Transcript A case of myopathy associated with monoclonal gammopathy

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:
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No ptosis or opthalmoparesis
No facial weakness
Normal speech
Full sternocleidomastoid and trapezius strength
Examination
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
Right
Left
Right
Left
Neck flexors
4
Iliopsoas
4
4
Neck extensors
5
Hip adductors
5
5
Deltoids
3
3
Hip abductors
5
5
Biceps
4-
4-
Quadriceps
5
5
Triceps
5
5
Hamstring
5
5
Wrist extensors
5
5
Tibialis anterior
5
5
Wrist flexors
5
5
Extensor Hallucis L.
5
5
Finger extensors
5
5
Peronei
5
5
Finger flexors
5
5
Tibialis posterior
5
5
Interossei
5
5
Gastrocnemius
5
5
Neurologic examination
Right
Left
Biceps
0
0
Brachioradialis
0
0
Triceps
0
0
Patella
0
0
Achilles
0
0
Plantar resp
Down Down
• Sensory exam – normal
• Gait and balance – difficulty getting up from
chair without using arms, waddling gait.
• Remaining neurologic exam normal
Exam…
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
Semithin: nemaline rods
Many fibers contain nonrimmed, empty vacuoles
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
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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.