Case Study 23
Craig Horbinski, M.D., Ph.D.
The patient is a 57 y/o female with a past medical history
significant for acute intermittent porphyria. She recently
experienced muscle cramps that began in her legs and
progressed to her upper extremities. CPK is over 1000, LDH
level of 128 (normal). On ROS, she states that she has had
chronic back pain for several years, but that she started to have
right leg pain unrelated to her spasms ever since her lumbar
surgery for a ruptured disc in 2007, with residual foot drop and
sciatic nerve problem from the knee up with the feeling of her leg
being "hot". On inspection, her right calf was a ½ inch smaller in
circumference than the left calf. The right gastrocnemius muscle
was therefore biopsied. Motor nerve conduction studies
showed low amplitude to left tibial nerve with prolonged distal
latency to right tibial and right median nerves. All other findings
normal. Concentric EMG performed to the bilateral lower limbs
showed fibrillations, positive wave and complex repetitive
discharges in distal and proximal muscles, right leg worse than
left. Motor unit potentials demonstrate increased amplitude,
polyphasity with mild decreased recruitment in right L4, L5, S1
and left L3, L5 myotomes.
Question 1
Describe the biopsy and stains.
Click on the following links to view slides:
H&E, NADH, ATPase 9.4, ATPase 4.3, Esterase
Answer
Hematoxylin and eosin stained frozen sections show large
clusters of angulated atrophic fibers scattered throughout
the specimen. Nuclear clumps are present, as is
tendon. The perimysial and endomysial space shows
increased cellularity, but degenerating fibers or
inflammatory infiltrates are not seen. Rare regenerating
fibers are present. NADH reacted sections reveal abundant
targetoid fibers and dark atrophic fibers. Esterase reactivity
is increased in the angulated atrophic fibers. ATPase
reacted sections reveal loss of the normal checkerboard
pattern with a Type 1 to Type 2 fiber ratio of 3:1 and no
selective myofiber atrophy.
Question 2
What do these findings mean—what is the diagnosis, and
how do these findings support such a diagnosis?
Answer
This biopsy is showing classic neurogenic changes, both active and chronic. First off, there are a lot of
atrophic fibers in clusters, many of which are angulated. Primary myopathic diseases, on the other
hand, tend to produce atrophic rounded fibers scattered in between normally-sized myofibers.
Second, the presence of nuclear clumps that appear to be outside any myofibers is a sign of severe
myofiber atrophy (the myofibers are so atrophic, you can’t see their cytoplasm any more). This sort of
thing is more suggestive of neurogenic rather than myopathic causes.
Third, target fibers are seen on the NADH stain—the myofibers with dark rings in the center (they’re so
prominent you can even see them on the H&E). This is unequivocal, specific proof that there’s nothing
inherently wrong with the muscle, it’s a problem with the motor nerve. Seeing some dark atrophic
fibers on the NADH stain helps, too.
Fourth, the “active” part of the neurogenic changes comes from the increased esterase reactivity in
many of the angulated atrophic fibers plus the darkly staining fibers on NADH.
Finally, the “chronic” part comes from the fact that this muscle no longer shows a nice even distribution
of type 1 (dark on ATPase pH 4.3) and type 2 fibers (dark on ATPase 9.4). This tissue has undergone
denervation in the past with subsequent reinnervation. The myofibers will change their type in
response to whatever nerve is reinnervating them—if it’s a type 1 nerve fiber, the myofibers will
become type 1 fibers and vice versa. Since nerves tend to reinnervate multiple adjacent myofibers at
a time, an ATPase stain will show large areas of only one fiber type. This is one of the few key facts
you need to know for the general anatomic pathology board exams regarding nonneoplastic muscle
and nerve pathology.
This patient therefore has a serious active problem with her motor nerve that has been going on for
awhile. It is important to note that the gastrocnemius muscle often shows mild “neurogenic changes”
even in a healthy person. Also, that muscle is highly tendinous, and any muscle near a tendon
insertion site might show some pseudo-myopathic changes like split fibers, rounded atrophy, or
internalized nuclei.
Question 3
Do these findings fit with the clinical history?
Answer
Absolutely. AIP itself can cause neuropathies, plus the
woman had lumbar spine surgery for a ruptured disc with
persistent sciatica and right foot drop. It’s conceivable
that the motor fibers innervating the gastrocnemius have
been affected by both the AIP and mechanical
compression from the spine (if the ruptured disc affected
both the dorsal and ventral roots).
Question 4
On the ATPase stains, what finding in many of the
atrophic clusters is a little worrisome for a disease far
worse than AIP or herniated disc? (It’s also hinted at in
the EMG study report.)
Answer
Many of the clusters of atrophic myofibers have an equal mix of type
1 and type 2 fibers. In typical neurogenic-related muscle conditions,
the atrophic fiber clusters will be all of one type—i.e., within a
specimen you will see both fiber types affected, but each individual
cluster should be only one type, signifying reinnervation. In primary
motor neuron disease, a.k.a. amyotrophic lateral sclerosis, the
affected muscle will often contain both fiber types in the same cluster
of atrophic myofibers. Furthermore, detecting muscle fibrillations on
EMG is a sign that motor innervation is severely compromised,
causing the sarcolemmal membranes to become irritable and
spontaneously depolarize. It’s as if they’re getting bored with the lack
of stimulation. Fibrillations are not specific for ALS, but that disease is
one of the most common causes of muscle fibrillations. In this
context it’s probably wiser to not mention this possibility, since there
are already two other plausible causes for the neurogenic changes. If
this unfortunate patient does indeed have ALS, the pathology report is
still valid, and at any rate ALS is a clinical diagnosis.