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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. Clinical history.
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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.
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
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.
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
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.
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
Neurologic examination • Muscle bulk: • Significant atrophy of the shoulder girldle muscles, proximal arms, paraspinal muscles, and mild atrophy of the quadriceps. • Muscle tone normal
Neurologic examination • Sensory exam – normal • Gait and balance – difficulty getting up from chair without using arms, waddling gait. • Remaining neurologic exam normal
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.
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
H&E and Trichrome: degenerating/atrophic fibers appearing more darkly stained
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
NADH and COX stains show an abundance of lobulated, “trabecular” fibers
H&E: small group of angular, atrophic fibers NADH: a few angular, atrophic fibers with excessive NADH activity
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.
Diagnosis? SPORADIC LATE ONSET NEMALINE MYOPATHY (SLONM)
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.
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
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
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
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
SLONM NEUROLOGY 2005;65:1158–1164 Accumulation of rods is accompanied by progressive dissolution of other organelles and atrophy of the muscle fiber
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….
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)
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
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.