Transverse Myelitis Plus Syndrome and Acute Disseminated Encephalomyelitis Plus Syndrome a Case Series of 5 Children

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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, Children’s Medical Center Dallas. These cases were notable because they provided evidence of autoimmune events affecting the central nervous system but with Author Affiliations: Children’s additional peripheral axonal pathology. Medical Center Dallas, Dallas, Texas (Morriss); Department of Neurology and Neurotherapeutics, University of CONCLUSIONS AND RELEVANCE We describe these cases with respect to findings that suggest Texas Southwestern, Dallas (DeSena, a variant of these conditions that have concomitant nerve-root involvement. These patients Graves, Greenberg); Department of had worse outcomes than typical patients with transverse myelitis/acute disseminated Pediatrics, University of Texas encephalomyelitis, and these observations build on previous work by other investigators that Southwestern, Dallas (DeSena, Graves, Greenberg); Department of highlighted persistent flaccid paralysis and electrophysiological evidence of axonal loss Radiology, University of Texas portending a poorer prognosis. Furthermore, these cases suggest a potential role for Southwestern, Dallas (Morriss). approaching how we classify subtypes of transverse myelitis and acute disseminated Corresponding Author: Benjamin M. encephalomyelitis. Greenberg, MD, MHS, Department of Neurology and Neurotherapeutics, University of Texas Southwestern, JAMA Neurol. 2014;71(5):624-629. doi:10.1001/jamaneurol.2013.5323 5323 Harry Hines Blvd, Dallas, TX Published online March 17, 2014. 75390-8806 (benjamin.greenberg @utsouthwestern.edu).

ransverse myelitis (TM) and acute disseminated encephalomyelitis (ADEM) are infrequent causes of Report of Cases T acute paralysis in children, affecting both the upper and lower extremities and, in severe cases, resulting in blad- Children’s Medical Center Dallas institutional review board ap- der and bowel dysfunction. Early recognition is crucial proval was obtained, allowing for retrospective medical rec- because prompt aggressive treatment may reduce the ord review; patient consent was waived. extent of the sequelae of the disease. Despite early aggressive treatment, a percentage of children will go on to have Case 1 disabilities resulting in permanent functional impairment.1 A 13-year-old girl presented in late September 2009 with an as- At our center, we identified a subset of children who were cending paralysis over the course of 48 hours. On initial pre- initially identified as having TM, TM with brainstem exten- sentation, she was noted to have severe flaccid weakness in sion, or ADEM based on examination and imaging, but both of her lower extremities, with her left lower extremity af- follow-up magnetic resonance imaging (MRI) was found to fected more than her right lower extremity. Her reflexes were have either proximal ventral nerve-root enhancement or absent at her patellars and ankles bilaterally, and she had a diffuse cauda equina enhancement. These patients may downgoing plantar response bilaterally. She had a sensory level represent a novel subset of TM and ADEM or an entirely dis- on the right at the T10 dermatome. Sensation was impaired to tinct entity. pin, temperature, and light touch, although it was normal in

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Figure 1. Magnetic Resonance Imaging for Case 1

A B

C D

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-Barré syndrome (C and D, arrowheads).

her lower extremities distally to vibration and propriocep- chronic denervation and reinervation in all L4-L5 muscles of tion. She had an MRI of her spinal cord that showed intramed- the left leg and absent motor units in her left tibialis anterior. ullary increased T2 signal from T11 to L2, predominantly af- Although initially nonambulatory, she was able to improve sub- fecting the gray and white matter of the anterior spinal cord stantially with near-normal strength in her right lower extrem- bilaterally, without contrast enhancement on postcontrast T1- ity (at least 4/5 in all muscle groups) and more severe weak- weighted images. She had a white blood cell (WBC) count of 0 ness in her left hip flexors (4−/5) and left dorsiflexors (2/5). She μL and red blood cell (RBC) count of 0 μL in her cerebrospinal currently is able to ambulate with unilateral support for short fluid (CSF) and normal CSF glucose and protein levels. The and moderate distances, and her urinary retention present on workup findings were negative for enterovirus, herpes sim- initial admission has resolved (Figure 1). plex virus (HSV), Epstein-Barr virus (EBV), fungal and acid- fast bacilli infections, syphilis, neurosarcoidosis, and neuro- Case 2 myelitis optica. The IgG synthesis rate and index were normal. A 14-year-old boy presented in June 2009 with a rapidly pro- Despite not meeting typical criteria for idiopathic TM, the pa- gressive flaccid paralysis and burning pain involving both lower tient received 5 days of high-dose steroids, with no clear re- extremities over approximately 72 hours along with severe uri- sponse, followed by 5 rounds of plasma exchange, with some nary retention. He was presumptively treated with intrave- improvement. Approximately 2 weeks after her initial presen- nous immunoglobulin (IVIG) owing to initial concern for Guil- tation, a repeat MRI of the spinal cord was performed, and the lain-Barré syndrome. After failure to improve, he was patient was noted to have developed diffuse contrast enhance- transferred to our facility and was noted to have weakness in ment of ventral nerve roots. A nerve conduction study (NCS)/ all muscle groups in his lower extremities, rated as a 2/5 in large electromyogram (EMG) was not obtained acutely, although muscle groups in both legs, and absent reflexes in his patel- NCS/EMG obtained approximately 8 months later showed se- lars and ankles bilaterally. On initial assessment, he said he had verely decreased amplitudes in the left peroneal motor re- pain in his lower extremities, with some decrease to pain and sponses with a normal distal latency and conduction veloc- light touch noted only in his feet bilaterally. His spinal cord was ity. And she had EMG findings consistent with active and imaged by MRI, revealing increased intramedullary T2 signal

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within the anterior spinal cord from T11 to the conus medul- ralysis of his lower extremities progressing to weakness in his laris and diffuse enhancement of his ventral nerve roots on con- upper extremities, dysarthria, and dysphagia. He had marked trast-enhanced T1-weighted images. An NCS/EMG revealed find- weakness in his lower extremity hip flexors, hamstrings, and ings consistent with an acute motor axonal neuropathy. A repeat dorsiflexors (1/5) bilaterally and mild weakness in his upper ex- of this study approximately 12 months later again showed de- tremities (ranging from a 4−4+/5, depending on the muscle creased amplitudes, consistent with an axonal neuropathy, in group). Reflexes were intact in his upper extremities, being 2+/4 bilateral tibial and peroneal nerves, which was worse on his right bilaterally and were symmetric, and he had absent ankle re- side. Analysis of the CSF showed a WBC count of 8/μL, RBC flexes bilaterally and an absent right patellar reflex, although count of 0/μL, an elevated CSF protein level to 148 mg/dL, and his left was 2+/4. He had no noted sensory level, and his sen- a normal CSF glucose level. The workup results were negative sation to pain, temperature, vibration, and proprioception was for EBV, varicella zoster (VZV), HSV, West Nile (WN) virus, cy- normal in his upper and lower extremities. An MRI of his spi- tomegalovirus (CMV), Lyme disease with negative antibody test- nal cord was performed and demonstrated diffuse, patchy con- ing results for ganglioside antibodies, Sjögren syndrome anti- trast enhancement at multiple cord levels within the antero- gen A (SS-A), Sjögren syndrome antigen B (SS-B), lateral spinal cord extending up to the caudal medulla. ribonucleoprotein (RNP), Scl-70 antibodies, and antinuclear an- Cerebrospinal fluid analysis demonstrated a WBC count of 4 tibody (ANA). The patient was subsequently treated with high- μL and an RBC count of 1861 μL, with normal CSF protein and dose steroids for 5 days, intravenous (IV) cyclophosphamide glucose levels. Results from testing for WN virus and other ar- (1000 mg/m2) and plasma exchange. He minimally improved in boviruses, mycoplasma, influenza, CMV, EBV, and HSV were his lower extremity weakness and now only ambulates with bi- negative. Test results for ganglioside, double-stranded DNA, lateral support, requiring a wheelchair for longer distances. His RNP, SS-A, SS-B, and Scl-70 antibodies were all negative. Oli- urinary retention also improved, obviating the need for inter- goclonal bands were normal, with a normal IgG synthesis rate mittent catheterization, although he continues to have uri- but increased IgG index of 1.16. Testing results for anti– nary urgency and occasional incontinence. aquaporin-4 antibodies were also negative. Because of the extensive spinal cord involvement, he was aggressively treated Case 3 with concomitant high-dose steroids and plasma exchange for A 9-year-old girl presented in late August 2012 with pain in her a total of 7 exchanges, with modest improvement in his up- right lower extremity followed by weakness and sensory per extremities but minimal improvement in lower extremity changes. Her tone was noted to be reduced on initial examina- function. Approximately 2 weeks following his initial presen- tion, with mild weakness in the bilateral lower extremities that tation, a repeat spinal MRI was performed demonstrating dif- was worse on the right (about 4−/5 in proximal muscles), al- fuse ventral nerve-root enhancement, with mild improve- though the examination was limited by pain. She had absent re- ment in the enhancing intramedullary spinal cord lesions. In flexes in the bilateral patellars and ankles and a downgoing plan- addition, an NCS/EMG showed a mild decrease in amplitude tar response. She had no noted sensory level, and sensation to of his left tibial motor response only,with all other nerves tested light touch, pin, temperature, vibration, and proprioception having normal amplitudes, distal latencies, F-wave re- were normal in both lower extremities. She was suspected to sponses, and conduction velocities, as well as normal needle have Guillain-Barré syndrome, although an MRI obtained shortly EMG testing of all muscles tested in his lower extremities. He after hospitalization showed increased T2 signal in her spinal was then treated with IVIG for 5 days followed by IV cyclo- cord from T10 to T12, predominantly within the dorsal spinal phosphamide (1000 mg/m2). Following the IVIG and IV cyclo- cord. There was diffuse postcontrast enhancement of her cauda phosphamide, he modestly improved, although he still re- equina. Findings from an NCS/EMG obtained about 4 to 5 days quires bilateral support to stand and cannot walk. His NCS/ after the onset of her symptoms were normal. A lumbar punc- EMG finding was similar when he was tested approximately ture revealed a WBC count of 10 μL and RBC count of 10 μL in 4 weeks later, despite his modest improvements (Figure 2). the CSF, with normal CSF glucose and protein levels. Labora- tory testing results were negative for WN virus and all other ar- Case 5 boviruses; varicella zoster; mycoplasma; Lyme disease; hu- A 29-month-old girl presented in September 2012 following a man T-cell lymphotrophic virus type 1; human febrile illness with an unsteady gait that progressed over 48 immunodeficiency virus; HSV; hepatitis viruses A, B, and C; hours to refusal to walk. Her strength, reflexes, and sensation CMV; and EBV. Results from antibody testing for double- to light touch and pain were assessed to be normal on exami- stranded DNA, ANA, RNP, SS-A, SS-B, and Scl-70 antibodies were nation initially, although later examinations resulted in diffi- also negative. She had minimal response to high-dose steroids culty in assessing her strength, coordination, and sensation ow- for 5 days and was given IVIG, with good improvement. She ini- ing to fussiness. Magnetic resonance imaging of the brain and tially presented requiring unilateral support but was able to am- spine was performed that showed multifocal cerebral, cer- bulate without difficulty and had a complete recovery at the time ebellar, and dorsal spinal cord T2 hyperintense lesions with- of her 3-month follow-up after rehabilitation. out contrast enhancement. However, there was diffuse cauda equina enhancement along the nerve roots of her lower spi- Case 4 nal cord. She initially responded well to steroids, with near- An 8-year-old boy presented in September 2012 to our emer- complete resolution of symptoms. However, she presented gency department after awakening with complete flaccid pa- again within a week with more extensive brain and spinal cord

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Figure 2. Magnetic Resonance Imaging for Case 4

A B

C D

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 good response at our first clinic visit, she deteriorated follow- exchange followed by IVIG and IV cyclophosphamide owing ing completion of her steroid taper approximately 6 weeks af- to the continued radiologic and clinical progression. During this ter her initial discharge, with new enhancing lesions on her admission, because of persistent fussiness, her examination brain MRI, requiring re-escalation of steroids and another dose continued to be challenging, although her reflexes were noted of IV cyclophosphamide (Figure 3). 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 Discussion consistent with optic neuritis later in her course—this corre- sponded to the radiologic progression for which we escalated An acute myelitis with features of peripheral nerve involve- therapy. Coupled with her prior nerve-root enhancement, an ment has been described with WN virus, polio, or poliolike vi- NCS/EMG was obtained and was noted to be normal. Follow- ruses, certain vaccinations, and Lyme disease.2-10 Our case se- ing the IVIG and cyclophosphamide therapy, she clinically re- ries illustrates that ventral nerve-root inflammation or diffuse sponded well and subsequently had a near-complete recov- cauda equina inflammation may be found in patients present- ery 4 weeks following discharge. Her CSF showed a WBC count ing with clinical and MRI features of idiopathic TM (as in pa- of 2 μL, RBC count of 1178 μL, and normal CSF glucose and pro- tients 1-3), idiopathic TM with brainstem extension (as in pa- tein levels. Additional testing results for CMV, varicella zos- tient 4), or ADEM (as in patient 5). Of note, all of these patients ter, HSV, Lyme disease, WN virus and other common arbovi- presented in the mid to late summer, suggestive of a com- ruses, parvovirus B19, human herpes virus-6, and EBV were mon, yet unidentified, viral or other microbial etiology. All of negative. Test results for anti–aquaporin-4 antibodies, RNP, the patients had incomplete recoveries and/or particularly ag- SS-A, SS-B, Scl-70 antibodies, and ANA were negative; a posi- gressive disease courses, and the patients with isolated ven- tron-emission tomographic scan demonstrated no findings sug- tral root enhancement had the most residual disability. The gestive of neoplasm or sarcoidosis. She had 0 oligoclonal bands findings on imaging were time dependent (delayed from ini- and a normal IgG synthesis index and rate. Despite an initial tial presentation); thus, it is unknown whether the frequency

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Figure 3. Magnetic Resonance Imaging for Case 5

A B

C D

E F

Initial magnetic resonance imaging of the brain and spine in case 5 show a axial images of the brain. Magnetic resonance imaging studies performed 4 subtle increased T2 signal in the cervical spinal cord (A, arrowhead) and diffuse weeks later demonstrated progression of the size of the lesions in the spinal enhancement in the roots of the cauda equina (B, arrowhead). C, There are cord (D, arrowhead) with the development of intense enhancement (E, circle). multifocal demyelinating lesions on the fluid-attenuated inversion recovery F, Lesions in the brain had also progressed in size and number.

of proximal root involvement in idiopathic TM is simply un- unknown, but this finding has been described in a number of derestimated or these cases may represent a distinct patho- infections that can affect anterior horn cells. All of the pa- physiologic mechanism. Whether the enhancing nerve roots tients presented with flaccid paralysis, and 3 of the patients on MRI represent antigen-driven inflammation or blood- had evidence of possible axonal loss, indicated by decreased brain barrier breakdown relative to neuronal degeneration is amplitudes of affected areas. Other investigators have noted

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the involvement of nerve roots in certain patients with TM, and Because of the diagnostic implications of TM, we argue that our findings are also in agreement with previous findings that neuroimaging should be considered in all cases of acute in- persistent flaccid paralysis and evidence of axonal loss, either flammatory demyelinating polyradiculoneuropathy. In pa- by NCS or by T1 hypointensities in the cord, are likely associ- tients diagnosed as having TM, follow-up imaging of the spi- ated with a higher risk for incomplete motor recovery.9,11-13 Ex- nal cord should be considered in patients not responding to tensive neurophysiological work done by Kalita and therapy. The finding that some, but not all, of our patients dem- colleagues14-16 also noted this association and further postu- onstrated abnormal findings on NCS/EMG is intriguing, and we lated that weakness, as evident on NCS/EMG, may indicate a feel these patients were either etiologically and/or pathophysi- particular threshold of anterior horn cells has been lost. In their ologically distinct from TM and ADEM with pure central ner- work, they found a high correlation between abnormal NCS and vous system involvement. It has been our practice to treat these prognosis.14-16 In addition, the fact that these patients can pre- patients more aggressively because of our concern about their sent with marked flaccid paralysis and areflexia, making them overall prognosis, although we recognize that further re- clinically indistinguishable from acute inflammatory demy- search may uncover findings that would refute this ap- elinating polyradiculoneuropathy, is notable. Many of these proach. Our observations build on those of previous investi- TM plus cases may be missed and could account for patients gators, and we argue that these patients, many of whom have with acute inflammatory demyelinating polyradiculoneuropa- suboptimal outcomes, should also be a focus for study and/or thy who are labeled as nonresponders. should have their own classification under the TM rubric.

ARTICLE INFORMATION Assessment Subcommittee of American Academy 9. Martens-Le Bouar H, Korinthenberg R. Accepted for Publication: September 30, 2013. of Neurology. Evidence-based guideline: clinical Polyradiculoneuritis with myelitis: a rare differential evaluation and treatment of transverse myelitis: diagnosis of Guillain-Barré syndrome. Published Online: March 17, 2014. report of the Therapeutics and Technology Neuropediatrics. 2002;33(2):93-96. doi:10.1001/jamaneurol.2013.5323. Assessment Subcommittee of the American 10. Chua HC, Tjia H, Sitoh YY. Concurrent myelitis Author Contributions: Drs DeSena and Greenberg Academy of Neurology. Neurology. and Guillain-Barré syndrome after varicella had full access to all of the data in the study and 2011;77(24):2128-2134. infection. Int J Clin Pract. 2001;55(9):643-644. take responsibility for the integrity of the data and 2. Sato N, Watanabe K, Ohta K, Tanaka H. Acute the accuracy of the data analysis. 11. Pidcock FS, Krishnan C, Crawford TO, Salorio CF, transverse myelitis and acute motor axonal Trovato M, Kerr DA. Acute transverse myelitis in Study concept and design: DeSena, Graves, neuropathy developed after vaccinations against Greenberg. childhood: center-based analysis of 47 cases. seasonal and 2009 A/H1N1 influenza. Intern Med. Neurology. 2007;68(18):1474-1480. Acquisition of data: DeSena, Graves. 2011;50(5):503-507. Analysis and interpretation of data: All authors. 12. Yiu EM, Kornberg AJ, Ryan MM, Coleman LT, Drafting of the manuscript: DeSena, Morriss, 3. De Cauwer H, Declerck S, De Smet J, et al. Motor Mackay MT. Acute transverse myelitis and acute Greenberg. neuron disease features in a patient with disseminated encephalomyelitis in childhood: Critical revision of the manuscript for important neuroborreliosis and a cervical anterior horn lesion. spectrum or separate entities? J Child Neurol. intellectual content: All authors. Acta Clin Belg. 2009;64(3):225-227. 2009;24(3):287-296. Obtained funding: Greenberg. 4. Tripp A. Acute transverse myelitis and 13. Knebusch M, Strassburg HM, Reiners K. Acute Administrative, technical, and material support: Guillain-Barre overlap syndrome following influenza transverse myelitis in childhood: nine cases and Graves, Greenberg. infection. CNS Spectr. 2008;13(9):744-746. review of the literature. Dev Med Child Neurol. Study supervision: Graves, Greenberg. 5. Bernard G, Riou E, Rosenblatt B, Dilenge ME, 1998;40(9):631-639. Conflict of Interest Disclosures: Dr DeSena’s Poulin C. Simultaneous Guillain-Barré syndrome 14. Kalita J, Misra UK. Neurophysiological studies in fellowship was provided by the Transverse Myelitis and acute disseminated encephalomyelitis in the acute transverse myelitis. J Neurol. Association. Dr Greenberg has consulted for pediatric population. J Child Neurol. 2000;247(12):943-948. DioGenix, Elan, and Biogen Idec; has previously 2008;23(7):752-757. 15. Misra UK, Kalita J. Can electromyography given expert testimony; and has received 6. Howell KB, Wanigasinghe J, Leventer RJ, Ryan grants/grants pending with the Accelerated Cure predict the prognosis of transverse myelitis? MM. Concomitant transverse myelitis and acute J Neurol. 1998;245(11):741-744. Project, the Guthy-Jackson Charitable Foundation, motor axonal neuropathy in an adolescent. Pediatr and Amplimmune. Dr Greenberg has also received Neurol. 2007;37(5):378-381. 16. Kalita J, Misra UK, Mandal SK. Prognostic payment for or has given lectures for the Multiple predictors of acute transverse myelitis. Acta Neurol 7. Sejvar JJ. West Nile virus and “poliomyelitis.” Sclerosis Association of America and Medilogix, and Scand. 1998;98(1):60-63. he has stock/stock options with DioGenix. No other Neurology. 2004;63(2):206-207. disclosures were reported. 8. Samoilovich EO, Feldman EV, Yermalovich MA, Protas II, Titov LP. Vaccine-associated paralytic REFERENCES poliomyelitis and other diseases with acute flaccid 1. Scott TF, Frohman EM, De Seze J, Gronseth GS, paralysis syndrome in Belarus. Cent Eur J Public Weinshenker BG; Therapeutics and Technology Health. 2003;11(4):213-218.

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