Syringomyelia and Complex Regional Pain Syndrome as Complications of Multiple Sclerosis

Asha Das, MD; K. Puvanendran, FRCP

Objective To describe a patient from Southeast Asia with the optic-spinal
phenotype of multiple sclerosis who developed syringomyelia and resultant
complex regional pain syndrome (formerly named reflex sympathetic dystrophy).

Design Case report.

Setting Department of neurology at a tertiary care hospital in the Republic
of Singapore.

Patient A 53-year-old Chinese woman with a history of optic neuritis
developed an episode of left hemiparesis leading to a diagnosis of multiple
sclerosis. Serial neuroimaging studies revealed an active demyelinating
plaque in the cervical area that later progressed into a syrinx. Over a
period of 1 year she also developed signs of sympathetic dysfunction
including Horner syndrome of the left eye and complex regional pain syndrome
in the left hand.

Conclusions A case of the optic-spinal phenotype of multiple sclerosis that
is commonly observed in Southeast Asia is described. This characteristically
tissue-destructive form of multiple sclerosis resulted in syringomyelia
complicated by a complex regional pain syndrome. Possible pathogenic
mechanisms for these associations are discussed.

Arch Neurol. 1999;56:1021-1024

MULTIPLE SCLEROSIS (MS) is a chronic demyelinating disorder with a wide range
of clinical manifestations that reflects multifocal areas of central nervous
system myelin destruction. Multiple sclerosis is an uncommon disease in
Southeast Asia; its typical presentation is as a disorder of optic-spinal
dysfunction. Invariably, the spinal form of this illness is manifest as
transverse myelitis.1 We present an unusual case of a patient with MS who
developed syringomyelia and resultant complex regional pain syndrome (CRPS),
formerly known as reflex sympathetic dystrophy.

REPORT OF A CASE

A 56-year-old Chinese woman with an unremarkable medical history presented at
age 43 years with right optic neuritis. Later, at age 53 years, she had a
second bout of optic neuritis affecting her left eye. Both episodes were
treated with pulsed high-dose intravenous methylprednisolone. During her
second bout of optic neuritis, she also complained of vague pain in her left
hand and forearm that was characterized by cramps and spasms. At that time,
results of her neurological examination were remarkable only for left optic
neuritis and left arm strength of 4/5. Notably, her reflexes were symmetric.
In June 1995, a magnetic resonance imaging (MRI) scan of the brain performed
as part of her evaluation showed no evidence of demyelination. Because of
persistent complaints of pain and spasms in her left arm, MRI scans of the
brain and cervical spine were repeated 2 months later. Biparietal lesions
that were hyperintense on T2-weighted images and that did not enhance with
gadolinium were present; these hyperintensities were suggestive of nonacute
demyelinating lesions. The cervical spine showed no evidence of
demyelination. A lumbar puncture was unremarkable (white blood cell count,
0.002109/L; glucose, 3.5 mmol/L [63 mg/dL], total protein, 0.3 g/L) and
cerebrospinal fluid oligoclonal bands were not detected. In the setting of 2
bouts of optic neuritis, an episode of left hemiparesis, and her neuroimaging
findings, the patient was diagnosed as having MS.

Fourteen months later (October 1996), the patient had a recurrent episode of
pain in her left hand and forearm and weakness in her left arm and leg. The
left hand and forearm pain was again characterized by vague dysesthesias. She
also complained of a constant burning pain in the same region, which did not
conform to a pattern of dermatomal or peripheral nerve injury. A neurological
examination at this time was notable for left optic atrophy, left afferent
pupillary defect, and left hemiparesis with diminished left arm (2/5) and
left leg (4/5) strength. In addition, left thenar wasting was observed. Her
reflexes were present symmetrically with bilateral flexor plantar responses.
Although she complained of sensory disturbances in the left arm, no sensory
loss or suspended sensory level was apparent on extensive testing. Treatment
with high-dose intravenous methylprednisolone resulted in mild improvement in
her symptoms. Repeated MRI scans of the brain and cervical spine (October
1996) showed several areas of hyperintensity on T2-weighted images in the
deep cerebral white matter that did not enhance with contrast on T1-weighted
images. A long segment of increased signal on T2-weighted images was present
in the cervical cord extending from the level of C2 to C5 with slight
expansion. This cervical cord lesion enhanced after gadolinium administration
at its middle and inferior portions. These neuroimaging findings suggested
the presence of an active, demyelinating plaque spanning from C2 to C4
(Figure 1). Nerve conduction and electromyographic studies to further assess
the left thenar eminence atrophy showed no evidence of neuropathy. Evoked
studies were remarkable for prolonged bilateral visual evoked potentials,
affecting the left side more than the right. Somatosensory evoked potentials
were notable for a conduction abnormality between the left lumbar and left
thoracic cord. Brainstem auditory evoked potentials were abnormal on the
right side, suggestive of an auditory conduction abnormality in the brainstem.

Over the next year, the patient complained of pain in her left hand and
forearm, which she described as a constant burning. She also observed that
the nails and skin of her left hand appeared shinier and less wrinkled than
the right hand. At the time of her neurological examination in October 1997,
she had developed Horner syndrome in the left eye with ptosis, miosis, and
enophthalmos. Her left afferent pupillary defect persisted. Her left
hemiparesis had improved and her strength remained at 4/5. The thenar
eminence and interossei muscles of her left hand were atrophied. Her reflexes
continued to remain brisk and symmetric. The skin of her left hand appeared
red, shiny, and unwrinkled. Compared with the right hand, her left hand was
intermittently edematous, indurated, hyperhidrotic, mottled, and cool to
touch (Figure 2). These findings suggested a CRPS involving the left hand.
Laboratory data including complete blood cell count; electrolytes; glucose,
calcium, and magnesium levels; liver function tests; and collagen vascular
markers were all unremarkable. A repeated MRI scan of the cervical spine
showed that on T1-weighted images, after gadolinium administration, no
enhancement was noted in or around the hypodense area from C3 to C7 to
suggest the presence of an active demyelinating plaque. On T2-weighted
images, hyperintensity was present from C2 to C7. No cord swelling was
observed. These neuroradiologic findings were consistent with a syrinx
formation (Figure 3). The signs and symptoms of sympathetic dysfunction,
particularly her CRPS, have been recalcitrant to conventional treatment
options of tricyclic antidepressants, anticonvulsants, and physiotherapy.
Further treatment considerations include a trial of gabapentin.

COMMENT

Our patient's clinical course is characterized solely by optic nerve and
cervical cord involvement. She does not fulfill strict criteria for Devic
neuromyelitis optica, which include a severe transverse myelitis and an acute
unilateral or bilateral optic neuropathy developing within days or weeks of
each other.2 However, she clearly manifests an optic-spinal phenotype of MS.
During the course of her illness, the patient initially developed a
demyelinating plaque in the cervical area that over a year progressed to a
syrinx. The clinical manifestations of our patient's cervical syrinx included
segmental weakness and atrophy of the left hand and an ipsilateral Horner
syndrome. Although the pathogenesis of this syrinx is unclear, we can
postulate on its cause. We do know that the gross pathological manifestation
of MS is characterized by areas of focal demyelination commonly referred to
as MS plaques.2 These plaques are frequently found in areas adjacent to
cerebrospinal fluid pathways.3 The spectrum of pathology observed in MS
includes primary demyelination with little oligodendrocyte damage, extensive
oligodendrocyte loss in the course of demyelination, and primary
oligodendrocyte damage involving not only myelin and oligodendrocytes but
also axons and astrocytes.4 In our patient's case, she is likely to have had
an active MS plaque in the cervical region demonstrated on MRI scan by
gadolinium enhancement. Later, the plaque may have undergone degenerative
change with resultant cervical syrinx formation involving areas of the plaque
site and spinal cord rostral to this plaque. The necrotic process may have
begun centrally, extending rostrally and caudally from the poles of the
lesion.5 Alternatively, a syrinxlike lesion may have developed following
atrophy of the swollen spinal cord that had undergone demyelinative
changes.6, 7 The spinal cord lesions typically associated with Devic
neuromyelitis optica are characterized by demyelination, inflammation, and
necrosis.8, 9 Our patient with the optic-spinal phenotype of MS is likely to
have undergone tissue destruction and necrosis resulting in a cervical cord
syrinx that has persisted for 3 years.

Since the coexistence of syrinx formation in MS is uncommon, the neurological
prognosis of such coexistence remains to be elucidated. A spectrum of spinal
cord lesions has been reported in association with MS. In a series by Kato et
al7 of 37 patients with clinically diagnosed MS with spinal cord lesions,
cervical cord lesions occurred more frequently than other spinal cord
lesions. At the thoracic level, higher thoracic lesions occurred more often
than lower level lesions. Characteristically, these lesions were swollen and
enhanced after gadolinium administration in patients with a disease duration
of less than 3 years, and atrophic change was observed in patients with a
disease duration of greater than 7 years. Syrinxlike lesions were found in 4
patients.7 To begin to determine the prognosis of the coexistence of syringes
in MS we reviewed previous case reports.5, 10-14 Remarkably, a majority of
the cases reported appeared in the Japanese literature. Since the
optic-spinal form of MS is more common in Asian countries and the acute
demyelinating spinal cord lesions may have subsequent development of
myelomalacia or frank cavitary degeneration, syringes that are the result of
spinal disease may occur more frequently in this population. Of the 7 case
reports, all but 1 were women. The age range of the patients was from 26 to
40 years. Four cases involved syringes in the cervical cord and 3 were in the
thoracic cord. Unlike the presentation in our case, not all these cases of
spinal cord lesions and subsequent syrinx formation were accompanied or
preceded by visual symptoms. These cases suggest that the prognosis of MS
with syrinx formation is variable, even following repeated episodes of
myelopathy.

Recently, Vernant et al15 described a syndrome of recurrent optic
neuromyelitis with endocrinopathies in 8 Antillean women. All 8 women had a
demyelinating disease involving only the spinal cord and optic nerves. In 7
cases, the neurologic examination revealed a bandlike, dissociated sensory
loss and in 2 of these cases there was anterior horn cell involvement or
amyotrophy. Cavitation of the cervical cord was noted in 3 and in 1 of the 3,
Horner syndrome was observed. All 8 patients had evidence of endocrinopathies
resulting in amenorrhea, galactorrhea, hypothyroidism, hyperphagia, or
diabetes insipidus.15 Our patient is similar to these described patients in
that throughout the course of her illness, clinical manifestations have been
limited to the optic nerves and spinal cord and neuroimaging studies showed a
cavitation of the spinal cord. However, our patient is postmenopausal and did
not demonstrate any evidence of hypothalamic or hypophyseal dysfunction.

Coincident to the development of a syrinx, our patient also developed signs
of sympathetic dysfunction including Horner syndrome in the left eye and
left-hand CRPS type I. In our patient, frequent and periodic neuroimaging
studies exclude any other cause for the Horner syndrome apart from the
development of a syrinx. Although the descending sympathetic fibers are
largely or totally uncrossed, their exact course is not clear. Presumably,
fibers from the lateral hypothalamic area run dorsal to the red nucleus, then
descend in the lateral tegmentum of the midbrain, pons, and medulla to the
intermediolateral cell column of the spinal cord.16 Our hypothesis is that
the syrinx involved the fibers to the left intermediolateral cells disrupting
sympathetic flow and resulting in Horner syndrome of the left eye and
left-hand CRPS. Complex regional pain syndrome is a pain syndrome that
usually develops after an initiating noxious event. Typically, evidence of
edema, changes in skin blood flow, abnormal sudomotor activity in the region
of the pain, and allodynia or hyperalgesia are observed. The site is usually
the distal aspect of an affected extremity.17 Of the wide variety of
precipitating factors that can cause injury to peripheral or central neural
tissue, syringomyelia is a central nervous system cause of CRPS.18-20

Autonomic dysfunction likely contributes to the pathophysiology of CRPS. When
a peripheral nerve is injured, vasodilatory neuropeptides, including
substance P, are released from stimulated cutaneous nerves with cell bodies
in the dorsal root ganglia. Excessive vasodilation and increased vascular
permeability result in the affected limb becoming edematous and causing the
cutaneous nerves to be further activated. Stimulated cutaneous neurons
normally have an inhibitory influence on sympathetic activity at the level of
entry of the dorsal root ganglia in the cord. In CRPS, this inhibition is
lost, resulting in a hyperactive somatosympathetic reflex.21, 22 The cause of
our patient's CRPS is also likely due to the cervical syrinx formation. She
had no preceding peripheral nerve injury and the distribution of the pain is
not in a dermatomal or peripheral nerve pattern. We postulate that due to the
syrinx formation, the intermediolateral cell column is stimulated rather than
inhibited by branches of second-order sensory neurons. The hyperresponsive
sympathetic vasoconstrictor motor fibers severely restrict blood flow to the
affected area, resulting in cyanosis, mottling, and hypothermia. This
somatosympathetic reflex is likely responsible for our patient's
intermittently edematous, mottled, and cold hand.

This case report highlights the peculiar optic-spinal phenotype of MS that is
observed in Southeast Asia. The association of syrinx in the setting of MS is
rare. However, since degeneration and necrosis of demyelinating lesions
characterize the optic-spinal phenotype of MS, an increased risk of syrinx
formation is likely to exist. Newer techniques including magnetic resonance
cysternography may be useful in confirming the diagnosis of syringes.

Author/Article Information

>From the Departments of Neurology, National Neuroscience Institute/Tan Tock
Seng Hospital (Dr Das) and Singapore General Hospital (Dr Puvanendran),
Singapore.

Corresponding author: Asha Das, MD, Department of Neurology, National
Neuroscience Institute/Tan Tock Seng Hospital, Moulmein Road, Singapore
308443 (e-mail: Asha_Das@notes.ttsh.gov.sg).
Accepted for publication February 8, 1999.

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