A case of myopathy associated with monoclonal gammopathy

1. A case of myopathy associated with monoclonal gammopathy Cecile L. Phan, M.D., F.R.C.P.C. Eddie L. Patton, M.D. Yadollah Harati, M.D., F.A.C.P.

2. Clinical history • A previously healthy and athletic 52 year old male presented in August 2009 with a history of progressive weakness and muscle loss. • Late 2008 – early 2009 noticed right arm weakness, had difficulty washing and combing hair. • March 2009 – could not lift a gallon of milk with the right arm • April 2009 – left arm became equally weak; could not get up from a sitting or lying position, difficulty climbing stairs, frequent falls. • Also noticed gradual loss of muscle bulk through this time period

3. Clinical history • Evaluated by orthopedic and neurosurgery before referral to Baylor Neurology for EMG/NCS and consultation. • Initial EMG/NCS in June 2009 showed a moderate, generalized myopathy without any spontaneous activity. NCS normal. CPK was 950 U/L. • Repeat EMG/NCS in August 2009 showed scattered fibrillations and positive sharp waves in several proximal right arm muscles and left middle paraspinous muscles in addition to myopathic units. CPK was 736 U/L. • Referred to Neuromuscular Clinic for a muscle biopsy.

4. Clinical history • PMHx and Sx: • Hypertension • Dyslipidemia: • On fenofibrate (Tricor) since June 2008. Stopped the medication in April 2009 without any improvement in symptoms • Type 2 diabetes mellitus • Depression • Right inguinal hernia repair • Lasik surgery

5. Clinical history • Medications: • Toprol, Avalide, Metformin, Cymbalta, Claritin • SHx: • Geologist • Married, 1 grown daughter • No smoking, drinking, illicit drugs use • FHx: • Non contributory • ROS: • Fatigue • No other constitutional symptoms.

6. Examination • General examination was within normal limits • Neurologic exam: • Mental status normal • Cranial nerves: • No ptosis or opthalmoparesis • No facial weakness • Normal speech • Full sternocleidomastoid and trapezius strength

7. Examination

9. Neurologic examination • Muscle bulk: • Significant atrophy of the shoulder girldle muscles, proximal arms, paraspinal muscles, and mild atrophy of the quadriceps. • Muscle tone normal

10. Neurologic examination

11. Neurologic examination • Sensory exam – normal • Gait and balance – difficulty getting up from chair without using arms, waddling gait. • Remaining neurologic exam normal

12. Exam…

13. Investigations • SPEP with immunofixation: • IgG lamda monoclonal protein, 0.9 g/dL • Skeletal survey - normal • TSH, RF, ANA, RPR negative or normal • First muscle biopsy of the left quadriceps muscle was performed to avoid a severely atrophic, possibly end stage biceps muscle. This only showed very mild neurogenic atrophy without reinnervation. • A second muscle biopsy of the left biceps muscle was performed.

14. H&E: increased variability in fiber size and shape with atrophic and hypertrophic fibers, rounding of fibers, and increase in the number of fibers with internal nuclei

15. H&E and Trichrome: degenerating/atrophic fibers appearing more darkly stained

16. Trichrome: one atrophic fiber at higher magnification. It contains densely packed, centrally located granular rods resembling nemaline which give the darkly stained appearance on H&E and Trichrome

17. Semithin: nemaline rods

18. Many fibers contain non-rimmed, empty vacuoles

19. NADH and COX stains show an abundance of lobulated, “trabecular” fibers

20. H&E: small group of angular, atrophic fibers NADH: a few angular, atrophic fibers with excessive NADH activity

21. Summary • A 54 year old male with an 8-9 months history of progressive proximal weakness and muscle atrophy, elevated CPK, monoclonal gammopathy, and generalized myopathic motor units with spontaneous activity on EMG/NCS. • Muscle biopsy showed a severe chronic myopathy with an abundance of atrophic fibers containing nemaline, fibers with empty vacuoles, lobulated fibers, and neurogenic atrophy.

22. Diagnosis? SPORADIC LATE ONSET NEMALINE MYOPATHY (SLONM)

23. Historical background • Nemaline myopathy was initially described in 1963 as a non-progressive myopathy of infancy. • Adult onset form of the disease was first described in 1966 by A.G. Engel. • Most, if not all, adult-onset cases in the literature have been sporadic and only in 1 case has a mutation of ACTA1 (α-actin) been identified. • Nemaline myopathy or the formation of nemaline has been associated with a variety of conditions.

24. Historical background • HIV / AIDS • Monoclonal gammopathy • Dermatomyositis • Hypothyroidism • Alcoholic myopathy • Mitochondrial myopathy • Muscular dystrophies • Glycogen storage diseases • Chronic renal failure • Chloroquin myopathy • Denervation and Tenotomy • Charcot Marie Tooth

25. NEUROLOGY 2005;65:1158–1164 • Largest series of patients with SLONM up to date • 14 patients observed at the Mayo clinic between 1975 – 2003 • Important clinical, electrophysiological, pathological features of SLONM were described

26. SLONM • Clinical features: • Present after age 40 with subacutely evolving weakness • Weakness is typically limb-girldle pattern, but can also present with distal weakness, dysphagia, head drop, or even respiratory failure. • Findings on investigations: • EMG/NCS – myopathic features with fibrillation potentials • Monoclonal gammopathy is a frequent associated finding • CPK normal or below normal limits

27. SLONM • Pathologic findings: • Light microscopy: • As the rods increase in number, the fibers decrease in size  atrophic fibers often completely filled with rods • Can be easily missed unless run Trichrome stain on frozen sections at thickness of 2-4 μm and view at high resolution • Large vesicular nuclei, focal cytoplasmic basophilia, small vacuoles commonly seen in rod bearing fibers • Lobulated fibers • Can see minor inflammatory changes • No congophilic deposits

28. SLONM NEUROLOGY 2005;65:1158–1164 Accumulation of rods is accompanied by progressive dissolution of other organelles and atrophy of the muscle fiber

29. SLONM • Prognosis: • Patients with monoclonal gammopathy have worse prognosis (5 out of 7 patients died from respiratory failure within 2-6 years; 3 died despite immunotherapy) • Those without monoclonal gammopathy none died of the disease • HOWEVER….

30. Treatment of SLONM associated with gammopathy • Recent reports of SLONM/MGUS patients successfully treated with melphalan and stem cell transplantation. • Several case reports of SLONM/MGUS patients responding to intermittent IVIg +/- other immunosuppressants (Prednisone, IV methylprednisolone, mycophenolate mofetil)

31. Back to our patient • He was started on IVIg at 0.4 g/kg daily for 5 days on a monthly basis. • He received 2 rounds of treatment so far with improvement in his daily function – walking better, hands strength improved, able to dress himself. • On examination there is some improvement of hip flexors strength, but upper limbs strength remain unchanged. • In previous case reports patients generally made gradual improvement over 12-24 months

32. Conclusion • Sporadic late onset nemaline myopathy is a very rare cause of subacute onset weakness in adults • Check for monoclonal protein • High index of suspicion for SLONM in patients with MGUS • Worth a trial of IVIg +/- other immunosuppressants.