A double-blind, randomized, controlled study of two dose strengths of dalfampridine extended release on walking deficits in ischemic stroke.

BACKGROUND: Stroke-induced ischemia affects both cortex and underlying white matter. Dalfampridine extended release tablets (D-ER) enhance action potential conduction in demyelinated axons, which may positively affect post-stroke recovery. OBJECTIVE: Based on promising preliminary data, we compared efficacy of D-ER administered at 7.5 mg or 10 mg with placebo on post-stroke ambulation. Primary study outcome (response) was a ≥20% increase on the 2-minute walk test (2 MinWT) at 12 weeks after first drug administration. METHODS: This was a multicenter, randomized, placebo-controlled, 3-arm, parallel-group, safety and efficacy trial. After obtaining baseline measures of 2 MinWT, Walk-12, and Timed Up and Go, subjects entered a 2-week, single-blind placebo run-in period and were randomized 1:1:1 to receive 7.5 mg D-ER, 10 mg D-ER, or placebo, dosed twice-daily for 12 weeks. Follow-up evaluations occurred at weeks 14 and 16 when subjects were off study drug. RESULTS: The study was terminated early with 377 of planned 540 patients enrolled, due to no treatment effect. At week 12, mean increase in distances walked in 2 minutes were similar among the 3 study groups (14.9±40.0 feet; 19.4±39.6 feet; and 20.4±38.3 feet for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively). The proportion of subjects who showed ≥20% improvement on 2 MinWT at week 12 was 13.5%, 14.0%, and 19.0%, for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively; these were nonsignificant changes from baseline for all groups. CONCLUSIONS: D-ER at either a 7.5-mg or 10-mg dose did not significantly increase performance on the 2 MinWT in stroke survivors with gait impairment, although this study was terminated early before full enrollment. (Clinical Trial # NCT02271217).

Rabies encephalomyelitis: clinical, neuroradiological, and pathological findings in 4 transplant recipients.

BACKGROUND: Three patients received solid organ transplants from a common donor and were subsequently discharged from the hospital following an uneventful hospital course. Within 30 days, all 3 organ recipients returned to the hospital with varying symptoms that progressed to rapid neurological deterioration, coma, and death. OBJECTIVE: To describe the clinical, neuroradiological, and pathological findings of rabies virus infection in organ transplant recipients infected from a common donor. DESIGN: Case series involving a common donor and 3 organ recipients ascertained through review of clinical course and autopsy findings. A fourth case was determined by review of pending autopsy cases in which death occurred within the same time interval. Portions of postmortem central nervous system and organ tissues were frozen and formalin-fixed. Fluids and tissues were also collected for cultures, serology, and molecular studies. Postmortem fluids and tissues and antemortem fluids and tissues from all 4 transplant recipients and serum and banked lymphocyte or spleen cells from the donors were sent to the Centers for Disease Control and Prevention for further evaluation. SETTING: Transplant unit of an urban teaching hospital. RESULTS: Antemortem cerebrospinal fluid analysis for 3 of the 4 recipients was consistent with a viral etiology. Neuroimaging and electroencephalogram studies were suggestive of an infectious encephalitis or a toxic encephalopathy. Initial laboratory testing did not demonstrate an infectious etiology. Postmortem histologic analysis, immunohistochemistry, electron microscopy, and direct fluorescence antibody testing revealed rabies virus infection. Serological testing done postmortem confirmed rabies virus infection in the common donor. CONCLUSIONS: These cases demonstrate a risk for transmitting rabies virus infection through solid organ and tissue transplantation, and this diagnosis should be considered in any rapidly progressing neurological disease.

Transmission of rabies virus from an organ donor to four transplant recipients.

BACKGROUND: In 2004, four recipients of kidneys, a liver, and an arterial segment from a common organ donor died of encephalitis of an unknown cause. METHODS: We reviewed the medical records of the organ donor and the recipients. Blood, cerebrospinal fluid, and tissues from the recipients were tested with a variety of assays and pathological stains for numerous causes of encephalitis. Samples from the recipients were also inoculated into mice. RESULTS: The organ donor had been healthy before having a subarachnoid hemorrhage that led to his death. Encephalitis developed in all four recipients within 30 days after transplantation and was accompanied by rapid neurologic deterioration characterized by agitated delirium, seizures, respiratory failure, and coma. They died an average of 13 days after the onset of neurologic symptoms. Mice inoculated with samples from the affected patients became ill seven to eight days later, and electron microscopy of central nervous system (CNS) tissue demonstrated rhabdovirus particles. Rabies-specific immunohistochemical and direct fluorescence antibody staining demonstrated rabies virus in multiple tissues from all recipients. Cytoplasmic inclusions consistent with Negri bodies were seen in CNS tissue from all recipients. Antibodies against rabies virus were present in three of the four recipients and the donor. The donor had told others of being bitten by a bat. CONCLUSIONS: This report documenting the transmission of rabies virus from an organ donor to multiple recipients underscores the challenges of preventing and detecting transmission of unusual pathogens through transplantation.