Research

Case Report/Case Series

Transverse Myelitis Plus Syndrome and Acute Disseminated

Encephalomyelitis Plus Syndrome
A Case Series of 5 Children
Allen DeSena, MD, MPH; Donna Graves, MD; Michael C. Morriss, MD; Benjamin M. Greenberg, MD, MHS

IMPORTANCE Classically, transverse myelitis and acute disseminated encephalomyelitis are

considered central nervous system demyelinating conditions. In both conditions, the spinal
cord is involved to varying degrees, and there is a variety of presentations, usually involving
some degree of progressive paralysis of the upper and/or lower extremities. Treatment
usually consists of high-dose intravenous steroids in addition to plasma exchange and/or
intravenous immunoglobulin. In some cases, immunosuppressive medications, such as
intravenous cyclophosphamide, have been used with variable success. Cases with atypical
features on examination, imaging, or with neurophysiological studies may be helpful in
shedding light on the etiology and/or pathophysiology because many of these patients have
permanent disabilities despite appropriate treatment.
OBSERVATIONS This case series presents 5 pediatric cases observed from 2009-2012 at our
medical center, Childrens Medical Center Dallas. These cases were notable because they
provided evidence of autoimmune events affecting the central nervous system but with
additional peripheral axonal pathology.
CONCLUSIONS AND RELEVANCE We describe these cases with respect to findings that suggest
a variant of these conditions that have concomitant nerve-root involvement. These patients
had worse outcomes than typical patients with transverse myelitis/acute disseminated
encephalomyelitis, and these observations build on previous work by other investigators that
highlighted persistent flaccid paralysis and electrophysiological evidence of axonal loss
portending a poorer prognosis. Furthermore, these cases suggest a potential role for
approaching how we classify subtypes of transverse myelitis and acute disseminated
encephalomyelitis.
JAMA Neurol. 2014;71(5):624-629. doi:10.1001/jamaneurol.2013.5323
Published online March 17, 2014.

ransverse myelitis (TM) and acute disseminated

encephalomyelitis (ADEM) are infrequent causes of
acute paralysis in children, affecting both the upper
and lower extremities and, in severe cases, resulting in bladder and bowel dysfunction. Early recognition is crucial
because prompt aggressive treatment may reduce the
extent of the sequelae of the disease. Despite early aggressive treatment, a percentage of children will go on to have
disabilities resulting in permanent functional impairment.1
At our center, we identified a subset of children who were
initially identified as having TM, TM with brainstem extension, or ADEM based on examination and imaging, but
follow-up magnetic resonance imaging (MRI) was found to
have either proximal ventral nerve-root enhancement or
diffuse cauda equina enhancement. These patients may
represent a novel subset of TM and ADEM or an entirely distinct entity.
624

Author Affiliations: Childrens

Medical Center Dallas, Dallas, Texas
(Morriss); Department of Neurology
and Neurotherapeutics, University of
Texas Southwestern, Dallas (DeSena,
Graves, Greenberg); Department of
Pediatrics, University of Texas
Southwestern, Dallas (DeSena,
Graves, Greenberg); Department of
Radiology, University of Texas
Southwestern, Dallas (Morriss).
Corresponding Author: Benjamin M.
Greenberg, MD, MHS, Department of
Neurology and Neurotherapeutics,
University of Texas Southwestern,
5323 Harry Hines Blvd, Dallas, TX
75390-8806 (benjamin.greenberg
@utsouthwestern.edu).

Report of Cases
Childrens Medical Center Dallas institutional review board approval was obtained, allowing for retrospective medical record review; patient consent was waived.

Case 1
A 13-year-old girl presented in late September 2009 with an ascending paralysis over the course of 48 hours. On initial presentation, she was noted to have severe flaccid weakness in
both of her lower extremities, with her left lower extremity affected more than her right lower extremity. Her reflexes were
absent at her patellars and ankles bilaterally, and she had a
downgoing plantar response bilaterally. She had a sensory level
on the right at the T10 dermatome. Sensation was impaired to
pin, temperature, and light touch, although it was normal in

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Figure 1. Magnetic Resonance Imaging for Case 1

A

A, The patient presented with

multifocal areas of increased T2 signal
in the distal spinal cord on magnetic
resonance imaging consistent with
acute disseminated
encephalomyelitis (arrowhead).
B, At initial presentation, there was
no abnormal enhancement in the
roots of the cauda equina. On
follow-up imaging 2 weeks later, the
patient had developed intense
contrast enhancement in the ventral
roots of the cauda equina in a typical
pattern for Guillain-Barr syndrome
(C and D, arrowheads).

her lower extremities distally to vibration and proprioception. She had an MRI of her spinal cord that showed intramedullary increased T2 signal from T11 to L2, predominantly affecting the gray and white matter of the anterior spinal cord
bilaterally, without contrast enhancement on postcontrast T1weighted images. She had a white blood cell (WBC) count of 0
L and red blood cell (RBC) count of 0 L in her cerebrospinal
fluid (CSF) and normal CSF glucose and protein levels. The
workup findings were negative for enterovirus, herpes simplex virus (HSV), Epstein-Barr virus (EBV), fungal and acidfast bacilli infections, syphilis, neurosarcoidosis, and neuromyelitis optica. The IgG synthesis rate and index were normal.
Despite not meeting typical criteria for idiopathic TM, the patient received 5 days of high-dose steroids, with no clear response, followed by 5 rounds of plasma exchange, with some
improvement. Approximately 2 weeks after her initial presentation, a repeat MRI of the spinal cord was performed, and the
patient was noted to have developed diffuse contrast enhancement of ventral nerve roots. A nerve conduction study (NCS)/
electromyogram (EMG) was not obtained acutely, although
NCS/EMG obtained approximately 8 months later showed severely decreased amplitudes in the left peroneal motor responses with a normal distal latency and conduction velocity. And she had EMG findings consistent with active and

chronic denervation and reinervation in all L4-L5 muscles of

the left leg and absent motor units in her left tibialis anterior.
Although initially nonambulatory, she was able to improve substantially with near-normal strength in her right lower extremity (at least 4/5 in all muscle groups) and more severe weakness in her left hip flexors (4/5) and left dorsiflexors (2/5). She
currently is able to ambulate with unilateral support for short
and moderate distances, and her urinary retention present on
initial admission has resolved (Figure 1).

Case 2
A 14-year-old boy presented in June 2009 with a rapidly progressive flaccid paralysis and burning pain involving both lower
extremities over approximately 72 hours along with severe urinary retention. He was presumptively treated with intravenous immunoglobulin (IVIG) owing to initial concern for Guillain-Barr syndrome. After failure to improve, he was
transferred to our facility and was noted to have weakness in
all muscle groups in his lower extremities, rated as a 2/5 in large
muscle groups in both legs, and absent reflexes in his patellars and ankles bilaterally. On initial assessment, he said he had
pain in his lower extremities, with some decrease to pain and
light touch noted only in his feet bilaterally. His spinal cord was
imaged by MRI, revealing increased intramedullary T2 signal

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within the anterior spinal cord from T11 to the conus medullaris and diffuse enhancement of his ventral nerve roots on contrast-enhanced T1-weighted images. An NCS/EMG revealed findings consistent with an acute motor axonal neuropathy. A repeat
of this study approximately 12 months later again showed decreased amplitudes, consistent with an axonal neuropathy, in
bilateral tibial and peroneal nerves, which was worse on his right
side. Analysis of the CSF showed a WBC count of 8/L, RBC
count of 0/L, an elevated CSF protein level to 148 mg/dL, and
a normal CSF glucose level. The workup results were negative
for EBV, varicella zoster (VZV), HSV, West Nile (WN) virus, cytomegalovirus (CMV), Lyme disease with negative antibody testing results for ganglioside antibodies, Sjgren syndrome antigen A (SS-A), Sjgren syndrome antigen B (SS-B),
ribonucleoprotein (RNP), Scl-70 antibodies, and antinuclear antibody (ANA). The patient was subsequently treated with highdose steroids for 5 days, intravenous (IV) cyclophosphamide
(1000 mg/m2) and plasma exchange. He minimally improved in
his lower extremity weakness and now only ambulates with bilateral support, requiring a wheelchair for longer distances. His
urinary retention also improved, obviating the need for intermittent catheterization, although he continues to have urinary urgency and occasional incontinence.

Case 3
A 9-year-old girl presented in late August 2012 with pain in her
right lower extremity followed by weakness and sensory
changes. Her tone was noted to be reduced on initial examination, with mild weakness in the bilateral lower extremities that
was worse on the right (about 4/5 in proximal muscles), although the examination was limited by pain. She had absent reflexes in the bilateral patellars and ankles and a downgoing plantar response. She had no noted sensory level, and sensation to
light touch, pin, temperature, vibration, and proprioception
were normal in both lower extremities. She was suspected to
have Guillain-Barr syndrome, although an MRI obtained shortly
after hospitalization showed increased T2 signal in her spinal
cord from T10 to T12, predominantly within the dorsal spinal
cord. There was diffuse postcontrast enhancement of her cauda
equina. Findings from an NCS/EMG obtained about 4 to 5 days
after the onset of her symptoms were normal. A lumbar puncture revealed a WBC count of 10 L and RBC count of 10 L in
the CSF, with normal CSF glucose and protein levels. Laboratory testing results were negative for WN virus and all other arboviruses; varicella zoster; mycoplasma; Lyme disease; human T-cell lymphotrophic v irus type 1; human
immunodeficiency virus; HSV; hepatitis viruses A, B, and C;
CMV; and EBV. Results from antibody testing for doublestranded DNA, ANA, RNP, SS-A, SS-B, and Scl-70 antibodies were
also negative. She had minimal response to high-dose steroids
for 5 days and was given IVIG, with good improvement. She initially presented requiring unilateral support but was able to ambulate without difficulty and had a complete recovery at the time
of her 3-month follow-up after rehabilitation.

Case 4
An 8-year-old boy presented in September 2012 to our emergency department after awakening with complete flaccid pa626

ralysis of his lower extremities progressing to weakness in his

upper extremities, dysarthria, and dysphagia. He had marked
weakness in his lower extremity hip flexors, hamstrings, and
dorsiflexors (1/5) bilaterally and mild weakness in his upper extremities (ranging from a 44+/5, depending on the muscle
group). Reflexes were intact in his upper extremities, being 2+/4
bilaterally and were symmetric, and he had absent ankle reflexes bilaterally and an absent right patellar reflex, although
his left was 2+/4. He had no noted sensory level, and his sensation to pain, temperature, vibration, and proprioception was
normal in his upper and lower extremities. An MRI of his spinal cord was performed and demonstrated diffuse, patchy contrast enhancement at multiple cord levels within the anterolateral spinal cord extending up to the caudal medulla.
Cerebrospinal fluid analysis demonstrated a WBC count of 4
L and an RBC count of 1861 L, with normal CSF protein and
glucose levels. Results from testing for WN virus and other arboviruses, mycoplasma, influenza, CMV, EBV, and HSV were
negative. Test results for ganglioside, double-stranded DNA,
RNP, SS-A, SS-B, and Scl-70 antibodies were all negative. Oligoclonal bands were normal, with a normal IgG synthesis rate
but increased IgG index of 1.16. Testing results for anti
aquaporin-4 antibodies were also negative. Because of the extensive spinal cord involvement, he was aggressively treated
with concomitant high-dose steroids and plasma exchange for
a total of 7 exchanges, with modest improvement in his upper extremities but minimal improvement in lower extremity
function. Approximately 2 weeks following his initial presentation, a repeat spinal MRI was performed demonstrating diffuse ventral nerve-root enhancement, with mild improvement in the enhancing intramedullary spinal cord lesions. In
addition, an NCS/EMG showed a mild decrease in amplitude
of his left tibial motor response only, with all other nerves tested
having normal amplitudes, distal latencies, F-wave responses, and conduction velocities, as well as normal needle
EMG testing of all muscles tested in his lower extremities. He
was then treated with IVIG for 5 days followed by IV cyclophosphamide (1000 mg/m2). Following the IVIG and IV cyclophosphamide, he modestly improved, although he still requires bilateral support to stand and cannot walk. His NCS/
EMG finding was similar when he was tested approximately
4 weeks later, despite his modest improvements (Figure 2).

Case 5
A 29-month-old girl presented in September 2012 following a
febrile illness with an unsteady gait that progressed over 48
hours to refusal to walk. Her strength, reflexes, and sensation
to light touch and pain were assessed to be normal on examination initially, although later examinations resulted in difficulty in assessing her strength, coordination, and sensation owing to fussiness. Magnetic resonance imaging of the brain and
spine was performed that showed multifocal cerebral, cerebellar, and dorsal spinal cord T2 hyperintense lesions without contrast enhancement. However, there was diffuse cauda
equina enhancement along the nerve roots of her lower spinal cord. She initially responded well to steroids, with nearcomplete resolution of symptoms. However, she presented
again within a week with more extensive brain and spinal cord

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Case Report/Case Series Research

Figure 2. Magnetic Resonance Imaging for Case 4

A

Magnetic resonance imaging of the

spine from case 4 shows diffuse
increased T2 signal and swelling in
the distal spinal cord (A, arrowhead),
but without enhancement in the
spinal cord lesions or the roots of the
cauda equina (B). Two weeks later, a
repeat magnetic resonance image
demonstrated improvement in the T2
signal and swelling in the distal spinal
cord (C), but interval development of
diffuse inflammatory enhancement in
the roots of the cauda equina (D,
arrowhead).

lesions. She was treated at that time with steroids and plasma
exchange followed by IVIG and IV cyclophosphamide owing
to the continued radiologic and clinical progression. During this
admission, because of persistent fussiness, her examination
continued to be challenging, although her reflexes were noted
to be absent in her lower extremities approximately 4 weeks
after her initial presentation. Her inability to ambulate well was
her most notable finding, but she also developed visual loss
consistent with optic neuritis later in her coursethis corresponded to the radiologic progression for which we escalated
therapy. Coupled with her prior nerve-root enhancement, an
NCS/EMG was obtained and was noted to be normal. Following the IVIG and cyclophosphamide therapy, she clinically responded well and subsequently had a near-complete recovery 4 weeks following discharge. Her CSF showed a WBC count
of 2 L, RBC count of 1178 L, and normal CSF glucose and protein levels. Additional testing results for CMV, varicella zoster, HSV, Lyme disease, WN virus and other common arboviruses, parvovirus B19, human herpes virus-6, and EBV were
negative. Test results for antiaquaporin-4 antibodies, RNP,
SS-A, SS-B, Scl-70 antibodies, and ANA were negative; a positron-emission tomographic scan demonstrated no findings suggestive of neoplasm or sarcoidosis. She had 0 oligoclonal bands
and a normal IgG synthesis index and rate. Despite an initial

good response at our first clinic visit, she deteriorated following completion of her steroid taper approximately 6 weeks after her initial discharge, with new enhancing lesions on her
brain MRI, requiring re-escalation of steroids and another dose
of IV cyclophosphamide (Figure 3).

Discussion
An acute myelitis with features of peripheral nerve involvement has been described with WN virus, polio, or poliolike viruses, certain vaccinations, and Lyme disease.2-10 Our case series illustrates that ventral nerve-root inflammation or diffuse
cauda equina inflammation may be found in patients presenting with clinical and MRI features of idiopathic TM (as in patients 1-3), idiopathic TM with brainstem extension (as in patient 4), or ADEM (as in patient 5). Of note, all of these patients
presented in the mid to late summer, suggestive of a common, yet unidentified, viral or other microbial etiology. All of
the patients had incomplete recoveries and/or particularly aggressive disease courses, and the patients with isolated ventral root enhancement had the most residual disability. The
findings on imaging were time dependent (delayed from initial presentation); thus, it is unknown whether the frequency

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Figure 3. Magnetic Resonance Imaging for Case 5

628

Initial magnetic resonance imaging of the brain and spine in case 5 show a
subtle increased T2 signal in the cervical spinal cord (A, arrowhead) and diffuse
enhancement in the roots of the cauda equina (B, arrowhead). C, There are
multifocal demyelinating lesions on the fluid-attenuated inversion recovery

axial images of the brain. Magnetic resonance imaging studies performed 4

weeks later demonstrated progression of the size of the lesions in the spinal
cord (D, arrowhead) with the development of intense enhancement (E, circle).
F, Lesions in the brain had also progressed in size and number.

of proximal root involvement in idiopathic TM is simply underestimated or these cases may represent a distinct pathophysiologic mechanism. Whether the enhancing nerve roots
on MRI represent antigen-driven inflammation or bloodbrain barrier breakdown relative to neuronal degeneration is

unknown, but this finding has been described in a number of

infections that can affect anterior horn cells. All of the patients presented with flaccid paralysis, and 3 of the patients
had evidence of possible axonal loss, indicated by decreased
amplitudes of affected areas. Other investigators have noted

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the involvement of nerve roots in certain patients with TM, and

our findings are also in agreement with previous findings that
persistent flaccid paralysis and evidence of axonal loss, either
by NCS or by T1 hypointensities in the cord, are likely associated with a higher risk for incomplete motor recovery.9,11-13 Extensive neurophysiologic al work done by Kalita and
colleagues14-16 also noted this association and further postulated that weakness, as evident on NCS/EMG, may indicate a
particular threshold of anterior horn cells has been lost. In their
work, they found a high correlation between abnormal NCS and
prognosis.14-16 In addition, the fact that these patients can present with marked flaccid paralysis and areflexia, making them
clinically indistinguishable from acute inflammatory demyelinating polyradiculoneuropathy, is notable. Many of these
TM plus cases may be missed and could account for patients
with acute inflammatory demyelinating polyradiculoneuropathy who are labeled as nonresponders.

ARTICLE INFORMATION
Accepted for Publication: September 30, 2013.
Published Online: March 17, 2014.
doi:10.1001/jamaneurol.2013.5323.
Author Contributions: Drs DeSena and Greenberg
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: DeSena, Graves,
Greenberg.
Acquisition of data: DeSena, Graves.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: DeSena, Morriss,
Greenberg.
Critical revision of the manuscript for important
intellectual content: All authors.
Obtained funding: Greenberg.
Administrative, technical, and material support:
Graves, Greenberg.
Study supervision: Graves, Greenberg.
Conflict of Interest Disclosures: Dr DeSenas
fellowship was provided by the Transverse Myelitis
Association. Dr Greenberg has consulted for
DioGenix, Elan, and Biogen Idec; has previously
given expert testimony; and has received
grants/grants pending with the Accelerated Cure
Project, the Guthy-Jackson Charitable Foundation,
and Amplimmune. Dr Greenberg has also received
payment for or has given lectures for the Multiple
Sclerosis Association of America and Medilogix, and
he has stock/stock options with DioGenix. No other
disclosures were reported.
REFERENCES
1. Scott TF, Frohman EM, De Seze J, Gronseth GS,
Weinshenker BG; Therapeutics and Technology

Because of the diagnostic implications of TM, we argue that

neuroimaging should be considered in all cases of acute inflammatory demyelinating polyradiculoneuropathy. In patients diagnosed as having TM, follow-up imaging of the spinal cord should be considered in patients not responding to
therapy. The finding that some, but not all, of our patients demonstrated abnormal findings on NCS/EMG is intriguing, and we
feel these patients were either etiologically and/or pathophysiologically distinct from TM and ADEM with pure central nervous system involvement. It has been our practice to treat these
patients more aggressively because of our concern about their
overall prognosis, although we recognize that further research may uncover findings that would refute this approach. Our observations build on those of previous investigators, and we argue that these patients, many of whom have
suboptimal outcomes, should also be a focus for study and/or
should have their own classification under the TM rubric.

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