1. EMG Blind Spots: What Your Study Can Miss Disorders of the NMJ W. David Arnold, MD AAPMR 2014

2. Outline Review of Prototypical NMJ Disorder, Myasthenia Gravis, and the General Approach to NMJ Disorders Review a series of 4 Cases to Highlight Potential Pitfalls and Key Concepts in NMJ Edx studies

3. Case 1: “Proximal Limb Weakness” 18 year old woman presents with a progressive proximal limb weakness is sent to the EMG Lab Limb Girdle Muscular Dystrophy? Examination: – 4 grade proximal limb weakness – Normal bulbar strength, sensation, and reflexes

4. Case 1: NCS and EMG Normal median sensory and motor response EMG: short duration, small amplitude motor unit action potentials with early recruitment without fibrillations

5. Case 1: Proximal Limb Weakness (Cont.) EMG and NCS: Non-irritable myopathy Diagnostic consideration was given to a possible limb girdle muscular dystrophy Muscle Biopsy: normal Thoughts?

6. Case 1: Additional Studies Repetitive ulnar nerve stimulation at 3 Hz ~50% decrement SFEMG Increased jitter and blocking

7. Follow up Lab testing: – Elevated acetylcholine receptor antibodies Diagnosis: acetylocholine receptor antibody positive myasthenia gravis (MG) Treatment: Excellent response to pyridostigmine and immunomodulatory treatments

8. 338 charts of patients with NMJ disorders 6 patients underwent muscle biopsy for possible myopathy 2 with coexistent inflammatory muscle dz 4 with NMJ disorders mimicking myopathy (based on normal muscle bx) Consider RNS in patients with weakness Clinical Pearl of Case 1: Ask the Correct Question

9. MG MG is the most common NMJ disorder Prevalence of 20 in 100,000 and incidence of 2 per 100,000. (Phillips Ann N Y Acad Sci. 2003) Antibodies – Ach receptor antibodies (80%) – Muscle specific tyrosine kinase (MuSK) (10%) – Antibody negative (5%-10%) Treated with cholinesterase inhibitors and immunomodulatory treatments

10. NMJ Disorders: History Weakness: proximal muscles with fatigability – Severity of involvement: Ocular>bulbar>limb>respiratory Sensory: No sensory loss, paresthesia, or neuropathic pain Autonomic: dry mouth, blurry vision, impotence, constipation, and difficulty with urination – Some disorders such as Lambert Eaton myasthenic syndrome (LEMS) and botulism Generalized fatigue ≠ NMJ disorder

11. NMJ Disorders: Examination Weakness in proximal limb, ocular, and bulbar muscles – Distal or focal weakness may occur in 12% of MG (Wirtz et al 2002) – Extraocular and bulbar weakness are early and prominent in MG and botulism – Less prominent extraocular weakness in LEMS Reflexes are normal in postsynaptic disorders such as myasthenia gravis but characteristically absent or reduced in presynaptic NMJ d/o Sensory function is normal Pupillary responses are usually reduced in botulism

12. Post-synaptic NMJ disorders Sensory NCS -normal Motor NCS -usually normal CMAP amplitude EMG -Possibly short duration, low amplitude, unstable MUAP’s if severe (Jiggle) Slow RNS (3 Hz) -decrement (60-80% of generalized MG) CMAP with 10 sec exercise (or Rapid RNS, 20-50 Hz) -no increment CMAP with Exercise -no increment SFEMG -Jitter and blocking (95-98% MG) (Nl jitter in weak muscle ≠ MG)

13. Post-synaptic NMJ disorder

14. Pre-synaptic NMJ disorder Sensory NCS -normal Motor NCS -usually low CMAP amplitude EMG -Possibly short duration, low amplitude, unstable MUAP’s if severe -some disorders with fibrillations (botulism) Slow RNS (3 Hz) -decrement CMAP with 10 sec exercise (or Rapid RNS, 20-50 Hz) -increment 300% in one muscle or 100% in three (diagnostic for Lambert Eaton MS) SFEMG -Jitter and blocking (jitter and blocking decrease with increasing firing rate)

15. Presynaptic NMJ Pre-exercise Post-exercise 350% increment following 10 seconds exercise

16. Case 2: Dysarthria 64 year old woman with symptoms of progressive dysarthria and facial weakness is sent to the EMG Lab Possible myasthenia gravis? Examination – Mild facial and moderate tongue weakness – Tongue fasciculations – Normal limb strength – Generalized Brisk reflexes and jaw jerk

17. Case 2: Nerve Conduction Studies Median and ulnar sensory responses are normal Median and ulnar motor responses are normal Repetitive nerve stimulation at 3 Hz -Orbicularis Oris with >20% decrement Myasthenia Gravis?

18. Case 2: Electromyography Single Fiber EMG -Increased jitter and blocking in frontalis and extensor digitorum EMG Fibrillations/fasciculations/ dec recruitment/enlarged motor unit action potentials (mentalis and tongue) Limb muscles normal Jitter and Blocking

19. Example: Post-synaptic NMJ disorder Case 2

20. Clinical Pearl of Case 2: Not all that Jitters is Myasthenia the “False Positive” test Amyotrophic Lateral Sclerosis & NMJ transmission defect Severe decrement frequently seen on RNS (reported up to 35% of CMAP amplitude) (I have seen up to 50%) Increased decrement correlates with faster progression and worse prognosis Daube 2004; Wang 2001 SFEMG: increased jitter and block may be early finding, prior to denervation (also seen in early reinnervation) Axonal Stimulation SFEMG: lack of facilitation with increasing frequency of stimulation Arimura 1995

21. Case 3: Seronegative MG A 58 year old woman with a 30 year history of seronegative myasthenia gravis PMH: poliomyelitis at age 6 requiring ventilation support in an iron lung for a month PE: normal CN exam, severe proximal limb weakness with fatigability, normal sensation and reflexes

22. Case 3: Seronegative MG 3Hz RNS with up to 70% decrement in proximal muscles She describes dramatic improvement with pyridostigmine Worsening with prednisone No improvement with IVIG or PLEX Ideas?

23. Clinical Pearl of Case 3: Hoof beats (aka decrement)? Don’t assume it is a horse (MG) – Multiple NMJ disorders may fall within this clinical presentation Seronegative (autoimmune) MG Congenital Myasthenic syndromes Other neuromuscular disorders with secondary NMJ effects or clinical patterns similar to NMJ disorders

24. Congenital Myasthenic Syndrome Historical points in case 3 suggesting this possibility: – No clear response to immunomodulation – Atypical phenotype (Severe disease with minimal to no bulbar involvement) – PMH of “polio” after which she states she was “normal” in every way until developing weakness in her 20’s – On more direct questions she described being a “blue baby” at birth Electrodiagnosis of CMS

25. Case 4: MG second opinion 45 year old man with progressive ptosis, dysphagia FH: mother with “seronegative myasthenia gravis” Examination: bilateral ptosis and extraocular muscle weakness without clear fatigability; mild proximal limb weakness Antibody testing: AChR and MuSK Antibodies (-) EMG and NCS: decrement on repetitive nerve stimulation studies Diagnosed with seronegative myasthenia gravis but then had minimal response to immune therapies and pyridostigmine? Ideas?

26. Case 4: Repeat EMG and NCS NCS: multiple mononeuropathies c/w the patient’s known HNPP RNS: normal SFEMG: mildly increased jitter in frontalis with no blocking EMG: Short duration small amplitude motor unit action potentials with sparse fibrillations in proximal limb and facial muscles

27. Case 4: Pre and Post Surgery Images

28. Clinical Pearl of Case 4: When in doubt, trust your exam… double check technique Movement artifact is significant challenge in repetitive nerve stimulation and can lead to false positive tests Our patient: Lacked clinical features of fatigability or response to treatment Diagnosed with oculopharyngeal muscular dystrophy (OPMD) – Autosomal dominant slowly progressive hereditary muscle disorder – GCG repeat expansion (8-13) – Often mistaken for seronegative MG – Typically later/less involvement of extraocular muscles

29. Thanks! Questions? William.arnold@osumc.edu

30. References 1.Phillips LH, 2nd. The epidemiology of myasthenia gravis. Annals of the New York Academy of Sciences. Sep 2003;998:407-412. 2.Wirtz PW, van Dijk JG, van Doorn PA, et al. The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology. Jul 27 2004;63(2):397-398. 3.Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. Journal of neurology, neurosurgery, and psychiatry. Dec 2002;73(6):766-768. 4.Mongiovi PC, Elsheikh B, Lawson VH, Kissel JT, Arnold WD. Neuromuscular junction disorders mimicking myopathy. Muscle & nerve. Nov 2014. 5.Stalberg EV, Sonoo M. Assessment of variability in the shape of the motor unit action potential, the "jiggle," at consecutive discharges. Muscle & nerve. Oct 1994;17(10):1135-1144. 6.Baslo MB, Deymeer F, Serdaroglu P, Parman Y, Ozdemir C, Cuttini M. Decrement pattern in Lambert-Eaton myasthenic syndrome is different from myasthenia gravis. Neuromuscular disorders : NMD. Jul 2006;16(7):454-458. 7.Sanders DB, Cao L, Massey JM, Juel VC, Hobson-Webb L, Guptill JT. Is the decremental pattern in Lambert-Eaton syndrome different from that in myasthenia gravis? Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. Jun 2014;125(6):1274-1277. 8.Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle & nerve. Sep 2001;24(9):1236-1238.