Hypothesis: Central nervous system delivery of cyclosporine A for therapy of progressive multifocal leukoencephalopathy

Focosi, Daniele; Kast, Richard E.; Maggi, Fabrizio; Vatteroni, L; Ceccherini‐Nelli, Luca; Petrini, Mario

doi:10.1016/j.jcv.2007.04.004

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…The tissues were lung, diaphragm, cervical spinal cord, brain stem, or the carotid and aortic bodies sensing pH, O 2 , and CO 2 (Focosi et al , 2007; Gonzalez et al , 1994). WNV-positive immunostaining or histopathology was observed only in the brain stems or cervical spinal cords, but not in the other tissues.…”

Section: Resultsmentioning

confidence: 99%

Neurological suppression of diaphragm electromyographs in hamsters infected with West Nile virus

et al. 2010

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To address the hypothesis that respiratory distress associated with West Nile virus (WNV) is neurologically caused, electromyographs (EMGs) were measured longitudinally from the diaphragms of alert hamsters infected subcutaneously (s.c.) with WNV. The EMG activity in WNV-infected hamsters was consistently and significantly (P ≤ 0.001) less than that of sham-infected animals, beginning with suppression at day 3 and continuing to beyond day 17 after viral challenge. Of the tissues known to affect respiration, i.e., lung, diaphragm, cervical spinal cord, brain stem, and the carotid or aortic bodies, foci of WNV-immunoreactive neurons were only observed in the brain stems and some cervical spinal cords from EMG-suppressed animals. To confirm the involvement of the brain stem and spinal cord, WNV was injected directly in the ventrolateral medulla containing respiratory functions using stereotaxic surgery and into the cervical cord at the C4 vertebral level. As with subcutaneous WNV-challenge, hamsters developed EMG suppression of the diaphragm within 4 days. Since WNV-positive neurons were only sporadically identified in EMG-suppressed animals as early as day 3, a plausible mechanism of EMG suppression may involve regulation of diaphragm activity via vagal afferents acting on respiratory control system neurons in the brain stem. Brain auditory evoked response (BAER) was performed to determine if generalized brain stem neuropathy was the cause of diaphragmatic EMG suppression. Since deficiencies of BAER were only observed after day 11, which is long after diaphragm EMGs became suppressed, multiple phases of WNV-induced neurological disease are likely. These data establish that WNV infection of hamsters causes electrophysiological suppression of the diaphragm either directly by lesions in the brain stem and cervical spinal cord, or indirectly by altered vagal afferent function. This WNV-induced EMG-suppression may be analogous to conditions leading to respiratory distress of WNV-infected human patients.

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Section: Resultsmentioning

confidence: 99%

Neurological suppression of diaphragm electromyographs in hamsters infected with West Nile virus

et al. 2010

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“…PML is currently not curable. Many case reports exist describing potential therapies including cytosine arabinoside,5 interferon,6 cyclosporin A,7 cidifovir,4 mirtazapine4 8 alone or in various combinations. Few case series or well-controlled clinical trials exist, and therefore, it is difficult to assess the safety and efficacy of each agent.…”

Section: Discussionmentioning

confidence: 99%

Mefloquine in the treatment of progressive multifocal leukoencephalopathy

Gofton

Alkhotani

O'Farrell

et al. 2010

Journal of Neurology, Neurosurgery & Psychiatry

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Mefloquine, an antimalarial medication with efficacy against JC virus, was used to treat progressive multifocal leukoencephalopathy. A 54-year-old woman with sarcoidosis presented with a progressive cerebellar syndrome. MRI showed lesions affecting the right cerebellum that progressed over time to the brainstem. JC virus was found in the cerebrospinal fluid (CSF), and brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy. Mefloquine 1000 mg/week was initiated 6 months after symptom onset. Clinical progression stopped immediately, and JC virus became undetectable in the CSF. No clinical or imaging evidence of disease progression has occurred over 20 months of follow-up. This is the first report of successful treatment of progressive multifocal leukoencephalopathy with mefloquine.

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Progressive Multifocal Leukoencephalopathy: What’s New?

et al. 2010

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Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.

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Hypothesis: Central nervous system delivery of cyclosporine A for therapy of progressive multifocal leukoencephalopathy

Cited by 3 publications

References 18 publications

Neurological suppression of diaphragm electromyographs in hamsters infected with West Nile virus

Neurological suppression of diaphragm electromyographs in hamsters infected with West Nile virus

Mefloquine in the treatment of progressive multifocal leukoencephalopathy

Progressive Multifocal Leukoencephalopathy: What’s New?

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