophy

- CSF Protein: ~ NL

- NCS: Purely Motor – Demyelinating (+/- Conduction Block) (Sensory should be NL)

- α-GM1 IgM Ab specific (but <50% Sens). Unecessary for dx, & does not predict rx resp) **Also, ↓GM1 titers may be seen in axonal GBS & idiopathic CIDP

- Rx: IVIG (Nsteroids or plasmapharesis – may worsen)

- 2^nd line: IV Cytoxan (0.5-1.0mg/m2 qMon, 70% success)

MADSAM:Multifocal Acquired Demyelinating Sensory & Motor (Neuropathy)

- AKA: “Multifocal CIDP” or “Lewis-Sumner Syndrome”

- Distribution: may follow P.N.’s (Chronic Multiple Mononeuropathies)

- Initially UE, then distal LE

+Pain/Paresthesias

- Cranial nerves possibly

- EMG/NCS: Both motor & sensory demyelinating

- CSF: ↑ Prot 60-80%

- May see pressure palsies (as in Hereditary Neuropathy)

- Rx: As w/ CIDP

Axonal:

? Toxic:

? Alcohol

? Arsenic

? Drugs (INH–B6, Dilantin, Statin, Penicillamine, ChemoRx

? AIDP

? Chemotherapy:

? Vincristine (Sensorimotor/Cranial)

? Cisplatin (Sensory)

? Adriamycin

EMG/NCS

Sarah Youssof, MD. Reviewed by Perry Shieh, MD. 6/07

Types of studies:

1. Sensory/mixed nerve: CNAP (compound nerve AP)

2. Motor: CMAP (compound muscle AP)

3. Late responses (F waves – reflect proximal conduction; A waves – ephaptic transmission, demyelinating sign; H waves – analogous tmonosynaptic reflex)

4. Needle EMG

5. Repetitive nerve stimulation

a. Low frequency (3Hz): decremental response in MG

b. High frequency (>20 Hz): incremental response in LEMS, botulism

6. Single-fiber EMG: very sensitive for NM disease, non-specific, look for jitter (varying motor unit response latency reflecting abnormal NM junction)

NCS:

Demyelinating features:

Prolonged distal latency

Slow conduction velocity

Conduction block (>50% drop in amplitude on proximal stim c/w distal stim)

Temporal dispersion

Prolonged F-wave latency

Axonal features:

Decreased amplitude

May see mild slowing (loss of faster fibers)

Acute axonal injury can look like conduction block

Needle EMG:

Resting muscle
Insertional activity	Minimal in normal muscle
Spontaneous activity	Muscle membrane irritability: fibrillation potentials positive sharp waves complex repetitive discharges myotonia	Nerve irritability: fasciculations cramps myokymia neuromyotonia
Activated muscle	Myopathic findings:	Neuropathic findings:
Motor unit morphology	low amplitude mixed duration polyphasic	high amplitude long duration polyphasic
Recruitment pattern	early occasionally reduced	Reduced

Note: Normal values for NCS must be obtained independently for each lab. These values are provided as general guidelines.

RADIOLOGY Updated by Sarah Kremen, MD. Reviewed by NorikSalamon, MD, 6/06

CT

Good for emergencies or patients with contraindication tMRI (pace maker). Gray matter denser (whiter), white matter less dense (darker), CSF dark. Assesses bleed, masses with edema, fractures, hydrocephalus and old strokes well. Not as good for acute stroke, small masses, and viewing posterior fossa. Blood and calcification are white.

CT Angiogram: Used tassess for arterial blockages, aneurysm, dissections, stenoses. Alsgood tlook at venous thrombosis.

CT Perfusion: Assesses areas of decreased blood flow, tassess “at-risk” areas from vascular stenoses – used often in patients whcannot get MRI.

MRI Sequences:

DWI (Diffusion Weighted Image): Used for acute ischemia which shows up as white from 15 minutes t2 weeks. This is a T2-based scan, scan use as poor man’s T2, and will alssee T2 shine through if old lesions are present.

ADC (Attenuated Diffusion Coefficient): Companion tDWI, used tconfirm acute ischemia, which shows up as dark.

PWI (Perfusion Weighted Imaging): Assesses areas of decreased blood flow – show up as white. Good tassess “at-risk”areas from vascular stenoses

T1: Anatomic study. Gray matter gray, white matter white, CSF dark. Used tsee encephalomalacia, or with contrast for tumor.

T2: Shows pathology. Gray matter white, white matter gray, CSF white. Best for showing white matter abnormalities like stroke, MS. Use this alstevaluate the posterior fossa.

FLAIR: (Fluid attenuated inversion recovery): T2 with fluid suppressed. Gray matter white, white matter gray, but CSF dark. Allows you tassess cortical abnormalities, as well as white matter edema very well (tumor edema, MS, old strokes). Alsa good way tlook for subarachnoid blood in the sulci.

GRE (Gradient Echo): Assess bleeding which shows up as dark. Alsgood or better than CT for intraparenchymal microhemorrhage (bleed) but not SAH.

MR Angiogram: Used tassess for arterial blockages in aortic arch, neck, or head; tends tovercall severity of stenoses.

PET Scan:

FDG: used tdelineate tumor, surgically respectable focus in epilepsy, and work up of dementia subtype. Can use F-DOPA PET in some movement disorders or brain tumor.

MR spectroscopy: used tidentify areas of abnormality such as tumor by spectroscopy, creates metabolite spectra maps. Choline peak (seen at 3.2 ppms): signal of cellular membrane synthesis; increased peak with of building or tearing down membrane, high choline peak is seen in both infection and tumor. Creatine peak (seen at 3.0 ppms): creatine associated with cellular energy metabolism, and peak should remain stable. NAA (seen at 2ppms): associated with neuronal and axonal integrity, usually the tallest peak, in the center. Lipid and lactate peaks: seen only with distructive processes, suggestive of necrosis, as in tumor, infarct, dementia or metabolic disorders.

If choline:creatine peak > 2.5, usually tumor.

Differential of Hyper/Hypodensity on CT

Hypodensity on CT: air, fat

Hyperdensity on CT: bone, contrast, densely packed cells (lymphoma, medulloblastoma, etc)

MRI Blood Age - how tfigure out how old the bleed is

A few notes:

The periphery of the blood is always more advanced

GRE cannot show oxyhemoglobin

FLAIR may show SAH blood in CSF space (bright instead of dark space)

Mnemonic: “itty bitty baby dodo” (I-D, B-D, B-B. D-D, starting with deoxyhemoglobin)

Time	Type of blood	T1	T2
<12 hrs	Oxyhemoglobin	Isointense (may be dark)	Bright or Isointense
12 hrs – 3 d	Deoxyhemoglobin	Isointense (may be dark)	Dark
3 – 7 days	Intracellular methemoglobin	Bright	Dark
7-14 days	Extracellular methemoglobin	Bright	Bright
>2 weeks	Hemosiderin	Dark	Very dark

Differential of Hypo/Hyperintensities on MRI

In general, pathological processes are usually dark on T1 and bright on T2.

Sequence	Bright	Dark
T1	Fat, constrast, subacute blood (met-hgb, protein), turbulent flow, free radicals (eg in abscess wall)	CSF, Ca2+
T2	Fat (can alsbe isointense), edema, CSF	Air, bone, fast flow, acute blood, chronic blood (hemosiderin, /ferritin), Ca2+, protein, free radicals, densely packed cells, metal
GRE	Normal blood flow	Blood (thrombus, fat, calcium

Differential Diagnosis of Hyperintensity on DWI:

Infarction (arterial or venous), prion disease, abscess, active MS, densely packed cell tumor, prolonged seizure (usually gyriform), vasculitis, migraine (this is rare), epidermoid cyst, post-anoxic event.

A matched hypointense ADC map indicates cytotoxic edema, seen in infarct, or seizure, for example. A matched hyperintense ADC map indicates T2 shine through.

SEIZURES/EPILEPSY: ANTIEPILEPTICS – Side Effects

phenytoin

**worsens myoclonic and absence**

Dosing

corrected level: Measured total concentration / [ (0.2 x albumin) + 0.1] )

http://www.globalrph.com/phenytoin.cgi

for status

20mg/kg

Get trough a 3 hours after load

goal is 25mg/kg after load

typical dose is 200-400 qhs

Side effects

dose-dep: Diplopia, Ataxia, Nystagmus, Sedation

Rules of thumb

horizontal nystagmus if therpeutic

nystagmus on primary gaze if supratherapeutic

idiosyncratic side effects: Anemia, Malignant hyperthermia, Hypotension, Cardiac arrhythmias, Lupus-like syndrome, Rash, inc Stevens Johnson syndrome, Hepatitis, Pseudolymphoma/lymphadenopathy

chronic side effects: Peripheral neuropathy, Gingival hypertrophy, Hirsuitism, Osteopenia, Folate deficiency, Intermediate teratogenesis, Coarse facial features

lowers OCP effectiveness (also VPA)

folate deficiency, vit D

cerebellar atrophy

hypotension

the propylene glycol induces dose-dependent hypotension

red glove

if infused too quickly, phenytoin comes out of solution and crystalizes - this causes local necrosis

Mechanism: Na

Excretion: Liver

nonlinear excretion

interaction

warfarin, anticonvulsants, VPA lowers

other

administered in propylene glycol becasue phenytoin is insoulable

surveillance

LFTs

fosphenytoin

needs 8-15 min for conversion to phenytoin

soluable in water, so no need for propylene glycol and no infusion reaction

phenobarb

dose-dependent side effects: Sedation, Depression, Cognitive impairment, Blurred vision, Dizziness, Ataxia

Idiosyncratic side effects: Rash, Hyperactivity, Hepatitis, Aplastic anemia, Can exacerbate 10 Gen Sz

Chronic side effects: Osteomalacia, Folate deficiency, Cerebellar degen, Connective tissue d/o frozen shoulder, Neuropathy, Teratogen, Coarse faces

GABA agonist, Na, T Ca, Glutamine

liver with renal excretion

cognitive

asplastic anemia

vit D, K deficiency

decreases others

LFTs

primidone

Na, GABA, glutamine

sedation/cognitive

D, K

turns to phenobarb

same side effects as PB

VPA

Mechanism: Na, GABA, T Ca

indication: JME

Side effects

Dose depeendent side effects: Tremor, GI upset

Idiosyncratic side effects: Pancreatitis (up to 1/200), Hepatic failure, Hyperammonemia, Thrombocytopenia, Depletes carnitine, Rash, Coma/ Enceph, Pedal edema

Decreases platlet effectiveness (neurosurgeons hate this!?)

Chronic use side effects: Weight gain, Hair loss, Polycystic ovary, Osteoporosis, Teratogen

Other indications: mood stabilization

Liver metabolism

2-3 x / day

SE: cognitive less, liver, hepatitis, GI, weight gain, thin hair, pancreatitis, menstrual, thrombicytopenia

enzyme inhibitor: increases other drugs

LFTs

Carbamazepine

Na

typical 300-900 BID

Dizziness

Dose-dependent: Ataxia, Diplopia, N/V, Sedation, Mild leukopenia, Hyponatremia, Bradyarrhythmia, Elevated LFT

Idiosyncratic: Rash, Aplastic anemia (2/mil), Agranulocytosis (6/mil), Weight gain, Can exacerbate 10 Gen Sz, and Myoclonus

Chronic: Osteopenia, Aplastic anemia (2 per 575,000), Pancreatitis, teratogenesis, Wt Gain, Neuropathy

Liver

like phenytoin Ses – no cosmetic Ses

no loading dose

**autoinduction**

cognitive, nystagmus, rash, aplastic, leukopenia, hypersens, hyponatremia

enzyme inducer

LFT, CBC, Na level

oxcarbamazepine

typical 200-400mg BID

dose-dependent: Dizziness/Ataxia, Diplopia, Sedation, GI upset, Hyponatremia, Nausea/Vomiting

idiopathic: Rash (25% cross reactivity with CBZ)

chronic: Osteopenia

less liver, no autoinduction

interferes with OCPs

200 oxcarb = 300 carbamazepine

benzo

GABAa

liver

neuropenia

ethosuxamide

T Ca

dose-dependent side effects: Sedation, Headache

idiosyncratic side effects: Rash, Psychiatric, Lupus-like syndrome, Can exacerbate Primary Gen Sz

Chronic side effects: unk

GI, cognitive, rash, stevens, aplastic/agranulocytosis

felbamate

liver and kidney

dose-dependent side effects: Anxiety, Insomnia, Ataxia, Headache

idiosyncratic side effects: Rash, Aplastic anemia, Hepatic failure

chronic side effects: Weight loss/decreased appetite

apastic and hepatotox

retic count, CBC, LFT

Tigabine

aka Gabatril

GABA uptake

dose-dependent side effects: Sedation, Dizziness, Nausea, Cognitive slowing

idiosyncratic side effects: Rash, can provoke gen nonconv status = “spike-wave coma”, Knee buckling, Encephalopathy, Can Exacerbate Myoclonus, psychosis

chronic side effects: unknown

liver

cognitive, GI, tremor

Gabapentin

GABA

dose-dependent side effects: Sedation, Dizziness, Ataxia

idiosyncratic side effects: Rash, Behavior changes, Myoclonus, Pedal edema, Can exacerbate 10 Gen Sz

chronic side effects: Probably low teratogenesis, Wt Gain

renal

no monitoring

Lamotrigine

liver

dose-dependent side effects: Dizziness, Ataxia, Sedation, Insomnia

idiosyncratic side effects: Benign rash in 5 to 10%. 0.1% SJS, Can Exacerbate Myoclonus

chronic side effects: Folate antagonist, Probably low teratogenesis

Other considerations: mood stabilization

Titration: slow due to risk of TEN

Na, glutamate

rasj severe

Levitaracetam

less bursts

renal

dose-dependent side effects: Sedation, Dizziness, Behavioral Change, Depression, Irriability

8-10% mood symptoms [[file lev_tpm_se_eff.pdf | paper comparing Keppra and Topamax side effects]]

idiosyncratic and chronic side effects: unknown

Status loading dose (Soss): 4-4.5 g, start 1500-2000mg BID

8 hour 1/2 life in serum, 12 h 1/2 life in CNS

Topiramate

Na, GABA, NMDA

liver metabolism, 80% eliminted urine unchanged

CA inhibitor: renal stones, angle closure glaucoma, paresthesias

dose-dependent side effects: Cognitive slowing, Word-finding diff, Paresthesias, Weight loss, Dizziness

Idiosyncratic side effects: Rash, **Narrow-angle glaucoma**, **Metabolic acidosis**, Paresthesias (benign)

Chronic side effects: **Renal stones (1-2%)**, Weight loss, Osteopenia

Titration: slow due to risk of psychosis

Interesting: incidence of aphasia at high dose

Zonisamide

T Ca, GABA

liver, renal excretion 1/3

CA: stone

cognitive: slurred

rash, sulfa

Dose-dependent side effects: Sedation/ataxia, Confusion, Dizziness, Paresthesia, Weight loss

Idiosyncratic side effects: Rash (inc Stevens Johnson), Sulfa allergy, Hypohidrosis and hyperthermia, Anorexia, Photosensitivity

Chronic side effects: Renal stones, Weight loss

Indication: progressive myoclonic epilepsies, JME

60 hour 1/2 life in serum, 120 hour 1/2 life in red cells (!)

Vigabatrin

GABA breakdown

field constriction

infantile spasms

Pregabalin

partial, renal

ketogenic diet

starvation 4 days

3-4 g fat: 1 g carb

surgery – refractory in 1/3

Drug-drug Interactions

LTG and GPN enhances CBZ toxicity

VPA increase level of LTG

Non-enzyme-inducing AEDs: acetazolamide, clobazam, clonazepam, ethosuximide, gabapentin, levetiracetam, Piracetam, pregabalin, Valproate sodium, valproic acid, divalproex sodium, tiagabine, Vigabatrin, zonisamide, lamotrigine

Enzyme-inducing AEDs: Carbamazepine (CBZ), Oxcarbazepine (OXC), Phenobarbital (PB), Phenytoin (PHT), Primidone (PRI), rufinamide, Topiramate (TPX)

Non-enzyme-inducing AEDs

acetazolamide

clobazam

clonazepam

ethosuximide

gabapentin

levetiracetam

Piracetam

pregabalin

Valproate sodium, valproic acid, divalproex sodium

tiagabine

Vigabatrin

zonisamide

lamotrigine

Enzyme-inducing AEDs

Carbamazepine (CBZ)

Oxcarbazepine (OXC)

Phenobarbital (PB)

Phenytoin (PHT)

Primidone (PRI)

rufinamide

Topiramate (TPX)