Longitudinally extensive transverse myelitis.

REVIEW URRENT C OPINION

Longitudinally extensive transverse myelitis W. Oliver Tobin, Brian G. Weinshenker, and Claudia F. Lucchinetti

Purpose of review Longitudinally extensive transverse myelitis (LETM) is a frequently devastating clinical syndrome which has come into focus for its association with neuromyelitis optica (NMO). Recent advances in the diagnosis of NMO have led to very sensitive and specific tests and advances in therapy for this disorder. LETM is not pathognomonic of NMO, therefore it is important to investigate for other causes of myelopathy in these patients. This review aims to discuss recent advances in NMO diagnosis and treatment, and to discuss the differential diagnosis in patients presenting with LETM. Recent findings Fluorescence-activated cell sorting and cell binding assays for NMO-IgG are the most sensitive for detecting NMO spectrum disorders. Patients who have a clinical presentation of NMO, who have been tested with older ELISA or immunofluorescence assay and been found to be negative, should be retested with a fluorescence-activated cell sorting assay when available, particularly in the presence of recurrent LETM. Novel therapeutic strategies for LETM in the context of NMO include eculizumab, which could be considered in patients with active disease who have failed azathioprine and rituximab. Thorough investigation of patients with LETM who are negative for NMO-IgG may lead to an alternate cause for myelopathy. Summary LETM is a heterogeneous condition. Novel treatment strategies are available for NMO, but other causes need to be excluded in NMO-IgG-seronegative patients. Keywords longitudinally extensive transverse myelitis, myelitis, neuromyelitis optica

INTRODUCTION Transverse myelitis is defined as the development of an inflammatory spinal cord syndrome with a nadir between 4 h and 21 days following the onset of symptoms [1]. The syndrome can be roughly divided into two groups based on whether the syndrome is complete (bilateral, motor, sensory and autonomic, typically with a long spinal cord lesion on MRI) or partial (unilateral, motor or sensory, typically with a short spinal cord lesion on one side of the spinal cord). However, the clinical and radiologic findings do not always co-associate. Longitudinally extensive transverse myelitis (LETM) is generally taken to mean myelitis which extends over a continuous lesion which is at least 3 vertebral segments in length [2,3]. A number of conditions can be associated with LETM, although neuromyelitis optica (NMO) is the most frequent, followed by spinal cord infarction and parainfectious myelopathy in one series [4]. The identification of a humorally mediated mechanism of pathology in patients with NMO [5], followed by the discovery of a highly specific and sensitive serological biomarker, NMO-IgG [6],

has focused attention on longitudinally extensive lesions of the spinal cord. However, the cause of longitudinal myelopathy is not NMO in all patients. In this review, we will discuss recent advances in the field of NMO, along with discussing other potential causes in patients with longitudinally extensive myelopathies.

NEUROMYELITIS OPTICA Neuromyelitis optica, as initially described by Devic and Gault in 1924, was a syndrome of bilateral optic neuritis and transverse myelitis [7,8]. Although previously considered an aggressive variant of multiple Department of Neurology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA Correspondence to Claudia F. Lucchinetti, MD, Department of Neurology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. Tel: +1 507 266 3196; fax: +1 507 538 7060; e-mail: clucchinetti@ mayo.edu Curr Opin Neurol 2014, 27:279–289 DOI:10.1097/WCO.0000000000000093

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Demyelinating diseases

KEY POINTS Longitudinally extensive transverse myelitis is a clinical and radiological finding with a diverse range of causes. Cell-based NMO-IgG testing assays are more sensitive and specific than ELISA or immunofluorescence methods. Patients with proven NMO require long-term immunosuppression. Preventive treatments targeting aquaporin-4 are currently under investigation.

sclerosis (MS), the discovery of a highly specific serum autoantibody in 2004, NMO-IgG, provided the first biomarker that reliably distinguished NMO from MS and other central nervous system (CNS) inflammatory demyelinating disorders [6]. Typical MRI features of NMO-associated myelopathy are demonstrated in Fig. 1. Lesions tend to be central, with associated mass effect and contrast enhancement in acute lesions. In contrast to MS, T1 hypointensity and a predilection for spinal cord gray matter are typical for NMO [9]. Mass effect is likely due to edema in the cord, exacerbated by abnormal water homeostasis in the affected neurons and astrocytes. In contrast to MS, NMO does not appear to be

associated with secondary progression [10]. Accumulation of disability is directly related to relapse frequency and severity, underscoring the need for aggressive relapse prevention. The discovery of NMO-IgG has been incorporated into diagnostic criteria enhancing both the sensitivity as well as specificity [11]. Furthermore, it facilitated an appreciation of a spectrum of presentations of NMO, expanding the disease phenotype. In particular, patients who have an episode of myelitis, who are NMO-IgG-seropositive, have a high likelihood of both optic neuritis and of recurrent myelitis [3]. Patients with recurrent LETM who are NMO-IgG-seropositive follow a similar clinical course to patients with LETM-onset NMO. NMO-IgG-seronegative patients who fulfill the 2006 diagnostic criteria also behave similarly to seropositive patients who do not fulfill the criteria [12 ]. Furthermore, an expanding spectrum of clinical syndromes referred to as NMO spectrum disorders (NMOSDs) has been associated with NMO-IgG seropositivity, in the absence of fulfillment of NMO diagnostic criteria, and includes intractable nausea, vomiting and hiccups, oculomotor dysfunction, dysphagia, hypogeusia [13 ], central endocrinopathies (including syndrome of inappropriate antidiuretic hormone secretion) [14], posterior reversible encephalopathy [15], and encephalopathic symptoms mimicking acute disseminated encephalomyelitis (ADEM), especially in children &

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FIGURE 1. Neuromyelitis optica. (a) T2 sagittal and (b) T1 postcontrast sagittal images demonstrate high signal within the cord with associated edema and contrast enhancement, located in the cervical and thoracic cord (arrows). (c) T2 axial and (d) T1 postcontrast axial images demonstrate the predominant involvement of central gray matter (arrows). 280


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Longitudinally extensive transverse myelitis Tobin et al.

[14]. Updated diagnostic criteria, to be published in the near future, will more fully address the diagnostic role of NMO-IgG serostatus, as well as the expanding disease spectrum beyond the classic opticospinal manifestations of NMO.

Neuromyelitis optica testing strategy Early-generation assays to test for NMO-IgG involved an ELISA using the M1 isoform of aquaporin-4 (AQP4). The sensitivity of this approach is lower than that of newer techniques [12 ,16 ]. Specifically in the case of recurrent LETM, NMOIgG-negative adults are rare, with the use of recombinant assays demonstrating seropositivity in 89% of patients as compared to 76% of patients testing positive for NMO-IgG using the ELISA assay [16 ]. A blinded international collaborative comparison of the sensitivities of currently employed assay methodologies [indirect immunofluorescence, cell-based assay, ELISA, immunoprecipitation and fluorescence-activated cell sorting (FACS)] confirmed that cell-based assays with recombinant protein that detect antibodies directed to native AQP4 antigen (tetrameric proteins that form supramolecular aggregates in cell membranes) are more sensitive than ELISA-based assays using recombinant protein and more sensitive than older tissue-based immunofluorescence assays. Cell-based recombinant protein assays should be used when available [17]. &

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Aquaporin-4 and NMO-IgG pathogenicity NMO-IgG targets AQP4, the most abundant water channel protein in the CNS, mainly expressed on astrocytic foot processes at the blood–brain barrier, subpial and subependymal regions [18]. The localization of AQP4 in the astrocytic foot processes surrounding endothelial cells is consistent with the role of astrocytes in the development, function, and integrity of the interface between brain parenchyma and perivascular space, and between brain and cerebrospinal fluid (CSF), and serves to mediate water flux [19]. NMO pathology is characterized by a loss of AQP4 immunoreactivity, variable lymphocytic and granulocytic infiltration (both eosinophils and neutrophils), perivascular deposition of immunoglobulins and activation of complement, precisely corresponding to the localization of AQP4 located on astrocytic end-feet that envelop the blood vessels [5,20,21]. The loss of AQP4 immunoreactivity on spinal cord biopsy has also helped differentiate NMO from spinal cord tumors [22 ]. A spectrum of astrocytic pathological alterations have been described in NMO lesions ranging from profound destruction to reactive gliosis, as well as proliferation of astrocyte progenitors [22 ,23 ]. The &

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dissociation between selective astrocyte damage in the setting of relative myelin preservation underscores that NMO should more appropriately be classified as an autoimmune astrocytopathy, rather than a CNS-demyelinating disorder [23 ]. There is evidence to implicate NMO-IgG as the pathogenic agent in patients with NMOSDs [24]. AQP4 expression is highest in tissues with the greatest susceptibility to NMO [25 ] and the antibody titer correlates with disease activity in individual patients, although not across patients [26]. AQP4 forms tetramers in plasma membranes and further aggregates in the cell plasma membrane in supramolecular lattice assemblies [25 ]. Furthermore, invitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, and initiates rapid downregulation of AQP4 via endocytosis/degradation, activation of the lytic complement cascade [18], and concomitant loss of Na-dependent glutamate transport and loss of the excitatory transporter EAAT2 [27] and isoform-specific outcomes [24]. When NMO-IgG binds to AQP4, the M1 isoform is completely internalized, but M23 resists internalization and aggregates into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG [24]. NMO-IgG binding to either isoform also impairs water flux directly, independently of antigen down-regulation or complement activation. These in-vitro studies support several possible mechanisms that might contribute to demyelination in NMO [18]. Aquaporin-4 is also expressed in astrocyte-like ‘supportive cells’ in sensory organs including retinal ¨ ller cells [28], Hensen’s and Claudius’ cells in Mu inner ear [21], and support cells in olfactory epithelium [29]. AQP4 expression is particularly strong in optic nerve and spinal cord, the major tissues affected in NMO [25 ]. Outside of the CNS, AQP4 is expressed at the basolateral membrane in epithelial cells in kidney, airways, and gastrointestinal organs and, at a low level, in skeletal muscle [25 ]. The extent to which NMO pathology extends to these peripheral AQP4-expressing tissues remains to be clarified. &

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Treatment Treatment of NMO is directed at treatment of the acute relapse and prevention of further relapse. Although clinical trials have not been conducted, acute relapses are generally treated, usually successfully, with intravenous steroids [30]. Plasma exchange has been shown to be beneficial in unselected patients with demyelinating disease [31] and in patients with NMO [32 ,33].


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Patients typically respond by the third treatment of plasma exchange, suggesting that, although NMOIgG titers are dramatically reduced by plasma exchange [32 ], the mechanism of recovery may be related to faster acting humoral factors that impair neurotransmission. There is a therapeutic rationale for the use of intravenous immunoglobulin (IVIG) for treatment of NMO [34]. It has been successfully used both for treatment of acute attacks (10 patients with 11 attacks – improvement noted in 5 attacks) [35 ] and for attack prevention (n ¼ 8, reducing relapse rate from 1.8 per year to 0.006 following treatment) [36 ]. However, studies to date have had few patients, and were retrospective, without randomization or blinding. The best success at prevention of NMO relapses was initially achieved through global immunosuppression with agents such as azathioprine [37,38], or mycophenolate mofetil [39]. Other agents that have been used include mitoxantrone, cyclophosphamide, methotrexate, and prednisone [30]. These agents have only been assessed in small uncontrolled studies. This, along with problems associated with global immunosuppression, has led to investigation of the use of more selective agents. The antiCD20 monoclonal antibody, rituximab, has been shown in two retrospective studies to reduce relapse rates in patients with refractory NMO [40,41]. The treatment is generally safe and well tolerated, and has recently been shown to persist at least to 5 years of treatment in patients whose rituximab dose was titrated to CD27þ memory B-cell percentage in peripheral blood [42 ]. There have been reports of a transient increase of NMO-IgG in the first 2 weeks following rituximab infusion, presumably secondary to the effects of increased B-cell activating factor (BAFF) on plasmablasts, raising concerns of a theoretical increase in the risk of NMO relapse in the first few weeks of treatment [43]. The terminal complement inhibitor, eculizumab, has recently been suggested to dramatically reduce attack frequency in a small group of NMO patients with refractory disease based on an uncontrolled open-label study in patients with very active disease at the time of enrollment [44 ]. This protective effect while on treatment was apparently rapidly lost following drug discontinuation. A larger long-term prospective placebo-controlled study is currently being planned (NCT01892345). There have been three case reports [26,45 ,46 ] and a small case series (n ¼ 3) [47 ] of treatment-resistant patients stabilizing following treatment with the interleukin (IL)-6 receptor antagonist tocilizumab. Current treatments largely address the pathological consequences of NMO, but not the underlying &

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cause. Future treatment directions may focus on upstream targets, such as supramolecular aggregates of AQP4 or drivers of persistent B-cell activation. Novel therapeutic options under investigation include a nonpathogenic monoclonal IgG antibody, aquaporumab [48], a human antibody derived from clones of CSF B cells from patients with NMO, engineered to bind with high affinity to AQP4 but not to have complement activating or antibody-dependent cell-mediated cytotoxicity activity. It has been shown to reduce the severity of brain lesions after intracerebral injection of complement and AQP4-IgG and reduce pathology in a spinal cord slice NMO model [49 ]. Several small molecules with similar function are also under investigation. &

Overlap between nonorgan-specific immunity and neuromyelitis optica ¨ gren’s syndrome [50] and systemic lupus erythSjo ematosus (SLE) [51] have been associated with LETM. However, LETM in this setting is typically associated with the presence of AQP4-IgG, which is ¨ gren’s syndrome not detected in patients with Sjo and SLE who do not have myelitis or optic neuritis [52]. As such, it is likely that patients with LETM ¨ gren’s or SLE indicates the preswith comorbid Sjo ence of NMO rather than a vasculitic or other complications of their connective tissue disease. NMO is commonly associated with other nonorgan-specific autoimmune disease.

Future research directions Progress has been made in the study of the pathogenesis of NMO that has implicated the importance of both complement-dependent and complementindependent mechanisms of tissue damage, which has led to promising novel therapeutic directions. Clinical trials assessing agents for treatment of acute NMO relapses include cinryze (a C1-esterase inhibitor) (NCT01759602), bevacizumab (NCT01777412), umbilical cord mesenchymal stem cell therapy (NCT01364246), autologous hematopoietic stem cell transplant (NCT01339455), as well as a phase 3 clinical trial of eculizumab for treatment of acute relapses (NCT01892345). A trial investigating maintenance plasma exchange for prevention of relapses is also underway (NCT01500681). Recently, myelin-oligodendrocyte glycoprotein (MOG)-directed autoantibodies have been demonstrated in a small number of patients with an NMO phenotype, some of whom tested positive [53 ] and some negative for NMO-IgG [54,55 ]. Different from AQP4-IgG-associated NMO, NMO in the context of MOG antibodies was associated with conus &

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involvement, simultaneous optic neuritis and myelitis, a tendency not to relapse and with more favorable clinical outcomes [55 ]. These findings are preliminary and require confirmation. Furthermore, whether effective treatments differ in MOG-associated and AQP4-associated patients is unknown. &&

NON-NEUROMYELITIS OPTICA CAUSES OF LONGITUDINALLY EXTENSIVE TRANSVERSE MYELITIS Although the majority of recent research has focused on NMO and related disorders, there are other important causes of LETM, some of which we will discuss below.

Compressive myelopathy Although compressive myelopathy may ordinarily be thought of as an acute process, chronic compressive myelopathy in the setting of cervical

spondylosis may present as subacute or chronic myelopathy and lead to imaging findings of LETM [56 ]. Disruption of the blood–brain barrier at the point of maximal stenosis may lead to ‘pancake-like’ focal enhancement (Fig. 2). This ‘pancake-like’ enhancement pattern may differentiate compressive myelopathy from other causes of T2 high signal within the cord with which it is commonly confused. This is particularly important because compression may be surgically correctable. &

Sarcoidosis Sarcoidosis is a granulomatous disease of uncertain cause, with a predilection for the respiratory system, although approximately 5% of patients with sarcoidosis have CNS involvement. Patients who present with myelopathy typically present with a subacute myelopathy, without definitive relapses [57]. MRI of the spinal cord typically demonstrates a thoracic or cervical intramedullary high-signal

FIGURE 2. Compressive myelopathy. (a) T2 sagittal and (b) T1 postcontrast sagittal images demonstrate high signal within the cervical cord, associated degenerative disk disease and ‘pancake-like’ enhancement at the point of maximal stenosis (arrows). (c) T2 sagittal and (d) T1 postcontrast sagittal images following decompressive laminectomy demonstrate persistent enhancement despite surgical decompression. 1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins


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FIGURE 3. Neurosarcoidosis. (a) T2 sagittal and (b) T1 postcontrast sagittal images demonstrate high signal within the dorsal cervicothoracic cord and associated nodular posterior cord enhancement (arrow).

lesion on T2 and fluid attenuated inversion recovery MRI, with approximately half of the patients having leptomeningeal involvement (Fig. 3). Almost all patients demonstrate contrast enhancement [57]. The pattern of enhancement, along with the clinical findings, may prompt some clinicians to treat on the basis of clinical and imaging findings alone, when there is no demonstrable disease outside the CNS that is amenable for biopsy and definitive diagnosis. Fluorodeoxyglucose (FDG)-PET imaging has been shown to be useful for demonstration of a myelopathy in patients with neurosarcoidosis [58 ], even in the absence of MRI changes [59]. However, FDG-PET is a relatively nonspecific imaging modality and cannot differentiate between neoplastic myelopathy and neurosarcoidosis-related myelopathy [58 ]. Definite diagnosis of neurosarcoidosis can be made in the presence of a biopsy demonstrating classical appearing noncaseating granulomas, associated with a typical clinical picture of a subacute to chronic progressive myelopathy. In most cases, a biopsy site outside of the brain or spinal cord, particularly hilar or thoracic lymph nodes, can yield a pathological diagnosis. Isolated neurosarcoidosis is thought to occur in approximately one in five cases of neurosarcoidosis. Occasionally, spinal cord biopsy may be necessary to reach a definitive diagnosis [57]. CSF angiotensin-converting enzyme levels are rarely helpful, with high false-negative (45–82%) [57,60] and false-positive rates (5–13%) [60]. There are no prospective treatment trials for patients with neurosarcoidosis. Prolonged treatment with corticosteroids is considered first-line treatment, along with steroid-sparing agents. Tumor necrosis factor (TNF)-a inhibitors have been successfully used by some authors and appear to be a promising alternative [61]. As a word of caution, &

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there have been case reports of systemic sarcoidosis developing in patients with rheumatoid arthritis treated with TNF-a inhibitors [62 ,63]. &

Behçet’s disease Neuro-Behçet’s is a small-vessel systemic vasculitis of unknown cause, and is typically associated with systemic features of Behçet’s disease, such as aphthous and genital ulcers, pathergy, uveitis and iritis. It has rarely been associated with longitudinal cord lesions [64 ]. Neurological deficits have a poor prognosis, with almost half of all patients with neuroBehçet’s having an Expanded Disability Status Scale score of at least 6 at 10 years following diagnosis [65]. Typical CNS lesions due to neuro-Behçet’s are masslike lesions at junctional areas such as the cervicomedullary junction or the ponto-medullary junction (Fig. 4). There is a lack of randomized controlled trials for treatment, and limited published data on myelopathy in these patients. There have been reported treatment successes using cyclophosphamide [66], mycophenolate [67], infliximab [68] and tocilizumab [69,70]. &

Paraneoplastic and other autoimmune myelopathies Flanagan et al. [71] reported a cohort of patients with isolated paraneoplastic myelopathies. These patients typically presented with a progressive or subacute myelopathy (Fig. 5). Among this cohort, 47% of patients had LETM, 50% had symmetric tract or gray matter-specific signal abnormality. This tract or gray matter-specific signal abnormality enhanced following contrast administration in 87% of patients. Myelopathy preceded a cancer diagnosis Volume 27 Number 3 June 2014



FIGURE 4. Behçet’s disease. (a) T2 axial and (b) T1 axial postcontrast sagittal images demonstrate mass-like enhancing lesions at the ponto-midbrain junction (arrow).

in 18 patients. A neural antibody was detected in 25/ 30 patients, including amphiphysin (9/30), collapsin response-mediator protein-5 (CRMP-5) (9/30), or type 1 antineuronal nuclear autoantibody (ANNA-1) antibodies (2/30). Neurological prognosis in these patients was poor, despite treatment of their malignancy, although 6/20 treated with corticosteroids responded favorably to treatment. Symmetrical tract-specific myelopathies associated with T2 signal abnormality and occasionally gadolinium enhancement confined to tracts, such as the corticospinal tract, is an important clue that a myelopathy may be paraneoplastic.

Dural arteriovenous fistula A subacute to chronic progressive myelopathy in a patient with a longitudinally extensive spinal cord

lesion extending into the conus who complains of exertion-related worsening of weakness should raise suspicion for a dural arteriovenous fistula (DAVF). Middle-aged and elderly men are most likely to have a DAVF. DAVFs are typically located in the thoracolumbar region and their presence is often revealed by the detection of ‘flow voids’ on the surface of the caudal spinal cord on T2 weighted MRI, reflecting dilated veins [73] (Fig. 6). Diagnosis is often delayed and patients are commonly misdiagnosed as ‘transverse myelitis’. In a Mayo Clinic series, the average time of symptom duration was almost 2 years [73]. Spinal angiography usually localized the fistula in a nerve root and almost all patients benefited from obliteration of the DAVF which arrested further deterioration. Obliteration can be achieved surgically or through an endovascular approach.

FIGURE 5. Paraneoplastic LETM. (a) T2 sagittal, (b) T2 axial and (c) postcontrast T1 sagittal MRI of thoracic cord, demonstrating a longitudinally extensive area of abnormal T2 signal with contrast enhancement. LETM, longitudinally extensive transverse myelitis. Reproduced with permission from [72]. 1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins


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FIGURE 6. Spinal dural arteriovenous fistula. (a) T2 sagittal MRI and (b) MR angiogram of thoracic spine demonstrate high signal in the thoracolumbar spine with associated flow voids surrounding the cord, shown to be blood vessels on MR angiogram. MR, magnetic resonance.

DIAGNOSTIC APPROACH We have outlined several common causes of LETM above, and the recent advances in outlining their clinical features, investigational approach and treatment. Other important causes of LETM include spinal infarction, infectious myelitis (including herpes zoster, flavivirus, enterovirus, rabies and parasitic infections) and demyelinating diseases such as MS and ADEM. An in-depth discussion of all these causes is outside the scope of this article. Other less frequent causes of LETM include the recently described mutations in the gene encoding a nuclear pore complex, RANBP2. An autosomal-dominant missense mutation in this gene has been found in a 36-year-old lady with a steroid-responsive longitudinal extensive transverse myelitis with symmetrical thalamic lesions [74 ]. There has also been a recent case described of subacute sclerosing &

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panencephalitis presenting with optic neuropathy and myelopathy [75]. These syndromes are rare, but important to identify. To aid clinicians, and in an attempt to rationalize the diagnostic approach in patients presenting with LETM, Table 1 outlines some diagnostic clues. As a general approach, common and treatable conditions associated with LETM should be excluded initially, followed by investigation for rarer causes, as described above.

CONCLUSION Longitudinal extensive transverse myelitis is usually idiopathic or associated with NMO, but a variety of other causes need to be considered, particularly individualized to risk factors (e.g. vascular risk factors suggest infarction) and clinical setting (e.g. fever Volume 27 Number 3 June 2014


Longitudinally extensive transverse myelitis Tobin et al. Table 1. Other causes of longitudinally extensive transverse myelitis with diagnostic clues Cause

Clinical

Radiology

Spinal infarction

Sudden onset

Anterior gray matter involvement

Laboratory

History of vascular disease

‘Pencil-like’ longitudinal lesion

Spinal dural arteriovenous (AV) fistulas

Usually elderly men Thoracolumbar location [72] Symptoms worsen with erect posture or Valsalva maneuver

Flow voids on MRI spine T2 hyperintensity on MRI extends into conus Spinal angiogram may demonstrate feeding vessel

Compressive lesions

Gradual onset symptoms May have a history of neck pain or radicular symptoms

‘Pancake-like’ enhancement at the & point of maximal stenosis [56 ] Associated degenerative disk disease

Metabolic (B12, copper)

Possible history of gastric bypass or malabsorption syndrome

Selective involvement of the dorsal columns [76]

Low serum B12 or copper levels Macrocytosis Associated neuropathy on nerve conduction studies

Autosomal dominant

Ventricular garlands on MRI brain [77]

Rosenthal fibers on brain biopsy

Progressive bulbar and spinal dysfunction

Usually associated with spinal cord atrophy, but can be associated with longitudinal high signal lesions in the cervical cord [77] PET scan demonstrating malignancy Syrinx may be associated with ependymoma or hemangioblastoma

GFAP mutation

Alexander disease

Primary spinal cord neoplasm

Gradual symptom onset without remissions

Demonstration of malignancy on spinal cord biopsy Neoplastic cells in spinal fluid

Paraneoplastic

Systemic symptoms or signs of malignancy

Tract specific involvement Enhancement following gadolinium administration

Detection of paraneoplastic antibody in serum or spinal fluid

ADEM

Associated encephalopathy More common in children

Cerebral white matter changes

Leukocytosis on spinal fluid analysis

Multiple sclerosis

May have Lhermitte’s symptom Associated with other features of multiple sclerosis (e.g. history or optic neuritis or internuclear ophthalmoplegia)

Eccentric lesions on axial spinal cord images

Oligoclonal bands Leukocytosis on spinal fluid analysis

Infectious

Signs of systemic infection (fever, herpetic rash) Prominent residual amyotrophy (enterovirus and flavivirus) Travel to endemic region (schistosomiasis, other parasitic infections)

Diffuse cord edema Root involvement (syphilis) Grey matter involvement (enterovirus and flavivirus)

Detection of infectious agent in the spinal fluid Leukocytosis on spinal fluid analysis

ADEM, acute disseminated encephalomyelitis; GFAP, glial fibrillary acidic protein; LETM, longitudinally extensive transverse myelitis.

suggests infectious myelopathy). Ruling out treatable causes, such as compressive myelopathy, should be an initial diagnostic priority. Careful delineation of clinical, radiographic and laboratory findings can aid the clinician in confirming a diagnosis and selecting the appropriate treatment. Acknowledgements None. Conflicts of interest W.O.T. reports no disclosures.

C.F.L. receives royalties from the publication of Blue Books of Neurology: Multiple Sclerosis 3 (Saunders Elsevier, 2010), may accrue revenue for a patent regarding aquaporin-4 associated antibodies for diagnosis of neuromyelitis optica and has received research support from Koltan Pharmaceuticals, National Institutes of Health, Department of Defense, and the Guthy-Jackson Charitable Foundation. B.G.W. serves on adjudication panel for Medimmune. He has received payment for consultation from Elan Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Ono Pharmaceuticals, CHORD Therapeutics, and Chugai Pharmaceuticals. He receives license royalties



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from RSR Ltd. for a patent regarding AQP4-associated antibodies for diagnosis of neuromyelitis optica.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499–505. 2. Tartaglino LM, Friedman DP, Flanders AE, et al. Multiple sclerosis in the spinal cord: MR appearance and correlation with clinical parameters. Radiology 1995; 195:725–732. 3. Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol 2006; 59:566–569. 4. Debette S, de Seze J, Pruvo JP, et al. Long-term outcome of acute and subacute myelopathies. J Neurol 2009; 256:980–988. 5. Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 2002; 125 (Pt 7):1450–1461. 6. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364:2106–2112. 7. Devic E, editor. Mye´lite aigue¨ dorso-lombaire avec ne´vrite optique: Autopsie. Congre`s français de me´decine (Premiere Session; Lyon, 1894; proce`sverbaux, me´moires et discussions; publie´s par M le Dr L Bard); 1895; Paris: Asselin et Houzeau, Louis Savy. 8. Jarius S, Wildemann B. The history of neuromyelitis optica. J Neuroinflammation 2013; 10:8. 9. Nakamura M, Miyazawa I, Fujihara K, et al. Preferential spinal central gray matter involvement in neuromyelitis optica: an MRI study. J Neurol 2008; 255:163–170. 10. Wingerchuk DM, Pittock SJ, Lucchinetti CF, et al. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007; 68:603–605. 11. Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66:1485–1489. 12. Jiao Y, Fryer JP, Lennon VA, et al. Updated estimate of AQP4-IgG serostatus & and disability outcome in neuromyelitis optica. Neurology 2013; 81:1197– 1204. This study demonstrates that patients who are positive for NMO-IgG, but who do not fulfill the 2006 NMO diagnostic criteria have a similar clinical course to patients who do fulfil the 2006 criteria. It also underlines the low sensitivity of ELISA and immunofluourescence for detection of NMO-IgG. This will have an impact of future diagnostic criteria for NMO, and on decisions to treat patients with NMO-IgG. 13. Iones A, Howard J. Hypogeusia as a symptom of neuromyelitis optica & spectrum disorder. Mult Scler 2013; 19:1548–1549. First study to demonstrate hypogeusia as a symptom of neuromyelitis optica spectrum disorder. 14. Lotze TE, Northrop JL, Hutton GJ, et al. Spectrum of pediatric neuromyelitis optica. Pediatrics 2008; 122:e1039–e1047. 15. Magana SM, Matiello M, Pittock SJ, et al. Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology 2009; 72:712–717. 16. Jiao Y, Fryer JP, Lennon VA, et al. Aquaporin 4 IgG serostatus and outcome in & recurrent longitudinally extensive transverse myelitis. JAMA Neurol 2014; 71:48–54. This study demonstrates the high proportion of patients with recurrent LETM who have NMOSDs. These patients have a worse outcome when compared to patients with optic neuritis onset NMO. 17. Waters PJ, McKeon A, Leite MI, et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 2012; 78: 665–671. [discussion 9] 18. Hinson SR, Pittock SJ, Lucchinetti CF, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 2007; 69:1–11. 19. Nicchia GP, Nico B, Camassa LMA, et al. The role of aquaporin-4 in bloodbrain barrier development and integrity: studies in animal and cell culture models. Neuroscience 2004; 129:935–945. 20. Roemer SF, Parisi JE, Lennon VA, et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 2007; 130 (Pt 5):1194–1205. 21. Misu T, Fujihara K, Kakita A, et al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 2007; 130 (Pt 5):1224–1234.

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22. Sato DK, Misu T, Rocha CF, et al. Aquaporin-4 antibody-positive myelitis initially biopsied for suspected spinal cord tumors: diagnostic considerations. Mult Scler 2014; 20:621–626. First study to demonstrate that loss of immunoreactivity for AQP4 on spinal cord biopsies can help to differentiate between spinal cord tumours and NMO. 23. Lucchinetti CF, Guo Y, Popescu BF, et al. The pathology of an autoimmune & astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol 2014; 24:83–97. Review study demonstrating the pathology underlying NMO, along with discussion of implications for other astrocyte-dependent conditions. 24. Hinson SR, Romero MF, Popescu BF, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A 2012; 109:1245–1250. 25. Matiello M, Schaefer-Klein J, Sun D, Weinshenker BG. Aquaporin 4 expres& sion and tissue susceptibility to neuromyelitis optica. JAMA Neurol 2013; 70:1118–1125. Study demonstrating that AQP4 expression is highest in tissues with the greatest susceptibility to NMO and that supramolecular aggregates of AQP4 were overrepresented in the optic nerve and spinal cord relative to other CNS tissue. 26. Takahashi T, Fujihara K, Nakashima I, et al. Antiaquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007; 130:1235–1243. 27. Apiwattanakul M, McKeon A, Fryer JP, et al. AQP4-IgG immunoprecipitation assay optimization. Clin Chem 2009; 55:592–594. 28. Li J, Patil RV, Verkman AS. Mildly abnormal retinal function in transgenic mice without Muller cell aquaporin-4 water channels. Invest Ophthalmol Vis Sci 2002; 43:573–579. 29. Lu DC, Zhang H, Zador Z, Verkman AS. Impaired olfaction in mice lacking aquaporin-4 water channels. FASEB J 2008; 22:3216–3223. 30. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol 2008; 10:55–66. 31. 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. 32. Kim SH, Kim W, Huh SY, et al. Clinical efficacy of plasmapheresis in patients & with neuromyelitis optica spectrum disorder and effects on circulating antiaquaporin-4 antibody levels. J Clin Neurol 2013; 9:36–42. This is the first case series demonstrating efficacy of plasmapheresis for treatment of acute relapses in patients with NMO. NMO-IgG titers were dramatically reduced by treatment, and most patients responded by the third treatment of plasma exchange. 33. Watanabe S, Nakashima I, Misu T, et al. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler 2007; 13:128–132. 34. Wingerchuk DM. Neuromyelitis optica: potential roles for intravenous immunoglobulin. J Clin Immunol 2013; 33 (Suppl 1):S33–S37. 35. Elsone L, Panicker J, Mutch K, et al. Role of intravenous immunoglobulin in the & treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler 2014; 20:501–504. Only study demonstrating efficacy of IVIG in treatment of acute NMO attacks. Study had 10 patients with 11 attacks. There was no control arm. 36. Magraner MJ, Coret F, Casanova B. The effect of intravenous immunoglobulin & on neuromyelitis optica. Neurologia 2013; 28:65–72. Largest study to date (n ¼ 8) of IVIG for attack prevention in NMO. This study demonstrated a relapse rate reduction from 1.8 per year to 0.006 following treatment. There was no control arm. 37. Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 1998; 51:1219–1220. 38. Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011; 77:659– 666. 39. Jacob A, Matiello M, Weinshenker BG, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 2009; 66:1128–1133. 40. Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005; 64:1270–1272. 41. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008; 65:1443–1448. 42. Kim SH, Huh SY, Lee SJ, et al. A 5-year follow-up of rituximab treatment in & patients with neuromyelitis optica spectrum disorder. JAMA Neurol 2013; 70:1110–1107. Longest follow-up study of patients treated with rituximab for NMO. The effect of rituximab was found to last for at least 5 years in patients whose dose was titrated to CD27þ B-cell counts in peripheral blood. 43. Nakashima I, Takahashi T, Cree BA, et al. Transient increases in antiaquaporin-4 antibody titers following rituximab treatment in neuromyelitis optica, in association with elevated serum BAFF levels. J Clin Neurosci 2011; 18:997–998. 44. Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive & relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013; 12:554–562. First open-label cohort study of eculizumab for the prevention of NMO relapses. This demonstrated a reduction in attack frequency and severity with treatment. It will be followed by a planned phase 3 study. &



Longitudinally extensive transverse myelitis Tobin et al. 45. Komai T, Shoda H, Yamaguchi K, et al. Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: a case report. Mod Rheumatol 2013. [Epub ahead of print] One of the three case reports demonstrating a reduction in relapse frequency in a patients with NMOSD who was treated with tocilizumab. 46. Araki M, Aranami T, Matsuoka T, et al. Clinical improvement in a patient with && neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol 2013; 23:827–831. One of the three case reports demonstrating stabilization of treatment resistant patients with NMO following treatment with the IL-6 receptor antagonist, tocilizumab. 47. Ayzenberg I, Kleiter I, Schroder A, et al. Interleukin 6 receptor blockade in && patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 2013; 70:394–397. The only case series of three patients with NMO who did not respond to rituximab demonstrating stabilization following treatment with tocilizumab. 48. Verkman AS, Phuan PW, Asavapanumas N, Tradtrantip L. Biology of AQP4 and anti-AQP4 antibody: therapeutic implications for NMO. Brain Pathol 2013; 23:684–695. 49. Tradtrantip L, Ratelade J, Zhang H, Verkman AS. Enzymatic deglycosylation & converts pathogenic neuromyelitis optica antiaquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol 2013; 73:77–85. First study to demonstrate the potential theraputic role of deglycosylated AQP4 IgG, demonstrating its potential to reduce the severity of brain lesions after intracerebral injection of complement and AQP4-IgG in mouse models and to reduce pathology in a spinal cord slice model. 50. Kahlenberg JM. Neuromyelitis optica spectrum disorder as an initial presentation of primary Sjogren’s syndrome. Semin Arthritis Rheum 2011; 40:343–348. 51. Espinosa G, Mendizabal A, Minguez S, et al. Transverse myelitis affecting more than 4 spinal segments associated with systemic lupus erythematosus: clinical, immunological, and radiological characteristics of 22 patients. Semin Arthritis Rheum 2010; 39:246–256. 52. Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non organspecific autoimmunity. Arch Neurol 2008; 65:78–83. 53. Woodhall M, Coban A, Waters P, et al. Glycine receptor and myelin oligo& dendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci 2013; 335:221–223. Study demonstrating a low rate of myelin oligodendrocyte glycoprotein protein antibodies in Turkish patients with NMO who did not have NMO-IgG detected. 54. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012; 79:1273–1277. 55. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG && antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014; 82:474–481. This study outlines the clinical differences between patients with NMOSD who have NMO-IgG or myelin oligodendrocyte glycoprotein protein antibodies detected. 56. Flanagan EP, Marsh RW, Weinshenker BG. Teaching neuroimages: ‘pan& cake-like’ gadolinium enhancement suggests compressive myelopathy due to spondylosis. Neurology 2013; 80:e229. This case report demonstrates the typical ‘pancake-like’ enhancement pattern at the point of maximum stenosis that may suggest compressive myelopathy as the cause of spinal cord signal changes. 57. Sohn M, Culver DA, Judson MA, et al. Spinal cord neurosarcoidosis. Am J Med Sci 2014; 347:195–198. 58. Flanagan EP, Hunt CH, Lowe V, et al. [18F]-Fluorodeoxyglucose–positron & emission tomography in patients with active myelopathy. Mayo Clin Proc 2013; 88:1204–1212. Study demonstrating the utility of FDG-PET for differentiating nonsarcoid inflammatory spinal disease from malignancy. FDG-PET was unable to differentiate patients with a sarcoid myelopathy from patients with spinal cord malignancy. &

59. Huang JF, Aksamit AJ, Staff NP. MRI and PET imaging discordance in neurosarcoidosis. Neurology 2012; 79:1070. 60. Joseph FG, Scolding NJ. Sarcoidosis of the nervous system. Practical Neurol 2007; 7:234–244. 61. Sodhi M, Pearson K, White ES, Culver DA. Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis. Respir Med 2009; 103:268–273. 62. Dragnev D, Barr D, Kulshrestha M, Shanmugalingam S. Sarcoid panuveitis & associated with etanercept treatment, resolving with adalimumab. Br Med J Case Rep 2013; bcr2013200552. One of a number of case reports of systemic sarcoidosis developing in patients with rheumatoid arthritis treated with TNF-a inhibitors. 63. Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab. J Cutan Pathol 2012; 39:289–293. 64. Graham D, McCarthy A, Kavanagh E, et al. Teaching NeuroImages: long& itudinally extensive transverse myelitis in neuro-Behcet disease. Neurology 2013; 80:e189–e190. One of few case reports of LETM in neuro-Behçet disease. 65. Siva A, Kantarci OH, Saip S, et al. Behcet’s disease: diagnostic and prognostic aspects of neurological involvement. J Neurol 2001; 248:95– 103. 66. Ait Ben Haddou EH, Imounan F, Regragui W, et al. Neurological manifestations of Behcet’s disease: evaluation of 40 patients treated by cyclophosphamide. Rev Neurol (Paris) 2012; 168:344–349. 67. Shugaiv E, Tuzun E, Mutlu M, et al. Mycophenolate mofetil as a novel immunosuppressant in the treatment of neuro-Behcet’s disease with parenchymal involvement: presentation of four cases. Clin Exp Rheumatol 2011; 29 (4 Suppl 67):S64–S67. 68. Borhani Haghighi A, Safari A, Nazarinia MA, et al. Infliximab for patients with neuro-Behcet’s disease: case series and literature review. Clin Rheumatol 2011; 30:1007–1012. 69. Urbaniak P, Hasler P, Kretzschmar S. Refractory neuro-Behcet treated by tocilizumab: a case report. Clin Exp Rheumatol 2012; 30 (3 Suppl 72):S73– S75. 70. Shapiro LS, Farrell J, Haghighi AB. Tocilizumab treatment for neuro-Behcet’s disease: the first report. Clin Neurol Neurosurg 2012; 114:297–298. 71. Flanagan EP, McKeon A, Lennon VA, et al. Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 2011; 76:2089– 2095. 72. Keegan BM, Pittock SJ, Lennon VA. Autoimmune myelopathy associated with collapsin response-mediator protein-5 immunoglobulin G. Ann Neurol 2008; 63:531–534. 73. Atkinson JL, Miller GM, Krauss WE, et al. Clinical and radiographic features of dural arteriovenous fistula, a treatable cause of myelopathy. Mayo Clin Proc 2001; 76:1120–1130. 74. Wolf K, Schmitt-Mechelke T, Kollias S, Curt A. Acute necrotizing encephalo& pathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis. J Neurol 2013; 260:1545–1553. First study to describe myelitis as a presenting feature of an ANE1 mutation. This enters the differential of patients with myelitis and a family history of neurological disease. 75. Raut TP, Singh MK, Garg RK, Naphade PU. Subacute sclerosing panencephalitis presenting as neuromyelitis optica. Br Med J Case Rep 2012; bcr2012006764. 76. Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copper deficiency myelopathy: a study of 25 cases. Neuroradiology 2006; 48:78–83. 77. van der Knaap MS, Ramesh V, Schiffmann R, et al. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006; 66:494–498.



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Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis.

Neuromyelitis optica spectrum disorders: beyond longitudinally extensive transverse myelitis.

An Uncommon Cause of Longitudinally Extensive Transverse Myelitis.

Longitudinally extensive transverse myelitis as presenting manifestation of small cell carcinoma lung.

A rare association of tuberculous longitudinally extensive transverse myelitis (LETM) with brain tuberculoma.

Longitudinally extensive transverse myelitis and meningitis due to a rare infectious cause.

Quantitative analysis of aquaporin-4 antibody in longitudinally extensive transverse myelitis.

Efficacy of infliximab in neuro-Behçet's disease presenting with isolated longitudinally extensive transverse myelitis.

Aquaporin 4 IgG serostatus and outcome in recurrent longitudinally extensive transverse myelitis.

Longitudinally extensive transverse myelitis with intramedullary metastasis of small-cell lung carcinoma: an autopsy case report.

Longitudinally extensive transverse myelitis: a rare association with common variable immunodeficiency.

Longitudinally extensive myelitis in MS mimicking neuromyelitis optica.

Longitudinally extensive transverse myelitis in neuromyelitis optica: a prospective study of 13 Caucasian patients and literature review.

Differentiation of neuromyelitis optica spectrum disorders from ultra-longitudinally extensive transverse myelitis in a cohort of Chinese patients.

Pediatric Acute Longitudinal Extensive Transverse Myelitis Secondary to Neuroborreliosis.

Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis.

Bartonella-Associated Transverse Myelitis.

Longitudinally extensive myelopathy in children.

Survival in traumatic transverse myelitis.

Urinary dysfunction in transverse myelitis.

An Unusual Presentation of Dengue Fever: Association with Longitudinal Extensive Transverse Myelitis.

Recurrent longitudinal extensive transverse myelitis in a neuro-Behçet syndrome treated with infliximab.

Lower motor neuron paralysis with extensive cord atrophy in parainfectious acute transverse myelitis.

Post-varicella acute transverse myelitis.