Slide 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.


Slide 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


Slide 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.


Slide 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


Slide 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.


Slide 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


Slide 7

Examination


Slide 8


Slide 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


Slide 10

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


Slide 11

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


Slide 12

Exam…


Slide 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.


Slide 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


Slide 15

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


Slide 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


Slide 17

Semithin: nemaline rods


Slide 18

Many fibers contain nonrimmed, empty vacuoles


Slide 19

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


Slide 20

H&E: small group of
angular, atrophic fibers

NADH: a few angular,
atrophic fibers with
excessive NADH activity


Slide 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.


Slide 22

Diagnosis?
SPORADIC LATE ONSET NEMALINE
MYOPATHY (SLONM)


Slide 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.


Slide 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


Slide 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


Slide 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


Slide 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


Slide 28

SLONM
NEUROLOGY
2005;65:1158–1164

Accumulation of
rods is accompanied
by progressive
dissolution of other
organelles and
atrophy of the
muscle fiber


Slide 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….


Slide 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)


Slide 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


Slide 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.