Daniel F. Hanley

Vidarabine versus Acyclovir Therapy in Herpes Simplex Encephalitis

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

Treadmill Exercise Rehabilitation Improves Ambulatory Function and Cardiovascular Fitness in Patients With Chronic Stroke A Randomized, Controlled Trial

Background and Purpose— Physical inactivity propagates disability after stroke through physical deconditioning and learned nonuse. We investigated whether treadmill aerobic training (T-AEX) is more effective than conventional rehabilitation to improve ambulatory function and cardiovascular fitness in patients with chronic stroke. Methods— Sixty-one adults with chronic hemiparetic gait after ischemic stroke (>6 months) were randomized to 6 months (3×/week) progressive T-AEX or a reference rehabilitation program of stretching plus low-intensity walking (R-CONTROL). Peak exercise capacity (Vo2 peak), o2 consumption during submaximal effort walking (economy of gait), timed walks, Walking Impairment Questionnaire (WIQ), and Rivermead Mobility Index (RMI) were measured before and after 3 and 6 months of training. Results— Twenty-five patients completed T-AEX and 20 completed R-CONTROL. Only T-AEX increased cardiovascular fitness (17% versus 3%, &dgr;% T-AEX versus R-CONTROL, P<0.005). Group-by-time analyses revealed T-AEX improved ambulatory performance on 6-minute walks (30% versus 11%, P<0.02) and mobility function indexed by WIQ distance scores (56% versus 12%, P<0.05). In the T-AEX group, increasing training velocity predicted improved Vo2 peak (r=0.43, P<0.05), but not walking function. In contrast, increasing training session duration predicted improved 6-minute walk (r=0.41, P<0.05), but not fitness gains. Conclusions— T-AEX improves both functional mobility and cardiovascular fitness in patients with chronic stroke and is more effective than reference rehabilitation common to conventional care. Specific characteristics of training may determine the nature of exercise-mediated adaptations.

Rat spinal cord neurons contain nitric oxide synthase

We describe the distribution and characteristics of nitric oxide synthase-containing neurons in rat spinal cord using a polyclonal affinity-purified antibody against rat cerebellar nitric oxide synthase. Numerous neurons were stained throughout the entire rostrocaudal extent of the spinal cord. Cell bodies, dendrites and axons stained in a uniform manner. Nitric oxide synthase immunoreactivity was intense in neurons of laminae I-IV and X throughout the entire spinal cord. Neurons in the intermediolateral cell column of the thoracic and lumbar spinal cord were also intensely stained for nitric oxide synthase. The sacral cord demonstrated substantial nitric oxide synthase immunostaining within lamina VII. For the entire cord, scattered neurons in laminae V, VI, VII, and VIII were weakly positive. In addition, punctate nitric oxide synthase staining throughout laminae I, III and surrounding some large motor neurons in the ventral horn suggested the presence of nitric oxide synthase at synapses. Axons and dendritic terminals located in the gray and white matter were also stained. The majority of nitric oxide synthase positive neurons in the intermediolateral cell column were double-labelled by subcutaneously injected FluoroGold confirming that these cells were preganglionic autonomic neurons. Most NADPH-diaphorase-stained neurons were also nitric oxide synthase-positive. The distribution of nitric oxide synthase-containing neurons in spinal cord suggests that nitric oxide plays a role in spinal cord neurotransmission including: preganglionic sympathetic and parasympathetic, somatosensory, visceral sensory and possibly motor pathways. In particular, the autonomic nervous system appears enriched with nitric oxide synthase immunoreactivity. The precise role of each neuron type remains to be demonstrated in physiologic and pathophysiologic paradigms.

Treatment of refractory intracranial hypertension with 23.4% saline.

ObjectiveTo evaluate the effect of intravenous bolus administration of 23.4% saline (8008 mOsm/L) on refractory intracranial hypertension (RIH) in patients with diverse intracranial diseases.DesignRetrospective chart review.SettingA neurosciences intensive care unit in a university hospital.Patients

Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema : Effect on intracranial pressure and lateral displacement of the brain

OBJECTIVE To determine the effect of continuous hypertonic (3%) saline/acetate infusion on intracranial pressure (ICP) and lateral displacement of the brain in patients with cerebral edema. DESIGN Retrospective chart review. SETTINGS Neurocritical care unit of a university hospital. PATIENTS Twenty-seven consecutive patients with cerebral edema (30 episodes), including patients with head trauma (n = 8), postoperative edema (n = 5), nontraumatic intracranial hemorrhage (n = 8), and cerebral infarction (n = 6). INTERVENTION Intravenous infusion of 3% saline/acetate to increase serum sodium concentrations to 145 to 155 mmol/L. MEASUREMENTS AND MAIN RESULTS A reduction in mean ICP within the first 12 hrs correlating with an increase in the serum sodium concentration was observed in patients with head trauma (r2 = .91, p = .03), and postoperative edema (r2 = .82, p = .06), but not in patients with nontraumatic intracranial hemorrhage or cerebral infarction. In patients with head trauma, the beneficial effect of hypertonic saline on ICP was short-lasting, and after 72 hrs of infusion, four patients required intravenous pentobarbital due to poor ICP control. Among the 21 patients who had a repeat computed tomographic scan within 72 hrs of initiating hypertonic saline, lateral displacement of the brain was reduced in patients with head trauma (2.8 +/- 1.4 to 1.1 +/- 0.9 [SEM]) and in patients with postoperative edema (3.1 +/- 1.6 to 1.1 +/- 0.7). This effect was not observed in patients with nontraumatic intracranial bleeding or cerebral infarction. The treatment was terminated in three patients due to the development of pulmonary edema, and was terminated in another three patients due to development of diabetes insipidus. CONCLUSIONS Hypertonic saline administration as a 3% infusion appears to be a promising therapy for cerebral edema in patients with head trauma or postoperative edema. Further studies are required to determine the optimal duration of benefit and the specific patient population that is most likely to benefit from this treatment.

Intraventricular thrombolysis speeds blood clot resolution: Results of a pilot, prospective, randomized, double-blind, controlled trial

OBJECTIVEAnimal models and clinical studies suggest that intraventricular thrombolysis improves clot resolution and clinical outcomes among patients with intraventricular hemorrhage. However, this intervention may increase the rates of rebleeding and infection. To assess the safety and efficacy of intraventricular thrombolysis, we conducted a pilot, randomized, double-blind, controlled, multicenter study. METHODSPatients with intraventricular hemorrhage requiring ventriculostomy were randomized to receive intraventricular injections of normal saline solution or urokinase (25,000 international units) at 12-hour intervals. Injections continued until ventricular drainage was discontinued according to prespecified clinical criteria. Head computed tomographic scans were obtained daily, for quantitative determinations of intraventricular hemorrhage volumes. The rate of clot resolution was estimated for each group. RESULTSTwelve subjects were enrolled (urokinase, seven patients; placebo, five patients). Commercial withdrawal of urokinase precluded additional enrollment. The urokinase and placebo groups were similar with respect to age (49.6 versus 55.2 yr, P = 0.43) and presenting Glasgow Coma Scale scores (7.14 versus 8.00, P = 0.72). Randomization to the urokinase treatment arm (P = 0.02) and female sex (P = 0.008) favorably affected the clot resolution rate. The sex-adjusted clot half-life for the urokinase-treated group was reduced 44.6%, compared with the value for the placebo group (4.69 versus 8.48 d). CONCLUSIONIntraventricular thrombolysis with urokinase speeds the resolution of intraventricular blood clots, compared with treatment with ventricular drainage alone.

Intensive blood-pressure lowering in patients with acute cerebral hemorrhage

BACKGROUND Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. METHODS We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. RESULTS Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). CONCLUSIONS The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

Treadmill Exercise Activates Subcortical Neural Networks and Improves Walking After Stroke A Randomized Controlled Trial

Background and Purpose— Stroke often impairs gait thereby reducing mobility and fitness and promoting chronic disability. Gait is a complex sensorimotor function controlled by integrated cortical, subcortical, and spinal networks. The mechanisms of gait recovery after stroke are not well understood. This study examines the hypothesis that progressive task-repetitive treadmill exercise (T-EX) improves fitness and gait function in subjects with chronic hemiparetic stroke by inducing adaptations in the brain (plasticity). Methods— A randomized controlled trial determined the effects of 6-month T-EX (n=37) versus comparable duration stretching (CON, n=34) on walking, aerobic fitness and in a subset (n=15/17) on brain activation measured by functional MRI. Results— T-EX significantly improved treadmill-walking velocity by 51% and cardiovascular fitness by 18% (11% and −3% for CON, respectively; P<0.05). T-EX but not CON affected brain activation during paretic, but not during nonparetic limb movement, showing 72% increased activation in posterior cerebellar lobe and 18% in midbrain (P<0.005). Exercise-mediated improvements in walking velocity correlated with increased activation in cerebellum and midbrain. Conclusions— T-EX improves walking, fitness and recruits cerebellum-midbrain circuits, likely reflecting neural network plasticity. This neural recruitment is associated with better walking. These findings demonstrate the effectiveness of T-EX rehabilitation in promoting gait recovery of stroke survivors with long-term mobility impairment and provide evidence of neuroplastic mechanisms that could lead to further refinements in these paradigms to improve functional outcomes.

Treatment of Intraventricular Hemorrhage With Urokinase Effects on 30-Day Survival

BACKGROUND AND PURPOSE Intraventricular hemorrhage (IVH) remains associated with high morbidity and mortality. Therapy with external ventricular drainage alone has not modified outcome in these patients. METHODS Twelve pilot IVH patients who required external ventricular drainage were prospectively treated with intraventricular urokinase followed by the randomized, double-blinded allocation of 8 patients to either treatment or placebo. Observed 30-day mortality was compared with predicted 30-day mortality obtained by use of a previously validated method. RESULTS Twenty patients were enrolled; admission Glasgow Coma Scale score in 11 patients was </=8; 10 patients had pulse pressure <85 mm Hg. Mean+/-SD ICH volume in 16 patients was 6.21+/-7.53 cm(3) (range 0 to 23.88 cm(3)), and mean+/-SD intraventricular hematoma volume was 44.26+/-31.65 cm(3) (range 1.31 to 100.36 cm(3)). Four patients (20%) died within 30 days. Predicted mortality for these 20 patients was 68.42% (range 3% to 100%). Probability of observing </=4 deaths among 20 patients under a 68.42% expected mortality is 0.000012. CONCLUSIONS Intraventricular urokinase may significantly improve 30-day survival in IVH patients. On the basis of current evidence, a double-blinded, placebo-controlled, multicenter study that uses thrombolysis to treat IVH has received funding and began January 1, 2000.

Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial

INTRODUCTION Compared to ischemic stroke, intracerebral hemorrhage (ICH) is easily and rapidly identified, occurs in younger patients, and produces relatively small initial injury to cerebral tissues--all factors suggesting that interventional amelioration is possible. Investigations from the last decade established that extent of ICH-mediated brain injury relates directly to blood clot volume and duration of blood exposure to brain tissue. Using minimally-invasive surgery plus recombinant tissue plasminogen activator (rtPA), MISTIE investigators explored aggressive avenues to treat ICH. METHODS We investigated the difference between surgical intervention plus rtPA and standard medical management for ICH. Subjects in both groups were medically managed according to standard ICU protocols. Subjects randomized to surgery underwent stereotactic catheter placement and clot aspiration. Injections of rtPA were then given through hematoma catheter every 8 h, up to 9 doses, or until a clot-reduction endpoint. After each injection the system was flushed with sterile saline and closed for 60 min before opening to spontaneous drainage. RESULTS Average aspiration of clots for all patients randomized to surgery plus rtPA was 20% of mean initial clot size. After acute treatment phase (aspiration plus rtPA), clot was reduced an average of 46%. Recorded adverse events were within safety limits, including 30-day mortality, 8%; symptomatic re-bleeding, 8%; and bacterial ventriculitis, 0%. Patients randomized to medical management showed 4% clot resolution in a similar time window. Preliminary analysis indicates that clot resolution rates are greatly dependent on catheter placement. Location of ICH also affects efficacy of aggressive treatment of ICH. CONCLUSION There is tentative indication that minimally-invasive surgery plus rtPA shows greater clot resolution than traditional medical management.