Download Diagnosis and Management of Acute Myelopathies

ORIGINAL ARTICLE
Diagnosis and Management of Acute Myelopathies
Adam I. Kaplin, MD, PhD,* Chitra Krishnan, MHS,† Deepa M. Deshpande, MS,†
Carlos A. Pardo, MD,† and Douglas A. Kerr, MD, PhD†
Background: Acute myelopathies represent a heterogeneous group
of disorders with distinct etiologies, clinical and radiologic features,
and prognoses. Transverse myelitis (TM) is a prototype member of
this group in which an immune-mediated process causes neural
injury to the spinal cord, resulting in varying degrees of weakness,
sensory alterations, and autonomic dysfunction. TM may exist as
part of a multifocal CNS disease (eg, MS), multisystemic disease
(eg, systemic lupus erythematosus), or as an isolated, idiopathic
entity.
Review Summary: In this article, we summarize recent classification and diagnostic schemes, which provide a framework for the
diagnosis and management of patients with acute myelopathy. Additionally, we review the state of current knowledge about the
epidemiology, natural history, immunopathogenesis, and treatment
strategies for patients with TM.
Conclusions: Our understanding of the classification, diagnosis,
pathogenesis, and treatment of TM has recently begun to expand
dramatically. With more rigorous criteria applied to distinguish
acute myelopathies and with an emerging understanding of immunopathogenic events that underlie TM, it may now be possible to
effectively initiate treatments in many of these disorders. Through
the investigation of TM, we are also gaining a broader appreciation
of the mechanisms that lead to autoimmune neurologic diseases in
general.
Key Words: transverse myelitis, myelopathy, neuroinflammatory
(The Neurologist 2005;11: 2–18)
A
lthough several cases of “acute myelitis” were described
as early as 1882, it was not until 1948 that Dr SuchettKaye,1 an English neurologist at St. Charles Hospital in
London, first used the term acute transverse myelitis. Dr
From the *Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; and the
†Department of Neurology, Johns Hopkins Transverse Myelitis Center,
Baltimore, Maryland.
Reprints: Adam I. Kaplin, MD, PhD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Osler 320,
600 N. Wolfe Street, Baltimore, MD 21287-5371. E-mail: akaplin@
jhmi.edu.
Copyright © 2005 by Lippincott Williams & Wilkins
ISSN: 1074-7931/05/1101-0002
DOI: 10.1097/01.nrl.0000149975.39201.0b
2
Suchett-Kaye used this term to designate a case of rapidly
progressive paraparesis with a thoracic sensory level, occurring as a postinfectious complication of pneumonia. Several
attempts at providing diagnostic criteria for acute transverse
myelitis (TM) have been made over the past half-century,
culminating in the nosology established by the International
Transverse Myelitis Consortium Working Group in 2002.2 It
is this set of criteria for TM that will be employed in this
review article.
TM is a rare syndrome with an incidence of between 1
and 8 new cases per million people per year.3 TM is characterized by focal inflammation within the spinal cord, and
clinical manifestations are due to resultant neural dysfunction
of motor, sensory, and autonomic pathways within and passing through the inflamed area. There is often a clearly defined
rostral border of sensory dysfunction and evidence of acute
inflammation demonstrated by a spinal MRI and lumbar
puncture. When the maximal level of deficit is reached,
approximately 50% of patients have lost all movements of
their legs, virtually all patients have some degree of bladder
dysfunction, and 80% to 94% of patients have numbness,
paresthesias, or bandlike dysesthesias.3– 8 Autonomic symptoms consist variably of increased urinary urgency, bowel or
bladder incontinence, difficulty or inability to void, incomplete evacuation or bowel constipation, and sexual dysfunction.9 Like MS,10 TM is the clinical manifestation of a variety
of disorders, with distinct presentations and pathologies.11
Recently, we proposed a diagnostic and classification scheme
which has defined TM as either idiopathic or associated with
a known inflammatory disease (ie, multiple sclerosis, systemic lupus erythematosus, Sjögren syndrome, or neurosarcoidosis).2 Patients with TM should be offered immunomodulatory treatment such as steroids and plasmapheresis,
though there is yet no consensus as to the most appropriate
strategy. Most TM patients have monophasic disease, while
up to 20% will have recurrent inflammatory episodes within
the spinal cord (JHTMC case series).12,13
TM exists on a spectrum of neuroinflammatory CNS
conditions (Table 1), characterized by abrupt neurologic
deficits associated with inflammatory cell infiltrates and demyelination. This can occur as a single episode (eg, TM,
optic neuritis 关ON兴, or acute disseminated encephalomyelitis
The Neurologist • Volume 11, Number 1, January 2005
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TABLE 1. Spectrum of Neuroinflammatory Conditions of
CNS
CNS Conditions
Transverse myelitis
Optic neuritis
Neuromyelitis optica
Acute disseminated
encephalomyelitis
Multiple sclerosis
Region
Recurrence
(%)
Spinal cord
Optic nerve
Spinal cord and optic
nerve
Brain and spinal cord
Yes (20)
Yes (24)
Yes (100)
Optic nerve, brain, and
spinal cord
Yes (100)
No
关ADEM兴) or as a multiphasic condition (eg, recurrent TM,
recurrent ON, neuromyelitis optica 关NMO兴, and MS). The
pathophysiological cause of recurrence is not currently
known but is of obvious clinical significance. This spectrum
of neuroinflammatory CNS conditions also varies based on
regional involvement of the CNS, ranging from monofocal
involvement (eg, TM involving the spinal cord and isolated
ON involving the optic nerve) to multifocal involvement (eg,
ADEM involving the brain and spinal cord, NMO involving
the optic nerve and spinal cord, and MS involving anywhere
in the central neuraxis). What accounts for this regional
specificity is a subject of considerable research interest, for
which there is no current consensus explanation. Presumably,
this regional specification could result from differences inherent in CNS tissue at different sites (such as varying
threshold for injury or distinct localization of signal transduction machinery or antigens) or from differential access to
distinct regions of the CNS by exogenous pathogenic mechanisms.
Acute Myelopathies
found to have TM have been studied at the JHTMC (unpublished data). Indeed, all patients who met criteria for the
diagnosis of TM and had tissue sampling of the spinal cord
(biopsy or autopsy) had inflammatory changes. These pathologic abnormalities invariably included focal infiltration by
monocytes and lymphocytes into segments of the spinal cord
and perivascular spaces and astroglial and microglial activation (Fig. 1). The magnitude and extension of these inflammatory features vary and are determined by the etiological
factors and the temporal profile of the myelopathic changes.
The presence of white matter changes, demyelination and
axonal injury is prominent in postinfectious myelitis. However, involvement of the central compartment of the cord,
gray matter, or neurons is also prominent in some cases, a
finding that supports the view that in TM both gray and white
matter compartments may be equally affected. In some biopsies obtained during the acute phases of myelitis, infiltration
of CD4⫹ and CD8⫹ lymphocytes, along with an increased
presence of monocytes, is quite prominent. In biopsies obtained during subacute phases of myelopathic lesions, prominent monocyte and phagocytic-macrophage infiltration is
observed. In some cases, autoimmune disorders such as
systemic lupus erythematosus (SLE) lead to vasculitic lesions
that produce focal areas of spinal cord ischemia without
prominent inflammation.17 These immunopathological obser-
We proposed a diagnostic and classification
scheme which has defined transverse myelitis
(TM) as either idiopathic or associated with a
known inflammatory disease.
IMMUNOPATHOGENESIS OF TM
The pathology of acute myelopathies reflects the heterogeneous nature of these disorders. Few studies to date
have described the pathology of acute myelitis, and the
majority of these pathologic descriptions are clinicopathological case reports.14 –16 Pathologic data from autopsies and
biopsies of suspicious spinal cord lesions from patients later
© 2005 Lippincott Williams & Wilkins
FIGURE 1. Histology of transverse myelitis (TM). A, Myelin
staining of cervical spinal cord section from a patient who died
during a subacute stage of TM. There are a few myelinated
areas left (asterisk) and foci of cystic degeneration in the
anterior horns (arrow). The remaining spinal cord shows
chronic inflammation and demyelination (LFB/HE stain). B,
Perivascular infiltration by inflammatory cells in an area of
active inflammation in a patient with TM. C, Infiltration by
microglial cells in an area of inflammation (HLA-Dr immunostain). D, High-magnification view of few myelinated fibers left
in areas of active inflammation (arrows) (LFB/HE stain).
3
Kaplin et al
vations further confirm that TM is an immune-mediated
disorder that involves cellular reactions and perhaps humoral
factors that injure compartments of the spinal cord.
Overview of Immunopathogenesis of TM
The immunopathogenesis of disease-associated TM is
varied. For example, pathologic data confirm that many cases of
lupus-associated TM are associated with a CNS vasculitis,18 –20
while others may be associated with thrombotic infarction of the
spinal cord.21,22 Neurosarcoid is often associated with noncaseating granulomas within the spinal cord,23 while TM associated
with MS often has perivascular lymphocytic cuffing and mononuclear cell infiltration with variable complement and antibody
deposition.24 Since these diseases have such varied (albeit
poorly understood) immunopathogenic and effector mechanisms, instances of disease-associated TM will not be further
discussed here. Rather, the subsequent discussion will focus on
findings potentially related to idiopathic TM.
In TM patients, it is likely that there is
abnormal activation of the immune system
resulting in inflammation and injury within the
spinal cord.
The Neurologist • Volume 11, Number 1, January 2005
from these studies is that a vaccination may induce an
autoimmune process resulting in TM. However, it should be
noted that extensive data continue to overwhelmingly show
that vaccinations are safe and are not associated with an
increased incidence of neurologic complications.26 –32 Therefore, such case reports must be viewed with caution, as it is
entirely possible that 2 events occurred in close proximity by
chance alone or for reasons that are only incidentally related
to the vaccination procedure.
Parainfectious TM
In 30% to 60% of the idiopathic TM cases, there is an
antecedent respiratory, GI, or systemic illness.4 – 6,8,11,25 The
term parainfectious has been used to suggest that the neurologic injury may be associated with direct microbial infection
and injury as a result of the infection, direct microbial
infection with immune-mediated damage against the agent, or
remote infection followed by a systemic response that induces neural injury. An expanding list of antecedent infections is now recognized, including herpes viruses and Listeria
monocytogenes, though in most of these cases, causality has
not been established.
Though in these cases the infectious agent is required
within the CNS, other mechanisms of autoimmunity discussed below, such as molecular mimicry and superantigenmediated disease, require only peripheral immune activation
and may account for other cases of TM.
Molecular Mimicry
Most patients have CSF pleocytosis and blood-brain
barrier breakdown within a focal area of the spinal cord, and
conventional treatments are aimed at ameliorating immune
activation. In 30% to 60% of idiopathic TM cases, there is an
antecedent respiratory, gastrointestinal or systemic illness.3– 6,8,11,25 In TM patients, it is likely that there is abnormal activation of the immune system resulting in inflammation and injury within the spinal cord. Thus, an understanding
of the immunopathogenesis of TM must account for abnormal or excessive incitement of immune activation, and effector mechanisms by which immune activation leads to CNS
injury.
Putative Mechanisms of Immune Activation
Postvaccination TM
It is widely reported in neurology texts that TM is a
postvaccination event, despite there being evidence of correlation but not causation at the present time. Several reports of
TM following vaccination have been recently published,
including following an influenza26 and booster hepatitis B
vaccination.27 Autopsy evaluation of patients with postvaccination TM revealed lymphocytic infiltration of the spinal
cord with axonal loss and demyelination. The suggestion
4
Molecular mimicry as a mechanism to explain an inflammatory nervous system disorder has been best described
in Guillain-Barré syndrome (GBS). First referred to as an
“acute postinfectious polyneuritis” by W. Osler in 1892, GBS
is preceded in 75% of cases by an acute infection.33–36
Campylobacter jejuni infection has emerged as the most
important antecedent event in GBS, occurring in up to 41% of
cases.37– 40 Human neural tissue contains several subtypes of
ganglioside moieties within their cell walls.41,42 A characteristic component of human gangliosides, sialic acid,43 is also
found as a surface antigen on C. jejuni within its lipopolysaccharide (LPS) outer coat.44 Antibodies against C. jejuni
that cross-react with gangliosides have been found in serum
from patients with GBS45– 47 and have been shown to bind
peripheral nerves, fix complement and impair neural transmission in experimental conditions that mimic GBS.41,48 –50
Susceptibility to the development of GBS is also dependent
on host genetic factors, which are at least partly mediated by
HLA alleles.43,60
Molecular mimicry in TM may be associated with the
development of autoantibodies in response to an antecedent
infection. This etiology was postulated to be involved in the
case of a patient who contracted TM following infection with
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
Enterobium vermicularis (perianal pinworm) and was found
to have elevated titers of cross-reacting antibodies.61
Microbial Superantigen-Mediated Inflammation
Another link between an antecedent infection and the
development of TM may be the fulminant activation of
lymphocytes by microbial superantigens (SAGs). SAGs are
microbial peptides that have a unique capacity to stimulate
the immune system and may contribute to a variety of
autoimmune diseases. The best-studied SAGs are staphylococcal enterotoxins A through I, toxic shock syndrome toxin-1 and Streptococcus pyogenes exotoxin, though many
viruses encode SAGs as well.51–54 SAGs activate T-lymphocytes in a unique manner compared with conventional antigens: instead of binding to the highly variable peptide groove
of the T cell receptor, SAGs interact with the more conserved
V␤ region.55–58 Additionally, unlike conventional antigens,
SAGs are capable of activating T lymphocytes in the absence
of costimulatory molecules. As a result of these differences,
a single SAG may activate between 2% and 20% of circulating T-lymphocytes compared with 0.001% and 0.01% with
conventional antigens.59 – 61 Stimulation of large numbers of
lymphocytes may trigger autoimmune disease by activating
autoreactive T-cell clones.62,63
Humoral Derangements
Either of the above processes may result in abnormal
immune function with blurred distinction between self and
nonself. The development of abnormal antibodies potentially
may then activate other components of the immune system
and/or recruit additional cellular elements to the spinal cord.
Recent studies have emphasized distinct autoantibodies in
patients with NMO64 – 68 and recurrent TM.12,13,69 The high
prevalence of various autoantibodies seen in such patients
suggests polyclonal derangement of the immune system. It
may also be that some autoantibodies initiate a direct and
selective injury of neurons that contain antigens that crossreact with antibodies directed against infectious pathogens.
However, it may not just be autoantibodies, but high
levels of even normal circulating antibodies that have a
causative role in TM. A case of TM was described in a patient
with extremely high serum and CSF antibody levels to
hepatitis B surface antigen following booster immunization.70
Such circulating antibodies may form immune complexes
that deposit in focal areas of the spinal cord. Such a mechanism has been proposed to describe a patient with recurrent
TM and high titers of hepatitis B surface antigen.71 Circulating immune complexes containing HbsAg were detected in
the serum and CSF during the acute phase and the disappearance of these complexes following treatment correlated with
functional recovery.
Several Japanese patients with TM were found to have
much higher serum IgE levels than MS patients or controls (360
© 2005 Lippincott Williams & Wilkins
Acute Myelopathies
versus 52 versus 85 U/mL).72 Virtually all of the patients in this
study had specific serum IgE to household mites (Dermatophagoides pteronyssinus or Dermatophagoides farinae), while less
than one third of MS and control patients did. One potential
mechanism to explain the TM in such patients is the deposition
of IgE with subsequent recruitment of cellular elements. Indeed,
biopsy specimens of 2 TM patients with elevated total and
specific serum IgE revealed antibody deposition within the
spinal cord, perivascular lymphocyte cuffing, and infiltration of
eosinophils.73 It was postulated that eosinophils, recruited to the
spinal cord, degranulated and induced the neural injury in these
patients.
Putative Mechanisms of Immune-Mediated
CNS Injury
We recently have carried out a series of investigations
that describe immune derangements in TM patients (Kaplin et
al, unpublished data). We have found that interleukin 6 (IL-6)
levels in the spinal fluid of TM patients were markedly
elevated compared with control patients and to MS patients.
While relatively low levels of IL-6 in MS patients did not
correlate with disability, IL-6 levels in TM patients strongly
correlated with and were highly predictive of disability. IL-6
levels in TM patients’ CSF correlated with nitric oxide (NO)
metabolites, which also correlated with disability. We suggest, therefore, that marked up-regulation of IL-6 as a result
of immune system activation correlates with increased NO
production and that this elevation is etiologically related to
tissue injury leading to clinical disability in TM.
IL-6 levels in TM patients strongly correlated
with and were highly predictive of disability.
DEFINING TM
Historical Classifications of TM
Acute transverse myelopathy (which includes noninflammatory causes) and TM have often been used interchangeably
throughout the published literature. One report established the
following criteria for transverse myelopathy: bilateral spinal
cord dysfunction developing over a period of ⬍ 4 weeks with a
well-defined upper sensory level, no antecedent illness, and
exclusion of compressive etiologies.11 Subsequently, these criteria were altered to include only those patients who developed
motor, sensory, and sphincter dysfunction acutely over ⬍ 14
days, whereas patients with other neurologic disease or underlying systemic diseases were excluded.5 Other authors then
defined TM as acutely developing paraparesis (no specification
of a time to maximum deficit) with bilateral sensory findings and
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Kaplin et al
impaired sphincteric function, a spinal segmental level of sensory disturbance, a stable nonprogressive course (to distinguish
from progressive spastic paraparesis), and no clinical or laboratory evidence of spinal cord compression.3 Patients were excluded if they had progressive spastic paraparesis, a patchy
sensory deficit or hemicord syndrome, syphilis, severe back
trauma, metastatic cancer, or encephalitis. To further separate
diseases with distinct etiologies, suggested criteria for TM were
revised to include only those patients who progressed to maximum deficit within 4 weeks and to exclude other known diseases
including arteriovenous malformations of the spinal cord, human T-cell lymphotropic virus-1 infection, and sarcoidosis.4
With use of these criteria, cases of TM were classified as
parainfectious, related to MS, spinal cord ischemia, or idiopathic.
Most recently, acute noncompressive myelopathies were
classified according to an etiologic scheme74: (1) those related to
MS; (2) systemic disease (eg, SLE, antiphospholipid syndrome,
Sjögren disease); (3) postinfectious; (4) delayed radiation myelopathy; (5) spinal cord infarct; and (6) idiopathic myelopathy.
The presence of MS or systemic disease was determined by
standard criteria,75–77 whereas parainfectious myelopathies were
diagnosed on the basis of positive IgM serology or a 4-fold or
greater increase in IgG levels on 2 successive tests to a specific
candidate/infectious agent. Delayed radiation myelopathy was
diagnosed according to clinical history, and spinal cord infarction was diagnosed on the basis of appropriate clinical and
imaging findings in the absence of other likely etiologies. Idiopathic transverse myelopathy was defined in those individuals
that could not be otherwise categorized and constituted 16.5% of
this series.
We recently proposed a set of diagnostic criteria that
served to distinguish TM from noninflammatory myelopathies and to distinguish idiopathic TM from TM associated
with multifocal CNS and multisystemic inflammatory disorders. These criteria are summarized in Table 2. A diagnosis of
TM requires evidence of inflammation within the spinal cord.
Because spinal cord biopsy is not a practical option in the
routine evaluation of these patients, spinal MRI and CSF
analysis are the only tools currently available to determine the
presence of inflammation within the involved lesion. Gado-
TABLE 2. Diagnostic Criteria for Transverse Myelitis
Diagnostic criteria
Sensory, motor, or autonomic dysfunction attributable to the
spinal cord
Bilateral signs and/or symptoms
Clearly defined sensory level
Inflammation defined by CSF pleocytosis or elevated IgG index
or gadolinium enhancement
Progression to nadir between 4 hours and 21 days
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linium-enhanced spinal MRI and a lumbar puncture are
mandatory in the evaluation of suspected TM, and we proposed that abnormal gadolinium enhancement of the spinal
cord or CSF pleocytosis or elevated CSF IgG index be
required for a diagnosis of TM.2 If none of the inflammatory
criteria are met at symptom onset, MRI and lumbar puncture
evaluation should be repeated between 2 and 7 days following symptom onset to determine if these inflammatory criteria
are met. IgG synthesis rate is a less specific indicator of CNS
inflammation than is CSF IgG index78,79 and should not be
used in the diagnosis. Vascular myelopathies can be differentiated from TM by a progression of symptoms to maximal
severity in less than 4 hours and the lack of inflammation as
defined above. However, these criteria do not completely
distinguish vascular myelopathies from TM, since myelopathies associated with venous infarcts or with vascular malformations may be more slowly progressive and may meet
the other criteria for TM (though not an elevated IgG index).
Differentiating idiopathic TM from TM attributed to an
underlying disease is also important. Many systemic inflammatory disorders (eg, sarcoidosis, SLE, Behçet disease, Sjögren
syndrome) may involve the nervous system and TM may be one
of the possible presentations. Therefore, all patients presenting
with TM should be investigated for the presence of systemic
inflammatory disease. Important historical information should
be obtained from the patient regarding the presence of rashes,
night sweats, oral or genital ulcers, sicca symptoms, shortness of
breath, pleuritic pain, or hematuria. Examination should attempt
to detect the presence of uveitis or retinitis, decreased lacrimation or salivation, skin rash (malar, livedo reticularis, erythema
nodosum), oral or genital ulcers, adenopathy, pleuritic or pericardial friction rub, or organomegaly. Laboratory studies should
include the following: CBC with differential and smear, ANA,
SS-A, SS-B, ESR, ACE, and complement. Additional laboratory
testing may be required if signs of a systemic vasculitis are
detected.
From this evaluation, it may be possible to distinguish
idiopathic TM from disease-associated TM (ie, TM associated with multifocal CNS disease or systemic inflammatory
disease). This distinction is important since patients at high
risk of developing MS may be evaluated more closely or may
be offered immunomodulatory treatment.80 Similarly, patients with disease-associated TM may need to be closely
followed for recurrent systemic and neurologic complications
and should be offered immunosuppressive treatment to decrease the risk of recurrence.
NATURAL HISTORY OF TM
Epidemiology and Clinical Presentation of TM
TM affects individuals of all ages, with bimodal peaks
between the ages of 10 and 19 years and 30 and 39 years.3– 6
There are approximately 1400 new cases diagnosed in the
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
United States per year, and approximately 34,000 people
have chronic morbidity from TM at any given time. Approximately 28% of reported TM cases are in children (JHTMC
case series). There is no sex or familial predisposition to TM.
A preceding illness including nonspecific symptoms
such as fever, nausea, and muscle pain has been reported in
about 40% of pediatric cases within 3 weeks of the onset of
the disorder (JHTMC case series).25,81 Thirty percent of all
cases of pediatric TM cases referred to an academic center
had a history of an immunization within 1 month of the onset
of symptoms (JHTMC case series). Although a history of an
immunization preceding the onset of TM is commonly reported, the relationship to this event is unclear because of
insufficient data.
TM is characterized clinically by acutely or subacutely
developing symptoms and signs of neurologic dysfunction in
motor, sensory and autonomic nerves, and nerve tracts of the
spinal cord. Weakness is described as a rapidly progressive
paraparesis starting with the legs that occasionally progresses
to involve the arms as well. Flaccidity maybe noted initially,
with gradually appearing pyramidal signs by the second week
of the illness. A sensory level can be documented in most
cases. The most common sensory level in adults is the
midthoracic region, though children may have a higher frequency of cervical spinal cord involvement and a cervical
sensory level.82 Pain may occur in the back, extremities, or
abdomen. Paresthesias are a common initial symptom in
adults with TM but are unusual for children.83 Autonomic
symptoms consist variably of increased urinary urgency,
bowel or bladder incontinence, difficulty or inability to void,
incomplete evacuation, or bowel constipation.9 Also commonly the result of sensory and autonomic nervous system
involvement in TM is sexual dysfunction.84,85 Genital anesthesia from pudendal nerve involvement (S2-S4) results in
impaired sensation in men and women. Additional male
sexual problems with parasympathetic (S2-S4) and sympathetic (T10-L2) dysfunction in TM patients include erectile
dysfunction, ejaculatory disorders and difficulty reaching
orgasm. Corresponding female sexual problems include reduced lubrication and difficulty reaching orgasm.
In addition to the signs and symptoms of direct spinal
cord involvement by the immune system in TM, there also
appears to be indirect effects manifested as depression and
selective cognitive impairment that are reminiscent of what
has been described in MS (unpublished observations).86 This
depression or cognitive impairment does not correlate significantly with the patient’s degree of physical disability and can
have lethal consequences, resulting in suicide in severe cases
if left untreated. In fact, in our case series depression resulting
in suicide is the leading cause of mortality, accounting for
60% of the deaths we have seen in our clinic (unpublished
observations).
© 2005 Lippincott Williams & Wilkins
Acute Myelopathies
When the maximal level of deficit is reached, approximately 50% of patients have lost all movements of their legs,
virtually all patients have some degree of bladder dysfunction, and 80% to 94% of patients have numbness, paresthesias, or bandlike dysesthesias.3– 8 In more than 80% of cases,
patients reach their clinical nadir within 10 days of the onset
of symptoms.81 Although the temporal course may vary,
neurologic function usually progressively worsens during the
acute phase from between 4 and 21 days.2
A spinal MRI and lumbar puncture often show evidence of acute inflammation.3–5,8,11,87,88 In our case series of
170 idiopathic TM cases, spinal MRI showed a cervical T2
signal abnormality in 44% and a thoracic T2 signal abnormality in 37% of cases. Five percent of patients had multifocal lesions and 6% showed a T1 hypointense lesion. This
corresponded to the following clinical sensory levels: 22%
cervical, 63% thoracic, 9% lumbar, 6% sacral, and no sensory
level in 7%. The rostral-caudal extent of the lesion ranged
from 1 vertebral segment in many to spanning the entire
spinal cord in 2 patients. In 74% of patients, the lesion also
enhanced with gadolinium. Forty-two percent of patients had
a CSF pleocytosis, with a mean WBC count of 38 ⫾ 13 cells
(range 0 –950 cells). Fifty percent of the patients revealed an
elevated protein level (mean protein level 75 ⫾ 14 mg/dL).
Table 3 lists some of the radiologic features that distinguish
various acute myelopathies.
Seventy-five percent to 90% of TM patients
experience monophasic disease and have no
evidence of multisystemic or multiphasic
disease.
Monophasic Versus Recurrent TM
Seventy-five percent to 90% of TM patients experience
monophasic disease and have no evidence of multisystemic
or multiphasic disease. Most commonly, symptoms will stop
progressing after 2 to 3 weeks, and spinal fluid and MRI
abnormalities will stabilize and then begin to resolve. There
are several features, however, that predict recurrent disease
(Table 4). Patients with multifocal lesions within the spinal
cord, demyelinating lesions in the brain, oligoclonal bands in
the spinal fluid, mixed connective tissue disorder, or serum
autoantibodies (most notably SS-A) are at a greater risk of
recurrence.89 Preliminary studies suggest that patients who
have persistently abnormal CSF cytokine profiles (notably
IL-6) may also be at increased risk for recurrent TM, though
these findings must be validated before they are used clini-
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Kaplin et al
TABLE 3. Suggestive Imaging Features to Diagnose Acute Myelopathies
Imaging Features
Potential Diagnosis
Blood within the spinal cord (bright and dark T1 and
T2 signal)
Flow voids within spinal cord
Central T2 signal abnormality
Ring-enhancing lesion
Acute loss of vertical intervertebral disc height and
corresponding T2 signal abnormality
Fusiform lesion extending over ⬎ 3 spinal cord segments
T2 bright lesion in white matter occupying less than 2
spinal cord segments in rostral-caudal extent and less
than 50% of the cord diameter
T2 spinal cord lesion adjacent to disk herniation or
spondylitic ridge but lack of spinal cord compression
Vascular malformation such as cavernous angioma or dural AV
fistula
Dural AV fistula or AVM
Venous hypertension
Infection or tumor (but consider course of IV steroids to rule
out inflammatory process before progressing to biopsy)
Consider fibrocartilaginous embolism
Consider neuromyelitis optica or disease-associated TM
Consider MS
Consider dynamic spinal cord compression only during flexion
or extension (flexion-extension x-ray to determine the
presence of abnormal spinal column mobility; MRI in flexion
or extended position instead of in neutral position)
TABLE 4. Distinguishing Features Between Recurrent and Monophasic Transverse Myelitis
Characteristics
Monophasic
Spinal MRI
Single T2 lesion
Brain MRI
Blood serology
SS-A
CSF oligoclonal bands
Systemic disease
Optic nerve involvement
Normal
Normal
Negative
Negative
None
No
cally (Kaplin et al, unpublished data). At the current time, we
do not understand the relative contribution of these factors to
gauge whether chronic immunomodulatory treatment is warranted in high-risk patients.
Prognosis
Some patients with TM may experience recovery in
neurologic function, regardless of whether specific therapy is
instituted. Recovery, if it occurs, should begin within 6
months, and most patients show some restoration of neurologic function within 8 weeks (JHTMC case series).83 Recovery may be rapid during months 3 to 6 after symptom
onset and may continue, albeit at a slower rate, for up to 2
years.81,82 Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae,
one third are left with moderate degree of permanent disability, and one third have severe disabilities.5,6,11,25,81 Knebusch
et al81 estimated that a good outcome with normal gait, mild
urinary symptoms, and minimal sensory and upper motor
8
Recurrent
Multiple distinct lesions or fusiform lesion extending over
⬎ 3 spinal cord segments
T2/FLAIR abnormalities
⬎ 1 autoantibody (ANA, dsDNA, phospholipid, c-ANCA)
Positive
Positive
Connective tissue disorder
Likely
neuron signs occurred in 44%. A fair outcome with mild
spasticity but independent ambulation, urgency and/or constipation, and some sensory signs occurred in 33%, and a
poor outcome with the inability to walk or severe gait
disturbance, absence of sphincter control, and sensory deficit
in 23%. The patient cohort we follow at Johns Hopkins is
more severe, with only 20% experiencing a good outcome by
those definitions, likely a reflection of referral bias to a
tertiary-care center. Symptoms associated with poor outcome
include back pain as an initial complaint, rapid progression to
maximal symptoms within hours of onset, spinal shock, and
sensory disturbance up to the cervical level.83
The presence of 14-3-3 protein, a marker of neuronal
injury, in the CSF during the acute phase may also predict a
poor outcome.90 Our recent studies suggest that CSF IL-6
levels at acute presentation are proportional to, and highly
predictive of, long-term disability (Kaplin et al, unpublished
data). If confirmed by future studies, the finding that IL-6
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
levels are proportional to disability in subjects prior to treatment could provide a much-needed biomarker to help guide
the aggressiveness of interventions employed in treating patients presenting with acute TM.
CLINICAL EVALUATION AND TREATMENT OF
PATIENTS WITH TM
Evaluation of Patients With Acute
Myelopathies
We recently proposed a systematic diagnostic approach
for evaluating patients with acute myelopathies.2 The algorithm
is shown in Figure 2. The first priority is to rule out a compressive lesion. If a myelopathy is suspected based on history and
physical examination, a gadolinium-enhanced MRI of the spinal
Acute Myelopathies
cord should be obtained as soon as possible. If there is no
structural lesion such as epidural blood or a spinal mass, then the
presence or absence of spinal cord inflammation should be
documented with a lumbar puncture. The absence of pleocytosis
would lead to consideration of noninflammatory causes of myelopathy such as arteriovenous malformations, epidural lipomatosis, fibrocartilaginous embolism, or possibly early inflammatory myelopathy (ie, a false-negative CSF). In the presence of an
inflammatory process (defined by gadolinium enhancement,
CSF WBC pleocytosis, or elevated CSF immunoglobulin index), one should determine whether there is an infectious cause.
Viral polymerase chain reaction assays should be performed to
determine whether there is the presence of viral particles within
the CNS (herpes simplex 1 and 2, varicella zoster, cytomegalo-
FIGURE 2. Acute myelopathies: a diagnostic approach.
© 2005 Lippincott Williams & Wilkins
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The Neurologist • Volume 11, Number 1, January 2005
Kaplin et al
virus, Epstein-Barr virus, and enterovirus). Detection of Lyme
disease of the CNS typically is based on antibody detection
methods (ELISA with confirmatory Western blot) and the CSF/
serum index is often helpful in determining whether there is true
neuroborreliosis.91 Evidence of M. pneumoniae infection may
be determined by seroconversion, which is defined by a 4-fold
increase in titer or a single titer of ⱖ 1:128.
Recovery may be rapid during months 3 to 6
after symptom onset and may continue, albeit
at a slower rate, for up to 2 years.
The next priority is to define the regional distribution of
demyelination within the CNS, since several disorders (ie, multiple sclerosis or ADEM) may present with TM as the initial
manifestation of disease or in the setting of multifocal disease. A
gadolinium-enhanced brain MRI and visual evoked potential
should be ordered to look for these entities. The absence of
multifocal areas of demyelination would suggest the diagnosis
of isolated TM and lead to appropriate treatment measures.2
TM is often misdiagnosed as acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or GuillainBarré syndrome (GBS), because both conditions may present
with rapidly progressive sensory and motor loss involving
principally the lower extremities. Table 5 illustrates key
differential points between these 2 conditions. A pure paraplegia or paraparesis with a corresponding distribution of
sensory loss may favor TM, while GBS may present with a
gradient of motor and sensory loss involving the lower
extremities greater than the upper extremities. When weakness and sensory loss involves both the upper and lower
extremities equally with a distinct spinal cord level, then TM
involving the cervical region is more likely. Pathologically
brisk deep tendon reflexes are supportive of TM. However,
patients with fulminant cases of TM that includes significant
destruction of spinal cord gray matter may present with
hypotonia and have decreased or absent deep tendon reflexes.
Urinary urgency or retention is a common early finding in
TM and is less common in GBS. In GBS, dysesthetic pain,
involvement of the upper extremity and cranial nerve 7, and
absent deep tendon reflexes involving the upper extremities
are more common findings. An MRI of the spinal cord may
show an area of inflammation in TM but not in GBS.
Although cerebrospinal fluid findings in TM are not consistent and an elevated cell count may be absent, there is usually
a moderate lymphocytic pleocytosis and elevated protein
level. This is in contrast to the albuminocytologic dissociation of the CSF seen in GBS.81
Differential Diagnoses/Noninflammatory
Myelopathies
As indicated above, the suggested diagnostic algorithm
and criteria first distinguish inflammatory from noninflammatory myelopathies. If the history and evaluation do not
suggest a systemic or a CNS inflammatory process, then
consideration should be given to ischemic, metabolic, or
structural causes of myelopathy. Vascular myelopathy may
be fairly easy to recognize in the setting of an anterior spinal
artery infarct (sudden onset of symptoms with relative preservation of posterior column function). Or it may be more
difficult to recognize in the setting of a venous infarct or a
TABLE 5. Distinguishing Features Between Guillain-Barré Syndrome and Transverse Myelitis
Characteristics
Transverse Myelitis
Motor findings
Sensory findings
Paraparesis or quadriparesis
Usually can diagnose a spinal cord level
Autonomic findings
Early loss of bowel and bladder control
Cranial nerve findings
Electrophysiologic findings
None
EMG/NCV findings may be normal or may
implicate the spinal cord: prolonged central
conduction on somatosensory evoked potential
(SEP) latencies or missing SEP in conjunction
with normal sensory nerve action potentials
Usually a focal area of increased T2 signal with or
without gadolinium enhancement
Usually, CSF pleocytosis and/or increased IgG index
MRI findings
CSF
10
Guillain-Barré Syndrome
Ascending weakness LE ⬎ UE in the early stages
Ascending sensory loss LE ⬎ UE in the early
stages
Autonomic dysfunction of the cardiovascular
(CV) system
EOM palsies or facial weakness
EMG/NCV findings confined to the PNS: motor
and/or sensory nerve conduction velocity
reduced, distal latencies prolonged; conduction
block; reduced H reflex usually present
Normal
Usually, elevated protein in the absence of CSF
pleocytosis
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
vascular malformation. Venous infarction may be suspected
when a clinical history and serologic studies are suggestive of
a prothrombotic state (deep venous thrombosis, pulmonary
embolus, livedo reticularis, antiphospholipid antibodies, factor V Leiden mutation, APC resistance, or prothrombin gene
mutation). A vascular malformation (dural AV fistula, AVM,
cavernous angioma) may be suspected if the imaging suggests the presence of flow voids or bleeding into the spinal
cord. A dural AV fistula is most likely to occur in men older
than 40 years old and may present with a “stuttering” or
progressive myelopathy. Patients with a dural AV fistula may
report a postural dependence of symptoms and pain is usually
a prominent feature. Spinal angiography is the diagnostic
study of choice to define the presence of a vascular malformation. Surgical or endovascular treatment may result in
stabilization or clinical improvement in a substantial proportion of patients.92–94
Fibrocartilaginous embolism is a rare (though likely
underreported) cause of acute myelopathy.95–98 In most reported cases, there has been a sudden increase in intrathoracic
or intraabdominal pressure prior to the onset of symptoms,
and in several autopsies, fibrocartilaginous material was
found to have embolized to the spinal cord. The most likely
explanation for these findings is that the nucleus pulposus
herniated vertically into the vertebral body sinusoids in response to markedly elevated pressure, followed by further
herniation through vascular channels into the spinal cord
parenchyma. Fibrocartilaginous embolism should be suspected in a patient with a sudden onset of myelopathy that
reaches its maximal severity within hours in a patient with an
antecedent elevation of intraabdominal or intrathoracic pressure. Imaging may show acute loss of intervertebral disk
height and vertebral body end-plate changes adjacent to an
area of T2 signal abnormality within the spinal cord.
Radiation myelopathy may develop at any time up to 15
years following ionizing radiation. Pathologic studies show
preferential involvement of myelinated tissue and blood vessels and it is likely that cellular death of oligodendrocytes and
endothelial cells contributes to the clinical disorder.99 Patients may present with slowly progressive spasticity, weakness, hyperreflexia and urinary urgency. There is often a
corresponding T2 signal abnormality that is nonenhancing
and preferentially affects the more superficial spinal cord
white matter. Though anticoagulation100,101 or hyperbaric
oxygen102–104 has been proposed as a treatment option, neither has been clearly shown to be effective in patients with
radiation myelopathy.
Discrimination from Multiple Sclerosis
TM can be the presenting feature of MS. Patients who
are ultimately diagnosed with MS are more likely to have
asymmetric clinical findings, predominant sensory symptoms
with relative sparing of motor systems, MR lesions extending
© 2005 Lippincott Williams & Wilkins
Acute Myelopathies
over fewer than 2 spinal segments, abnormal brain MRI, and
oligoclonal bands in the CSF.74,87,105–108 A patient with
monofocal CNS demyelination (TM or ON) whose brain
MRI shows lesions consistent with demyelination109 has an
83% chance of meeting clinical criteria for MS over the
subsequent decade compared with 11% of such patients with
normal brain MRI.110
MANAGEMENT OF TM
Intravenous Steroids
Intravenous steroid treatment is often instituted for
patients with acute TM. Corticosteroids have multiple mechanisms of action including antiinflammatory activity, immunosuppressive properties, and antiproliferative actions.111,112
Though there is no randomized double-blind placebo-controlled study that supports this approach, evidence from
related disorders and clinical experience support this treatment.113–117 Additionally, there are several small studies
which support the administration of corticosteroids in patients
with TM.118 –121 A study of 5 children with severe TM who
received methylprednisolone (1 g/1.73 m2/d) for 3 or 5
consecutive days followed by oral prednisone for 14 days
reported beneficial effects compared with 10 historic controls.120 In the steroid-treated group, the median time to
walking was 23 days versus 97 days, full recovery occurred
in 80% versus 10%, and full motor recovery at 1 year was
present in 100% versus 20%. No serious adverse effects from
the steroid treatments occurred.
The available evidence suggests that
intravenous steroids are somewhat effective if
given in the acute phase of TM.
Other investigations have suggested that intravenous
steroid administration may not be effective in TM patients.81,83,122 The most significant of these manuscripts122
compared 12 TM patients seen between 1992 and 1994 who
did not get steroids with 9 patients seen between 1995 and
1997 who did. Although the authors claimed that there was
no statistically significant difference in the outcomes between
the groups, it is evident that the TM patients who received
steroids were more likely to recover, and fewer had a poor
outcome on the Barthel Index (33% versus 67%). Therefore,
the available evidence suggests that intravenous steroids are
somewhat effective if given in the acute phase of TM.
However, these studies did not rigorously define TM and
11
Kaplin et al
therefore likely included patients with noninflammatory myelopathies.
At our center, we routinely offer intravenous methylprednisolone (1000 mg) or dexamethasone (200 mg) for 3 to
5 days unless there are compelling reasons to avoid this
therapy. The decision to offer continued steroids or add a new
treatment is often based on the clinical course and MRI
appearance at the end of 5 days of steroids.
Plasma Exchange (PLEX)
PLEX is often initiated if a patient has moderate to
severe TM (ie, inability to walk, markedly impaired autonomic function, and sensory loss in the lower extremities)
and exhibits little clinical improvement after instituting 5 to 7
days of intravenous steroids. PLEX is believed to work in
autoimmune CNS diseases through the removal of specific or
nonspecific soluble factors likely to mediate, be responsible
for, or contribute to inflammatory-mediated target organ
damage. PLEX has been shown to be effective in adults with
TM and other inflammatory disorders of the CNS.123–125
Predictors of good response to PLEX include early treatment
(less than 20 days from symptom onset), male sex, and a
clinically incomplete lesion (ie, some motor function in the
lower extremities, intact or brisk reflexes).126 It is our experience that PLEX may significantly improve outcomes of
patients with severe (though incomplete) TM and who have
not significantly improved on intravenous steroids.
It is our experience that plasma exchange
(PLEX) may significantly improve outcomes of
patients with severe (though incomplete) TM
and who have not significantly improved on
intravenous steroids.
Other Immunomodulatory Treatment
No controlled information currently exists regarding
the use of other treatment strategies in patients with acute
TM. Some clinicians consider pulse dose intravenous cyclophosphamide (500 –1000 mg/m2) for patients with TM that
continues to progress despite intravenous steroid therapy.
Cyclophosphamide, a bifunctional alkylating agent, forms
reactive metabolites that cross-link DNA. This results in
apoptosis of rapidly dividing immune cells and is believed to
underlie the immunosuppressive properties of this medication. It is the experience at our center that some patients will
respond significantly to intravenous cyclophosphamide, and
this treatment is worthy of consideration while we await
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The Neurologist • Volume 11, Number 1, January 2005
double-blinded placebo trials. However, cyclophosphamide
should be administered under the auspices of an experienced
oncology team, and caregivers should monitor the patient
carefully for hemorrhagic cystitis and cytopenias.
CSF filtration is a new therapy, not yet available in the
United States, in which spinal fluid is filtered for inflammatory factors (including cells, complement, cytokines, and
antibodies) prior to being reinfused into the patient. In a
randomized trial of CSF filtration versus PLEX for AIDP,
CSF filtration was better tolerated and was at least as effective.127 Clinical trials for CSF filtration are currently being
initiated.
Chronic immunomodulatory therapy should be considered for the small subgroup of patients with recurrent TM.
Although the ideal treatment regimen is not known, we
consider a 2-year course of oral immunomodulatory treatment in patients with 2 or more distinct episodes of TM. We
most commonly treat patients with azathioprine (150 –200
mg/d), methotrexate (15–20 mg/wk) or mycophenolate (2–3
g/d), though oral cyclophosphamide (2 g/kg/d) may also be
used in patients with systemic inflammatory disease. On any
of these medicines, patients must be followed for transaminitis or leukopenias.
Long-Term Management
Many patients with TM will require rehabilitative care
to prevent secondary complications of immobility and to
improve their functional skills. It is important to begin occupational and physical therapies early during the course of
recovery to prevent the inactivity related problems of skin
breakdown and soft tissue contractures that lead to loss of
range of motion. The principles of rehabilitation in the early
and chronic phases after TM are summarized in Table 6.
During the early recovery period, family education is essential to develop a strategic plan for dealing with the challenges
to independence following return to the community. Assessment and fitting for splints designed to passively maintain an
optimal position for limbs that cannot be actively moved is an
important part of the management at this stage.
The long-term management of TM requires attention to
a number of issues. These are the residual effects of any
spinal cord injury including TM. In addition to chronic
medical problems, there are the ongoing issues of ordering
the appropriate equipment, reentry into the school for children and community, and coping with the psychologic effects
of this condition by the patients and their families.
Patients with TM should be educated about the effect of
TM on mood regulation and routinely screened for the development of symptoms consistent with clinical depression. Patient
warning signs that should prompt a complete evaluation for
depression include failure to progress with rehabilitation and
self-care, worsening fixed low mood or pervasive decreased
interest, and social and professional withdrawal. A preoccupa© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
tion with death or suicidal thoughts constitutes a true psychiatric
emergency and should lead to prompt evaluation and treatment.
All patients should be educated about 3 main points related to
depression. First, patients should be educated that depression in
TM is similar to other neurologic symptoms patients endure,
being mediated by the effects of the immune system on the
brain. Depression is remarkably prevalent in TM, occurring in
up to 25% of patients at any given time, and is largely independent of the patient’s degree of physical disability. Depression is
not due to personal weakness or the inability to “cope.” Second,
depression in TM can have devastating consequences; not only
can depression worsen physical disability (such as fatigue, pain,
and decreased concentration) but it can have lethal consequences. Suicide is the leading cause of death in TM, accounting
for 60% of the deaths in the JHTMC since its inception. Third,
despite the severity of the clinical presentation of depression in
many patients with TM, these patients generally show a very
robust response to combined aggressive psychopharmacologic
and psychotherapeutic interventions. Complete symptom remission is the rule rather than the exception with appropriate
recognition and treatment of TM depression.
Spasticity is often a very difficult problem to manage. The
goal is to maintain flexibility with a stretching routine using
exercises for active stretching and a bracing program with splints
for a prolonged stretch. These splints are commonly used at the
ankles, wrists, or elbows. An appropriate strengthening program
for the weaker of the spastic muscle acting on a joint and an
aerobic conditioning regimen are also recommended. These
interventions are supported by adjunctive measures that include
antispasticity drugs (eg, diazepam, baclofen, dantrolene, tizanidine, and tiagabine), therapeutic botulinum toxin injections, and
serial casting. The therapeutic goal is to improve the function of
the patient in performing specific activities of daily living (ie,
feeding, dressing, bathing, hygiene, mobility) through improving the available joint range of motion, teaching effective compensatory strategies, and relieving pain.
Another major area of concern is effective management
of bowel function. A high-fiber diet, adequate and timely
fluid intake, and medications to regulate bowel evacuations
are the basic components to success. Regular evaluations by
medical specialists for adjustment of the bowel program are
recommended to prevent potentially serious complications.
Bladder function is almost always at least transiently
impaired in patients with TM. Immediately after the onset of
TM, as in the aftermath of traumatic spinal cord injury, there
is frequently a period of transient loss or depression of neural
activity below the involved spinal cord lesion. This phenomenon is often referred to as “spinal shock,” which lasts about
3 weeks, during which there is an interruption of descending
excitatory influence with resultant bladder flaccidity. Following this period, bladder dysfunction can be classified into 2
syndromes involving either upper motor neurons (UMN) or
lower motor neurons (LMN).
© 2005 Lippincott Williams & Wilkins
Acute Myelopathies
Sympathetic input to the bladder, which promotes urine
storage, originates at levels T10-L2 of the spinal cord and
travels via the hypogastric nerve. Afferent input to the urinary
tract is provided by the sacral (S2-S4) spinal cord through the
pelvic nerve. Efferent parasympathetic input to the bladder,
which mediates detrusor contractions, is carried by the pelvic
nerve (S2-S4). UMN bladder dysfunction results from lesions
above S1-S2 and is characterized by reflexive emptying with
bladder filling if the injury is complete and urge incontinence
if the neurologic involvement is incomplete. In addition,
detrusor-sphincter dyssynergia results from impaired communication between the sacral and brain stem micturition centers. In the case of UMN dysfunction, anticholinergic medications, ␣-blockers, or electric stimulation is used to restore
adequate bladder storage and drainage. LMN bladder dysfunction with either direct involvement of S2-S4 or indirect
involvement including the conus medullaris and cauda equina
results in detrusor areflexia and requires clean intermittent
self-catheterization.
TM-induced sexual dysfunction involves similar innervation and analogous syndromes as those found in bladder
dysfunction. Spinal cord segments S2-S4 relay afferent sensory fibers from the genitalia via the pudendal nerves and
supply parasympathetic input via the pelvic nerves. Parasympathetic stimulation initiates and maintains penile erection in
men and clitoral and labial engorgement and vaginal lubrication in women. Sympathetic fibers from T10-L2 provide
the major stimulus for ejaculation and orgasm but can also
mediate erections through mechanisms that are less well
understood. Reflex erections in response to tactile stimulation
are parasympathetically mediated through a local sacral (S2S4) reflex arc and tend to occur in patients with UMN lesions.
Psychogenic erections are sympathetically mediated through
sympathetic pathways that exit the spinal cord at T10-T12
and allow many patients with LMN lesions of the sacral
reflex arc to achieve erections through psychogenic stimulation. Treatment of sexual dysfunction should take into account baseline function before the onset of TM and begins,
with adequate education and counseling about the known
physical and neurologic changes that TM has on sexual
functioning. Patients should be encouraged to discuss their
concerns with their doctors, as well as their partners. Because
of the similarities in innervation between sexual and bladder
function, patients with UMN-mediated sexual dysfunction
should be encouraged to empty their bladders before sexual
stimulation to prevent untimely incontinence. The mainstays
of treatment of erectile dysfunction in men are inhibitors of
cGMP phosphodiesterase, type 5, which will allow most of
men with TM to achieve adequate erections for success in
intercourse through a combination of reflex and/or psychogenic mechanisms. Although less effective in women, these
same types of medications have been shown capable of
enhancing sexual functioning in women.
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The Neurologist • Volume 11, Number 1, January 2005
Kaplin et al
TABLE 6. Chronic Management of Patients with Transverse Myelitis
Early Rehabilitation
General
Consider inpatient rehabilitation
Daily land-based and/or water-based therapy for 8–12 wk
Daily weight bearing for 45–90 min
Bone densitometry: vitamin D, Ca
Screen for depression
Demoralization
Individual and group support. Useful resource is TM
Association (TMA) (www.myelitis.org)
Development of problem-focused coping skills. All
members of medical care providers could contribute
(neurologist, physiatrist, PT, OT, psychiatrist,
psychologist, SW, etc)
Depression
Education about depression as a manifestation of brain
involvement in conjunction with stressful circumstance
Warning about the lethality of depression (with suicide
being one of the leading causes of death in TM)
Treatment of depression with antidepressants and talk
therapy. SSRIs are common first-line agents, but
consider TCA if there is the possibility of
simultaneously treating depression, incontinence, and
neuropathic pain with a single agent.
Bladder dysfunction
If postvoid residual is ⬎ 80 mL, consider clean
intermittent catheterization
Anticholinergic Rx if urgency
Cranberry juice for urine acidification
Bowel dysfunction
High-fiber diet, increased fluid intake
Digital disimpaction
Bowel program: colace, Senokot, Dulcolax, docusate PR,
bisacodyl in water base, MiraLax, enemas PRN
Weakness
Passive and active ROM
Splinting or orthoses when necessary
Pain or dysesthesias
ROM exercises
Gabapentin, carbamazepine, nortriptyline, tramadol
Avoid narcotics if possible
Late Rehabilitation
Examine for scoliosis
Serial flexion/extension x-ray of back to follow angle
Fatigue: Amantadine, Methylphenidate, Modafinil, CoQ10
Bone densitometry: vitamin D, Ca, Bisphosphonate therapy
Screen for depression
Biannual national TM symposiums organized through the
JHTMC and TMA
Establish local TMA support group if none exists
Referral to psychiatrist if diagnosis is in doubt, initial trials of
antidepressant treatment is unsuccessful, or if there is
concern about suicide potential
Ensure caregiver is receiving sufficient support to prevent
burnout
Urodynamics study for irritative or obstructive symptoms
Anticholinergic drug if detrusor hyperactive; adrenergic blocker
if sphincter dysfunction
Cranberry juice/vitamin C for urine acidification
Consider sacral nerve stimulation
High-fiber diet, increased fluid intake
Digital disimpaction
Bowel program: colace, Senokot, Dulcolax, docusate PR,
bisacodyl in water base, MiraLax, enemas PRN
Passive and active ROM
Splinting or orthoses if needed
Continued land and water therapy
Ambulation devices
Daily weightbearing for 45–90 minutes
Orthopedics evaluation if joint imbalance
ROM exercises
Gabapentin, carbamazepine, nortriptyline, tramadol
Topical lidocaine (patch or cream)
Intrathecal baclofen or opioids
(Continued)
14
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
Acute Myelopathies
TABLE 6. (Continued)
Early Rehabilitation
Spasticity
ROM exercises
Aquatherapy
Baclofen, tizanidine, diazepam, botulinum toxin,
tiagabine
Late Rehabilitation
ROM exercises
Aquatherapy
Baclofen, tizanidine, diazepam, botulinum toxin, tiagabine
Intrathecal baclofen trial
Sexual dysfunction
Phosphodiesterase V inhibitors
SPECULATIONS ON FUTURE TREATMENTS
OF TM
Work over the last few years has begun to reveal
fundamental immune abnormalities in patients with TM and
related neuroimmunologic disorders. The generation of autoantibodies and the presence of abnormally elevated cytokine
levels in the spinal fluid are likely to be important immunopathogenic events in many patients with TM. Though TM is
a heterogeneous syndrome that is associated with distinct
pathologies, recent classification strategies have attempted to
identify patients with likely similar immunopathogenic
events. While current therapies are largely nonspecific, future
therapies will be more specifically targeted to those critical
immunopathogenic events in TM. For example, evolving
strategies will more effectively identify autoantibodies and
the antigen to which they respond,128,129 making it possible to
develop specific targets to block the effects of these autoantibodies. Additionally, several strategies exist and more are
currently being developed that specifically alter cytokine
profiles or the effects of these cytokines within the nervous
system. However, a cautionary note exists from recent studies
examining TNF-␣ modulation in patients with multiple sclerosis or systemic rheumatologic disease: paradoxical demyelination may be triggered by TNF-␣ reduction in the
blood.130 These findings may suggest that secondary alterations in immune system function may occur in response to
blockade of any single pathway and that a “cocktail approach” aimed at halting multiple proinflammatory pathways
may be ideal.
Future research will attempt to elucidate individual
predispositions and environmental triggers to immune overactivation. A more comprehensive understanding of the
mechanisms of tissue insult will lead to the development of
rational therapeutics geared to intervene at various steps of
the signal transduction pathways leading to injury. For those
patients who have already undergone extensive neurologic
injury as a result of TM, neurorestorative treatments (perhaps
involving stem cells) offer the best hope for meaningful
functional recovery.
© 2005 Lippincott Williams & Wilkins
Phosphodiesterase V inhibitors
CONCLUSION
TM is a clinical syndrome caused by focal inflammation of the spinal cord. Many cases are postinfectious and are
thought to be due to a transient abnormality in the immune
system that results in injury to a focal area of the spinal cord.
Recent studies have emphasized the need to classify TM
according to whether there is evidence of systemic disease or
multifocal CNS disease. The importance of this may be that
distinct treatment strategies are offered to patients with distinct forms of TM. Though the causes of TM remain unknown, recent advances have suggested specific cytokine
derangements that likely contribute to sustained disability due
to injury of motor, sensory, or autonomic neurons within the
spinal cord. Future research will attempt to define triggers for
the immune system derangements, effector mechanisms that
propagate the abnormal immune response, and cellular injury
pathways initiated by the inflammatory response within the
spinal cord. Ultimately, this may allow us to identify patients
at risk for developing TM, specifically treat the injurious
aspects of the immune response, and/or offer neuroprotective
treatments which minimize the neural injury that occurs in
response to the inflammation.
ACKNOWLEDGMENT
We acknowledge the support and efforts of the Transverse Myelitis Association (TMA) and its president Sanford
Siegel. The TMA serves a critical role to the TM community
and to researchers striving to understand and treat this disorder. We also acknowledge financial support of the Katie
Sandler Fund for TM research and the Claddagh Foundation
to the Johns Hopkins TM Center. We thank the Noel P. Rahn
Fellowship for support (AIK).
REFERENCES
1. Suchett-Kaye AI. Acute transverse myelitis complicating pneumonia.
Lancet. 1948;255:417.
2. Transverse Myelitis Consortium Working Group. Proposed diagnostic
criteria and nosology of acute transverse myelitis. Neurology. 2002;59:
499 –505.
3. Berman M, Feldman S, Alter M, et al. Acute transverse myelitis:
15
Kaplin et al
incidence and etiologic considerations. Neurology. 1981;31:966 –971.
4. Jeffery DR, Mandler RN, Davis LE. Transverse myelitis: retrospective
analysis of 33 cases, with differentiation of cases associated with multiple
sclerosis and parainfectious events. Arch Neurol. 1993;50:532–535.
5. Christensen PB, Wermuth L, Hinge HH, et al. Clinical course and
long-term prognosis of acute transverse myelopathy. Acta Neurol
Scand. 1990;81:431– 435.
6. Altrocchi PH. Acute transverse myelopathy. Arch Neurol. 1963;9:21–29.
7. Misra UK, Kalita J, Kumar S. A clinical, MRI and neurophysiological
study of acute transverse myelitis. J Neurol Sci. 1996;138:150 –156.
8. Lipton HL, Teasdall RD. Acute transverse myelopathy in adults: a
follow-up study. Arch Neurol. 1973;28:252–257.
9. Sakakibara R, Hattori T, Yasuda K, et al. Micturition disturbance in
acute transverse myelitis. Spinal Cord. 1996;34:481– 485.
10. Lucchinetti CF, Brueck W, Rodriguez M, et al. Multiple sclerosis:
lessons from neuropathology. Semin Neurol. 1998;18:337–349.
11. Ropper AH, Poskanzer DC. The prognosis of acute and subacute
transverse myelopathy based on early signs and symptoms. Ann Neurol. 1978;4:51–59.
12. Tippett DS, Fishman PS, Panitch HS. Relapsing transverse myelitis.
Neurology. 1991;41:703–706.
13. Pandit L, Rao S. Recurrent myelitis. J Neurol Neurosurg Psychiatry.
1996;60:336 –338.
14. Nagaswami S, Kepes J, Foster DB, et al. Necrotizing myelitis: a
clinico-pathologic report of two cases associated with diplococcus
pneumoniae and mycoplasma pneumoniae infections. Trans Am Neurol
Assoc. 1973;98:290 –292.
15. Mirich DR, Kucharczyk W, Keller MA, et al. Subacute necrotizing
myelopathy: MR imaging in four pathologically proved cases. AJNR
Am J Neuroradiol. 1991;12:1077–1083.
16. Katz JD, Ropper AH. Progressive necrotic myelopathy: clinical course
in 9 patients. Arch Neurol. 2000;57:355–361.
17. de Macedo DD, de Mattos JP, Borges TM. 关Transverse myelopathy and
systemic lupus erythematosus: report of a case and review of the
literature兴. Ar Qneuropsiquiatr. 1979;37:76 – 84.
18. Piper PG. Disseminated lupus erythematosus with involvement of the
spinal cord. JAMA. 1953;153:215–217.
19. Adrianakos AA, Duffy J, Suzuki M, et al. Transverse myelitis in
systemic lupus erythematosus: report of three cases and review of the
literature. Ann Intern Med. 1975;83:616 – 624.
20. Nakano I, Mannen T, Mizutani T, et al. Peripheral white matter lesions
of the spinal cord with changes in small arachnoid arteries in systemic
lupus erythematosus. Clin Neuropathol. 1989;8:102–108.
21. Sinkovics JG, Gyorkey F, Thoma GW. A rapidly fatal case of systemic
lupus erythematosus: structure resembling viral nucleoprotein strands
in the kidney and activities of lymphocytes in culture. Texas Reports
Biol Med. 1969;27:887–908.
22. Weil MH. Disseminated lupus erythematosus with massive hemorrhagic manifestations and paraplegia. Lancet. 1955;75:353–360.
23. Ayala L, Barber DB, Lomba MR, et al. Intramedullary sarcoidosis
presenting as incomplete paraplegia: case report and literature review.
J Spinal Cord Med. 2000;23:96 –99.
24. Garcia-Zozaya IA. Acute transverse myelitis in a 7-month-old boy.
J Spinal Cord Med. 2001;24:114 –118.
25. Paine RS, Byers RK. Transverse myelopathy in childhood. Am J Dis
Child. 1968;85:151–163.
26. Patja A, Paunio M, Kinnunen E, et al. Risk of Guillain-Barré syndrome
after measles-mumps-rubella vaccination. J Pediatr. 2001;138:250 –254.
27. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré
syndrome following vaccination in the National Influenza Immunization
Program, United States, 1976 –1977. Am J Epidemiol. 1979;110:105–123.
28. Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and
clinical evaluation of Guillain-Barre syndrome reported in association
with the administration of swine influenza vaccines. Am J Epidemiol.
1984;119:841– 879.
29. Merelli E, Casoni F. Prognostic factors in multiple sclerosis: role of
intercurrent infections and vaccinations against influenza and hepatitis
B. Neurol Sci. 2000;21(4 suppl 2):S853–S856.
30. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and
the risk of multiple sclerosis. N Engl J Med. 2001;344:327–332.
16
The Neurologist • Volume 11, Number 1, January 2005
31. Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of
relapse in multiple sclerosis: Vaccines in Multiple Sclerosis Study
Group. N Engl J Med. 2001;344:319 –326.
32. Moriabadi NF, Niewiesk S, Kruse N, et al. Influenza vaccination in
MS: absence of T-cell response against white matter proteins. Neurology. 2001;56:938 –943.
33. Dowling PC, Cook SD. Role of infection in Guillain-Barré syndrome:
laboratory confirmation of herpesviruses in 41 cases. Ann Neurol.
1981;9(suppl):44 –55.
34. Sanders EA, Peters AC, Gratana JW, et al. Guillain-Barré syndrome after
varicella-zoster infection: report of two cases. J Neurol. 1987;234:437–439.
35. Tsukada N, Koh CS, Inoue A, et al. Demyelinating neuropathy associated
with hepatitis B virus infection: detection of immune complexes composed
of hepatitis B virus surface antigen. J Neurol Sci. 1987;77:203–216.
36. Thornton CA, Latif AS, Emmanuel JC. Guillain-Barré syndrome associated with human immunodeficiency virus infection in Zimbabwe.
Neurology. 1991;41:812– 815.
37. Rees JH, Soudain SE, Gregson NA, et al. Campylobacter jejuni infection
and Guillain-Barré syndrome. N Engl J Med. 1995;333:1374 –1379.
38. Mishu B, Ilyas AA, Koski CL, et al. Serologic evidence of previous
Campylobacter jejuni infection in patients with the Guillain-Barré
syndrome. Ann Intern Med. 1993;118:947–953.
39. Hariharan H, Naseema K, Kumaran C, et al. Detection of Campylobacter jejuni/E. coli infection in patients with Guillain-Barré syndrome by serology and culture. New Microbiol. 1996;19:267–271.
40. Jacobs BC, Endtz H, Van der Meche FG, et al. Serum anti-GQ1b IgG
antibodies recognize surface epitopes on Campylobacter jejuni from
patients with Miller Fisher syndrome. Ann Neurol. 1995;37:260 –264.
41. Kusunoki S, Shiina M, Kanazawa I. Anti-Gal-C antibodies in GBS
subsequent to mycoplasma infection: evidence of molecular mimicry.
Neurology. 2001;57:736 –738.
42. Jacobs BC, Endtz HP, Van der Meche FG, et al. Humoral immune
response against Campylobacter jejuni lipopolysaccharides in GuillainBarré and Miller Fisher syndrome. J Neuroimmunol. 1997;79:62– 68.
43. Lee WM, Westrick MA, Macher BA. High-performance liquid chromatography of long-chain neutral glycosphingolipids and gangliosides.
Biochim Biophys Acta. 1982;712:498 –504.
44. Moran AP, Rietschel ET, Kosunen TU, et al. Chemical characterization
of Campylobacter jejuni lipopolysaccharides containing N-acetylneuraminic acid and 2,3-diamino-2,3-dideoxy-D-glucose. J Bacteriol. 1991;
173:618 – 626.
45. Gregson NA, Rees JH, Hughes RA. Reactivity of serum IgG anti-GM1
ganglioside antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain-Barré syndrome
(GBS). J Neuroimmunol. 1997;73:28 –36.
46. Jacobs BC, Hazenberg MP, Van Doorn PA, et al. Cross-reactive
antibodies against gangliosides and Campylobacter jejuni lipopolysaccharides in patients with Guillain-Barré or Miller Fisher syndrome.
J Infect Dis. 1997;175:729 –733.
47. Hao Q, Saida T, Kuroki S, et al. Antibodies to gangliosides and
galactocerebroside in patients with Guillain-Barre syndrome with preceding Campylobacter jejuni and other identified infections. J Neuroimmunol. 1998;81:116 –126.
48. Goodyear CS, O’Hanlon GM, Plomp JJ, et al. Monoclonal antibodies
raised against Guillain-Barré syndrome-associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze
muscle-nerve preparations. J Clin Invest. 1999;104:697–708.
49. Plomp JJ, Molenaar PC, O’Hanlon GM, et al. Miller Fisher anti-GQ1b
antibodies: alpha-latrotoxin-like effects on motor end plates. Ann Neurol. 1999;45:189 –199.
50. O’Hanlon GM, Paterson GJ, Veitch J, et al. Mapping immunoreactive
epitopes in the human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies. Acta Neuropathol (Berl).
1998;95:605– 616.
51. Bohach GA, Fast DJ, Nelson RD, et al. Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related
illnesses. Crit Rev Microbiol. 1990;17:251–272.
52. Bohach GA. Staphylococcal enterotoxins B and C: structural requirements for superantigenic and entertoxigenic activities. Prep Biochem
Biotechnol. 1997;27:79 –110.
© 2005 Lippincott Williams & Wilkins
The Neurologist • Volume 11, Number 1, January 2005
53. Betley MJ, Borst DW, Regassa LB. Staphylococcal enterotoxins, toxic
shock syndrome toxin and streptococcal pyrogenic exotoxins: a comparative study of their molecular biology. Chem Immunol. 1992;55:1–35.
54. Zhang J, Vandevyver C, Stinissen P, et al. Activation and clonal
expansion of human myelin basic protein-reactive T cells by bacterial
superantigens. J Autoimmun. 1995;8:615– 632.
55. Kappler J, Kotzin B, Herron L, et al. V beta-specific stimulation of
human T cells by staphylococcal toxins. Science. 1989;244:811– 813.
56. Hong SC, Waterbury G, Janeway CA Jr. Different superantigens
interact with distinct sites in the Vbeta domain of a single T cell
receptor. J Exp Med. 1996;183:1437–1446.
57. Webb SR, Gascoigne NR. T-cell activation by superantigens. Curr
Opin Immunol. 1994;6:467– 475.
58. Acha-Orbea H, MacDonald HR. Superantigens of mouse mammary
tumor virus. Annu Rev Immunol. 1995;13:459 – 486.
59. Brocke S, Gaur A, Piercy C, et al. Induction of relapsing paralysis in
experimental autoimmune encephalomyelitis by bacterial superantigen.
Nature. 1993;365:642– 644.
60. Racke MK, Quigley L, Cannella B, et al. Superantigen modulation of
experimental allergic encephalomyelitis: activation of anergy determines outcome. J Immunol. 1994;152:2051–2059.
61. Brocke S, Hausmann S, Steinman L, et al. Microbial peptides and
superantigens in the pathogenesis of autoimmune diseases of the
central nervous system. Semin Immunol. 1998;10:57– 67.
62. Kotzin BL, Leung DY, Kappler J, et al. Superantigens and their
potential role in human disease. Adv Immunol. 1993;54:99 –166.
63. Vanderlugt CL, Begolka WS, Neville KL, et al. The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol Rev. 1998;164:63–72.
64. Fukazawa T, Hamada T, Kikuchi S, et al. Antineutrophil cytoplasmic
antibodies and the optic-spinal form of multiple sclerosis in Japan.
J Neurol Neurosurg Psychiatry. 1996;61:203–204.
65. Leonardi A, Arata L, Farinelli M, et al. Cerebrospinal fluid and
neuropathological study in Devic’s syndrome: evidence of intrathecal
immune activation. J Neurol Sci. 1987;82:281–290.
66. O’Riordan JI, Gallagher HL, Thompson AJ, et al. Clinical, CSF, and
MRI findings in Devic’s neuromyelitis optica. J Neurol Neurosurg
Psychiatry. 1996;60:382–387.
67. Reindl M, Linington C, Brehm U, et al. Antibodies against the myelin
oligodendrocyte glycoprotein and the myelin basic protein in multiple
sclerosis and other neurological diseases: a comparative study. Brain.
1999;122(pt 11):2047–2056.
68. Haase CG, Schmidt S. Detection of brain-specific autoantibodies to
myelin oligodendrocyte glycoprotein, S100beta and myelin basic protein in patients with Devic’s neuromyelitis optica. Neurosci Lett.
2001;307:131–133.
69. Garcia-Merino A, Blasco MR. Recurrent transverse myelitis with unusual
long-standing Gd-DTPA enhancement. J Neurol. 2000;247:550 –551.
70. Renard JL, Guillamo JS, Ramirez JM, et al. 关Acute transverse cervical
myelitis following hepatitis B vaccination: evolution of anti-HBs antibodies兴. Presse Med. 1999;28:1290 –1292.
71. Matsui M, Kakigi R, Watanabe S, et al. Recurrent demyelinating
transverse myelitis in a high titer HBs-antigen carrier. J Neurol Sci.
1996;139:235–237.
72. Kira J, Kawano Y, Yamasaki K, et al. Acute myelitis with hyperIgEaemia and mite antigen specific IgE: atopic myelitis. J Neurol Neurosurg Psychiatry. 1998;64:676 – 679.
73. Kikuchi H, Osoegawa M, Ochi H, et al. Spinal cord lesions of myelitis
with hyperIgEemia and mite antigen specific IgE (atopic myelitis)
manifest eosinophilic inflammation. J Neurol Sci. 2001;183:73–78.
74. de Seze J, Stojkovic T, Breteau G, et al. Acute myelopathies: clinical,
laboratory and outcome profiles in 79 cases. Brain. 2001;124(pt 8):
1509 –1521.
75. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Assessment of the
European classification criteria for Sjogren’s syndrome in a series of
clinically defined cases: results of a prospective multicentre study: the
European Study Group on Diagnostic Criteria for Sjogren’s Syndrome.
Ann Rheum Dis. 1996;55:116 –121.
76. Lockshin MD, Sammaritano LR, Schwartzman S. Validation of the
Sapporo criteria for antiphospholipid syndrome. Arthritis Rheum. 2000;
© 2005 Lippincott Williams & Wilkins
Acute Myelopathies
43:440 – 443.
77. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the
classification of systemic lupus erythematosus. Arthritis Rheum. 1982;
25:1271–1277.
78. Rudick RA, French CA, Breton D, et al. Relative diagnostic value of
cerebrospinal fluid kappa chains in MS: comparison with other immunoglobulin tests. Neurology. 1989;39:964 –968.
79. Hung KL, Chen WC, Huang CS. Diagnostic value of cerebrospinal
fluid immunoglobulin G (IgG) in pediatric neurological diseases.
J Formos Med Assoc. 1991;90:1055–1059.
80. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a
therapy initiated during a first demyelinating event in multiple sclerosis: CHAMPS Study Group. N Engl J Med. 2000;343:898 –904.
81. Knebusch M, Strassburg HM, Reiners K. Acute transverse myelitis in
childhood: nine cases and review of the literature. Dev Med Child
Neurol. 1998;40:631– 639.
82. Pidcock F, Krishnan C, Kerr DA. Acute transverse myelitis in childhood:
center based analysis of 40 children. 2003. Cur Ther Neurol Dis. In press.
83. Dunne K, Hopkins IJ, Shield LK. Acute transverse myelopathy in
childhood. Dev Med Child Neurol. 1986;28:198 –204.
84. Burns AS, Rivas DA, Ditunno JF. The management of neurogenic
bladder and sexual dysfunction after spinal cord injury. Spine. 2001;
26(24 suppl):S129 –S136.
85. DasGupta R, Fowler CJ. Sexual and urological dysfunction in multiple
sclerosis: better understanding and improved therapies. Curr Opin
Neurol. 2002;15:271–278.
86. Patten SB, Metz LM. Depression in multiple sclerosis. Psychother
Psychosom. 1997;66:286 –292.
87. Scott TF, Bhagavatula K, Snyder PJ, et al. Transverse myelitis: comparison with spinal cord presentations of multiple sclerosis. Neurology.
1998;50:429 – 433.
88. al Deeb SM, Yaqub BA, Bruyn GW, et al. Acute transverse myelitis:
a localized form of postinfectious encephalomyelitis. Brain. 1997;
120(pt 7):1115–1122.
89. Hummers LK, Krishnan C, Casciola-Rosen L, et al. Recurrent transverse myelitis associates with anti-Ro (SSA) autoantibodies. Neurology. 2004;62:147–149.
90. Irani DN, Kerr DA. 14-3-3 Protein in the cerebrospinal fluid of patients
with acute transverse myelitis. Lancet. 2000;355:901.
91. Wilske B. Microbiological diagnosis in Lyme borreliosis. Int J Med
Microbiol. 2002;291(suppl 33):114 –119.
92. Ferch RD, Morgan MK, Sears WR. Spinal arteriovenous malformations: a
review with case illustrations. J Clin Neurosci. 2001;8:299 –304.
93. Moriarity JL, Clatterbuck RE, Rigamonti D. The natural history of cavernous malformations. Neurosurg Clin North Am. 1999;10:411– 417.
94. Wityk RJ. Dural arteriovenous fistula of the spinal cord: an uncommon
cause of myelopathy. Semin Neurol. 1996;16:27–32.
95. Schreck RI, Manion WL, Kambin P, et al. Nucleus pulposus pulmonary
embolism: a case report. Spine. 1995;20:2463–2466.
96. Bots GT, Wattendorff AR, Buruma OJ, et al. Acute myelopathy caused
by fibrocartilaginous emboli. Neurology. 1981;31:1250 –1256.
97. Toro G, Roman GC, Navarro-Roman L, et al. Natural history of spinal
cord infarction caused by nucleus pulposus embolism. Spine. 1994;19:
360 –366.
98. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises: case 5–1991: a 61-year-old woman with an
abrupt onset of paralysis of the legs and impairment of the bladder and
bowel function. N Engl J Med. 1991;324:322–332.
99. Okada S, Okeda R. Pathology of radiation myelopathy. Neuropathology. 2001;21:247–265.
100. Liu CY, Yim BT, Wozniak AJ. Anticoagulation therapy for radiationinduced myelopathy. Ann Pharmacother. 2001;35:188 –191.
101. Glantz MJ, Burger PC, Friedman AH, et al. Treatment of radiationinduced nervous system injury with heparin and warfarin. Neurology.
1994;44:2020 –2027.
102. Asamoto S, Sugiyama H, Doi H, et al. Hyperbaric oxygen (HBO)
therapy for acute traumatic cervical spinal cord injury. Spinal Cord.
2000;38:538 –540.
103. Calabro F, Jinkins JR. MRI of radiation myelitis: a report of a case
treated with hyperbaric oxygen. Eur Radiol. 2000;10:1079 –1084.
17
The Neurologist • Volume 11, Number 1, January 2005
Kaplin et al
104. Angibaud G, Ducasse JL, Baille G, et al. 关Potential value of hyperbaric
oxygenation in the treatment of post-radiation myelopathies兴. Rev
Neurol (Paris). 1995;151:661– 666.
105. Ford B, Tampieri D, Francis G. Long-term follow-up of acute partial
transverse myelopathy. Neurology. 1992;42:250 –252.
106. Miller DH, Ormerod IE, Rudge P, et al. The early risk of multiple
sclerosis following isolated acute syndromes of the brainstem and
spinal cord. Ann Neurol. 1989;26:635– 639.
107. Ungurean A, Palfi S, Dibo G, et al. Chronic recurrent transverse
myelitis or multiple sclerosis. Funct Neurol. 1996;11:209 –214.
108. Bakshi R, Kinkel PR, Mechtler LL, et al. Magnetic resonance imaging
findings in 22 cases of myelitis: comparison between patients with and
without multiple sclerosis. Eur J Neurol. 1998;5:35– 48.
109. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic
criteria for multiple sclerosis: guidelines from the International Panel
on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121–127.
110. O’Riordan JI, Losseff NA, Phatouros C, et al. Asymptomatic spinal
cord lesions in clinically isolated optic nerve, brain stem, and spinal
cord syndromes suggestive of demyelination. J Neurol Neurosurg
Psychiatry. 1998;64:353–357.
111. Miller JA, Munro DD. Topical corticosteroids: clinical pharmacology
and therapeutic use. Drugs. 1980;19:119 –134.
112. Hallam NF. The use and abuse of topical corticosteroids in dermatology. Scott Med J. 1980;25:287–291.
113. Elovaara I, Lalla M, Spare E, et al. Methylprednisolone reduces
adhesion molecules in blood and cerebrospinal fluid in patients with
MS. Neurology. 1998;51:1703–1708.
114. Sellebjerg F, Christiansen M, Jensen J, et al. Immunological effects of
oral high-dose methylprednisolone in acute optic neuritis and multiple
sclerosis. Eur J Neurol. 2000;7:281–289.
115. Williams CS, Butler E, Roman GC. Treatment of myelopathy in
Sjogren syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol. 2001;58:815– 819.
116. Dumas JL, Valeyre D, Chapelon-Abric C, et al. Central nervous system
sarcoidosis: follow-up at MR imaging during steroid therapy. Radiology. 2000;214:411– 420.
117. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled
trial of methylprednisolone or naloxone in the treatment of acute
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
spinal-cord injury: results of the Second National Acute Spinal Cord
Injury Study. N Engl J Med. 1990;322:1405–1411.
Defresne P, Meyer L, Tardieu M, et al. Efficacy of high dose steroid
therapy in children with severe acute transverse myelitis. J Neurol
Neurosurg Psychiatry. 2001;71:272–274.
Lahat E, Pillar G, Ravid S, et al. Rapid recovery from transverse
myelopathy in children treated with methylprednisolone. Pediatr Neurol. 1998;19:279 –282.
Sebire G, Hollenberg H, Meyer L, et al. High dose methylprednisolone in
severe acute transverse myelopathy. Arch Dis Child. 1997;76:167–168.
Kennedy PG, Weir AI. Rapid recovery of acute transverse myelitis
treated with steroids. Postgrad Med J. 1988;64:384 –385.
Kalita J, Misra UK. Is methyl prednisolone useful in acute transverse
myelitis? Spinal Cord. 2001;39:471– 476.
Weinshenker BG. Plasma exchange for severe attacks of inflammatory
demyelinating diseases of the central nervous system. J Clin Apheresis.
2001;16:39 – 42.
Weinshenker BG. Therapeutic plasma exchange for acute inflammatory
demyelinating syndromes of the central nervous system. J Clin Apheresis. 1999;14:144 –148.
Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial
of plasma exchange in acute central nervous system inflammatory
demyelinating disease. Ann Neurol. 1999;46:878 – 886.
Keegan M, Pineda AA, McClelland RL, et al. Plasma exchange for
severe attacks of CNS demyelination: predictors of response. Neurology. 2002;58:143–146.
Wollinsky KH, Hulser PJ, Brinkmeier H, et al. CSF filtration is an
effective treatment of Guillain-Barre syndrome: a randomized clinical
trial. Neurology. 2001;57:774 –780.
Robinson WH, Steinman L, Utz PJ. Protein arrays for autoantibody
profiling and fine-specificity mapping. Proteomics. 2003;3:2077–2084.
Robinson WH, Fontoura P, Lee BJ, et al. Protein microarrays guide
tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.
Nat Biotechnol. 2003;21:1033–1039.
Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring
during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44:2862–2869.
84 BILLION IN 150,000 ⴙ/- YEARS*
Reliable Ways to Get Down to a Healthy,
Peaceful, Worldly One Billion:
Drive 50 on the 65 MPH beltway.
Eat bacon, butter, and eggs each breakfast.
“Entertain” your neighbor’s wife when he is out of town.
Leave loaded rifles in the grandchildren’s closet.
Repair the rain spouts on your three-story house.
Volunteer to look for that elusive water on the moon.
Negotiate the intra-uterine onset week of personhood & humanness.
Agree that the persistent vegetative state arrives earlier in Republicans.
Truly patriotic seniors will stop eating at age 75, or maybe 73.
Bomb uncivilized nations with contraceptives and Krispy-Kremes.
Sell your stairstepper.
Ed Spudis, MD
*NEWSWEEK, JAN. 2003
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