Chitra Krishnan

Acute transverse myelitis in childhood: center-based analysis of 47 cases.

Objective: To relate clinical characteristics associated with acute transverse myelitis (ATM) in children with functional outcomes at follow-up. Methods: We identified 47 patients for whom ATM occurred under the age of 18 years. Chart analysis, clinical evaluation, and administration of functional measures were completed. Results: The age at onset clustered between ages 0 to 2 and 5 to 17. Febrile illness had occurred in 47% and vaccination in 28%. Major disability at the nadir of the clinical course was noted. Eighty-nine percent were unable to walk, required assisted ventilation, or both. At a median of 3.2 years after acute illness, 43% were unable to walk 30 ft and 21% required a walker or other support, 68% experienced urinary urgency, 50% required bladder catheterization, 54% were troubled by persistent dysesthesias, and 75% had numbness. Factors associated with a better functional outcome included older age at time of diagnosis, shorter time to diagnosis, lower sensory and anatomic levels of spinal injury, absence of T1 hypointensity on spinal MRI obtained during the acute period, lack of white blood cells in the CSF, and fewer affected spinal cord segments. Neither rapid progression to maximum impairment in less than 1 day nor any antecedent illness, immunization, or trauma was associated with a worse outcome. Conclusion: Persisting disability was present in many children with acute transverse myelitis. Urinary problems and sensory symptoms were the most common issues. Age at onset below 3 years was associated with worse functional outcomes.

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

Diagnosis and management of acute myelopathies

Background:Acute myelopathies represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. Transverse myelitis (TM) is a prototype member of this group in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations, and autonomic dysfunction. TM may exist as part of a multifocal CNS disease (eg, MS), multisystemic disease (eg, systemic lupus erythematosus), or as an isolated, idiopathic entity. Review Summary:In this article, we summarize recent classification and diagnostic schemes, which provide a framework for the diagnosis and management of patients with acute myelopathy. Additionally, we review the state of current knowledge about the epidemiology, natural history, immunopathogenesis, and treatment strategies for patients with TM. Conclusions:Our understanding of the classification, diagnosis, pathogenesis, and treatment of TM has recently begun to expand dramatically. With more rigorous criteria applied to distinguish acute myelopathies and with an emerging understanding of immunopathogenic events that underlie TM, it may now be possible to effectively initiate treatments in many of these disorders. Through the investigation of TM, we are also gaining a broader appreciation of the mechanisms that lead to autoimmune neurologic diseases in general.

Viral-Induced Spinal Motor Neuron Death Is Non-Cell-Autonomous and Involves Glutamate Excitotoxicity

Neuroadapted Sindbis virus (NSV) is a neurotropic virus capable of inducing the death of spinal motor neurons in mice and rats. In this study we investigated the mechanisms that underlie NSV-induced motor neuron death. We found that many degenerating spinal motor neurons were not infected directly with NSV, suggesting that bystander cell death occurs. An excitotoxic mechanism was confirmed when blockade of calcium-permeable AMPA receptors attenuated motor neuron death both in vitro and in vivo. Blockade of astroglial glutamate reuptake potentiated NSV-induced motor neuron loss in vivo, suggesting that astrocyte-mediated removal of perisynaptic glutamate is important in limiting NSV-induced excitotoxic injury. Astroglial glutamate transport was reduced markedly in the spinal cord during NSV infection, in advance of motor neuron injury in susceptible mice. In contrast, we found 5.6-fold elevated glutamate uptake in the spinal cords of mice resistant to NSV-induced paralysis. Likewise, minocycline markedly increased spinal cord glutamate transport and protected mice from NSV-induced motor neuron death. These studies suggest that NSV infection triggers a cascade of events in the spinal cord resulting in impaired astrocytic glutamate transport and excitotoxic injury of motor neurons mediated via calciumpermeable AMPA receptors. Similar changes may occur in other motor neuron disorders such as amyotrophic lateral sclerosis or West Nile Virus-induced poliomyelitis, suggesting a common tissue injury pathway.

IDIOPATHIC TRANSVERSE MYELITIS: CORTICOSTEROIDS, PLASMA EXCHANGE, OR CYCLOPHOSPHAMIDE

Transverse myelitis is a focal disorder of the spinal cord in which an immune-mediated process results in neural injury. In this large retrospective study, we compare patients who received one of four treatments to identify the most effective therapies. We identified subsets of patients who received clinical benefit from plasma exchange or cyclophosphamide being included in their treatment regimen.

Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis

OBJECTIVE To explore the safety and effectiveness of high-dose cyclophosphamide (HiCy) without bone marrow transplantation in patients with aggressive multiple sclerosis (MS). DESIGN A 2-year open-label trial of patients with aggressive relapsing-remitting multiple sclerosis (RRMS) given an immunoablative regimen of HiCy (50 mg/kg/d for 4 consecutive days) with no subsequent immunomodulatory therapy unless disease activity reappeared that required rescue therapy. SETTING The Johns Hopkins University Multiple Sclerosis Center, Baltimore, Maryland. Patients A total of 21 patients with RRMS were screened for eligibility and 9 patients were enrolled in the trial. Patients were required to have 2 or more gadolinium-enhancing lesions on each of 2 pretreatment magnetic resonance imaging scans, at least 1 clinical exacerbation in the 12 months prior to HiCy treatment, or a sustained increase of 1.0 point or higher on the Expanded Disability Status Scale (EDSS) in the preceding year. Intervention Patients received 50 mg/kg/d of cyclophosphamide intravenously for 4 consecutive days, followed by 5 mug/kg/d of granulocyte colony-stimulating factor 6 days after completion of HiCy treatment, until the absolute neutrophil count exceeded 1.0 x 10(9) cells/L for 2 consecutive days. MAIN OUTCOME MEASURES The primary outcome of the study was the safety and tolerability of HiCy in patients with RRMS. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance images and a change in disability measures (EDSS and Multiple Sclerosis Functional Composite). RESULTS Nine patients were treated and followed up for a mean period of 23 months. Eight patients had failed conventional therapy and 1 was treatment naive. The median age at time of entry was 29 years (range, 20-47 years). All patients developed transient total or near-total pancytopenia as expected, followed by hematopoietic recovery in 10 to 17 days, stimulated by granulocyte colony-stimulating factor. There were no deaths or unexpected serious adverse events. There was a statistically significant reduction in disability (EDSS) at follow-up (mean [SD] decrease, 2.11 [1.97]; 39.4%; P = .02). The mean (SD) number of gadolinium-enhancing lesions on the 2 pretreatment scans were 6.5 (2.1) and 1.2 (2.3) at follow-up (81.4% reduction; P = .01). Two patients required rescue treatment with other immunomodulatory therapies during the study owing to MS exacerbations. CONCLUSION Treatment with HiCy was safe and well tolerated in our patients with MS. Patients experienced a pronounced reduction in disease activity and disability after HiCy treatment. This immunoablative regimen of cyclophosphamide for patients with aggressive MS is worthy of further study and may be an alternative to bone marrow transplantation. Published online June 9, 2008 (doi:10.1001/archneurol.65.8.noc80042).

Acute Transverse Myelitis

Acute noncompressive myelopathies were first recognized in the 19th century, and early pathologic studies identified both inflammatory and vascular etiologies.1-3 The terms acute transverse myelitis (ATM) and acute transverse myelopathy have been used interchangeably to describe a syndrome characterized by anterior and posterior (hence transverse) spinal cord impairment resulting in weakness, a sensory level, and autonomic dysfunction. Possible causes include vascular, infectious, neoplastic, collagen vascular, iatrogenic, and autoimmune etiologies.4 In addition, the syndrome can occur as part of CNS demyelinating disease such as neuromyelitis optica (NMO) or, uncommonly, typical multiple sclerosis (MS). Once such recognized causes are excluded, the question remains as to whether there exists a unique disease entity “idiopathic ATM.” Based on expert opinion, the Transverse Myelitis Consortium Working Group (TMCWG) proposed diagnostic criteria for idiopathic ATM.5 The clinical requirements include bilateral sensory, motor, or autonomic dysfunction referable to the spinal cord, with a clearly defined sensory level that progresses to the nadir over 4 to 21 days from onset. Neuroimaging, preferably MRI, is used to eliminate structural causes. Evidence to support an inflammatory etiology is also required; this may be demonstrated through MRI evidence of gadolinium diethylenetriamine penta-acetic acid (DPTA) enhancement within the cord or by CSF findings of pleocytosis or immunoglobulin G (IgG) index elevation. Patients meeting all diagnostic criteria are considered to have definite idiopathic ATM, whereas those who do not meet the MRI or CSF criteria for inflammation have possible idiopathic ATM. The intent of these criteria was to identify a relatively homogenous patient cohort for research. Because these criteria were based on expert opinion and not on observational studies, validation is an essential first step for use in better defining the natural history of ATM. In this issue, de Seze et al.6 report a multicenter retrospective review of 288 patients with acute myelitis at nine neurologic departments in France. Using the TMCWG criteria, they classified approximately 84% (n 243) as secondary to an identifiable cause and the remaining 16% as definite (n 31) or possible (n 14) idiopathic ATM. Brain MRI was normal in all patients. Spinal cord MRI revealed lesions extending over at least two vertebral segments in more than 95%, but enhancement of the spinal cord after gadolinium-DPTA infusion was present in only 38% of patients. Clinical outcome was poor in 36%, meaning death or inability to ambulate with aid, and the only predictor of this outcome was initial spinal shock. Twenty-four percent of patients declared a relapsing course during the 3.1-year mean follow-up. de Seze et al. demonstrated that the TMCWG clinical criteria can be used to identify a relatively homogenous patient cohort based on clinical features. It remains to be determined how to distinguish at disease onset idiopathic ATM patients who do not have evidence of disseminated CNS disease from those with MS or NMO. Indeed, MS and NMO cases comprised nearly 30% of this retrospective cohort. One of the diagnostic features of NMO is a cord lesion extending over three or more contiguous vertebral segments.7 The proportion of the de Seze sample meeting this criterion was not reported; however, it is likely that with longer follow-up, some of the idiopathic ATM patients, particularly those with a relapsing course, will “convert” to NMO. Despite these limitations, the proposed diagnostic criteria may define a subset of patients who share a common pathogenesis. If idiopathic ATM is in fact a distinct disease, it should be associated with unique biomarkers. Identification of such biomarkers will require the establishment of a large, wellcharacterized patient cohort, preferably prospectively gathered, from multiple collaborating centers.

The immune system and neuropsychiatric diseases

The immune system has a complex and dynamic relationship with the nervous system, both in health and disease. The immune system surveys the central and peripheral nervous systems, becoming activated in response to foreign substances, infectious particles or neoplasms. Conversely, the nervous system modulates immune system function both through the neuroendocrine axis and through vagus nerve efferents. In disease states, this dynamic relationship is perturbed, resulting in neuropsychiatric diseases. In this manuscript, we will summarize fundamental principles of the immune system and its interaction with the nervous system. We will describe the critical components of the adaptive and innate branches of the immune system and will describe important effectors and signalling pathways in each. By understanding the principles of the immune system and how these principles relate to nervous system function, the reader will be prepared to interpret subsequent manscripts in this issue.