Neurology

1. GCS 2. Headache 3. Migraine

4. Meningitis 5. Epilepsy

6. Multiple sclerosis 7. Myaesthenia gravis

8. Peripheral neuropathies 9. Parkinson disease

Editorial team Katie Newman, Rebecca Ng, Ashleigh Spanjers

Peer reviewed in 2011 by Pending

Total: 3/15 – 15/15

Minor brain injury ≥13

Moderate brain injury 9-12

Severe brain injury ≤8

NB: The phrase ‘GCS of 10’ is meaningless, you must break the figure down into its components, such

as E3V3M4=GCS 10

Marx J, Hockberger R, Walls R. Rosen’s Emergency Medicine-Concepts and clinical practice, 2-volume

set. 7th

ed. St. Louis: Mosby; 2009.

Headache Pain in the head!

DDx2,3,4 90% of benign h/aches=migraine, tension, or cluster h/ache Headache syndromes-

• Tension headache • Migraine (see separate sheet) • Cluster headache

o Brief attacks unilateral excruciating periorbital pain & autonomic sx occurring in series for wks-mths

• Sinus headache • Post-concussion

Drug or toxin-induced- • Medications-nitrates, dihydropyridine Ca channel

blockers, vasodilators, indomethacin, nalidixic acid, trimethoprim-sulfamethoxazole

• Food additives-MSG • Toxins-CO, lead, arsenic • Recreational drugs-inhalant abuse, cocaine, ETOH • ETOH/drug withdrawal • Hormonal (oestrogen, OCP) • Medication overuse (resolves or reverts to previous

pattern w/in 2 months after discontinuation of the drug)

Intracranial organic pathology- • Infection-meningitis, brain abscess, encephalitis (eg.

HSV), neuroTB, toxoplasmosis, African sleeping sickness, subdural empyema

• Intracranial mass-tumour, sarcoidosis • Haemorrhage-subarachnoid, hypertensive

parenchymal, subdural • Ischaemic conditions-stroke, TIA, vascular

malformations • Traumatic brain injury • Acute external headache (majority due to transient

intracranial)-spinal press dissociations eg.orgasm, cough, sneeze

• Low pressures h/ache-postLP, postraumatic CSF leak Other organic syndromes-

• Cranial bone pain-OM, MM, Paget disease of bone • Scalp pain-tinea capitis, tension from hair-pulling eg.

braids, external compression eg. swim-goggles, occipital neuralgia

• Vascular-temporal arteritis, carotid or vert art dissection

• Eye pain-acute glaucoma, optic neuritis, squinting • Ear pain-disorder of middle ear, nervus intermedius

neuralgia (felt deep in auditory canal) • Acute sinusitis • Dental pain-abscess, impacted tooth, TMJ syndrome • Facial nv pain-trigeminal neuralgia • Neck pain-cervical spine disease (greater occipital

neuralgia), whiplash • Acute febrile illness • Metabolic-hypoxia, hypercapnia, hypoglycaemia,

dialysis • HTN (see separate document)

Psychologic- • Dep, anx, hypochondriasis, malingering

Brain ‘freeze’- • Eg. gobbling ice-cream!

Qns to ask on Hx2,3,4 Time course and progression-

• Determine whether acute/acute, recurrent/chronic, progressive/chronic, non-progressive

Associated symptoms (see separate box below) Location-

• Generalised-idiopathic intracranial HTN, subarachnoid • Unilateral-migraine (becomes bilateral), temporal

arteritis, TIA, cluster, trigeminal neuralgia (2nd & 3rd divisions trigeminal nv distribution ie. lip, gum, cheek, chin)

• Temporal-temporal arteritis, cluster • Eyes-subarachnoid, cluster • Posterior neck-minor bleed in subarachnoid, tension

Character- • Subjective interpretation so variable�unspecific sign • Stabbing or burning-cluster, trigeminal neuralgia • Dull-sinusitis, post-concussive • Throbbing-migraine, acute febrile illness, post-

concussion (exacerbation) Severity-

• Baseline impt for noting effects of Rx • “Worst headache ever” w/ maximal pain at onset is

indicative of subarachnoid (may have preceding sentinel h/ache)

• Post-concussive worsens days-wks • Continuously worsening suggests mass lesion

Timing and onset- • First event?

o 1st persistent h/ache>50yrs is concerning • Sudden (subarachnoid, cluster, acute external) • Gradual (migraine, temporal arteritis)

Frequency and duration Precipitating factors-

• Aura, fortification hallucinations, drug use/withdrawal, stress, premenstrual period, position, orgasm, exertion, irregular sleep habits

Aggravating factors- • Standing or lying down (low press), • Rest (migraine, tension)

Alleviating factors PMHx

• Psychiatric disorders • Pain conditions • UTRI may precede sinusitis

Med Hx • New drugs • Possible causative agents (see DDx)

Family Hx • Migraine

Social Hx • Enviro hazards eg. fumes or duct containing lead,

nitrites, methemeoglobin formers (eg. aniline) • Diet, caffeine, smoking, ETOH and drug use • Stress

Pathophysiology2,3,4 • Many diff extra- & intracranial structures are sensitive

to pain incl skin, subut tissues, muscles, mucous membranes, larger BVs

• Small ↑ in ICP can cause pain

Ex2,3,4 • Most will have normal exam • Vitals

o Fever, HTN (may reflect increased ICP) • General inspection

o Agitation (cluster) o Petechial/purpuric rash (meningitis)

• Head o Haemotympanum (head trauma) o Tenderness over temporal artery (temporal

arteritis) o Papilloedema (increased ICP eg. mass lesion) o Horner’s syndrome (cluster) o Poor dentition (abscess)

• Neck o Neck muscle tenderness (tension) o Nuchal ridigity (meningitis)

• Neuro o Altered cognition (subarchnoid, infection, o Neuro abnormality

Possible associated Symptoms/Signs2,3,4 • Fever (temporal arteritis, meningitis) • Neck stiffness (subarachnoid, meningitis) • Photophobia, phonophobia, photopsia, homonymous

hemianopsia (migraine, TIA) • Lateralising neuro sx (migraine, TIA) • Nausea, vomiting (migraine, temporal arteritis, post-

concussive, intracranial mass, low press) • Dizziness (low press) • Intermittent claudication of jaw, facial pain ,

polymyalgia rheumatica (temporal arteritis) • Lacrimation, nasal congestion, rhinorrhoea, facial

swelling, miosis, ptosis (cluster) Neck

Ix2,3,4 Bloods

• If suspect temporal arteritis • ↑ ESR, mild leukocytosis, mild normochromic

normocytic anaemia, thrombocytosis

Neuroimaging • Not done routinely

CT if- • Sudden onset severe h/ache • Onset with exertion (10% risk identifiable organic

pathology) • ↓ cognition or alertness • Abnormal neuro findings on exam • Signs of meningitis

MRI if- • Suspect primary brain tumour, stroke

Other Special Tests • LP (if consider meningitis, or subarachnoid despite

normal CT) • Temporal artery biopsy gold-standard for temporal

arteritis

Acute Mx2,3,4 • See specific disease documents for recommendations if Dx made • Avoid precipitants

Pharmacologic • Paracetamol, 650mg orally, every 4-6hrs, or NSAIDs at usual effective dose, even in pts who have unsuccessfully tried

these at lower doses • Combination analgesics for moderately severe headaches unresponsive to acetaminophen or NSAIDs • Antidepressants in pts with chronic more severe headache • Referral to anaesthesiologist for epidural blood patch for post-LP headache

Non-pharmacologic • Massage of scalp and neck muscles, relaxation and stress reduction

Migraine Chronic, genetically determined, episodic, neurological disorder

Ex2,3,4 • Normal b/w episodes • HTN (2O pain)

Check for signs of more serious illness:

• Vitals: fever, bradycardia, ↑ BP • Neck stiffness, signs of meningeal irritation • Focal neuro findings

Presentation2,3,4 Headache!

• Intermittent unilateral (or hemicranial) throbbing crescendo-decrescendo h/ache

o Unilateral�generalises over time • Hrs to days-typically several hrs to 1d, rarely 1-2wks • Gradual onset-unilateral pain peaks in several hrs • Exacerbation by light, noise, movement • Alleviated by lying down in dark room with cool

compress applied to head, pressing on temples • Decreased ability to function

Associated Sx • Nausea, vomiting, LOA, diarrhoea • Photophobia, phonophobia

Aura • Visual sx (most common)-

o Visual phenomena-change in shape form, intensity over time

o Scotoma-slowly enlarging, change shape, move • Focal numbness/weakness • Vertigo

Prodome (days) • Photophobia, irritability, malaise, depression, food

cravings, exhilaration, anxiety Precipitating factors:

• Menses, perimenstrual period (oestradiol levels ↓) • Diet-tyramine, choc, MSG, bananas, nuts, wine, beet

aspartame (not proven) • Stress, stress alleviation • Altered sleep • Visual stimuli, odors • Smoking, ETOH, caffeine withdrawal • OCP o(‘off’ days), vasodilators

Psychiatric Sx • Memory changes, delirium, hallucinations, depression

Family hx of migraine

DDx2,3,4 • Tension h/ache

o Frequently co-exists, throughout head, bilateral pressure-like and non-throbbing, “tight band around head”, ≤1 of photophobia, phonophobia, or mild nausea

• Cluster h/ache o More common in men, strictly unilateral, <3hrs

• Subarachnoid haemorrhage (“worst h/ache ever”) o Severe, sudden-onset, “thunderclap” headache, 25%

have neuro findings on ex • Intracranial mass

o Subacute h/ache, worsening, in conjunction w/ development of new neuro signs or sx

• CNS infection o Severe, assoc w/ fever, altered consciousness

• Temporal arteritis o New-onset or worsening h/ache, >50yo, hx jaw

claudication, muscle pain, tenderness over temporal artery

• Cervical artery dissection o +/- neck pain, may have Horner’s syndrome or

tinnitus on same side as h/ache • Cavernous sinus thrombosis

o Assoc w/ fever, periorbital oedema

Ix2,3,4 Head CT or MRI In patients with:

• Unexplained neuro signs • Atypical h/ache features • H/aches that do not fill specific Dx criteria •

LP and CSF culture • If signs of meningeal irritation

Subtypes2,3,4 • Without aura (=‘common migraine’) • With aura (=‘classic migraine’) o W/migraine h/ache o W/non-migraine h/ache o W/out h.ache o Familial hemiplegic migraine (aura+motor

weakness, also present in ≥1 1st or 2nd degree relative)

o Sporadic hemiplegic migraine (aura+motor weakness)

o Basilar-type migraine (aura+ ≥2 fully reversible sx suggesting origin from brainstem and/or both hemispheres eg. dysarthria, vertigo, tinnitus, no motor weakness)

• Status migrainosus (unremitting, intractable h/ache >72hrs w/ <4hrs pain-free period while awake)

• Retinal migraine (repeated attacks monocular visual disturbance assoc w.migraine h/ache)

• Menstrual migraine

Mx2,3,4 Pharmacological Mild-mod:

• NSAIDs (or aspirin) or paracetamol monotherapy • Anti-emetics eg. metoclopramide • Hydration

Severe (non-preg): • Triptan

Severe, refractory to 1st-line therapies (non-preg): • Triptan+NSAIDs • Mg • Phenothiazines • Ergot alkaloids eg. Dihydroergotamine • Prochlorperazine • Opioid analgesics • Corticosteroids eg. Dexamethasone

Pregnant: • Paracetamol • Mg • Anti-emetics • Hydration

NB: Daily use of analgesic can increase h/ache (analgesic rebound)

• Do not neglect to treat co-existing depression • If sx linked to menstrual cycle consider cycle control

and Mg Non-pharmacological

• Cold (cold compress or frozen gel pack to head) • Constant temporal artery pressure (pressing temples) • Hyperbaric O2 therapy • Sleep hygiene (may ↓ frequency) • Trigger avoidance and behaviour modification

Surgery • Surgical deactivation of peripheral migraine trigger

site

5 Historical Features that Predict Dx2,3,4 1. pulsating 2. duration 4-72hrs 3. unilateral 4. nausea 5. disabling

Aetiology and Pathophysiology2,3,4 • Aetiology unknown!

o Evidence supports notion that brain in pts suffering from migraines is hyperexcitable to a variety of stimuli�neuronal depolarization more easily triggered

• Intracranial pain sensitive structures include dura at base of brain and intracranial BVs

• Previously postulated vascular-based phenomena (constriction and reflex dilation of cranial BVs) has been discredited

• Current theory defines neuro-biological disorder mediated by neurological events

o H/ache 2O to neurogenic inflammation of 1st division trigeminal sensory neurons innervating large vessels and meninges

o Activation of trigeminal neurons�dilatation of meningeal BVs, leakage of plasma proteins into surrounding tissues, and platelet activation

o Sensitised nerve fibres respond to previously ignored stimuli (eg. pulsations of meningeal vessels), now interpreted as painful

o Aura caused by fluctuating neuronal activity (cortical spreading depression) with initial wave of neuronal excitation across cortex, followed by prolonged period decreased neuronal activity, and finally neuronal recovery

o This process then activates trigeminovascular neurons

Epidemiology2,3,4 • 20-25% lifetime prevalence • F:M 3:1 • Onset <40yo • # and severity of h/aches ↓ w/ age • Typical migraine aura only occurs in 15-30% of pts • Risk factors include analgesic overuse and Viagra

Migraine Myths X OCP does not appear to have clinically important effect on headache activity in most women X Best current evidence does not support relationship b/w oral ingestion of biogenic amines and food intolerance reactions (eg. wine, tyramine, choc) √ migraine↔major depression

International Headache Society Diagnostic Criteria2,3,4 Migraine w/out aura

• ≥5 attacks lasting 4-72hrs (w/out successful Rx) with ≥2 of unilateral location, pulsating quality, mod-severe pain intensity, or aggravation by or causing avoidance of routine physical activity, and

• ≥1 of nausea and/or vomiting, or photophobia and phonophobia

Migraine with aura • Headache fulfilling criteria for ‘migraine w/out aura’

begins during aura or w/in 1hr following aura • ≥2 attacks with aura consisting of ≥1 of fully reversible

visual sx, fully reversible sensory sx, or fully reversible dysphagic sleep disturbance, and

• ≥2 of homonymous visual sx and/or unilateral sensory sx, ≥1 aura sx develops gradually over ≥5 mins, each sx lasting 5-60 mins

Meningitis Potentially life-threatening emergency due to inflammation of the leptomeninges2,3,4

Ex2,3,4 • Pallor or mottled skin • Rapidly evolving petechial or purpuric exanthema • Neck stiffness, meningismus • Impaired consciousness, confusion • Papilloedema • Focal neuro sx • CN palsies • Paralysis, coma • Shock-low BP, PR ↑ or N, mottled skin, cool

extremities, ↓ UO Signs of meningeal irritation aka. meningism (UNRELIABLE for Dx or ruling out meningitis): • H/ache, neck stiffness (nuchal rigidity), photophobia • Brudzinski sign (passive neck flexion�invol knee flex

in supine pt) (uncommon) • Kernig sign (pt supine and leg bent at hip and knee at

90 degree angles, further knee extension�resistance or pain) (uncommon)

Presentation2,3,4 Classic triad (low sensitivity for BM):

1. Fever 2. Neck stiffness 3. Altered mental status-confusion, altered consciousness

Other symptoms: • Non-blanching petechial or purpuric rash • Headache • Nausea and vomiting • Focal neurological deficit, abnormal eye movements • Seizures ‘Meningococcal disease’-abrupt onset, rapid progression,

significant morbidity and mortality Viral-typically self-limited w/ no serious sequelae

(mortality <1%), however impossible to differentiate b/w VM and BM clinically! Assoc clinical findings in enterovirus infections incl pharyngitis, pleurodynia, rash, pericarditis

Fungal-insidious onset with progressive severe h/ache, fever over wks-months, behavioural/personality ∆, sx of hydrocephalus (esp coccidioidal meningitis eg. impaired cognitive function, confusion, coordination disturbances) Consider in immunosuppressed, exposure to disturbed soil, bat caves, neutropenia, phagocyte dysfunction, neurosurgery

DDx2,3,4 • Drug-induced/chemical meningitis

o NSAIDs, trimethoprim/sulfamethoxazole, amoxicillin, ranitidine, IV immunoglobulin, vaccines, mAbs

• CT disorder o SLE, sarcoidosis, Behcet disease

• Carcinomatous meningitis • Other infections

o Parameningeal eg. cranial OM, subdural empyema o Abscesses, viral encephalitis

• Encephalitis (abnormal cerebral function, fever)

Ix2,3,4 Bloods • FBC (neutrophilia, ↓ plts), coag screen, CRP (↑), glucose,

cultures, molecular tests (mening/pneumococcal PCR) Swabs • Throat (1 bacteria, 1 viral) and rectal (viral) Imaging • Head CT (prior to LP if focal neuro deficit, hx CNS

disease, papilloedema, new-onset seizure, drowsiness, immunocompromised)-AFTER blood cultures, dexamethasone, and empirical Abs

Lumbar puncture • Opening press, glucose, ptn, WBC & differential,

microscopy & culture, molecular tests (Ag tests/PCR-N.meningitidis, S.pneumoniae, HiB, S.agalactiae, L.monocytogenes, enteroviruses)

• C/I: signs of ↑ ICP, skin infection at LP site, suspected SOL, imaging evidence of CI, coagulopathy, spinal sepsis

• High CSF ferritin and high CSF lactate in BM • Culture petechial fluid, sputum, secretions from

oropharynx, nose, ear

Mx2,3,6 Ideally obtain specimens for cultures before starting antibiotic, but if BM is possibility & LP going to be delayed, take blood cultures & give antibiotics ASAP! Empiric antibiotic therapy

• Start IV Abs ASAP after Dx suspected or proven • Ceftriaxone/cefotaxime+Vancomycin+Dexamethasone

(do not give immunocompromised) • Add ampicillin If >50yo or immunocompromised

(Listeria) Antibiotic chemoprophylaxis

• For close contacts if meningococcal disease or HiB • To eradicate asymptomatic carriage • Also pts who have only received benzylpenicillin as

this does not reliably clear nasal carriage • Ciprofloxacin (>12yo), rifampicin (child), ceftriaxone

(preg) Supportive care

• Bed rest, adequate O2, IVH, analgesia, anticonvulsant therapy, neuro obs

• Intubation and mechanical ventilation if decompensated shock (compensated shock plus hypotension)

Viral • Once proven, cease Abs and continue supportive care.

Consider antivirals if HSV, VZV, or CMV Fungal

• Amphotericin B+fluconazole (maintenance therapy) and therapeutic drainage of CSF (cryptococcal)

Classification2,3,4 Infectious

• Bacterial (BM) • Viral (VM) • Fungal-chronic or subacute, often systemic involvement • Spirochetal (neurosyphilis, Lyme disease) • Mycobacterial (TB, atypical mycobacteria)-consider in

hx of contact or resident in endemic area • Protozoan

Non-Infectious • Malignant-lymphoma, metastases, 1O neoplasms • Collagen vascular disorders-SLE, sarcoidosis, Behcets • Drugs (esp NSAIDs)

Aseptic=inflammatory cells in CSF but no readily cultivated organisms (most commonly viral)

Neonates Kids Adults Elderly Group B strep E.coli Proteus Pseudomonas Listeria

N.meningitidis S.pneumoniae H.influenzae B

N.meningitidis S.pneumoniae

S.pneumoniae N.meningitidis S.aureus Enterobacteria Listeria

CSF Appearance WBC and differential Protein Glucose CSF:plasma

Bacterial Turbid/purulent PMN pleocytosis NØ 80-95% Lymphocytes <50

↑ ↓ <1/2

Viral Clear/turbid Lymphocytes 10-100 N or ↑ May be ↓ >1/2

Fungal N or cloudy ↑ (mononucleated) ↑ ↓

Aetiology2,3,4 Bacteria (see table to right)-

• N.meningitidis serovars A (Africa), B (>60%),C (<35%),W135 (assoc w/ extra-meningeal disease), Y

• Immunocompetent: 80% by S.pneumoniae, N.meningitidis

• Immunocompromised: S.pneumoniae, L.monocytogenes, GN

• Also B.burgdorferi (Lyme disease), T.pallidum (Syphilis), Leptospira app. (Leptospirosis, Weil’s disease), Mycobacteria

Viral- • Human enteroviruses >85% VM (incl echo,

coxsackie A & B, numbered enteroviruses (70 & 71), arboviruses (incl SLE, Jap B, MV virus, kunjin), herpes viruses (esp HSV-2), mumps (10% of cases of mumps), adenovirus, measles, 10% of symptomatic HIV seroconversion

Fungal- • Cryptocococcus neoformans (usually HIV infected),

coccioioides immitis, histoplasmosis, candida Protozoa-

• Naegleria, Acanthoemeba

Pathophysiology 2 Bacterial

• Haematogenous spread of microbe to CNS (less frequently by direct extension from contiguous site)�invasion across BBB�microbes multiply in SA space�release of pro-inflammatory cytokines�influx of leucocytes into CSF�inflammation of subarachnoid space (fever, h/ache) and, subpial encephalopathy (meningismus, confusion, reduced [CSF] glucose)

• Release of inflammatory cytokines�neuronal injury and cell death (eg, obtundation, seizures, focal neuro sx, paralysis)�SIADH and cerebral oedema� raised ICP o N.meningitidis spread by droplets of mucosal contact o S.pneumoniae protection requires specific anti-pneumococal antibodies and intact RE system (elderly, alcoholics,

splenectomy, HIV +ve). Invasion follows nasopharyngeal colonization (10-30%) o Listeria aquired by ingestion (pate, soft cheeses)�bowel�multiples in liver�spreads via blood

Viral • Enteroviruses-faecal-oral spread, non-polio enteroviruses and arboviruses-replicate outside CNS in tissues (eg. Muscle,

liver, resp, GIT) and spread to CNS haematogenously • Viral penetration of blood-CSF barrier via infection of endothelial cells or migrating leukocytes�meningitis (may infect

neurons and glial cells�invasion across BBB�encephalitis or myleitis)�cellular immune reponse to viral infection of CNS�accumulation of lymphocytes within CSF�release of inflammatory cytokines (eg. IL-6, TNF)�increased permeability of BBB�diffusion of circulating immunoglobulins into CSF

Epidemiology2 • >50% meningitis-related hospital stay 2O to VM, 25% 2O

BM • Average mortality BM 21%, unfavourable outcome 34%

o Substantially higher in pts ≥45yo Carriage of N.meningitidis-

• 5% infants • 25% 19yo • 8% 50yo

Incidence of N.meningitidis- • 3 per 100,000 per year, 2/3 young kids, 2nd peak in teens

Listeria 25% mortality (50% if assoc med conditions)

Long-term Complications2,3 • Neuro-sensorineural deafness,

CN palsies, hemiparesis, epilepsy, impaired cognitive function

• Skin-necrosis +/- grafting • Serum sickness-arthritis,

fever, pericarditis at 1 wk

Microscopy • N.meningitidis: GN diplococci, grow on choc agar,

identify by PCR (blood or CSF) • S.pneumoniae: GP diplococci, alpha-haemolytic,

draughtsman colonies, carb capsule anti-phagocytic, produces toxins

• L.monocytogenes: GP rod

Risk Factors2,3 • Externally communicating dural fistula • Immunosuppression • Parameningeal sources of infection eg. Otitis, sinusitis • Prior neurosurgery • Skull fracture

Prevention����Vaccination! • Meningococcal ACWY (NOT B) • HiB • Pneumococcal

Epilepsy Recurrent unprovoked epileptic seizures; episodes of brain dysfunction related to an abnormal electrical discharge arising from cortical neurons. Epilepsy is a SYMPTOM, not a single disease7

Ex2,3 • Nystagmus (2O some antiepileptic drugs eg. phenytoin,

carbamazepine) • Stigmata of neurocutaneous syndromes • Neuro exam normal in most pts

Presentation2,3,7 • Recurrent episodes of transient alteration of awareness,

change in behaviour, or involuntary movements • Clinical manifestations of a particular seizure depend on

the portion of the brain that is activated • Hx from EYEWITNESS most important info for Dx

Features of epileptic seizures (see ‘Classification’ for specific assoc features):

• Premonitory sensation or experience (fear, epigastric sensation, déjà vu)

• Amnesia for ictal event • Confusion or disorientation during postictal period • Temporary aphasia • Automatisms-chewing, swallowing, gestures,

ambulation, mimicry • Staring and loss of contact with environment

Ask about ETOH, drug use, sleep deprivation (or shift work), previous CNS infection, stroke or brain tumour, head trauma, prior seizure events, mental retardation, dementia and FHx . Risk assessment incl driving, occupational hx, and hobbies.

DDx2,3,7 • Cardiogenic or vasovagal syncope

o Prodrome, duration <15secs, movements fragmentary & multifocal, rapid recovery 10-20secs

• Psychogenic seizures o Continuous limb shaking, variable maintenance of

consciousness, eye closure, side-to-side head shaking, pelvic thrusting, waxing/waning course, prolonged convulsive activity, & lack of response to BZDs

• Tic disorders o Usually involve head, neck, shoulders, & may be

temporarily suppressed • Tremors

o Involuntary, oscillatory movement of body part, rhythmic compared w/ movements due to partial seizures

• Transient global amnesia o >50yo, sudden onset amnesia lasts several hrs,

maintains alertness but confused, asks qns repeatedly • TIA

o May involve sensory, motor, speech, vestibular, or memory sx, lasts <20mins, can present with sudden alteration in consciousness or (rarely) focal motor movements

Non-epileptic Seizures: • Psychogenic or physiological seizures

o Eg. stress, metabolic derangement (↓ Na+, ↓ glucose) • Reflex seizures

o Seizures provoked habitually by external stimulus, or internal mental processes

• ETOH withdrawal seizures • Drug or other chemically induced seizures • Immediate and early posttraumatic seizures

Ix2,3,7 EEG +/- video or prolonged digital ambulatory monitoring • Often misinterpreted and leads to misdiagnosis • Distinctively epileptiform activity supports clinical Dx and

helps determine seizure/epilepsy type • Do NOT use to exclude Dx, or in isolation to Dx epilepsy Neuroimaging • To identify structural abnormalities that can cause certain

epileptic syndromes • MRI imaging of choice, CT if MRI C/I or unavailable • NOT routine if idiopathic generalized epilepsy • Indicated for new onset epilepsy in adults or in pts with

suggestion of focal onset based on hx, ex, or EEG Bloods Following seizure- • FBC, U&E, blood glucose, toxicology screen, serum

prolactin, serum CK Before starting antiepileptic meds- • FBC, U&E, BSL, LFTs, albumin levels (phenytoin &

valproate are highly ptn bound meds) • Anticonvulsant blood levels to determine compliance & in pts

w/breakthrough seizures, suspected toxicity, drug interactions

Classification2,3,7 Generalised-onset seizure (involving both hemispheres)

• Absence o Abrupt cessation of activity and responsiveness,

minimal assoc movements, automatisms, staring episodes, no aura/postictal state

Typical- o 5-10secs, minimal postictal confusion, usually

precipitated by hyperventilation and sometimes photic stimulation

Atypical- o Less distinct beginning and end, not usually

precipitated by hyperventilation or photic stimulation

• Myoclonic o Often early morning

• Clonic • Tonic • Tonic-clonic

o LOC, phasic tonic stiffening of limbs, followed by repetitive clonic jerking

o Often preceded by aura/premonitory sx o Most self-limited o Post-ictal confusion o Fever, nuchal rigidity, altered mental status

• Atonic (astatic) o Symptomatic gen. epilepsies (epileptic

encephalopathies) Partial-onset seizure (focal/localized) Temporal lobe most common area of onset

• Simple o Preservation of normal consciousness, “an aura”

• Complex o Alteration of consciousness and impaired

responsiveness at time of event, memory loss for clinical event

o Blank spell, motionless stare +/-automatic behaviour o Movement of one side or one specific part of the

body o Localized post-ictal paralysis (Todd’s paralysis)

• Secondary generalized (partial seizures evolving to secondary generalized seizures)

Mx2,3,7 Pharmacological

• Antiepileptic drugs (AEDs) are main Rx and effective in 60-70% pts • Generally recommended after 2nd epileptic seizure, once Dx confirmed • Considered after a 1st unprovoked seizure if pt has neuro deficit, EEG

shows unequivocal epileptic activity, pt/fam/carer consider risk of further seizures unacceptable, or brain imaging shows structural abnormality

• Monotherapy preferred, multiple medicines if # of monotherapy trials fail

First-line Drugs • Generalised tonic-clonic: carbamazepine (CBZ), lamotrigine (LAM),

valproate (VPA), topiramate (TOP) • Myoclonic: VPA • Atonic or tonic: LAM, VPA • Partial: CBZ, VPA, LAM, oxcarbazepine (OXCBZ), TOP • Absence: ethosuximide, LAM, VPA • Decision to discontinue if pt seizure-free >2yrs should be made by pt,

family, and specialist after full discussion of risks and benefits of w/drawal

Acute Seizure Mx • IV or rectal BZD+airway maintenance/supportive care

NB: Seizures on CBZ can be due to noncompliance or hyponatraemia (S/E) Non-Pharmacological

• Avoid precipitating factors o Sleep deprivation, fever, ETOH

• Counselling and education after suspected seizure, incl safety concerns o Bathing (thermostatically controlled taps), cooking, driving, using electrical equipment, injury prevention, first aid

Surgical

• In selected cases of medically refractive epilepsy o Vagus nerve stimulation o Resective epilepsy surgery

Aetiology2,3,7 • Depends on epilepsy syndrome or provoking element that initiated

epileptiform activity Idiopathic generalized:

• Presumed to be genetic in most cases • Anomalies in Na, K, Ca ion channels, as well as GABA R-mediated Cl

channel recognized Focal-onset:

• Often identifiable or presumed underlying structure cause eg. cortical malformations, dysplasias, neoplasms, infarcts, vascular malformations, areas of encephalomalacia from prior trauma, CNS infection* which sets up an epileptogenic focus

Other associated conditions: • Monogenic mendelian diseases eg. Fragile X syndrome, Rett syndrome • Inherited metabolic disorders • Alzheimer disease, Huntington disease • Stroke-risk of seizure activity 3x higher • *Infections include cystericercosis, malaria, bacterial meningitis, herpes

simplex encephalitis

Pathophysiology2,3,7 • Inappropriate hyperexcitability and

hypersynchrony • Due to abnormal excessive or synchronous

neuronal activity in the brain • Groups of neurons have abnormal capacity

to generate intrinsic discharge bursts, coupled with decreased GABA inhibition and activation of local recurrent excitatory currents

• Caused by neuronal recruitment and spreading due to combination of- o Enhanced connectivity o Enhanced excitatory transmission o Failure of inhibitory mechanisms o Changes in intrinsic neuronal properties

Complications:

• Status epilepticus=continuous seizures lasting ≥30mins or ≥2 discrete seizures without complete recovery of consciousness between seizures

Epidemiology2,3,7 • Epileptic seizures 1 in 20 • Recurrent epileptic seizures 1 in 200 • 1.8-2.6% lifetime prevalence • >60% long-term remission in developed

countries • Generalised tonic-clonic seizures represent

25% of all seizure types in epileptic pts

Women and Epilepsy2,3,7 Pregnancy

• Anticonvulsant drugs assoc w/major malformations (teratogenic potential) o Spina bifida w/VPA, CBZ

• Increased risk with multiple antiepileptic drugs and higher dosages

• BUT >90% women w/epilepsy on meds will have normal babies

• Epileptic seizures assoc w/↑ risk of antenatal hospitalization, intrauterine growth restriction, lower IQ & caesarean delivery

• Recommend folate supplements prior to conception/1st trim, anatomic US

Contraception

• No adverse effect on seizure frequency or severity

• However hepatic inducing AEDs (PHT, CBZ, PB, TOP, OXCBZ) mean OCP less effective

• Progesterone-only pill and implanon not recommended

• Depo-provera best option

Causes of Seizures: Sugar, sats Epilepsy Infection Z degrees celcius Uraemia Removing drugs, Rugby injury Eclampsia

Multiple Sclerosis (MS) Neurodegenerative inflammatory disease of the CNS characterised by episode neurological dysfunction in ≥2 areas of CNS separated in time and space2,3,4

Ex2,3,4,8 • Signs can be VERY variable • These patients are popular in exams so if an exam patient

has weird neuro signs you can’t explain, think MS! Cranial nerves-

• Papillitis, ↓ visual acuity, scotoma (usually central), relative afferent papillary defect (aka. Marcus Gunn pupil ), ↓ colour vision, pale optic disc (suggestive of optic neuritis)

• Internuclear opthalmoplegia- weakness of adduction in one eye as result of damage to ipsilateral medial longitudinal fasciculus, may be nystagmus in abducting eye, almost diagnostic in young adult

o Bilateral INO almost always caused by MS • Other HEENT findings including dysarthria, impaired

swallowing Neuro-

• UMN signs (weakness, spasticity, hyperreflexia, Babinski sign)

• Hemisensory loss, hemiparesis, spastic paraparesis • Posterior column sensory loss (proprioception, vibration) • Cerebellar signs:

o Poor balance, falls, limb incoordination, gait ataxia, tremor, monotonous speech

• Cognitive deficits: o Problems w/executive function, dementia

• Lhermitte sign-in patients w/cervical myelitis, electric sensation running down trunk, back or limbs w/neck flexion

o DDx: subacute combined degeneration of the cord, cervical spondylosis, cervical cord tumour, foramen magnum tumours, NO abuse

• Emotional lability Charcot’s triad for MS (nb Occurs in only 10% pts):

1)Nystagmus 2)Intention tremor 3)Scanning speech

Presentation2,3,4,8 • Careful hx very important-Dx depends on occurrence of

≥2 neuro episodes separated in time & place w/in CNS -See McDonald criteria p.501 Oxford Handbook (or google!) • Episodes of neurologic dysfunction that often recover

(but degree of recovery can vary) • Episodes affecting separate sites in CNS occur ≥30d apart

o Sensory sx (45%) o Optic neuritis (17%) o Insidious-onset motor sx (>40yo) (14%) o Limb ataxia and/or impaired balance (13%) o Diplopia and/or vertigo (13%) o Acute-onset motor sx (6%)

• Clinically isolated syndrome=episodes affect ≥1 site • 80% present w/CIS

Optic neuritis o Loss of visual acuity-unilateral, painful o eg. unexplained blindness for a week!

Myelitis (motor, sensory and/or sphincter problems) o Sensory more common o Lhermitte sign o Bladder and bowel dysfunction o “Band-like” abdo or chest press

Brainstem/cerebrum sx (double vision, facial pain, weakness and/or numbness)

o Ocular motor syndromes (internuclear opthalmoplegia/nystagmus)

o Hemisensory, crossed sensory syndromes o Hemiparesis o Trigeminal neuralgia o Hemifacial spasm

Cerebellar sx o Coordination probs-cerebellar outflow

tremor, acute ataxic sx Other paroxysmal sx

o Tonic spasms o Paroxysmal dysarthria/ataxia

• Uhthoff phenomenon-transient worsening of vision or other neuro sx w/↑ core temp eg. exercise, hot bath, fever

• Other presenting sx incl fatigue, ex intolerance, swallowing probs, temp sensitivity, urinary frequency, constipation, erectile dysfunction, anorgasmia, urine retention, incontinence-Do not be to shy to ask!

Generally early on relapses may be followed by remission and full recovery, however with time remissions are incomplete so disability accumulates (significant inter-individual variation)

Complications2,3,4 • ↑ risk of infection • Sexual dysfunction • Pressure ulcer • Spasticity/weakness • Depression o Major depression ~50% pts

• Cognitive impairment • Pseudobulbar affect (emotional incontinence) o Frequent involuntary episodes of crying &/or laughing

unrelated or disproportionate to situation and patients mood at time of episode

Classification2,3,4 • Relapsing-remitting MS (clinical majority of pts)

o Self-limited attacks of neuro dysfunction o Acute onset, evolution over days-wks o Variable degree of recovery, wks-mths o Neuro and sx stable b/w attacks o 50-65% enter 2O progressive MS

• 2O progressive MS o Begins as relapsing-remitting MS o Incomplete recovery b/w episodes o Attack rate of relapses ↓ o Steady ↓ of function

• 1O progressive MS o Steady ↓ of neuro function w/out attacks o 15-20% pts have progressive disease from onset

• Progressing-relapsing MS o Mixture of relapses and progression from onset

Terminology2,3,4 • Paraparesis=partial paralysis of the lower limbs • Papillitis=specific type of optic neuritis related to optic

nerve head, associated w/substantial losses in visual fields and pain on eye movement

• Marcus Gunn pupil=pupils constrict less when bright light swung from unaffected to affected eye (‘swinging-flashlight test’), affected eye still senses light (compared w/ total CN II lesion) and produces pupillary sphincter constriction (albeit ↓’d); ↓ pupillary response to light in

affected eye from afferent defect

DDx2,3,4 • ADEM o Monophasic illness, related but distinct entity, dramatic

post-viral or post-vacc dysfunction of CNS including encephalopathy, multiple brain lesion on MRI

• Cervical spine disorders�myelopathy-eg. cervical spondylosis o Sx & signs below neck (may have dizziness, h/ache)

• Ischemic cerebrovascular events eg. stroke, TIA o Hx indicates sudden onset sx, usually explainable on

basis of single neuro lesion rather than multiple • Leukodystrophies and mitochondrial diseases o Gradual onset memory or cognitive probs, sometimes

in setting of neuropathy • Sjogren’s syndrome o Dry eyes/mouth, joint stiffness & pain, neuro ex usu N

• Vit B12 deficiency o Numbness, fatigue, memory loss, posterior column loss

of sensation (vib, prop), ↑ reflexes • Peripheral neuropathy o Loss of sensation and reflexes in feet and hands

• Lymphoma o Gradual onset of severe disability

• Amyotrophic lateral sclerosis o Mixed UMN (↑ reflexes) and LMN (atrophy

w/fasciculations) signs, visual changes absent • Devic’s disease-aka neuromyelitis optica

Ix2,3,4 • Dx made by specialist mainly based of hx and clinical

exam with evidence of CNS lesions scattered in time and space, not attributable to other causes

Tests to confirm CNS lesions disseminated in space (ie. at separate locations)-

• MRI brain and spinal cord o Sensitive but not specific for plaque detection o Can provide evidence of lesions disseminated in time o Exclude other causes eg. cord compression

• Evoked potential studies (visual 1st choice) • CSF analysis or CT may be supportive of Dx, only

used when Dx remains uncertain or if alternative Dx being considered o CSF including oligoclonal bands of IgG on electrophoresis not present in serum

Bloods • Initial bloods should including FBC, comprehensive

metabolic panel, TSH, vit B12-these should all be normal

• Serum antimyelin antibodies (anti-MOG, anti-MBP) o Maybe associated w/demyelinating events, but high false +ve

• Anti-NMO (NMO-IgG)-highly specific for Devic’s disease

Mx2,3,4 Pharmacologic

• For acute relapse affecting function- o Corticosteroids (methyprednisolone) improve sx and disability, use sparingly as steroid S/E and doesn’t alter overall

prognosis o IVIG o Plasma exchange if severe worsening (quadriplegia over days-wks)

• Disease-modifying/immunomodulating therapies for relapsing-remitting, relapsing-progressive MS- o IFN-1beta and 1alpha, glatiramer

� ↓ relapses by ~30% in active relapsing-remitting MS, S/E flu-like sx, depression, abortion o Azathioprine

� ~as effective as IFNs for relapsing-remitting MS and is 20x cheaper! o Monoclonal antibodies

� ↓ relapses by 2/3 in relapsing-remitting MS, few S/E but antibody mediated resistance may develop, and possible development of multifocal leucoencephalopathy

• Mitoxantrone o Helps in 2O progressive MS, safety an issue though

• No effective Rx for 1O progressive MS Symptomatic Rx

• Sensory sx (pain, dysethesia) -low-dose anticonvulsants • Urinary probs -teach intermittent self-catheterisation, anticholinergics • Bowel probs -lactulose, loperamide • Tremor -propanolol (S/E ↓ BP, depression), primidone or clonazepam (S/E sedation) • Gait impairment -dalfampridine if physio alone insufficient

Non-pharmacologic • Physiotherapy +/- antispasticity meds

o For increased muscle tone, gait impairment • Exercise therapy

o Beneficial for patients not experiencing an exacerbation o Progressive resistance training of lower extremities, yoga, to improve functional capacity and fatigue

• Diet o Polyunsaturated fatty acids (no conclusive evidence of effect on MS)

• Multidisciplinary rehabilitation program o If sudden ↑ in disability or dependence o Support (equipment, personal care) in parallel with other med Rx

• Counseling o Emotional support, CBT if depressed o Do not forget caregivers and household members!

Epidemiology2,3,4 • Young adults, most commonly Dx 20-40yo • F:M ratio 3:1 • Most common cause of neuro disability among young

adults • WW incidence 3.6 per 100,000 person-years in women • WW incidence 2 per 100,000 person-years in men • Possible geographic gradient, w/↑ incidence at

latitudes closer to the poles

Aetiology2,3,4 • Combination of genetic predisposition and environmental influence

o 20-40x more common in 1st degree relatives o HLA haplotypes and IL region likely to be involved in genes

• Environmental factors include toxins, viral exposures (incl EBV, HHV-6), sunlight exposures (effect on vit D metabolism) • Relapses often triggered by infections, postpartum hormonal changes, & possibly surgical procedures, acute trauma or

stressful events • Classically viewed as disease of CNS white matter, but now substantial evidence supporting grey and white matter

involvement

Pathophysiology2,3,4 • Precise pathogenesis unknown • Debate as to whether MS represents single disease or syndrome of pathogenically hetergeneous pt subgroups • Pathologically characterised by multifocal areas of demyelination, loss of oligodendrocytes, and astrogliosis • Acute relapses with disturbances of CNS function are thought to be periods of ↑ inflam activity of immune system • Two distinct phases (overlap): Inflammatory and degenerative 1. Inflammatory o Lymphocytes w/encephalitogenic potential activated in periphery (by eg. infection, other metabolic stress)�attach to

receptor on endothelial cells (mediated by matrix metalloproteinases)�breach in BBB�upregulation of endothelial adhesion molecules and additional influx of inflam cells

o T-cells secrete inflam cytokines�direct toxicity and attract macrophages�contibuting to demyelination 2. Degenerative (reflects axonal degeneration and loss) o Demyelination�disrupts axonal support�destabilisation of axonal membrane potentials�distal & retrograde

degeneration o Inflam cells, antibodies, complement may contribute to axonal injury

• Lesion development unpredictable • End-point of chronic silent lesion w/out active inflammation • Basically,

o Demyelination of axon�↓ nv conduction and ↓ function o Remyelination of lesions occurs, however likely transient o Progressive loss of axons�irreversible disability

Four types of active lesions: I-demyelination, macrophage-related products (eg. TNF) II-Ig and complement present III-early loss of mylein-assoc glycoprotein, no remyelination (demyelination due to oligodendrocyte dysfunction) IV-apoptosis of oligodendrocytes through DNA fragmentation Grey matter lesions may also occur

Risk factors: • Genetic risks o HLA haplotypes incl DR15, DQ6, DR4

• Optic neuritis o ≤60% of pts eventually develop MS after single attack of ON

• Infective mononucleosis o Subsequent ↑ risk of developing MS

• Weak RF include smoking, vit D deficiency, AI disease

Myasthenia Gravis (MG) Chronic autoimmune disorder of post-synaptic membrane at skeletal neuromuscular junction2,3

Ex2,3,4,9

• Ptosis • ‘Peek sign’

o After brief opposition to sustained lid closure, the lids separate to show white sclerae

• Weakness of EOM (w/fatigability), diplopia • Limb weakness (w/fatigability)

o Normal peak muscle power on initial testing, loss of strength w/ repetitive movement pathognomonic

• Tendon reflexes normal • Myasthenic snarl on smiling

Presentation2,3,4,9

• Muscle weakness o Facial (ocular frequently involved at onset), limb,

trunk o Insiduous onset, vague o Worsens w/ continued activity, more profound at

end of day, improves w/ rest o Severity varies (respiratory muscles involved in

severe cases) • Fatigue

o Exertional • Drooping eyelids, double vision • Oropharyngeal dysphagia (can � pulmonary aspiration) • Dysarthria, nasal speech, chewing difficulties • Dyspnea • Sx fluctuating • Spontaneous remissions • No pain, sensory sx or autonomic disturbances

DDx2,3,4,9

Generalised Myasethenia: • Amytrophic lateral sclerosis

o Muscle weakness +/- atrophy, twitching, ‘limb onset’

• Lambert-Eaton myasthenic syndrome o Prominent proximal limb weakness,

diminished muscle stretch reflexes, autonomic sc, assoc w/small-cell lung cancer in 70% pts

• Botulism o Sx similar to MG, but ↓ BP, ↓ HR, diarrhea,

followed by constipation, and urinary retention

• Primary myopathies eg. progressive external opthalmoplegia, oculopharnygela muscular dystrophy o Gradually progressive muscle weakness

which is not fatigable • Chronic fatigue syndrome

Drug-induced Myasthenia: • Penicillamine known to cause MG

o After wks-mths of Rx, may remit on w/drawal of drug, but recovery slow or incomplete

• Steroids known to cause proximal myopathy • Drugs related to induction or worsening incl

phenytoin, ciuprofloxacin, aminoglycosides, others

Ocular Myasthenia: • Mitochondrial disease • Cranial neuropathy

Ix2,3,4,9

Blood Tests • Serum anti-AChR antibody analysis (90% pts) • Antimuscle tyrosine kinase (MuSK) antibody (3-7%pts) • Anti-skeletal muscle Ab (anti-striatal Ab) assoc

w/thymoma Edrophonium Test

• IV injection of synthetic anticholinesterase improves muscle strength for 2-10mins

Electrophysiological tests • To demonstrate underlying defect of NM transmission

Low-rate repetitive nerve stimulation (RNS) • Decremental pattern typical finding • Post-tetanic exhaustion • Limb muscles (facial muscle testing uncomfortable)

Single-fibre EMG • Shows ↑ variability in motor latencies or complete

failure of NM transmission in some muscle fibres Imaging

• Chest CT/MRI for thymoma Other

• Pulmonary function tests (incl forced vital capacity) • Ice application to shut eyelid (ptosis improve by >2mm)

Mx2,3,4,9

Pharmacological • Anticholinesterases eg. pyridostigmine,

neostigmine o ↑ local [Ach] in synaptic cleft o Improves muscle strength, rarely restore

to normal • Corticosteroids (worsen sx initially) eg.

prednisolone o Indicated in pts who do not respond to

anticholinesterases o Short-term benefit o For relapses

• Osteoporosis prophylaxis • IVIG

o Insufficient evidence to determine efficacy, and risk of infectious diseases, renal failure, aseptic meningitis

• Avoid drugs which may induce or exacerbate MG, or interfere w/drugs used to treat MG (heaps!)

Drugs which may induce/exacerbate/interfere w/ treating drugs:

• Penicillamine (induce, w/development of anti-AChR Abs)

• Mg sulfate C/I • Telithromycin (exacerbate) • Anticonvulsants (phenytoin, trimethadione),

antimicrobials (aminoglycosides, ciprofloxacin), beta blockers, corticosteroids, Li, procainamide

Subtypes2,3 Ocular myasthenia

• 15% cases confined to extrinsic ocular muscles Generalised myasthenia

• Weakness becomes generalised

Aetiology2,3,4,9

• Organ-specific, antibody-mediated autoimmune disorder • Antibodies against nicotinic AchR on post-synaptic muscle membrane at NMJ • Aetiology for synthesis of auto-immune antibodies unclear

o Genetic tendency, associated with HLA-B8 o Possible thymus involvement

� Thymic myoid cells express AchR, may trigger auto-antibody synthesis • Certain drugs may induce or exacerbate MG eg. Penicillamine, telithromycin, anticonvulsants (phenytoin,

trimethadione), others

Pathophysiology2,3,4,9

• Normal NMJ stimulation� release of Ach from motor nerve terminal in discrete packages�diffuse across synaptic cleft�bind to receptors on muscle end-plate�depolarise muscle-end plate region then muscle membrane�muscle contraction

• In MG have circulating autoantibodies against postsynaptic nicotinic acetylcholine (Ach) receptor�destruction of post-synaptic membrane and ↓ available binding sites for Ach

• ↓ functional binding sites�post-junctional membrane less sensitive to Ach and end-plate potential below threshold�probability nerve impulse will cause muscle action potential is reduced

• Inconsistent generation of muscle fibre action potentials manifests as skeletal muscle weakness Associated conditions:

• 70% Thymic lymphofollicular hyperplasia (if onset MG <40yo) • 10% thymoma, esp >40yo

Complications:

• Myasthenic crisis o Paralysis of resp muscles and resp failure during a relapse necessitating mechanical ventilation (if FVC

<20mL/kg). o Rx w/plasmapheresis or IV Ig and ID and treat trigger for relapse (eg. infection, meds)

• Neonatal MG o Newborns of affected mothers, failure to thrive, supportive Rx, good prognosis

• Major depression

Epidemiology2,3,4,9

• WW prevalence 100-200 per 1,000,000 • F:M 3:1 aged 20-40yrs • However M>F >50yo • F usually present during childbearing age • M typically develop sx at later age, median age

onset 7th decade

Mx Continued…2,3,4,9

Non-pharmacological • Inspiratory muscle training and diaphragmatic

breathing therapy Surgery

• Thymectomy o 18-65yo, especially <40yo, not indicated

in ocular myasthenia) o 60% response rate o May improve sx and reduce frequency

and severity of myasthenic crisis

Peripheral neuropathies (PN) Damage to nerves of the peripheral nervous system

Ex3,5,8 • ?Sensory vs motor vs mixed • Sensory-

o Typically symmetrical ‘glove and stocking’ loss to all modalities; if asym or confined to 1 limb suspect individual nv or nv root disease

o Two point discrimination (sharp vs blunt) most sensitive test of mild sensory impairment

• Motor- o Peripheral muscle weakness & wasting

• ?# nvs involved-mono, poly, or mononeuropathy multiplex

• ?territory of neuro deficit • Evaluate DTRs (↓ in root and peripheral nv disease)-

reinforced by having pt perform isometric contraction of other muscles (eg. teeth clenching)

Features of sensory impairment, distal muscle wasting & weakness, & loss of reflexes distinguish neuropathies from myopathies

Presentation3,5,8 • Most gradual onset & slow progression

o Acute onset in GB, porphyria, diphtheria, acute toxic & neuropathies following immunization

• Chronic PN tend to � sym, distal, mix motor+sensory o Asym in acute & chronic inflam & disease of small BVs o LL usually affected earlier & greater extent than UL

Sensory- • Numbness, tingling, pins & needles, burning, pain in

extremities • When large sensory fibres affected:

o Light touch, vibration & proprioception impaired w/ pain & temp sensation spared, ↓ reflexes

• When small fibres affected (amyloidosis, DM): o Tactile relatively spared, w/ loss of pain & temp,

autonomic dysfunction Motor- • Distal weakness eg. diff climbing stairs, undoing buttons;

muscle wasting, foot & wrist drop Autonomic- • Dryness/excessive sweating, postural hypotension,

impotence, urinary incontinence/retention, diarrhea/constipation etc

Disease-specific presentations: • DM-sym, mostly sensory ( ulcers of feet & Charcots

joints w/ assoc sensory ataxia) • ETOH-pain, numbness & wkness of extremities • Uraemia-sym distal mixed motor & sens • Hypothyroidism-distal sens w/burning & paraesthesias of

limbs, delayed relaxation phase of DTR • HIV (2 major forms)-[1] distal sym polyneuropathy

w/paraesthesias of feet & distal leg wkness [2] inflam demyelinating neuropathy w/progressive wkness in legs, pain in feet, gradual loss ankle & knee reflexes

• Sarcoidosis-CN palsies (usually CN VII), polyneuropathy

Ix3,5,8 Bloods All pts- • FBC, U&E incl Cr), ESR, BSL, LFTs, serum B12 and

folate, serum protein immunofixation electrophoresis, Appropriate pts- • TFTs, heavy metals, LP (suspected GBS), urinary

prophyrins, HIV, genetic testing Nerve Biopsy • For evaluation of suspected amyloid neuropathy,

mononeuropathy multiplex due to vascilitis, atypical forms of chronic inflam demyelinating polyneuroapthy

Nerve Conduction Studies • Measure predom large fibre function (ie. may be normal

in early course of small fibre neuropathy)

Mx3,5,8 • Specific Rx based on underlying disorder

Acute neuropathies- • GB, other neuropathies w/ acute involvement of resp

muscles: o Spirometry every 2-4 hrs initially

(intubation/tracheostomy & art ventilation may be necessary)

o Care of skin, bladder, bowels, mouth, pharynx & trachea

o Lung & UT infections require prompt Rx o Physio Rx & splints to prevent wrist or foot drops o Plasmapheresis & IV human immunoglobulin

hasten recovery in GB (corticosteroids do not) Chronic neuropathies-

• Specific Rx for underlying cause where indicated • Immunosuppressives and plasmapheresis or IV

immunoglobulin helpful • Remove offending agent • Physio, splints • Surg • Rehab

Pharmacological • For pain-opioids, TCAs, botulinum toxin (limited

evidence) Supportive Measures

• Incl physical therapy, emotional support

Classification3,5,8 Mono neuropathy: damage to single nv or nv group, usually trauma or entrapment Mononeuritis multiplex: painful asym asynchronous PN involving isolated damage to ≥2 separate nv areas, usually damage to blood supply to nvs (vasa nervorum) Polyneuropathy or peripheral neuritis: widespread sym process affecting PNS Autonomic neuropathy: damage to nvs of ANS, ie. non-voluntary, non-sensory nerves affecting most internal organs *See Endocrinology section for Diabetic PN

Epidemiology3,5,8 • Bilateral sensory deficits in elderly common • Prevalence of ≥ 1 bilateral sensory deficit-

o 26% 65-74yo o 36% 75-84yo o 54% 85yo+

DDx & Aetiology3,5,8 • Localised injury to nv trunks or roots, or vascular

occlusions in major nv trunks Trauma

• Compression entrapment neuropathies Drugs and other toxins

• Heavy metals (arsenic, lead, mercury, thallium, gold) • Organic industrial agents (acrylamide, hexacarbons etc) • Chemotherapy drugs (incl cisplatin, docetaxel,

etoposide) • Other drugs (incl chloramphenicol, Li, isoniazid,

pyridoxine, disulfiram, dapsone, ethionamide, metronidazole, gold, hydralazine, amiodarone, phenytoin)

• Generalized peripheral neuropathy may follow as an allergic reaction or immune response to vaccinations & injections of foreign proteins

Metabolic and endocrine • DM : autonomic dysfunction common; diabetic

amyotrophy (painful asym prox motor neuropathy affecting quads, hamstrings & gluteal muscles); isolated nv lesions also common

• Uraemia, hypothyroidism, acromegaly, porphyria, & recurrent attacks of hypoglycaemia (islet cell tumors)

Infections • Leprosy most common WW-Mycobacterium leprae

invades Schwann cell, spreads intracutaneously so that a patch of numbness may overlap peripheral nv territories

• Also TB of NS, diphtheria, neurosyphilis, HIV Inflammatory neuropathies: Guillain-Barre (acute inflammatory polyradiculoneuropathy)

• Immune basis, begins 7-10d post-infective illness • Predominantly motor, rapid onset, potentially fatal • Flaccid prox & dist muscle paralysis, ascending from

LL�UL • Reflexes ↓ or absent • CN may be affected • Parasthaesia or pain in lower limbs: weakness (prox

equal or > distal muscles as spinal roots involved) • Facial & bulbar paralysis common, weakness

extraoccular mm; reflexes ↓/absent, variable sensory loss • Sensory loss minimal or absent; sphincters are little

affected (vs transverse myelitis) • W/in 3-4/52: complete quadriparesis & resp paralysis

(can be fatal, however usually self-limiting) • 80% recover w/out any disability; some with long term

due to 2nd axonal degeneration • CSF-ptn ↑, cell count NOT ↑; circulating antimyelin ab

in acute phase (?combined humoral & cell-mediated response targeting myelin in peripheral nv & spinal root)

• ? viral/bacterial (Campylobacter jejuni) trigger, as these precede onset in 60% pt

Malignancies • Remote manifestation of malignancy in 5% of pt with

carcinoma & lymphoma • Predominantly sensory ganglionopathy w/ SCLC • Paraproteinaemias & dysproteinaemias often assoc w/

peripheral neuropathy Vitamin deficiencies

• B12: sens neuropathy w/ subacute combined degeneration of SC

• B1 (thiamine): esp in chronic alcoholism & nutritional disturbances-painful, sens neuropathy

• Alcoholism: pain in calves, burning feet & distal wkness (distal wasting, absent knee & ankle jerks, distal sensory impairment w/ tender calves) caused by Vitamin B deficiency rather than direct effects of ETOH

Pathophysiology3,5,8 • Individual nv fibres separated by endoneurium -a bundle of fibres�fascicle (surrounded by perineurium) -many fascicles�trunk (surrounded by epineurium) • Nv trunks receive blood from branches of regional

arteries • Small vessels penetrate epineurium & form

anastomoses w/in the trunk • Single nv fibres in fascicles may be myelinated or

unmyelinated o Satellite cells of PNS is Schwann cell, assoc with

both myelinated & unmyelinated axons • Motor axons from VH motor neurons, sensory axons

from DRG neurons • Postganglionic sympathetic axons are unmyelinated &

arise from neurons in thoracolumbar sympathetic chain • In PN distal parts of nvs usually involved 1st because of

distance from cell bodies�distal loss of sensation and/or motor function

• Destruction of axon�interference with nv conduction eg. lack of O2 from ↓ blood supply or inflam of BVs

Entrapment and Compression • Carpal tunnel (median nv)

o Esp women (obesity, myxoedema, acromegaly, fluid retention from OCP or pregnancy, arthritis of wrist or wrist trauma)

o Numbness & tingling in median nv distribution, esp at night (if chronic, see sensory loss & wasting of thenar muscles)

• Also ulnar nv at elbow, peroneal nv at neck of fibula, LCN of thigh at inguinal ligament, radial nv at spiral groove of radius

• Predisposing factors: repetitive trauma, DM, alcoholism Nerve Injuries Three disorders of function are recognized:

1.Neurapraxia: transient loss of function (block of conduction) following compression/mild trauma; spontaneous recovery in days-weeks (local demyelination, axon remaining intact)

2.Axonotmesis: in crush injury get prox degeneration of axon & sheath (Wallerian); neural sprouts repopulate the neurilemmal sheaths (tubes of Scwhann cell basement membrane)

3.Neurotmesis: whole nv truck severed & continuity of neurilemmal sheath lost; distal nv trunk cannot be reinnervated unless surg approximates distal & prox ends

DDx & Aetiology Continued…3,5,8 Connective tissue disease

• RA: sym sens or sensorimotor neuropathy; mononeuritis multiplex (arteritis & entrapment) also common in RA

• Polyarteritis nodosa, SLE & sarcoidosis cause mononeuritis multiplex

• Sjogrens may be assoc w/ PN Hereditary (and idiopathic): Charcot Marie Tooth

• Inherited (4:100 000); autosomal dominant • Sx begin 10-30 yrs: distal wasting LL & foot drop;

intrinsic hand muscles later, with mild distal sens loss & absent/↓ LL reflexes; foot high arch & retracted toes (pes cavus)

• Progresses slowly over many yrs, & most pt remain mobile into old age

DDx of PAINFUL peripheral neuropathy: • DM, ETOH, vit B1 or B12 def, carcinoma, porphyria,

arsenic or thallium poisoning

Parkinson Disease (PD) Progressive neurodegenerative movement disorder

Ex2,3,4,10 • Orthostatic hypotension • Bradykinesia-

o Tap index finger, thumb, or foot • Masking of facies, ↓ blink rate (sense of stare) • Speech-

o Quiet, stuttering, monotonous delivery w/out inflection

• Depressive features (common) • Resting tremor-

o Usually unilateral, at least initially o Observe when hands at rest! o “Pill-rolling”-supination/pronation, finger

flexion/extension o Distal limbs, rhythmic o Better with intention

• Rigidity- o Assess arm tone o “Cogwheel” rigidity-

• Impaired balance • Gait abnormalities-“festinating gait”

o ↓ arm swing esp corners o Difficulty initiating gait (freezing)-may overcome

if imagine line on floor, march, or count, as use slightly different part of the brain

o Stooped posture o Tendency to fall forwards or sideways, esp turning o Shuffling small steps w/rapid propulsion

• Handwriting sample o Tremor should disappear during writing o Handwriting small

Presentation2,3,4 • Insidious onset of sx • Initially affects 1 limb, spreads to involve others • Asymmetric involvement usually persists affecting

side of onset worst Cardinal features:

1. Bradykinesia/slowness 2. Resting tremor-↑ w/anxiety, disappears during

sleep, motor actions 3. Rigidity 4. Loss of postural reflexes/postural instability

Other features: • Loss of balance and falls • Fatigue • Impairment of dexterity and difficulty w/ADLs-

o Dressing, getting out soft chair/car, opening jars • Micrographia (∆ handwriting) • Neuropsychiatric sx (common)-

o Depression (58%) o Roughly 50% have apathy, anxiety, and/or

hallucinations (visual>auditory) • Autonomic sx-

o Orthostatic hypotension, constipation, urinary probs, pain/dysaesthesia, dysphagia, sialorrhoea

• REM sleep behaviour disorder-act out dreams

DDx2,3,4,10 • Drug-induced parkinsonism

o Hx of antipsychotics or antiemetics (eg. Metoclopramide), less commonly SSRIs, CCBs, Li

• Progressive supranuclear palsy o 60-80yo, ↓ vertical saccades (vertical gaze palsy),

postural instability & falls, bilateral signs, severe dysarthria, eventually dysphagia, tremor unusual

• Multiple system atrophy o 50-60yo, autonomic dysfunction, parkinsonism,

gait dysfunction, cerebellar signs • Dementia w/Lewy bodies

o Early cognitive impairment, delirium-like episodes (can be blackouts), hallucinations (visual)

• Corticobasal degeneration o Alien limb, myoclonus, cognitive impairment

• Essential tremor o w/action, absent at rest o NB: Can have essential tremor AND develop PD!

• Alzheimer disease w/parkinsonism o Dementia, aphasia

• Vascular parkinsonism o Worse in legs than arms, pyramidal signs,

prominent gait abnormality • Wilson disease

o Hepatic disease, sialorrhea, Kayser-Fleischer ring, tremor, dysarthria, fine motor control, seizures, personality change

• Normal press hydrocephalus o Dementia, incontinence, prominent gait abnormalities

• Severe depression

Ix2,3,4 • Dx often based on clinical findings alone • Positive response to PD meds is strong indication

of correct Dx Queen Square Brain Bank diagnostic criteria:

• Bradykinesia, with ≥1 of- o Muscle rigidity (eg. cogwheeling) o Resting tremor 4-6Hz o Postural instability (unrelated to sensory dysfunction)

• Long list of supportive criteria and exclusion criteria as well, eg. head injuries etc-google “Brain Bank criteria”

Diagnostic Testing • Levodopa and apomophine challenge

o Improvement of s confirms Dx when uncertainty Imaging

• CT and MRI may help exclude other Dx eg. vascular disease, normal press hydrocephalus o Normal in most pts w/ idiopathic PD o Advanced PD w/ dementia-cortical atrophy

• SPECT & PET scans have a role in measuring # DA transporters & receptors, w/ good sens & spec for PD BUT in WA isotopes too $ & not available

• MIBG cardiac scan has an emerging role- measures uptake of guanethidine in the heart, an amino acid analogue taken up my post-synaptic NA receptors o PD patients lose these receptors sometimes

before the development of PD sx; can be used to narrow Dx to PD, dementia with lewy bodies, or REM sleep behav disorder, which all show ↓

Genetic Testing • If young-onset or significant fam hx • Specific mutation may be identified

Classification2,3 • Juvenile <21yo • Young-onset 21-40yo

Mx2,3,4,10 • Progressive and incurable-multidisciplinary approach vital incl

neurologist, PD nurse, physio, OT, SW, GP, carers Pharmacologic

• Dopamine agonist and/or • MAO-B inhibitor • Levodopa-carbidopa (w/motor fluctuations on dopamine agonists)

o Gold-standard but end-of-dose wearing off and dopamine-induced dyskinesias develop over time (5-10yrs)

• Amantadine (↑ release DA) (L-Dopa related motor fluctuations, freezing)

• Domperidone (for N&V on dopamine agonist) • SSRI (for depression) • Atypical antipsychotics eg. quetiapine, olanzapine (for psychosis) NB: Distinguish drug-induced psychosis from disease progression

Drug toxicity • Probs such as nausea, postural hypotension, confusion, dystonias,

dyskinesias Surgical (to interrupt overactive basal ganglia circuits)

• Deep brain stimulation (subthalamic nucleus or globus pallidus) o Motor fluctuations and dyskinesias refractory to medications o Improves motor function, best med mx in advanced PD

• Other surgical options incl thalamotomy, pallidotomy Non-pharmacologic Education-

• Self-awareness of sx, drug side effects, triggers to seek med changes Physio and group rehabilitation programs

• ↑ function and ↑ QOL Speech therapy-

• Assist with voice projection eg. Lee Silverman Voice Technique • Assess & Mx swallowing difficulties

Psychology- • Assist with Mx anxiety & depression (common)

Social work • Community assistance, support, carers respite

Dietician- • ↑ risk poor nutrition, wt loss, loss muscle mass • Balanced diet incl adequate amounts fibre, fluid, & Ca

Aetiology2,3,10 • Unknown, 85% sporadic • Multiple genes identified-eg Parkin,

LRRK2, some AD, some AR o Often genes involved in proteosomal

degradation pathways o 10-15% familial clusters o <5% monogenic

• Environmental factors/exposures contribute to evolution of disease

• Parkinsonism syndromes assoc w/ o Hx being knocked unconscious o Long-term use of antipsychotics

• Smoking is protective factor!

Pathophysiology2,3,4,10 • Degeneration of nigrostriatal dopaminergic neurons in substantia nigra pars compacta (SNc)�↓ striatal dopamine levels

o Loss of dopaminergic cells extending from the SN in brainstem, to basal ganglia • Lewy bodies (intracytoplasmic eosinophilic inclusions) and neurites seen in brainstem and basal ganglia

o Lewy bodies and neuritis are composed of protein synuclein o Failure of protein clearance mechanisms

� Both ubiquetin/proteosome system and autophagy via lysosomes appear affected o Accumulation of toxic protein products-particularly alpha-synuclein, also ubiquetin o Neurones are partly protected by aggregating toxins in Lewy Bodies ie. LB are protective! o Distribution of Lewy bodies reflects pattern of disease

� Basal ganglia predominance-PD � Cortical predominance-dementia with Lewy bodies � However Lewy bodies spread throughout the brain as the disease progresses

o Alpha-synuclein has pathogenic role by binding to 14-3-3 in dopaminergic neurons in substantia nigra�neuronal cell death

• Cell loss also seen in locus ceruleus, dorsal nuclei of vagus, raphe nucleus, nucleus basalis of Meynert • ↓ activity of direct pathway & ↑ activity of indirect pathway�↑ inhibitory activity from globus pallidus internus

(GPi)/SN to thalamus�↓ output to cortex • Put simply, there is interference with instructions from the frontal cortex (planning area of the brain) getting to the

motor areas of the cortex o Excess stimulation of subthalamic nucleus (STN) and GPi�bradykinesia o Enhancement of long latency stretch reflexes�rigidity o Loss and/or dysfunction of postural righting reflexes�postural instability o Nigrostrial degeneration�inhibition of STN or GPi�tremor

Epidemiology2,3 • Slight M predominance • Majority >50yo • 5% <40yo (young onset PD) • Mean age onset 65yo • Overall age-adjusted prevalence WW is 1%

(1.6% in Europe) • Lowest prevalence in China, Japan, Africa

Complications: 2,3,4,10 • Dyskinesias-drug induced, ~painful • Development of dementia common • Pneumonia�death • ↑ risk of postop complications • ↑ pain-cramping & central neuropathic • Falls�fracture • Impaired speech-micrographia

Reference List: Neurology

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