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Neuromuscular Emergencies

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1 Neuromuscular Emergencies
July 28, 2010 Sandra Derghazarian

2 Outline Approach to rapidly progressing LMN weakness Myasthenic crisis

3 Intro Three major tasks:
Assess stability, signs of imminent resp failure Generate differential diagnosis Knowledge of localisation Knowledge of major disorders Determine management

4 Brief Review of Anatomy
Motor unit anatomy Anterior horn cell Its motor axon The synaptic cleft The muscle fibers it innervates Remember sensory and autonomic systems Many disorder with rapidly progressing peripheral neuropathic weakness will have sensory loss and dysautonomia Postganglionic unmyelinated sympathetic fibers join mixed nerves.

5 Classification Motor neuron Motor axon Neuromuscular junction Muscle
Loss of anterior horn cells Motor axon Disruption of myelin sheath Axonal degeneration Neuromuscular junction Pre-synaptic (e.g. Release of Ach) Post-synaptic (e.g. Abnormalities of Ach receptor) Muscle Membrane, contractile elements Genetic or acquired secondary (infex, inflamm, vasc.)

6 Approach to Determining Cause of Weakness
Knowledge of some of the possible disorders Focused history Physical exam Lab studies

7 Major Disorders Motor neuron ALS Poliomyelitis, West Nile virus
Level of motor unit Disorders causing rapidly progressing weakness Motor neuron ALS Poliomyelitis, West Nile virus Peripheral nerve Guillain-Barre syndrome/AIDP Tick paralysis Diphtheric, porphyric, arsenic neuropathy Shellfish poisoning Neuromuscular junction Myasthenia gravis Botulism Lambert-Eaten myasthenic syndrome Hypermagnesemia Muscle Acquired: Dermato- and polymyositis, Myoglobinuric myopathy, Hypokalemic paralysis, Toxic myopathy, Acute myopathy of intensive care Genetic disorders: X-linked dystrophies, myotonic dystrophy, acid maltase deficiency, mitochondrial

8 History – Key Elements Pre-existing NM disorder?
MG – exacerbation 2ary systemic illness, medication ALS – accelerated phase, decompensation 2ary pneumonia Pre-existing systemic disorder? Malignancy, CTD, sepsis What drugs is pt taking? Any recent illness? Diet in last 48 hours? Shellfish (saxitoxin, brevetoxin) Home-canned goods (botulinum toxin) Any possible exposure to tick bite, snake bite? Any sensory or autonomic symptoms? ICU patients Acute myopathy of ICU: secondary high dose steroids and neuromuscular blocking agents NMJ dysfctn 2ary renal failure and high dose mg Critical illness polyneuropathy: sensorimotor axonal peripheral neuropathy

9 Drugs Diuretics Hypokalemia Corticosteroids, statins, colchicine, cyclosporine, cocaine, chloroquine, L-tryptophan, penicillamine, zidovudine Myotoxic effect Amiodarone, cytarabine, streptokinase Demyelinating neuropathy Magnesium-containing antacids with pre-existing renal insufficiency Hypermagnesemia

10 Physical Exam Vital signs Unstable? Dysautonomia? Respiratory status

11 Signs of impending NM resp failure
Tachypnea, sinus tachycardia Staccato speech Inability to count to 20 Profound weakness of neck flexion Use of accessory muscles (visible, palpable) Orthopnea Paradoxical breathing pattern Signs of bulbar dysfunction (nasal voice, accumulation of saliva, weak cough)  think about aspiration!

12 Physical Exam

13 Physical Exam Vital signs Presence and pattern muscle weakness
Note any dysautonomia Presence and pattern muscle weakness Proximal (myopathy), distal (peripheral neuropathy) Symmetric, asymmetric Involvement of cranial muscles Reflexes Sensory changes Dysautonomia

14 Localisation of the Disorders
Clinical picture varies depending on which part of motor unit is involved Level of motor unit Key Clinical Feature Motor neuron Predominantly motor signs Often asymmetric Occasional sensory signs DTRs may be increased if ALS Peripheral nerve Weakness and sensory signs +/- autonomic signs +/- cranial muscles DTRs reduced or lost Autonomic signs: sweat glands, blood vessels, piloerector muscles

15 Localisation ctn’d Level of motor unit Key Clinical Features
Neuromuscular junction Involve cranial, limb girdle, proximal muscles +/- respiratory muscles Normal sensation (If presynaptic: +ve autonomic signs and post-exercise increase in strength If post-synaptic: fatigability) Muscle Predilection for neck, limb girdle, proximal muscles Possible cardiomyopathy Occasional resp muscle involvement Possible risk of myoglobinuria


17 Regroup Is respiratory failure imminent? Should ICU be involved?
Where can I localise motor findings? Does it fit with sensory findings? Does it fit with autonomic findings? Does it fit with the history? Can the history help me narrow things down?

18 Major Disorders Motor neuron ALS Poliomyelitis Peripheral nerve
Level of motor unit Disorders causing rapidly progressing weakness Motor neuron ALS Poliomyelitis Peripheral nerve Guillain-Barre syndrome Tick paralysis Diphtheric, porphyric, arsenic neuropathy Shellfish poisoning Neuromuscular junction Myasthenia gravis Botulism Lambert-Eaten myasthenic syndrome Hypermagnesemia Muscle Acquired: Dermato- and polymyositis, Myoglobinuric myopathy, Hypokalemic paralysis, Toxic myopathy, Acute myopathy of intensive care Genetic disorders: X-linked dystrophies, myotonic dystrophy, acid maltase deficiency, mitochondrial

19 Laboratory Studies CBC Lytes, Cr, BUN, Ca, Mg, PO4,
Anemia or leukocytosis - systemic disease Eosinophilia - possibly elevated in vasculitic neuropathy, porphyria Lytes, Cr, BUN, Ca, Mg, PO4, Liver enzymes (consider EtOH myotoxicity) CK (myopathy if very elevated) ESR (infectious or inflammatory disorders) CXR (pneumonia, atelectasis, elevated hemidiaphragm) EKG Changes associated with electrolyte imbalances Arrythmias 2ary to dysautonomia in GBS Axis deviation – may be suggestive of cardiomyopathy

20 Assess Respiratory Status
Tests in ER MIP MEP FVC ABG 20/30/40 rule VC: 20 ml/kg MIP: -30cmH20 MEP: +40cm H20

21 Myasthenic Crisis

22 Myasthenia Gravis Disorder of transmission across NM junction
Auto-immune and congenital form Epidemiology (auto-immune form): cases per million population Women > men (3:2) Bimodal incidence F: 20s, 30s; M: 50s, 60s 5-10% co-association with other auto-immune disorders

23 Classification Auto-immune – two forms Congenital
Acquired anti-AChR Abs (85%) Acquired anti-MuSK Abs, a muscle-specific TK 40-50% of anti-AChR seronegative pts Congenital Heterogeneous group (pre or post-synaptic) Of note: do not affect respiratory muscles therefore do not present with myasthenic crisis

24 Clinical Features Painless, fatigable weakness of voluntary muscles
Repeated activity  progressive paresis Rest  restoration of strength (at least partial) Usually insidious onset May occur more rapidly after precipitant (stress, infection) Association with thymic abnormalities 10-15% thymoma 50-70% thymic lymphoid hyperplasia Diplopia secondary to asymmetric weakness of the different muscles

25 Clinical Features Presenting symptoms: MuSK-MG Younger women
Predominantly facial, bulbar and respiratory weakness Relatively mild limb weakness Diplopia 50-64% Ptosis Generalised weakness 35% Leg weakness 10% Fatigue 9% Respiratory failure 1%

26 Severity Classification

27 Myasthenic Crisis Myasthenic weakness leading to respiratory failure and need for ventilatory assistance Severe weakness of respiratory muscles and/or Severe weakness of upper airway muscles (bulbar myasthenia)

28 Prevalence and Characteristics
Life-time prevalence: 20-30% Early onset  younger pt, median onset w/in 8 mos, fast recovery Late onset  older pts, later in dz course, slower recovery White pts respond more poorly than black pts Pregnancy aggravates MG in 30% of women High potential mortality of crisis

29 Precipitants Elements to look for in history/chart:
Poor control of generalised disease Medical treatment for bulbar myasthenia Steroids and anti-cholinesterases Use of certain drugs (next slide) Systemic infection, esp. of respiratory tract Aspiration Surgery Others (in refractory myasthenia): Emotional stress Hot environment Hyperthyroidism

30 Drugs Anticholinesterases can also lead to myasthenic crisis
Signs of excessive cholinergic activity Miosis, diarrhea, salivation, abdominal cramps, sweating, weakness

31 Investigations CBC, extended lytes, BUN, Cr, liver enzymes
CXR, U/A +/- blood cultures Obtain VC, MIP, MEP – 20/30/40 rule

32 Investigations Repetitive motor nerve stimulation Single fibre EMG
Stimulate motor nerve at 2-3 Hz and measure CMAP of stimulated muscle Positive if >er 10% decrement in amplitude of CMAP from the 1st to the 5th potential Positive in about 75% of patients with generalized MG, if Proximal & clinically involved muscles are tested Muscle is warm More than one muscle is tested Single fibre EMG Tensilon test not recommended in pt suspected of being in crisis False postive, false negative Risk of worsening muscle weakness in pts with anticholinesterase overdose Worsening of bulbar and respiratory symptoms in MuSK-MG Repetitive nerve stimulation — Repetitive nerve stimulation (RNS) studies demonstrate decrement in the amplitude of the compound muscle action potential after repetitive stimulation of the motor nerve to that muscle [34]. (See "Diagnosis of myasthenia gravis", section on 'Electrophysiologic confirmation'.) The orbicularis oculi may be studied in patients with OMG. Among patients with GMG, the sensitivity of RNS is greater than 70 percent [35]. In contrast, among patients with OMG, the sensitivity has been as low as 15 percent in some series and only slightly higher, 33 to 45 percent, in series where stimulation at multiple sites is performed [36,37]. The specificity is 89 percent; both false negatives and false positives do occur [21]. Single-fiber EMG — Single-fiber electromyography (SFEMG) identifies abnormal neuromuscular transmission by measuring temporal variability in the firing of adjacent motor nerve fibers from a single motor unit, a phenomenon called "jitter." SFEMG is more sensitive than repetitive nerve stimulation and may identify electrophysiologic abnormalities in clinically strong muscles. (See "Diagnosis of myasthenia gravis", section on 'Electrophysiologic confirmation'.) Depending on which and how many muscles are examined, the sensitivity of SFEMG for OMG is between 63 to 100 percent [38-40]. Evaluation of the orbicularis oculi and the superior rectus levator palpebrae complex increase the sensitivity in patients with OMG to over 95 percent [40,41]. However, this testing, particularly with examination of the superior rectus muscle, is available only at specialized centers with neuromuscular expertise. Abnormal jitter is not specific for myasthenia. However, while patients with MG generally have an otherwise normal standard EMG examination, other neuromuscular diseases that increase jitter do not. An exception may be in differentiating patients suspected of OMG from those with chronic progressive external ophthalmoplegia (CPEO). Two reports give conflicting data: in the presence of a normal needle EMG examination, one showed abnormal SFEMG in CPEO [42], while the other did not [43]

33 Management Monitoring of respiratory status
Recognition of impending resp failure Tachypnea, inability to count to 20, saliva pooling, nasal voice, NF weakness, paradoxical breathing Deciding when to intubate (Code status) 20/30/40 rule If in doubt, intubate ?BiPAP Limited experience. May reduce prolonged intubatn and trach

34 Management General Specific Stop any meds that may be contributing
Treat any infection Specific PLEX and IVIG comparable efficacy Based on clinical evidence, few RTCs Earlier response seen with PLEX More likely to extubate at 14 days, better 1-month functional outcome (Qureshi, et al. Neurology, 1999).

35 Management PLEX Removal of anti AChR and antiMuSK Abs
1 session/day x 5 No superiority of PLEX qd x 5 vs qod x 5 Rapid onset of action (3-10 days) Need central line with associated complications PTX, hemorrhage, line sepsis Caution in pts with sepsis, hypotension; may lead to increased bleeding and cardiac arrhythmias

36 Management IVIG 0.4gm/kg/day x 5 days
Easily administered and widely available Long duration of action May last as long as 30 days Side effects Anaphylaxis in IgA deficiency Renal failure, pulmonary edema Aseptic meningitis Thrombotic complications and stroke

37 MG – Overall Treatment Summary
1. Mild weakness: cholinesterase inhibitors 2. Moderate-marked localized or generalized weakness Cholinesterase inhibitors, and Thymectomy for patients under age yrs 3. Symptoms uncontrolled on cholinesterase inhibitors Prednisone if severe or urgent Azathioprine Prednisone failure Excessive prednisone side-effects 4. Plasma exchange or IV Ig Impending crisis; crisis Pre-operative boost Chronic disease refractory to drug therapy 5. If above fails Search for residual thymus tissue Cyclosporine or mycophenylate mofetil (Sem. Neurol., 2001;21: )

38 Guillain-Barre Syndrome

39 GBS Most common cause of acute and subacute generalised paralysis
Incidence of 0.4 to 1.7/ per yr Worldwide, all ages, both sexes Preceding mild resp or GI infection in 60% (1-3 wks) Campylobacter jejuni (26%), CMV, EBV, VZV Influenza, cocksackie, hepatitis A and B, HIV May also be preceded by: Surgery Immunisations

40 Typical Symptoms & Signs
Sensory Paresthesias and slight numbness distally earliest Sx Reduced proprioception and vibration sense (1 wk) Motor Weakness Evolves symmetrically over days to 1-2 weeks Usually LE before UE, proximal + distal +/- trunk, intercostal, neck, cranial muscles Progresses to total motor paralysis and respiratory failure in 5% of cases

41 Typical Symptoms & Signs
Reflexes Reduced and then absent Autonomic dysregulation Sinus tachycardia/bradycardia, facial flushing, labile BP, excess or loss of sweating, urinary retention Usually do not persist for >er 1 wk Other Myalgias (50%) in hips, thighs, back

42 Variants Fisher syndrome
Ophthalmoplegia, ataxia, areflexia +/- bilateral facial nerve paresis Associated with anti-GQ1b Ab Acute motor sensory axonal neuropathy (5% of GBS cases) Severe and diffuse axonal damage Abrupt and explosive onset Severe paralysis, minor sensory features Slow and poor recovery Pandysautonomia Severe orthostatic hypotension, anhidrosis, dry eyes and mouth, fixed pupils, arrhythmia, bowel/bladder dysfunction Areflexia without somatic motor/sensory involvement Other variants: Initial cervico-brachial-pharyngeal muscle involvement Generalised ataxia without dysarthria or nystagmus Facial and abducens weakness, distal paresthesias, proximal leg weakness

43 Laboratory Findings Most important: CSF, EMG CSF Normal pressure
Protein Early (1st 2 days): Usually normal (>85%) Later: High (66% in 1st week, 82% in 2nd week) Amount not correlated with clinical course or prognosis Acellular or few lymphocytes 10% : lymphocytes, decreases over 2-3 days; if not: other Dx Oligoclonal bands (10-30%)

44 Laboratory Findings EMG Abnormalities seen within first week of sx
Reduction in motor amplitude Slowed conduction velocities Conduction block in motor nerves Prolonged distal latencies (distal conduction block) Prolonged/absent F-responses (involvement of proximal parts of nerves and roots)

45 Laboratory Findings Hematology Biochemistry Liver enzymes
Abnormal only with infection or other disorder Biochemistry Mild-severe SIADH in 7-26% Liver enzymes Elevated <10% reflecting CMV or EBV infection ESR: Normal unless co-existing process

46 Diagnostic Criteria National Institute of Neurological Disorders and Stroke (NINDS) criteria are based on expert consensus. Required features include: Progressive weakness of more than one limb, ranging from minimal weakness of the legs to total paralysis of all four limbs, the trunk, bulbar and facial muscles, and external ophthalmoplegia Areflexia. While universal areflexia is typical, distal areflexia with hyporeflexia at the knees and biceps will suffice if other features are consistent. Supportive features include: Progression of symptoms over days to four weeks Relative symmetry Mild sensory symptoms or signs Cranial nerve involvement, especially bilateral facial nerve weakness Recovery starting two to four weeks after progression halts Autonomic dysfunction No fever at the onset Elevated protein in CSF with a cell count <10 mm3 Electrodiagnostic abnormalities consistent with GBS

47 Differential Diagnosis
Features suggesting another diagnosis: Sensory level, severe bladder or bowel dysfunction  Spinal cord syndrome Marked asymmetry  Mononeuritis multiplex/vasculitis CSF pleocytosis  Infectious disorders: viral, HIV, lyme, poliomyelitis Very slow nerve conduction velocities, multiple relapses or chronic course -> CIDP Persistent abdominal pain and psychiatric signs  Acute intermittent porphyria

48 Management General: Respiratory Recommend admission for observation
Can deteriorate rapidly in first days of presentation M&M: Respiratory failure, dysautonomia 25% will require mechanical ventilation Respiratory Measure MIP/MEP/FVC Decision to intubate should be based on downward trend Other measures of respiratory status same Counting to 20, strength of NF

49 Management Dysautonomia Other complications 10% develop hypotension
Volume, +/- pressors Hypertension IV labetolol Other complications Adynamic ileus PE Aspiration

50 Management PLEX and IVIG Steroids
No difference in efficacy between the two Indications for prompt initiation Respiratory failure Bulbar involvement Inability to walk without assistance Usually see these signs day 5-10 May occur anywhere from day 1 – week 3 Steroids No proven benefit

51 PLEX Regimen: 4-6 treatments on alternate days
Established usefulness in evolving phase If treated within 2 wks onset Decrease in LOS, ventilation, time to independent ambulation by approx. half Value less clear if started later than 2 wks after initial symptoms Predictors of response Age Preservation of motor CMAP amplitudes pre-PLEX

52 IVIG Dose: 0.4 gm/kg/day x 5 consecutive days
Cheaper, easier to administer Rare complications Renal failure, proteinuria, pulmonary edema Asceptic meningitis Anaphylaxis in IgA deficiency

53 Course and Prognosis Progressive symptoms : 1-4 weeks
Plateau: 2-4 weeks Recovery: A few weeks to months Recurrence: 5-10% Mortality 3-5% Cardiac arrest, ARDS, PTX, HemoTX, PE Pronounced disability: 10% Clinical prognostic indicators Greater age Rapid evolution; early and prolonged ventilatory assistance, rapid course Lack of treatment with IVIG or plasma exchange Laboratory EMG: severely reduced CMAP and widespread denervation

54 Pathogenesis Most evidence points to cell-mediated immunologic reaction directed at peripheral nerve May be precipitated by antecedent infection Antibodies against myelin components with complement-mediated damage T cells and macrophages become involved in process and lead to destruction of myelin/axon

55 Thank you

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