Chronic neurological disorders

Amyotrophic lateral sclerosis/Motor neuron disease/Lou Gehrig’s disease

• Rapidly progressive muscle atrophy and weakness due to combined upper and lower motor neuron degeneration
• Varying degrees of spasticity, hyperreflexia and paralysis
• Pathophysiology
  • Frontal cortical atrophy, degeneration of corticospinal and spinocerebellar tracts (lateral tracts), reduction in cervical and lumbar motor neurons and CN nuclei degeneration
  • Motor and sensory peripheral nerves undergo axonal degeneration and segmental demyelination

• Clinical features
  • UMN demyelination and dysfunction lead to spasticity, hyperreflexia and emotional lability
  • Limb weakness (LMN dysfunction) is the first presentation in 65% (oftne asymmetrical with wasting)
    • Classically affects small muscles of hand with fasciculation
  • Other LMN – Atrophy, cramps, fasciculations, dysarthria, dysphagia and difficult mastication are all common
  • Cognitive function, sensory neurons and autonomic neurons are usually spared
  • Despite relative sparing of face and eye movements, tongue atrophy can lead to monotone speech
  • Progressive respiratory muscle weakness leads to exertional dyspnoea and ultimately at rest
  • Overt dementia and parkinsonism occur in 15% +- apathy, poor attention, reduced social skills

• Diagnosis
  • Clinical diagnosis suspected if mixed upper and lower motor neuron dysfunction without other CNS dysfunction
  • Median time to diagnosis is 14 months
  • DDx includes diabetes, thyroid dysfunction, B12 deficiency, heavy metal toxicity, vasculitis and CNS/spinal cord tumors
  • Must exclude other inflammatory neuropathies including myaesthenia gravis
  • ALS Functional Rating Scale is a reliable diagnostic tool
• Treatment
  • Therapy aimed at enhancing muscle function (breathing, swallowing, speech
  • Riluzole modulates glutamate may prolong survival

• ED Care
  • Rare to present undiagnosed unless rapid disease progression or long period without medical care
  • Emergency management may be required for acute respiratory failure, aspiration pneumonia, choking
  • Blood gas analysis does NOT reliably predict impending respiratory failure
  • FVC < 25mL/kg or 50% decrease from predicted normal increases risk of aspiration and respiratory failure
  • Hospital admission indicated for impending respiratory failure, pneumonia, inability to control secretions or worsening overall status requiring placement

Myaesthenia gravis

• Autoimmune disease presenting with muscle weakness and fatigue with repetitive use
• ACh antibodies impair receptor fx at NMJ
• Weakness relieved by rest
• ED management includes diagnosis of cholinergic and myaesthenic crises with aggressive management of respiratory complications
• Twice as common in females and peak incidence is in young adult females with second peak in older males

• Pathophysiology
  • Marked decrease in number and fx of muscle ACh receptors leading to reduced muscle strength
  • ACh-R antibodies seen in 80% of patients
  • Disease severity is correlated to levels of Anti-AChR
  • Pathological autoimmune response thought to derive from dysfunction of thymus gland or immune response to exogenous infectious antigens with mimicry
  • 75% show histological thymic abnormality, 10% have thymoma and majority show thymic hyperplasia
  • Thymectomy improves symptoms in most patients (esp. if thymoma present)

• Clinical
  • General weakness, especially proximal extremity muscle groups, neck extensors and facial/bulbar muscles
    • As opposed to ALS with relative sparing of eye and facial muscles
  • Ptosis and diplopia are the most common presenting symptoms (20% of cases isolated to eye muscles)
  • Cogan lid twitch (eyes lowered for 10-20 seconds then droop or twitch when tries to raise them)
  • Ptosis, CN III, IV, VI weakness
  • Gaze palsies
  • INO or complete ophthalmoplegia
  • End-gaze nystagmus
  • Limb and trunk weakness can occur and is usually asymmetric
  • Symptoms usually worse at end of day or with prolonged muscle use i.e. prolonged reading, chewing during meal
  • Usually no sensory, reflex or cerebellar deficits
  • In elderly patients may be misdiagnosed as ischaemic stroke when new onset facial weakness is seen
  • Myaesthenic crisis = acute respiratory failure due to undiagnosed disease or inadequate drug therapy

• Diagnosis
  • Consider in any patient who complains of ocular disturbances or proximal weakness
  • Fluctuating symptoms is key
  • DDx
    • Congenital myaesthenia gravis
    • Lambert-Eaton syndrome (small cell lung cancer)
      • Pelvic and thigh muscle involvement predominates
      • Ocular and bulbar involvement is rare
      • Tendon reflexes are reduced or absent
    • Drug-induced myaesthenia (penicillamine, procainamide, quinines, aminoglycosides)
    • Botulism (descending paralysis)
    • Thyroid disorders
    • Intracranial mass lesions affecting eye function
    • CVA

• Diagnosis
  • Edrophonium administration (Tensilon test) – HISTORICAL
    • Acetylcholinesterase inhibitor that should improve symptoms/signs
    • Can cause profound weakness in other disorders of neuromuscular transmission so be prepared to intubate patient if diagnosis unclear
    • Highly specific but poor sensitivity
  • EMG shows post-synaptic NMG dysfunction with repetitive nerve stimulation
  • Serology for Anti-AChR is quite specific
• Treatment
  • Acetylcholinesterase inhibitors (physostigmine/neostigmine)
  • Thymectomy
    • Favourable response more likely if thymoma present, inadequate response to acetylcholinesterase inhibitors and short time from diagnosis to operative intervention
  • Chronic immunosuppression (prednisolone, azathioprine, cyclosporine or mycophenolate)
  • IVIG or plasma exchange for acute immune modulation in severe cases

• Factors that affect muscle weakness despite therapy
  • Asthma exacerbations
  • Infections
  • Menstruation
  • Pregnancy
  • Emotional stress
  • Hot weather
  • Pulmonary/renal/GI disease

• Drugs to avoid (reduce NM function)
  • Steroids – ACTH, methylpred, prednisolone (unless treating MG)
  • Anticonvulsants – Phenytoin, MgSO4, barbiturates, lithium
  • Antimalarials – Quinine, chloroquine
  • IV fluids – Hartmann’s
  • Antibiotics – Aminoglycosides, quinolones, macrolides, metronidazole
  • Psychotropics – Chlorpromazine, lithium, amitryptiline, droperidol, haloperidol
  • Antirheumatics – Penicillamine, colchicine
  • Cardiovascular – Quinidine, procainamide, beta-blockers (propranolol, sotalol), lignocaine, mag, verapamil
  • LA – Lignocaine, procaine
  • Analgesics – Opioids
  • Endocrine – Thyroxine
  • Eye drops – Timolol
  • Others – Diuretics
  • Paralytic agents (ALL)
    • Suxamethonium preferred but need higher dose (2mg/kg) due to inadequate ACh receptors for adequate paralysis
    • Alternatively half-dose rocuronium is also recommended

• Missed doses of acetylcholinesterase inhibitors
  • If in ED ensure patient receives usual doses
  • If missed dose, double the next one
  • If NBM, administer 1/30 of PO dose of pyridostigmine by slow IV infusion with neurology input
• Respiratory failure
  • May be precipitated by infection, surgery or rapid tapering of immunosuppressive agents
  • Have severely prolonged paralysis from non-depolarising NM blocking agents and unpredictable reaction to sux (+ hyperkalaemia)
  • Avoid if at all possible
  • Strategy recommended is low dose sedation without paralysis OR inhalational anaesthetic
  • If paralysis is absolutely necessary, use ½ dose non-depolarising agent

• Myaesthenic crisis
  • 15-20% of patients will suffer at least one episode of this
  • Can affect bulbar or respiratory function
  • May be spontaneous or due to intercurrent infection, pregnancy, surgery or drug delivery (see above)
  • Can last weeks to months
  • Incidence increases with age
  • Admit to ICU for supportive therapy, treatment of underlying precipitant +- MV
  • Avoid hypokalaemia, hypocalcaemia and hypermagnesaemia as can all worsen muscle weakness
  • High dose corticosteroids and plasma exchange may produce benefit within 24 hours if patient status cannot be rapidly improved by anticholinesterase dosing
  • Must be distinguished from cholinergic crisis (due to excessive cholinergic effects of acetylcholinesterase inhibitors)
  • Edrophonium testing (Tensilon test) used to be the mainstay of differentiation but less common now
    • 1mg Edrophonium IV (rapid onset 30 seconds; lasts 5-10 minutes)
    • Have atropine, crash cart and intubation equipment ready as can lead to bradycardia, AV block, AF and cardiac arrest
    • If leads to muscle fasciculations, respiratory depression or cholinergic symptoms (SLUDGE – Salivation, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis), miosis or bronchial secretions = Cholinergic crisis
      • No more edrophonium
      • Treatment with atropine (willl not reverse cholinergic effects (skeletal muscle weakness) but will reverse muscarinic effects)
    • If leads to resolution of muscle weakness within minutes = Myaesthenic crisis
      • Can give further edrophonium aliquots up to 10mg total
      • Needs IM or SC neostigmine 0.5mg OR PO Neostigmine 15mg
        • Clinical effect seen within 30 minutes and lasts up to 4 hours

Multiple sclerosis

• Combined motor, sensory, visual and cerebellar dysfunction due to CNS demyelination
• Paraesthesias, gait disturbance, extremity weakness, incoordination and visual disturbances are most common in relapsing-remitting
• Most patients have only mild-moderate lifetime disability with immunosuppressive and immunomodulatory agents
• Reduction of life expectancy averages 5-10 years
• Clinical subtypes
  • 90% relapsing remitting (relapses last weeks to months)
  • Relapsing and progressive
  • Chronic progressive (more common with advanced age)

• Pathophysiology
  • Immune-mediated inflammatory demyelination
  • Causes oligodendrocyte dysfunction with axonal myelin sheath damage, slowed nerve impulse conduction
  • Scattered cerebral and spinal plaques cause gliosis in predominantly white matter with relative axon sparing
  • Cranial nerve lesions cause optic neuritis + facial motor/sensory deficits

• Clinical features
  • Young person presenting multiple times with neurologic symptoms of disparate regions often with resolution of earlier symptoms
  • Lower extremity > upper extremity
  • Examination may show decreased strength, increased tone, hyperreflexia, clonus, positive Babinski, reduced vibriosense and joint proprioception and reduced pain and temperature sensation
  • Lhermitte sign = electric shock sensation or vibration or pain radiating down back and into arms/legs due to flexion of the neck
  • Rarely established MS patients may present with acute transverse myelitis
  • Vertigo may develop due to brainstem lesions

• Optic neuritis
  • Optic neuritis (acute or subacute central visual loss) may be the first sign in 30% of patients
  • Vision loss typically occurs over several days, is usually unilateral, often with retrobulbar pain or EOM pain that may be reproduced with orbital palpation
  • May have Marcus-Gunn pupil (RAPD)
  • Optic disc may appear pale
  • Visual disturbance often resolves over months
  • Blurred vision, red desaturation and/or eye pain occurs in most patients at some stage
  • Nystagmus, diplopia and INO are often seen
  • INO typically has impaired eye adduction on one side and horizontal nystagmus
  • Bilateral INO in otherwise healthy young person = MS until proven otherwise

• Dysautonomia
  • Vesicourethral dysfunction leading to urinary retention, urgency, frequency, stress or overflow incontinence
  • GI constipation or faecal incontinence
  • Sexual dysfunction (esp. males) may be a presenting symptom
• Cognition
  • Dementia, reduced motivation, depression and bipolar are seen in many patients
  • Cerebral MS (only 5% of patients) causes severe disabling reduced intellect and seizures
• Seizures
  • Generalised seizures are of equal incidence in MS vs. general population
  • Simple partial seizures occur twice as commonly in MS vs. general population
• Symptoms often worse with increased body temperature (exercise, fever, hot baths)
• Most acute exacerbations peak at 1 week and resolve over weeks to months
• Complete recovery from an acute exacerbation occurs early in disease course but less commonly in later year

• Diagnosis
  • Need 2 or more prolonged or worsening episodes of neurological dysfunction that suggest white matter or spinal cord dysfunction in 2 or more distinct locations
  • Optic, CSF and neuroimaging findings + typical dysautonomias all add to diagnostic accuracy
  • DDx includes SLE, Lyme disease, neurosyphilis, HIV, GBS
  • MRI T2 scans show multiple discrete lesions in supratentorial white matter, homogenous borders around ventricles or infratentorial or spinal cord lesions
  • CT may show cerebral atrophy, ventricular enlargement and low-density focal lesions in cerebrum, brainstem or optic nerves
  • CSF protein and gammaglobulin levels raised
  • Slight increase in CSF WCC up to 25/mm3 can be seen (mostly T lymphocytes)

• Treatment
  • Mitoxantrone
  • Glucocorticoids
  • Natalizumab
  • IFN-beta
  • Glatiramer
  • IVIG for postpartum exacerbations and relapsing-remitting disease not responsive to other agents

• Disposition
  • Identify complications such as respiratory distress, optic neuritis, pulmonary infections, severe constipation or worsening muscle weakness
  • Labile autonomic dysfunction means preparation for hypotensive crisis with RSI is crucial
  • Treat fevers aggressively
  • Test for UTI and pyelo in all patients, especially if residual volumes >100mL
  • Discharged patients should managed elevated residual volumes with intermittent sterile catheterisation vs. chronic IDC placement
  • Hospitalise for disease exacerbations or IV antibiotic/steroid requirements or if depression/suicidal

Transverse myelitis

• Involves gray and white matter suggesting not purely demyelinating but rather a mixed inflammatory condition affecting neurons, axons, oligodendrocytes and myelin
• 50% have antecedent respiratory, gastrointestinal or systemic infection
  • VZV, Herpes, Listeria
• Lupus-associated TM can be associated with CNS vasculitis or thrombotic infarction of the spinal cord
• Acquired CNS autoimmune disorders that can cause TM include MS, neuromyelitis optica and acute disseminated encephalomyelitis (ADEM)
  • May be initial demyelinating event of MS
  • TM manifesting as >3 spinal levels + bilateral optic neuritis = NMO
  • Also associated with paraneoplastic syndromes, neurosarcoidosis and systemic inflammatory autoimmune disorders
    • AS
    • Antiphospholipid antibody syndrome
    • RA
    • Scleroderma
    • Sjogrens
    • SLE

• Inflammatory disorder that presents with acute or subacute spinal cord dysfunction resulting in weakness, sensory alterations and autonomic dysfunction below level of lesion
• May be acute partial, acute complete or longitudinally extensive subtypes
• Bimodal peaks at 10-19yo and 30-39yo
• Gadolinium-enhancing spinal cord lesions and swelling on MRI with no evidence of cord compression to explain presentation
• CSF
  • Abnormal in 50%
    Moderate lymphocytosis (usually <100/mm3)
  • Elevated protein

• DDx
  • Other types of myelopathy: Compressive or non-inflammatory
    • Compressive: Discitis, osteomyelitis, traumatic epidural haematoma, disc herniation, fracture/dislocation, metastases
    • Non-inflammatory: Anterior spinal artery infarction, B12 deficiency, primary CNS lymphoma
  • Various disorders that cause secondary TM
  • Non-myelopathic mimics e.g. GBS

Lambert-Eaton syndrome

• Autoimmune syndrome with fluctuating weakness and fatigue, especially in proximal limb muscles due to Anti-voltage-gated Ca channels antibodies seen in small cell lung cancer
  • Thus impairs ACh release from presynaptic terminal
  • Seronegative form does exist
• Not fatiguable weakness like MG
• Lambert sign – Grasping examiners hand gets stronger with time
• Complain of myalgias, muscle stiffness (hip/shoulder), paraesthesias, metallic taste and dry mouth/impotence due to muscarinic cholinergic insufficiency
• Syndrome can precede diagnosis of malignancy by several years
• 50% of patients have concurrent small cell lung cancer and have more rapid disease progression
• Treatment
  • Supportive care
  • 3,4-diaminopyridine is first-line
  • Immunosuppression can also reduce symptom severity
  • Admit if infectious complications or severe disability occur

Parkinson’s disease

• Extrapyramidal movement disorder characterised by resting tremor, bradykinesia, hypertonia (cogwheel rigidity), akinesias and impaired postural reflexes
• Reduced functional dopaminergic receptors in substantia nigra
• Drug therapy aims to enhance central dopaminergic activity to balance excessive central cholinergic activity
• Pathophysiology
  • Cellular cytoplasmic inclusions (Lewy bodies) and extracellular pigment granules that stimulate macrophage activity
  • Substantia nigra shows depigmentation, dopaminergic neuron loss and gliosis
  • Decrease in overall level of striatal dopamine

• Clinical features
  • One or more of four hallmark signs
    • Resting tremor
    • Cogwheel rigidity
    • Bradykinease or akinesia
    • Impairment in posture
  • Premotor phase – Olfactory and constipation
  • Motor phase – Fluctuations and dyskinesias
  • Late-stage – Motor disability, freezing of gait, incontinence, orthostatic hypotension and dementia
  • Typically initial unilateral resting tremor in upper extremity (repetitive, slow-amplitude involving fingers and thumb (pill-rolling) five or more times per minute
  • Often tremor dissipates with voluntary movement
  • Often impulse control disorders apparent

• Diagnosis
  • DDx includes post-encephalitis, neurosyphilis, subacute spongiform encephalitis and AIDS
  • Parkinsonism can occur due to street drugs, toxins, neuroleptic agents, hydrocephalus, head trauma
  • Drug-induced Parkinson’s disease
    • Akinesia is the most common sign with resting tremor less common
    • Often short interval between onset and maximal disability, bilateral motor signs
  • CT and MRI mostly only show CNS atrophy

• Therapy
  • Anticholinergics – Benztropine
  • Dopaminergic agents – Amantadine, levodopa
  • Dopamine receptor agonists – Bromocriptine, pergolide
  • If severe motor dysfunction – MAOi (selegiline) and COMT inhibitiors (entacapone and tolcapone)
• Levodopa
  • Converted into dopamine by decarboxylases peripherally can cause anorexia, nausea and vomiting due to increased peripheral dopamine levels
  • If combined with carbidopa (peripheral decarboxylase inhibitor) smaller doses of levodopa are required and less side effects occur
  • Over time, effectiveness reduces, requiring dopamine agonist use
  • On-off phenomenon (often akinetic in morning before first dose) can be treated with long-acting preparations of combined levodopa/carbidopa
  • As drug effectiveness reduces over time or psychiatric side effects occur, a drug holiday for 1 week is often attempted with severe symptoms for that week followed by improved drug effectiveness lasting weeks to months

• Deep brain stimulation
  • Can treat advanced disease with motor symptoms and improve QoL
• Drug-induced Parkinsonism
  • Remove drug
• Special considerations
  • Severe pain is often a major component of undiagnosed Parkinsons or loss of medication efficacy
  • Most common cause of death in severe Parkinsons is respiratory failure, often due to off period weakness, respiratory distress +- aspiration pneumonia
  • Dopaminergic toxicity can include cardiac dysrhythmias, orthostatic hypotension, dyskinesias and dystonias + nightmares, hallucinations, paranoia and psychoses
  • Psychotropics (like haloperidol) risk tardive dyskinesia and should be avoided competely
  • Liaise with treating clinicians to determine if previous drug holidays have been successful and if dopaminergic excess seems a likely culprit
  • Parkinonism-hyperpyrexia syndrome – Similar to neuroleptic malignant syndrome – Rare and severe
• Emergency management
  • Prescribe usual medications at usual times
  • If NBM
    • May require NG tube solely for medication administration or Rotigotine patch application
    • Can safely omit Entacapone, Selegiline, Rasagiline and Amantadine
    • Levodopa/benserazide is available as a dispersible tablet and may have to convert modified release preparations to immediate release to crush and deliver via NG
    • If only on levodopa or dopamine agonists and NG not available, can convert to rotigotine transdermal patch as per conversion tables
  • If acutely confused
    • Lorazepam is the agent of choice
    • Do NOT prescribe haloperidol, chlorpromazine or other antipsychotic agents
  • If nausea/vomiting
    • Do not prescribe metoclopramide, droperidol or prochlorperazine
    • Domperidone, ondansetron and cyclizine are the agents of choice

Poliomyelitis

• Neurotropic enterovirus causing paralysis through motor neuron destruction, muscle denervation and atrophy
• Still endemic in India, Pakistan, Afghanistan and Nigeria
• Postpolio syndrome
  • Presents with recurrence of motor symptoms after latent period of several decades
  • Disease onset is 25-30 years after initial infection
• Pathophysiology
  • Oral-oral in developed countries vs. faecal-oral in developing countries due to poor sanitation
  • Reproduces in GI-associated lymphoid tissue (GALT)
  • Oral secretion of virus lasts days vs. stool excretion for several weeks
  • Virus then spreads to large motor nuclei in spinal cord, brainstem and reticular formation
  • Neuron loss then leads to cycle of muscle denervation, reinnervation and loss of muscle function

• Clinical features
  • Acute poliomyositis
    • Asymptomatic in >90% of cases
    • Symptomatic infections 
      • 90% have minor viral illness with no paralysis (abortive polio)
        • Children may develop aseptic meningitis as infection resolves
      • 1-2% suffer major illness with neurological involvement
        • Often resolution of minor viral illness
        • Spinal anterior horn cells often most severely affected with asymmetric proximal limb weakness (especially lower extremities)
        • Flaccid and weak muscles, absent tendon reflexes and fasciculations characterise spinal polio
        • Sensory deficits not found on examination
        • Maximal paralysis within 5 days with muscle wasting over weeks + autonomic dysfunction
        • Most patients will demonstrate improved motor function over the next year

• 20% of polio patients with paralysis suffer bulbar polio
• Acute polio infection can also cause encephalitis (normally recover)
• Consider acute paralytic poliomyelitis if at-risk individual suffers acute febrile illness, aseptic meningitis and asymmetric flaccid paralysis with loss of deep tendon reflexes and normal sensation
• Throat and rectal swabs provide highest yield for pathogen
• DDx is GBS (but is symmetrical), peripheral neuropathies (infectious mononucleosis, Lyme, porphyria), inflammatory myopathies, electrolyte disturbances or other viruses (Coxsackieviruses, mumps, echoviruses, non-polio enteroviruses), acute spinal cord compression, vascular lesions, transverse myelitis (should all produce sensory level and sphincter disturbances)

• Post-polio syndrome
  • Muscle fatigue, joint pain or worsening of skeletal muscle deformities
  • Need stable recovery from previous acute paralytic poliomyelitis with residual muscle atrophy, weakness and areflexia with normal sensation in at least one limb
  • Treatment is symptomatic

Periodic paralysis

• Rare primary disorders, mostly autosomal dominant, producing episodic weakness
• Must be distinguished from electrolyte disturbances, myaesthenia gravis and TIA
• Underlying disorder of skeletal muscle ion channels
• Symptoms usually begin <25yo and follow rest/sleep rather than exertion
• Alertness is preserved and muscle strength between attacks is normal

• Hypokalaemic periodic paralysis
  • Mostly inherited but can be sporadic in association with thyrotoxicosis
  • Bulbar and respiratory muscles are rarely involved
  • Cardiac arrhythmias occur rarely
  • Degree of hypokalaemia during attacks is mild and patients respond rapidly to potassium administration
  • Prophylaxis by acetazolamide or treatment of concomitant hyperthyroidism but NOT oral potassium supplementation
• Hyperkalaemic periodic paralysis
  • Milder, almost always inherited and never requires ICU
  • Serum potassium may be modestly elevated during attacks
  • Patients respond to carbohydates and thiazides/acetazolamide are prophylactic

Chiari malformations

• Chiari I – Cerebellar tonsils >5mm below foramen magnum
• Chiari II (Arnold-Chiari) – Tonsils/vermis below foramen magnum + brainstem beaking and myelomeningocoele
• Chiari III – Rare. Small posterior fossa with high cervical or occipital encephalocoele with displacement of cerebellar structures into encephalocoele and inferior displacement of brainstem into spinal cord

Chiari I

• 40-75% have spinal cavitations (syringomyelia)
• Hydrocephalus in 10%
• 0.1-0.5% of population
• Usually presents insidiously ~18yo
• Complications
  • Occipital/nuchal headache most common – May be paroxysmal or dull/persistent. Often worse with valsalva
  • Cranial neuropathies
  • OSA
  • Oscillopsia, sensorineural hearing loss, sinus bradycardia, syncope, hiccups
  • UMN signs in limbs
  • Cerebellar symptoms/signs
  • Cervical syrinx complications (LMN upper limbs; UMN lower limbs usually)

Chiari II

• Malformation causes obstructive hydrocephalus in all patients
• Almost all have a myelomeningocoele
• Usually diagnosed in childhood due to concomitant myelomeningocoele

Last Updated on July 21, 2021 by Andrew Crofton