Chitra Krishnan

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (24)115.16 Total impact

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    ABSTRACT: This study was conducted to aid in the development of a multidisciplinary care center for patients with transverse myelitis. We surveyed the parents of 20 children diagnosed with transverse myelitis between the ages of 0.5 and 21 years to understand their experiences in navigating the health care system. We analyzed acute care events and long-term follow-up in relation to patient satisfaction. Results showed satisfactory ratings in the vicinity of 50% in key areas such as the articulation of a treatment plan. A significant disparity was found in the patients' desire for specialty care and their ability to procure such care. In all, 90% of patients expressed a desire to consult with a psychiatrist, but only 25% were successful in making a visit, a 64% deficit; 70% of respondents also desired to see a gastroenterologist, with only 25% actually doing so, leaving a 43% gap. Recommendations and patient opinions regarding the creation of a collaborative care environment are noted. Research with a larger sample will further elucidate the needs in transverse myelitis patient care.
    No preview · Article · Mar 2009 · Journal of child neurology
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    ABSTRACT: To explore the safety and effectiveness of high-dose cyclophosphamide (HiCy) without bone marrow transplantation in patients with aggressive multiple sclerosis (MS). 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. 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. 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). 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. 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).
    Full-text · Article · Jul 2008 · Archives of neurology
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    ABSTRACT: CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.
    Full-text · Article · May 2008 · Journal of Neuroimmunology
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    ABSTRACT: 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.
    No preview · Article · Jun 2007 · Neurology
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    ABSTRACT: To relate clinical characteristics associated with acute transverse myelitis (ATM) in children with functional outcomes at follow-up. 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. 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. 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.
    No preview · Article · Jun 2007 · Neurology
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    ABSTRACT: We explored the potential of embryonic stem cell-derived motor neurons to functionally replace those cells destroyed in paralyzed adult rats. We administered a phosphodiesterase type 4 inhibitor and dibutyryl cyclic adenosine monophosphate to overcome myelin-mediated repulsion and provided glial cell-derived neurotrophic factor within the sciatic nerve to attract transplanted embryonic stem cell-derived axons toward skeletal muscle targets. We found that these strategies significantly increased the success of transplanted axons extending out of the spinal cord into ventral roots. Furthermore, transplant-derived axons reached muscle, formed neuromuscular junctions, were physiologically active, and mediated partial recovery from paralysis. We conclude that restoration of functional motor units by embryonic stem cells is possible and represents a potential therapeutic strategy for patients with paralysis. To our knowledge, this is the first report of the anatomical and functional replacement of a motor neuron circuit within the adult mammalian host.
    Full-text · Article · Jul 2006 · Annals of Neurology
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    ABSTRACT: Transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord. Perivascular monocytic and lymphocytic infiltration, demyelination, and axonal injury are prominent histopathogic features of TM. The clinical manifestations of TM are consequent to dysfunction of motor, sensory, and autonomic pathways. At peak deficit, 50% of patients with TM are completely paraplegic (with no volitional movements of legs), virtually all have some degree of bladder dysfunction, and 80% to 94% have numbness, paresthesias, or band-like dysesthesias. Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae, one third are left with a moderate degree of permanent disability, and one third have severe disability. Recent studies have shown that the cytokine interleukin-6 may be a useful biomarker, as the levels of interleukin-6 in the cerebrospinal fluid of acute TM patients strongly correlate with and are highly predictive of disability. Clinical trials testing the efficacy of promising axonoprotective agents in combination with intravenous steroids in the treatment of TM are currently underway.
    No preview · Article · Jun 2006 · Current Neurology and Neuroscience Reports
  • Douglas Kerr · Chitra Krishnan · Michele L Pucak · Jessica Carmen
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    ABSTRACT: 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 manuscripts in this issue.
    No preview · Article · Jan 2006 · International Review of Psychiatry
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    D M Deshpande · C Krishnan · DA Kerr
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    ABSTRACT: Case report. We describe a patient who developed transverse myelitis (TM) following a nerve root injection of steroids and anesthetic at L2 for radicular pain. Baltimore, MD, USA. A 42-year-old woman developed progressive lower extremity weakness and paresthesias, a T12 sensory level and urinary urgency 8 h following the injection of Marcaine and Celestone into the left L2 nerve root. Magnetic resonance imaging showed T2 signal abnormality with gadolinium enhancement from T12 to the conus medullaris and there was no evidence of traumatic injury to the spinal cord. The patient had undiagnosed Behcet's disease (BD) and had experienced multiple episodes of pathergy: hyper-responsiveness of the skin to local trauma, resulting in inflammation and edema. Intravenous steroids were initiated and the patient experienced a near total clinical resolution and a complete radiologic resolution. Since the spinal cord inflammation developed after and immediately adjacent to local spinal trauma, we suggest that the TM in this patient was related to BD and was a pathergy response in the spinal cord.
    Preview · Article · Jan 2006 · Spinal Cord
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    ABSTRACT: 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.
    Full-text · Article · Nov 2005 · Journal of Clinical Investigation
  • Chitra Krishnan · Douglas A Kerr
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    ABSTRACT: Reports in the medical literature of "acute myelitis" date back to 1882 and are credited to H. C. Bastain, MD Lond, FRS, a consulting physician to what was then called University College Hospital and the National Hospital for the Paralysed and Epileptic (London, England).1 He described several cases of acute myelitis resulting in "softening of the spinal cord."2(p1531) He presented the pathologic findings of several autopsies from patients who died of the myelitis and divided the cases into those that he thought were due to "blood changes and toxins, often associated with feeble cardiac action, which may well act as causes of thrombosis in vessels of the spinal cord"2(p1532) and those that were due to acute inflammation. The "inflammatory" cases were postulated to be due to an infectious or an allergic mechanism.
    No preview · Article · Jul 2005 · JAMA Neurology
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    ABSTRACT: The authors report the clinical course and immune system response of a patient with disease-associated recurrent transverse myelitis (TM) following cerebral infection with Brucellosis melitensis. The patient suffered four recurrences of his TM (each at a distinct spinal cord level) over the course of 2 years following his initial presentation, which ultimately progressed to quadriplegia. He had progressively declining cerebrospinal fluid (CSF) brucella antibody titers, suggesting a postinfectious, rather than an infectious, etiology. The authors simultaneously examined the expression of multiple cytokines in the CSF of this patient using cytokine antibody arrays and found a marked elevation of interleukin (IL)-6, IL-8, and macrophage chemoattractant protein (MCP)-1 levels relative to controls. Quantitative enzyme-linked immunosorbent assay (ELISA) analysis of the CSF confirmed a 1700-fold elevation of IL-6 and more modest elevations of IL-8 and MCP-1. IL-6 levels returned to baseline following treatment of the patient with intravenous cyclophosphamide and plasma exchange and the patient experienced a significant and sustained recovery of function.
    No preview · Article · May 2005 · Journal of NeuroVirology
  • Douglas Kerr · Chitra Krishnan · Frank Pidcock

    No preview · Chapter · Apr 2005
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    ABSTRACT: 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. 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. 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.
    Full-text · Article · Feb 2005 · The Neurologist
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    ABSTRACT: First described in 1882, and termed acute transverse myelitis (TM) in 1948 (1), TM is a rare syndrome with an incidence of between one and eight new cases per million people per year (2). TM is characterized by focal inflammation within the spinal cord and clinical manifestations are caused by resultant neural dysfunction of motor, sensory, and autonomic pathways within and passing through the inflamed area. There is often a clearly defined rostral border of sensory dysfunction and evidence of acute inflammation demonstrated by a spinal magnetic resonance imaging (MRI) and lumbar puncture. When the maximal level of deficit is reached, approx 50% of patients have lost all movements of their legs, virtually all patients have some degree of bladder dysfunction, and 80 to 94% of patients have numbness, paresthesias, or band-like dysesthesias (2–7). Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty or inability to void, incomplete evacuation or bowel, constipation, and sexual dysfunction (8). Like multiple sclerosis (MS) (9), TM is the clinical manifestation of a variety of disorders with distinct presentations and pathologies (10). Recently, we proposed a diagnostic and classification scheme that has defined TM as either idiopathic or associated with a known inflammatory disease (i.e., MS, systemic lupus erythematosus [SLE], Sjogren’s syndrome, or neurosarcoidosis) (11). Most TM patients have monophasic disease, although up to 20% will have recurrent inflammatory episodes within the spinal cord (Johns Hopkins Transverse Myelitis Center [JHTMC] case series, unpublished data) (12,13).
    No preview · Chapter · Jan 2005
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    ABSTRACT: Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)–1 and tumor growth factor–β1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain. Ann Neurol 2005 An Erratum has been published for this article in Ann Neurol 57: 304, 2005.
    Full-text · Article · Jan 2005 · Annals of Neurology
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    ABSTRACT: 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 calcium-permeable 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.
    Full-text · Article · Sep 2004 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: We generated spinal motoneurons from embryonic stem (ES) cells to determine the developmental potential of these cells in vitro and their capacity to replace motoneurons in the adult mammalian spinal cord. ES cell-derived motoneurons extended long axons, formed neuromuscular junctions, and induced muscle contraction when cocultured with myoblasts. We transplanted motoneuron-committed ES cells into the spinal cords of adult rats with motoneuron injury and found that approximately 3,000 ES cell-derived motoneurons (25% of input) survived for >1 month in the spinal cord of each animal. ES cell-derived axonal growth was inhibited by myelin, and this inhibition was overcome by administration of dibutyryl cAMP (dbcAMP) or a Rho kinase inhibitor in vitro and in vivo. In transplanted rats infused with dbcAMP, approximately 80 ES cell-derived motor axons were observed within the ventral roots of each animal, whereas none were observed in transplanted rats not treated with dbcAMP. Because these cells replicate many of the developmental and mature features of true motoneurons, they are an important biological tool to understand formation of motor units in vitro and a potential therapeutic tool to reconstitute neural circuits in vivo.
    Full-text · Article · Jun 2004 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Transverse Myelitis (TM) is a clinical syndrome 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 multi-focal CNS disease (e.g. MS), multi-systemic disease (e.g. systemic lupus erythematosus), or as an isolated, idiopathic entity. In this article, we will summarize recent classification and diagnostic schemes (1), which provide a framework for the acute management of patients with TM. Additionally, we will review current concepts on the natural history, immunopathogenesis and treatment strategies for patients with TM.
    Full-text · Article · Jun 2004 · Frontiers in Bioscience
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    C Krishnan · J M Malik · DA Kerr
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    ABSTRACT: Case report. We describe a patient who developed a myelopathy associated with a noncompressive herniated cervical intervertebral disc at the same level. We provide clinical and radiological evidence that reveals that even though the disc herniation did not compress the spinal cord, it diminished venous blood flow out of the spinal cord, possibly resulting in a venous hypertensive myelopathy (VHM). Baltimore, MD, USA. A 29-year-old woman developed a cervical radiculopathy, followed by a slowly progressive cervical myelopathy associated with a herniated C5-C6 disc. Magnetic resonance imaging showed a noncompressive disc herniation, a swollen spinal cord with increased T2 signal most prominent at the site of the herniated disc, extending several levels above and below the disc. The patient was diagnosed with acute transverse myelitis (ATM) and was started on IV steroids. However, unlike most cases of transverse myelitis, spinal fluid analysis was noninflammatory. In contrast, several features suggested that the patient instead had VHM. We suggest that the disc herniation resulted in impaired drainage of blood from the spinal cord through compression of the venous plexus near the intervertebral foramen. Although the patient did not recover function following high-dose steroid administration, she recovered completely following C5-C6 discectomy and fusion. To our knowledge, this is the first report of likely VHM in the absence of a spinal arteriovenous malformation. We suggest that some patients diagnosed with ATM in the setting of extrinsic spinal column abnormalities may actually have a noninflammatory myelopathy associated with impaired spinal venous drainage.
    Preview · Article · May 2004 · Spinal Cord