Douglas A. Kerr

Recovery from paralysis in adult rats using embryonic stem cells

We explored the potential of embryonic stem cell–derived motor neurons to functionally replace those cells destroyed in paralyzed adult rats.

Aven, a Novel Inhibitor of Caspase Activation, Binds Bcl-xL and Apaf-1

Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.

Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients

Objective: To describe challenges in diagnosis and management of patients with clinical syndromes of immune reconstitution inflammatory syndrome (IRIS) involving the CNS. Methods: The authors describe three patients with clinically distinct neurologic manifestations of IRIS with HIV infection who presented as diagnostic and therapeutic challenges. Results: One patient with cryptococcal meningitis developed acute cerebellitis with mass effect and brainstem compression. Corticosteroid therapy was associated with complete resolution of the cerebellar lesion but the patient developed VZV encephalitis. Another patient with progressive multifocal leukoencephalopathy developed subacute progression of focal neurologic deficits associated with contrast enhancing lesions on brain MRI. This patient had spontaneous resolution of the lesion but was left with residual deficits. One patient developed a progressive dementing syndrome and deterioration over several months resulting in coma during combination antiretroviral therapy. A brain biopsy in this latter patient showed massive infiltration of T lymphocytes predominantly of the CD8 subtype. This patient had a significant improvement with corticosteroids and change in antiretroviral regimen although she was left with residual cognitive impairment. Conclusions: Immune reconstitution inflammatory syndrome should be suspected in patients who show clinical or radiologic deterioration following initiation of antiretroviral therapy accompanied with improvement in CD4 cell count and viral load. Some patients may respond to a brief course of treatment with corticosteroids.

Stem cell transplantation in multiple sclerosis: current status and future prospects

This article provides an overview of the current knowledge relating to the potential use of transplanted stem cells in the treatment of patients with multiple sclerosis (MS). Two types of stem cells, CNS-derived neural stem/precursor cells (NPCs) and bone marrow-derived mesenchymal stem cells (MSCs) are considered to provide reproducible and robust therapeutic effects when intravenously or intrathecally injected into both rodents and primates with experimental autoimmune encephalomyelitis. Furthermore, preliminary safety data concerning the use of intrathecally injected autologous MSCs in patients with progressive MS are available. We discuss how the data gathered to date challenge the narrow view that the therapeutic effects of NPCs and MSCs observed in the treatment of MS are accomplished solely by cell replacement. Both types of stem cell, when transplanted systemically, might instead influence disease outcome by releasing a plethora of factors that are immunomodulatory or neuroprotective, thereby directly or indirectly influencing the regenerative properties of intrinsic CNS stem/precursor cells.

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.

Distinct subtypes of myelitis in systemic lupus erythematosus

OBJECTIVE Myelitis causes pain, weakness, and sphincteric deficits, and is 1,000-fold more prevalent in patients with systemic lupus erythematosus (SLE) than in the general population. For the last century, descriptions of SLE myelitis have been primarily limited to case reports. In contrast, larger-scale cohort studies have revealed that myelitis occurring in the idiopathic demyelinating diseases (i.e., multiple sclerosis versus neuromyelitis optica) represents distinct syndromes. This study was undertaken to determine whether SLE myelitis similarly encapsulates distinct syndromes. METHODS We analyzed a cohort of 22 patients with SLE and myelitis. Patients were assessed for neurologic variables related to myelitis and for clinical and serologic features of SLE. Magnetic resonance images of the spine, cerebrospinal fluid profiles, and autoantibody profiles were obtained. RESULTS Eleven patients presented with signs of gray matter dysfunction (i.e., flaccidity and hyporeflexia), whereas 11 patients presented with signs of white matter dysfunction (i.e., spasticity and hyperreflexia). Patients with gray matter dysfunction were more likely to have irreversible paraplegia (P < 0.01), despite presenting with a monophasic versus polyphasic course (P = 0.01), higher levels of SLE activity (mean SLE Disease Activity Index 9.8 versus 2.0; P = 0.01), and a cerebrospinal fluid profile indistinguishable from bacterial meningitis. Prior to irreversible paraplegia, these patients presented with prodromes of fever and urinary retention, but were misdiagnosed by physicians of different specialties as having urinary tract infections. Patients with white matter dysfunction were more likely to meet criteria for neuromyelitis optica (P = 0.04) and were also more likely to have antiphospholipid antibodies (lupus anticoagulant) (P = 0.01). CONCLUSION Our findings indicate that SLE myelitis encapsulates 2 distinct and previously unrecognized syndromes that can be distinguished clinically by gray matter versus white matter findings. Recognition of fever and urinary retention as prodromes of irreversible paraplegia may allow earlier diagnosis and treatment in SLE patients presenting with gray matter findings.

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.

Cleavage of Cystatin C in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis.

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.