Professional Documents
Culture Documents
Journal of
CLINICAL
NEUROMUSCULAR
DISEASE
Dermatomyositis-Associated Sensory
Neuropathy: A Unifying Pathogenic
Hypothesis
Thy P. Nguyen, MD,* Carolyn Bangert, MD, Suur Biliciler, MD,*
Parveen Athar, MD,* and Kazim Sheikh, MD*
Abstract
Neuropathy as extramuscular manifestation of dermatomyositis (DM) is controversial due to uncommon occurrence, heterogeneity of associated nerve
pathology, and lack of unifying pathogenetic mechanism(s). We describe a patient with classic manifestations of DM and extramuscular manifestation
of neuropathy. Nerve pathology showed deposits of
terminal complement complex (C5b-9). Her examination showed mild proximal weakness, rash, and
sensory impairment in fingertips, toes, and nose.
EMG/NCS revealed irritable myopathy and mild
sensory neuropathy. Muscle biopsy showed features suggestive of DM, including deposition of
C5b-9. CK was elevated to 214 and ANA was positive
at 1:160. Etiological work up for neuropathy,
including diabetes, was negative. Sural nerve
biopsy at light level revealed very mild large fiber
sensory neuropathy. EM showed moderately severe
involvement of small sensory fibers. Neuropathy
may be an underrecognized manifestation of DM.
Nerve pathology demonstrating complementmediated damage could be a unifying mechanism
of muscle and nerve injury.
Key Words: neuropathy, peripheral nerve, dermatomyositis, complement, neuromyositis
diseases. Muscle pathology reveals perivascular, perimysial, and perifascicular inflammation, as well as perifascicular atrophy. This
pattern may be due to a complementmediated microangiopathy.1 DM has many extramuscular manifestations, including arthritis,
Raynaud phenomenon, lipodystrophy, cardiac
involvement, interstitial lung disease, and
GI ulceration due to vasculopathy. These
extramuscular manifestations do not have
a known pathophysiology. A reported, but
controversial extramuscular manifestation is
DM-associated neuropathy, neuromyositis.2
Neuropathy due to DM is difficult to diagnose
due to necessity of excluding other comorbid
etiologic conditions, heterogeneity of previous case reports, and muscular manifestations,
which may erroneously suggest nerve involvement (spontaneous electrical activity on EMG
due to irritable muscle fibers or polyphasia).
However, we describe a case of DM associated
with neuropathy. Extensive evaluation for
other etiologies of neuropathies was unremarkable. Additionally, we describe nerve
pathology that reveals a unique pathogenetic
mechanism for nerve involvement in DM.
INTRODUCTION
CASE REPORT
Dermatomyositis (DM) is a common
acquired inflammatory myopathy. DM is characterized by proximal symmetric myopathic
weakness with characteristic skin manifestations, including Gottron papules, heliotrope
rash, mechanics hands, shawl sign, and V
sign. DM is postulated to be autoimmune in
nature supported by serologic autoantibodies
and association with known autoimmune
Journal of
CLINICAL
NEUROMUSCULAR
DISEASE
Nguyen et al
DIAGNOSTIC STUDIES
Laboratory studies revealed a mildly
elevated creatine kinase 404 (normal ,200)
and antinuclear antibody level of 1:40 in
a speckled pattern. Diagnostic studies including testing for antibodies to SS-A, SS-B, Jo-1,
RNP, and double-stranded DNA were negative. Fasting blood glucose, oral glucose tolerance test, hemoglobin A1C, complement
levels, paraneoplastic panel, serum, and urine
protein electrophoresis were normal. EMG/
NCS revealed mildly irritable myopathy and
mild length-dependent neuropathy (Table 1).
Malignancy workup (including CT chest/
abdomen/pelvis) was negative.
PATHOLOGY
Muscle biopsy showed necrotic fibers
with perifascicular atrophy, perimysial inflammation, and myofibers undergoing degeneration (Figs. 1A, B, D). There was deposition of
C5b-9 in capillaries (Fig. 1C). Sural nerve biopsy
at light level revealed rare degenerating myelinated axons, several thinly myelinated fibers,
and regenerating axon clusters (Fig. 2A). Electron microscopy showed involvement of small
myelinated and unmyelinated sensory fibers
(Fig. 2B). Immunohistochemistry studies were
2014 Lippincott Williams & Wilkins
notable for deposition of C5b-9 in the perineurium and around small blood vessels and capillaries in the endoneurium. There were also rare
foci of inflammatory cells (Figs. 3B, C).
DISCUSSION
We propose that nerve involvement in
patients with DM is mediated through membrane attack complex (MAC) formation, leading to nerve injury. The complement systems
role continues to be elucidated in uninjured
and injured adult peripheral nerve. Additionally, adult peripheral nerves actually express
negative regulators of MAC activation, such
as CD59. These results are intuitive as MAC
acts to insert pores into cellular membranes,
leading to disruption and cellular death. Additionally, activated complement factors play
a role in myelin degradation in injured nerves
undergoing Wallerian degeneration. Terminal
complement components are reportedly present in different neuropathies, including diabetic neuropathy, Guillainbarre syndrome,
and amyloid neuropathy.36 Our patient had
endoneurial staining for C5b-9, which was
not present in a control nerve of a patient with
motor neuron disease. However, perineurial
staining for C5b-9 was found to be nonspecific
(Figs. 3A, B). Further case reports of nerve
immunohistochemical C5b-9 neoantigen staining in endoneurium in neuropathy would elucidate the specificity of the finding. The
presence of a unifying pathogenic mechanism
of injury (complement mediated) in both muscle and nerve supports the existence of possible DM-associated neuropathy.
Although the correlation of neuropathy
with DM is debated, it has been reported in
the literature. The entity of neuromyositis
was first reported in the 1890s.2 Kinney and
Maher7 described 2 cases of neuropathy associated with DM. By their pathologic studies,
even those 2 cases had heterogeneous characteristics. A 7-year-old child showed perineurial
inflammation with lymphocytes and plasma
cells only in the femoral nerves. Demyelination was also moderate and extensive. A 60year-old housewife had a moderate degree of
Dermatomyositis-Associated Neuropathy
Journal of
CLINICAL
NEUROMUSCULAR
DISEASE
Volume 16, Number 1
September 2014
Nerve
Recording Site
Median
APB left
Median
APB right
Ulnar
ADM left
Ulnar
ADM right
Tibial
AH left
Median
Ulnar
Radial
Sural
Digit II left
Digit V left
Snuffbox left
Lateral malleolus
left
Latency
(ms)
Amplitude
Conduction Velocity
(m/s)
48 (.49)
52
57
52
58
58
46
53
43
NR (.49)
NR (.49)
59
NR .39 m/s
APB, abductor pollicis brevis; ADM, abductor digiti minimi; EDB, extensor digitorum brevis.
NR indicates no response. Latencies for sensory nerves indicate peak latencies. Normal values are provided in
parentheses for our laboratory.
*Presence of bilateral median neuropathies at the wrist may have contributed to the patients hand paresthesias.
biopsy revealed mild loss of myelinated fibers, degenerated axoplasm, and axonal atrophy. EM revealed depletion of unmyelinated
fibers. Capillaries did not show endothelial
inclusions, and there was no evidence of
demyelination and remyelination.11 Additionally, Wang et al12 retrospectively reviewed
electrodiagnostic results of 186 patients with
DM/polymyositis and identified 14 patients
(7.5%) overall with polyneuropathy. The
heterogeneous pathologic findings could be
explained by malnourishment, vitamin deficiency, or other etiologies rather than true
neuromyositis. Extensive evaluation to
exclude subclinical diabetes, overlap syndrome with other connective tissue disorders, vasculitis, and underlying malignancy
is necessary. These prior case reports suggest
there is a possibility of DM-associated neuropathy, but understanding this process is
limited by heterogeneous findings on pathology and confounding comorbid factors.
www.jcnmd.com
10
Journal of
CLINICAL
NEUROMUSCULAR
DISEASE
Nguyen et al
FIGURE 1. A, Hematoxylin and eosin stain at 310. Arrow indicates a myofiber undergoing degeneration in the perifascicular region. Arrowhead indicates atrophic fibers in the perifascicular region.
Bar indicates 100 mm. B, ATPase 9.4 at 310 with perifascicular atrophy. C, Staining with C5b-9 at
350 shows staining of endomysial capillary (arrowhead). Bar indicates 20 mm. D, CD4 staining at
320 shows inflammatory cells within perimysium. Bar indicates 50 mm.
FIGURE 2. A, Epon section 350 shows myelin knuckles (straight arrows), regenerating axon clusters
(asterisks), thinly myelinated fiber (curved arrow), and axon undergoing degeneration (arrowhead).
Bar indicates 20 mm. B, EM, scale bar indicates 2 micrometers, showing simplification of remak
bundles (arrowheads), denervated Schwann cells (asterik), and normal appearing remak bundles
(arrows). C, CD4 staining showing rare T cells around perineurial blood vessels. D, CD68 staining
shows increased macrophage activity.
2014 Lippincott Williams & Wilkins
Dermatomyositis-Associated Neuropathy
Journal of
CLINICAL
NEUROMUSCULAR
DISEASE
Volume 16, Number 1
September 2014
FIGURE 3. C5b-9 staining at 320 of sural nerves from patients with motor neuron disease (A: MND;
negative control), DM (B: index case), and vasculitic neuropathy (C: vasculitis; positive control). Bar
indicates 50 mm. All specimens show perineurial staining suggesting that this is a nonspecific finding.
In contrast, endoneurial microvascular C5b-9 staining is seen in nerves from patients with DM (B;
arrows) and P-ANCApositive vasculitic neuropathy (C; arrows).
www.jcnmd.com
11