Neuromuscular Disorders

Neuromuscular DisordersPing-Wei ChenPGY 2 Emergency Medicine ResidentApril 8, 2010Thanks: Dr. Walker, Dr. Burton-MacLeod, Dr. Oster, Dr. BrownellWeaknessNon-NeuromuscularCardiovascularRespiratoryInfectiousMetabolicEndocrineToxicologicNeuromuscularBrainSpinal CordAnterior Horn CellPeripheral NerveNeuromuscular JunctionMusclePatients with neuromuscular disease are going to present with weakness and the most important differentiation to make is whether this is neuromuscular in origin or not.

By far, non-neuromuscular causes of weakness still dominate. Examples of these include the above. That is not to say that these etiologies cant cause neuromuscular pathology, but that an intrinsic neuromuscular problem is not the primary pathologic process in causing the weakness when we say non-neuromuscular.

Neuromuscular causes of weakness can include pathology anywhere along the tract from the brain all the way to the end organ of muscle. Our discussion today is mostly going to focus on causes of weakness that stem from pathology in the neuromuscular junction.2Localizing the Lesion: UMN vs LMNUpper motor neuronUnilateral symptomsIf bilateral symptoms, associatedAltered mental statusCranial nerve abnormalitiesIf bilateral symptoms and normal mental statusTHINK spinal cord

Once weve deduced that the weakness is caused by a neuromuscular etiology, we need to localize the lesion. This is best done by thinking of the neuromuscular tract as UMN versus LMN.

Usually unilateral symptoms. However, if bilateral symptoms from the brain, there is usually a chance in mental status given that something catastrophic has to have happened in both hemispheres of the brain or something has to be affecting the brainstem, where things are packed more closely together, however, you would see cranial nerve findings given their origins in the brainstem.

Therefore, if you see bilateral symptoms and there is normal mental status and cranial nerves, start thinking about spinal cord pathology.3Localizing the Lesion: UMN vs LMNReflexesSpasticityAtrophyFasciculationsBabinskisNerve Conduction TestingWeaknessUpper Motor NeuronhyperyesnonoupgoingnormalyesLower Motor NeuronhyponoyesyesdowngoingabnormalyesSome clues in physical exam to point towards UMN versus LMN pathology.4MyelopathyPathology of the spinal cordClinically:UMN signsAscending weaknessBowel/Bladder involvementSensory involvement (define level)Ascending weakness not so much that weakness migrates upwards but that everything below level of lesion will be affectedImportant hx: ?trauma, immunocompromise, anticoagulated, cancer5Anterior Horn CellUMN synapses with LMN hereClinically:Both UMN/LMN signsLittle/No sensory involvementBulbar symptoms (ALS)SpeechSwallowingChewing Prototypical disease = ALS, poliomyelitisNo sensory involvement = lesion is before where the sensory and motor neurons join to form the spinal nerve6NeuropathyPeripheral nerve pathologyClinically:LMN signsDistal to proximal involvementglove and stocking patternVaried sensory involvementDistal to proximal involvement longer axons get affected first.7Neuromuscular JunctionConnection between CNS and musclesClinically:Variable presentations of weaknessFatigability ProximalAscending vs DescendingNo sensory involvement

MyopathyMuscle pathologyClinically:LMN signsProximal > Distalmuscle tendernessMuscle tenderness in inflammatory etiologies9Case65M with weakness. 2x visits to GP in last 3 months for same.Notices:sometimes chokes on foodBlurry vision when tiredGeneralized fatigueEnough is enoughO/E:

Normal PERLRapid neurological exam otherwise normal.Any thoughts?

GP = exam no acute findings, CBC normal, folate/B12 normal, TSH normal

You can distinguish a third nerve palsy from MG: by virtue of fatiguability, pupil reactivity in MG (although diabetic third nerve palsy's often have pupilary sparing) and the "down and out" gaze deviation.10Myasthenia GravisRARERarely diagnosed in EDBi-modal age of onsetWomen 20-40Men 50-70Diagnosis is clinical + serological + neurophysiologicDr. Walker = 2 cases11Neuromuscular Junction

A quick review of the neuromuscular junction:

An action potential comes down the axon, this causes the opening of calcium channels allowing an influx of calcium into the nerve terminal. This in turn causes a release of acetylcholine by exocytosis into the synaptic cleft, which then binds to ACh receptors, causing an action potential in the muscle cell and muscle contraction.12Myasthenia GravisAutoantibodies against Nicotinic ACh receptorsDecreased number of post-synaptic ACh receptors Compete for binding on ACh receptors with ACh

Some thought that second pathophysiologic mechanism is autoantibodies to another protein involved in development of Ach receptor/NMJ junction.13Myasthenia GravisClinically:Fatigability of voluntary musclesBEWARE respiratory musclesOcular symptoms firstPtosis, diplopia, blurred visionNormal sensationNo pain

Fatigability voluntary muscles (Hallmark feature); respiratory drive preserved but muscles weakPtosis classically, worse at the end of the day

14Myasthenia GravisDiagnosisClinical + Further TestingEdrophonium/Ice Bag TestAnti-ACh Receptor AntibodyMuscle Specific Receptor Tyrosine Kinase AntibodyElectrophysiologic Tests

Myasthenic CrisisMG + Respiratory failure requiring intubation15%-20% MG patientsPrecipitantsInfection (most common)Medication changes SurgeryPregnancy/ChildbirthUnidentified (30%)

Infection common as many patients on immunomodulating drugsMedication changes anticholinesterase meds, cardiovascular meds (B-blockers, CCBs, antiarrhythmics), certain antibiotics (aminoglycosides, macrolides, tetracycline, clindamycin), phenytoin, steroids, thyroid supplements, other neuromuscular blocking meds.16Back to our patientWhen to intubate?Caution: Dont rely on work of breathing! SpirometryFVC 1L = intubateRate of decrease in FVCsooner rather than laterMG patients are weak and fatigable wont show increased work of breathing 17Cholinergic CrisisExcessive anticholinesterase medicationToo much Acetylcholine

AcetylcholineSuccinylcholineAnother entity causing weakness that complicated MG patients.Recall too much ACh is analogous to succinylcholine18Myasthenic VS Cholinergic CrisisMay be difficult to differentiateResponse to Edrophonium/Ice Bag TestPresence of muscarinic symptomsCholinergic crisis rare unless >> dose ingestedie: pyridostigmine >120mg every 3 hoursAssume weakness 2o worsening MG

Muscarinic Symptoms: SLUDGE (salivation, lacrimation, urination, defecation, GI hypermobility, emesis), diaphoresis, bradycardia, bronchorrhea, miosis19Edrophonium/Tensilon TestEdrophonium 135mg IVResponse 30-90s?Adverse effect?Max dose 10mg IVCaution Asthmatics/COPDAtropine at bedside!!

Measure distance between upper and lower eyelid in most affected eye

Edrophonium/Tensilon = acetylcholinesterase inhibitor20Ice Bag TestApply ice to most affected eye X 2 mins Measure distance between upper and lower eyelid in most affected eye

Mechanism of action unknown thought to decrease acetylcholinesterase activity21Myasthenia GravisManagementEmergency DepartmentIdentifySupportiveEarly intubation for respiratory failureNeurology/ICUAnti-cholinesterase MedicationsPyridostigmineImmunomodulationPlasmapheresis, IVIGGlucocorticoids, Azathioprine, Mycophenolate Mofetil, CyclosporineThymectomy

Rosens: Cholinergic drug therapy is not recommended for the treatment of MG in the emergency department

Even the rapid immunomodulating therapies take days to work. Chronic immunomodulating therapies take weeks to months to work.Thymus abnormalities have bee shown to be associated with MG (either hyperplasia or thymoma)Thymectomy has been shown to increase rate of medication free remission and becoming asymptomatic (both in those with thymoma and without)22Clinical PearlsDo spirometry!Insidious respiratory failureFVC 1L = ICU consult, FVC500ccSick Myasthenia Gravis patient?*Continue acetylcholinesterase inhibitor meds*Admitting Myasthenia Gravis patient?Neurology consultIf a MG patient is sick with another illness (minor or not), make sure they continue to get their acetylcholinesterase inhibitor meds before they have bulbar weakness and trouble swallowing.

Neurology wants to hear about admitted myasthenia gravis patients regardless of admitting diagnosis.23Case 62M with known small cell lung CaGeneralized leg weaknessDifficulty climbing stairs

Could this be Lambert-Eaton Syndrome?

As you and your preceptor are discussing neuromuscular disorders, you remember that there is an association between SCLC and Lambert-Eaton Syndrome. Could this be Lambert-Eaton Syndrome? How would you differentiate it from Myasthenia Gravis?24Lambert-Eaton SyndromeRAREStrong association with neoplasm (SCLC)Auto-antibodies to Voltage Gated Ca channelsDecreased release of ACh from pre-synaptic terminal

The weakness seen with LES is usually more chronic in nature and less severe than MG, however, there are always case reports of it being the same severity.

Diagnosis is based on Voltage Gated Calcium Channel antibody testing and neurophysiological testing.

Treatment is screening for malignancy, ACh release stimulating drugs, acetylcholinesterase inhibitors, or immunomodulation. 25Lambert-Eaton SyndromeClinically:Proximal muscle weakness (1 year oldDecrease mortality, disease duration (if given early)Unclear effect on ventilator dependenceSide effects: serum sickness, anaphylaxisHuman Botulism Immune Globulin (BIG-IV)