Short Report

Journal of

CLINICAL
NEUROMUSCULAR
DISEASE

Volume 16, Number 1

September 2014

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

( J Clin Neuromusc Dis 2014;16:711)

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

A 67-year-old, left-handed, white woman

presented with an acute constellation of
symptoms including rash and myalgias for 4
months before presentation. Her rash was
confined to face, upper back, and V distribution in her chest. Myalgias were characterized
by soreness of her neck and thighs. Two
months after her first symptoms, she began

From the Departments of

*Neurology, and Dermatology,
University of Texas Health
Science Center at Houston,
Houston, TX.
The authors report no conflicts of
interest.
Reprints: Thy P. Nguyen, MD,
Department of Neurology,
University of Texas Health
Science Center at Houston, 6431
Fannin Street, MSE 462 Houston,
TX (e-mail: thy.p.nguyen@uth.
tmc.edu).
Copyright 2014 by
Lippincott Williams & Wilkins

Journal of

CLINICAL
NEUROMUSCULAR
DISEASE

Volume 16, Number 1

September 2014

Nguyen et al

experiencing paresthesias on the tip of her

nose, bilateral hands, and bilateral feet. Medical history included hypertension, hyperlipidemia, and osteoarthritis. She denied any new
medications or recent travel. She was up to
date on her mammogram, annual pap smear
and colonoscopy. She did not smoke or drink
alcohol. Family history included an aunt with
myasthenia gravis and sister with Celiac disease. Her examination was remarkable for
erythema in malar distribution and V distribution on her neck. Strength examination was
preserved proximally and distally except mild
weakness of neck flexion and shoulder abduction, graded 4 of 5. Sensory examination was
normal to large fiber modalities. Pinprick was
reduced in the fingertips and feet. Reflexes
were preserved.

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

TABLE 1. Electrodiagnostic Study

Stimulation
Site
Wrist
Elbow
Wrist
Elbow
Wrist
Below elbow
Above elbow
Wrist
Below elbow
Above elbow
Ankle
Fibular head
Popliteal fossa
Ankle
Popliteal fossa
Wrist
Wrist
Radial bone
Lateral calf

Nerve

Recording Site

Median

APB left

Median

APB right

Ulnar

ADM left

Ulnar

ADM right

Peroneal EDB left

Tibial

AH left

Median
Ulnar
Radial
Sural

Digit II left
Digit V left
Snuffbox left
Lateral malleolus
left

Latency
(ms)

Amplitude

8.9 (,4.0)* 9.1 (.6.0 mV)

13.6
9.0
9.3*
6.8
13.9
6.2
3.0 (,3.0)
8.5 (.7.0 mV)
6.4
7.3
8.6
6.5
3.0
8.7
6.6
8.4
8.6
7.4
4.9 (,6.0)
4.8 (.2.5 mV)
12.0
4.6
13.6
4.6
6.0 (,6.0) 10.4 (.4.0 mV)
15.4
8.1
NR (,3.4)
NR (.10 mV)
NR (,3.0)
NR (.5 mV)
2.3 (,2.7) 19 mV (.10 mV)
NR (,4.5)
NR (.5 mV)

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.

demyelination without inflammation. Both of

these cases had severe malnourishment
related to dysphagia. Therefore, malnourishment is a confounding factor in both cases.
McEntee and Mancall8 described perineurial
lymphocytic infiltration and moderate demyelination with a few collections of inflammatory cells. Vogelgesang et al9 described
endothelial capillary ischemia similar to
muscle pathology on nerve biopsy. However, demyelination was not present and only axonal degeneration was found on light
microscopy.9 Matsui et al10 reported 2 patients, where nerve biopsy revealed endothelial vascular injury and immunohistochemical
stains revealed increased expression of
perivascular VEGF. More recently, Nomura
et al11 report an adult case of DM with severe
peripheral neuropathy. Electrodiagnostic
studies revealed the absence of SNAPs in
median, ulnar, and bilateral sural nerves
in a nonlength-dependent fashion. Nerve

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.
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Journal of

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Nguyen et al

Volume 16, Number 1

September 2014

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.

In summary, this case illustrates that

neuropathy could be part of the spectrum of
adult DM because neuropathic symptoms

temporally correlated with onset of muscle

and skin involvement in our patient. Additionally, extensive workup for other neuropathic

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).

etiologies was negative. Moreover, nerve

pathology demonstrating deposition of C5b-9
around small blood vessels and capillaries in
the endoneurium support the possibility that
complement-mediated damage could be a unifying pathogenic mechanism of muscle and
nerve injury due to DM.
REFERENCES
1. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet. 2003;362:971982.
2. Gowers WR. A lecture on polymyositis: delivered at
the National Hospital for the Paralysed and Epileptic.
Br Med J. 1899;1:6567.
3. Ramaglia V, Daha MR, Baas F. The complement system in the peripheral nerve: friend or foe? Mol Immunol. 2008;45:38653877.
4. Rosoklija GB, Dwork AJ, Younger DS, et al. Local
activation of the complement system in endoneurial
microvessels of diabetic neuropathy. Acta Neuropathol. 2000;99:5562.
5. Koski CL, Sanders ME, Swoveland PT, et al. Activation of terminal components of complement in

patients with Guillain-Barre syndrome and other

demyelinating neuropathies. J Clin Invest. 1987;80:
14921497.
6. Hafer-Macko CE, Dyck PJ, Koski CL. Complement
activation in acquired and hereditary amyloid
neuropathy. J Peripher Nerv Syst. 2000;5:131
139.
7. Kinney TD, Maher MM. Dermatomyositis: a study of
five cases. Am J Path. 1940;16:561594, 569.
8. McEntee WJ, Mancall EL. Neuromyositis: a reappraisal. Neurology. 1965;15:6975.
9. Vogelgesang SA, Gutierrez J, Klipple GL, et al. Polyneuropathy
in
juvenile
dermatomyositis.
J Rheumatol. 1995;22:13691372.
10. Matsui N, Mitsui T, Endo I, et al. Dermatomyositis
with peripheral nervous system involvement: activation of vascular endothelial growth factor (VEGF)
and VEGF receptor (VEGFR) in vasculitic lesions.
Intern Med. 2003;42:12331239.
11. Nomura M, Watanabe T, Mikami H, et al. Adult
dermatomyositis with severe polyneuropathy:
does neuromyositis exist? Neurol Sci. 2010;31:
373376.
12. Wang Y, Cui LY, Chen L, et al. Nerve conduction studies in patients with dermatomyositis or polymyositis.
Chin Med J (Engl). 2010;123:523526.

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