Gabapentin for parkinsonism: a double-blind, placebo-controlled, crossover trial.

PURPOSE: Gabapentin is a recently available anticonvulsant whose mechanism of action remains unknown. We suspected efficacy from serendipitous observations of gabapentin in patients with parkinsonism. This led us to a double-blind, placebo-controlled, crossover trial. PATIENTS AND METHODS: We administered gabapentin in a placebo-controlled, double-blind, crossover trial to 19 subjects with advanced parkinsonism. We measured the effect of placebo and gabapentin on subjects' symptoms with the Unified Parkinson's Disease Rating Scale, the Webster Scale, and the Hoehn and Yahr Scale. We assessed tremor with surface-recorded electromyography. RESULTS: Total Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo (P = 0.0005). Likewise, activities of daily living and examination subscore of the Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo but did not achieve statistical significance. Webster Scale showed improvement but neither Hoehn and Yahr Scale nor Webster Scale changes reached statistical significance. Tremor as measured by the Unified Parkinson's Disease Rating Scale improved with gabapentin but the use of the root mean square of the rectified electromyography as a measure of tremor activity was not statistically significant. CONCLUSIONS: This study demonstrates that gabapentin improves rigidity, bradykinesia, and tremor of parkinsonism including both Parkinson's disease and Parkinson's syndrome. The rigidity and bradykinesia of parkinsonism improve on the drug even when the effects of gabapentin on tremor are discounted.

Neuroprotective effects of early vs. late administration of dantrolene in experimental status epilepticus.

We examined the effects of dantrolene, an inhibitor of intracellular calcium release, on hippocampal neuronal damage associated with 140 min of limbic status epilepticus in the rat. Dantrolene (10 mg/kg i.p.) was administered after either 30 min or 140 min of status epilepticus. Early administration was associated with a significant reduction in the amount of neuronal injury in all hippocampal subregions, while late administration was associated with less neuronal injury in area CA3 only. These findings suggest that a substantial portion of seizure-induced hippocampal injury is associated with release of calcium from intracellular stores, and that early administration of dantrolene may be a useful adjunct to anticonvulsant treatment of status epilepticus.

Lithium attenuates the development of lesion-induced behavioral supersensitivity to apomorphine.

The unilateral nigrostriatal lesion preparation was used to examine the effect of long-term treatment with lithium on rotation in response to the dopamine agonists apomorphine and amphetamine. Rats with unilateral striatal denervation received daily injections of either lithium chloride or saline for 14 days, beginning 24 h after surgery. Rats treated with lithium showed a reversible reduction in apomorphine-induced contralateral rotation. Lithium treatment failed to substantially alter amphetamine-induced ipsilateral rotation. When treatment was initiated 14 days after surgery, rats treated with lithium showed no reduction in apomorphine-induced contralateral rotation. These findings suggest that lithium attenuates the development of lesion-induced behavioral supersensitivity but fails to alter supersensitivity which has developed previously.

Topiramate reduces neuronal injury after experimental status epilepticus.

Prolonged seizures are associated with injury to vulnerable neurons, particularly in the hippocampus. Identification of compounds that attenuate injury after prolonged seizures could be of value in the management of refractory status epilepticus. We hypothesized that topiramate, an anticonvulsant with multiple mechanisms of action, would attenuate hippocampal neuronal injury when given after experimental status epilepticus. Limbic status epilepticus was induced in adult male Wistar rats for 140 min by unilateral hippocampal electrical stimulation. Rats then received intraperitoneal injections of either vehicle (n=6) or topiramate at 20 mg/kg (n=6), 40 mg/kg (n=7) or 80 mg/kg (n=7). Three days later, hippocampal sections were processed for neuronal degeneration using a silver impregnation stain. Seizure-induced damage was assessed by measuring the density of silver staining in hippocampal regions CA1, CA3 and dentate hilus. Administration of topiramate at each dose was associated with a significant reduction in staining density bilaterally in area CA1 and the dentate hilus. Reduction in staining density in area CA3 was seen contralateral to the side of stimulation at the two higher topiramate doses only. The results indicate that administration of topiramate after experimental status epilepticus can attenuate seizure-induced hippocampal neuronal injury.

Swimming as a method for assessing motor cortex integrity in the rat.

Rats were tested on 6 measures of swimming behavior 1, 2 and 4 weeks after sham operations or bilateral motor cortex lesions that damaged the forelimb areas and axons controlling the axial musculature. Rats with lesions performed more forelimb kicks and showed larger body angles than control animals. Number of hindlimb kicks and speed were within normal limits. Thus, some measures of swimming can be affected by small motor cortex lesions that spare the hindlimb projections.

Effects of one- and two-stage lesions of the posterior hypothalamus on temperature regulation in the rat.

Rats received 1-stage bilateral and sequential unilateral (serial) lesions of the posterior hypothalamus and were tested for the ability to regulate body temperature after a lengthy recovery period. The groups with lesion differed from the sham-operated groups in the cold, although not under ambient or warm conditions. The fact that the serial lesion group performed the same as the 1-stage lesion groups in the cold is significant because earlier tests on these same animals revealed much better recovery after serial lesions in swimming, and a partial serial lesion effect in open field performance.

Undernutrition and recovery from brain damage: a preliminary investigation.

Rats undernourished early in life did not differ from control animals in acquiring a light-dark discrimination. Posterior cortical lesions impaired retention in both nutritional groups, but the relearning scores of the undernourished animals with lesions were significantly worse than those of the lesion group that had been well fed. Amphetamine was found to enhance recovery, especially in the undernourished group. These data thus show that early nutritional history can be an important factor in accounting for differences in performance following later, focal brain damage, but that pharmacological intervention still can be of great value in these cases.

Behavioral effects of early deprivation of nerve growth factor: some similarities with familial dysautonomia.

Female rats immunized with mouse nerve growth factor develop an antibody (anti-NGF) which reaches offspring through the placenta and via the milk. Pups exposed to maternal anti-NGF have fewer dorsal root and sympathetic neurons. When the offspring are examined on a wide variety of behavioral tests, they exhibit severe deficits in response to stress (ulceration, corticosterone levels), and mild deficits on some sensory and cognitive tasks. Exploratory and motor functions, however, are relatively normal. The pathologic and behavioral profiles of the animals closely mimic the sensory and sympathetic aspects of familial dysautonomia.

Baclofen suppresses bursting activity induced in hippocampal slices by differing convulsant treatments.

Epileptiform activity was induced in area CA3 of hippocampal slices by superfusion of medium containing 50 microM bicuculline and 3.5 mM K, 50 microM bicuculline and 5 mM K, 50 nM kainic acid and 3.5 mM K, or 7 mM K. Burst potentials were recorded at rates between 5 and 44/min, depending on the convulsant treatment. Baclofen reduced the frequency of burst firing in all slices tested in a dose-dependent manner, with little change in the morphology of individual bursts. Thus baclofen primarily affected the initiation of epileptiform discharges. IC50 values varied between 27 and 500 nM and were positively correlated with the rate of bursting. These experiments indicate that baclofen, at concentrations present in the CSF of patients treated for spasticity, has an anticonvulsant-like effect in the hippocampal formation and suggest that its mode of action is to reduce the excitability of pyramidal cells.

Electroencephalographic and histological characteristics of a model of limbic status epilepticus permitting direct control over seizure duration.

Status epilepticus is a neurological emergency associated with substantial morbidity and mortality. Experimental and clinical investigations suggest that prolonged seizure activity is associated with injury to vulnerable neurons. Compounds with neuroprotective properties may minimize such injury. Existing methods of inducing experimental status epilepticus result in seizure activity of variable duration and neuronal injury of variable degree. To minimize such variability, status epilepticus may be stopped with anticonvulsants, but this limits the ability to screen for independent neuroprotective properties. We have developed a simple and reliable non-pharmacological model of limbic status epilepticus in which the duration of status epilepticus is under direct experimental control. Status epilepticus is induced by continuous, unilateral hippocampal stimulation. Using this model, the degree of hippocampal pyramidal cell injury varies in direct proportion to status epilepticus duration across a range of 15-140 min. A progressive sequence of EEG changes unfolds with increasing status epilepticus duration, resembling that seen in other models. This model may serve as a reference against which the effects of potential neuroprotective compounds can be studied.

Diagnosis in Huntington disease.

We present a case of Huntington disease made complex by lack of adequate family history. We survey the available diagnostic neuroimaging studies: CT, MRI, PET and SPECT. We briefly review the neurophysiologic investigations. We present the newly available information on the discovery of the Huntington disease gene. Direct testing for the gene without complex linkage analysis will now be available.

Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia.

PURPOSE: To evaluate the effect of slow-frequency repetitive transcranial magnetic stimulation (SF-rTMS) on interictal epileptiform activity and seizure frequency in a patient with medically refractory partial seizures due to focal cortical dysplasia. METHODS: A 9-cm circular coil was positioned over the area of cortical dysplasia. One hundred stimuli given at 0.5 Hz at 5% below motor threshold were given biweekly for four consecutive weeks. The EEG was recorded for 30 min before and after the first 100 stimuli. The number of seizures during the month of stimulation was compared with that of the month before stimulation. RESULTS: Stimulation was associated with a 70% reduction in the frequency of seizures and a 77% reduction in the frequency of interictal spikes. No seizures occurred during stimulation. CONCLUSIONS: SF-rTMS was safe and well tolerated in this patient. The reduction in seizures and interictal spikes associated with SF-rTMS supports the concept of SF-rTMS-induced cortical inhibition.

Attenuation of gastric lesions by psychological aspects of aggression in rats.

Rats that fought with each other in response to electric shock showed reduced gastric lesions in comparison with animals that received the same shocks alone so that fighting behavior did not occur. Also, gastric lesions were similarly reduced in animals that fought even though they could not physically contact one another because of a barrier between them, so that the "protective" effect of fighting derived from release of, or display of, fighting behavior and did not require physical combat. A second experiment showed that animals that received shock together but did not engage in fighting behavior showed no reduction of gastric lesions, so that the protective effect of fighting was not an artifact of animals receiving shock together. Possible explanations for why fighting behavior reduces gastric lesions are discussed.

Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis.

OBJECTIVE: To examine the efficacy of gabapentin in the treatment of spasticity and painful muscle spasms in patients with multiple sclerosis. DESIGN: Double-blind, placebo-controlled crossover study. SETTING: Free-standing, 93-bed, university-affiliated rehabilitation hospital. PARTICIPANTS: There were 15 patients between the ages of 18 and 50 who had laboratory-supported definite multiple sclerosis with spasticity and leg cramps severe enough to interfere with daily activities, including sleep. INTERVENTION: The patients received the placebo or 400mg gabapentin orally three times a day for 48 hours with an 11-day washout period. If the patients were on currently accepted modes of therapy, including oral baclofen, their current medication was not changed. MAIN OUTCOME MEASURES: The outcome measures were Visual Faces Scale rating, Kurtzke Disability Scale, quantitative surface electromyography, Ashworth Scale, presence or absence of clonus in response to rapid ankle dorsiflexion and wrist extension, presence or absence of reflex withdrawal in response to nailbed pressure to the first finger, and assessment of Babinski response. RESULTS: Statistically significant improvements for the gabapentin treated patients were found in the Ashworth Scale, Visual Faces Scale, and Kurtzke Disability Scale. CONCLUSIONS: At a dose of 400mg orally three times a day, gabapentin may be of value in the treatment of the spasticity and painful muscle cramping experienced by patients with multiple sclerosis.

Efficacy of baclofen and phenobarbital against the kainic acid limbic seizure-brain damage syndrome.

Baclofen and phenobarbital were tested for anticonvulsant efficacy against limbic seizures produced by i.c.v. infusion of kainic acid (KA) in unanesthetized rats. All rats treated with KA alone developed a prolonged status epilepticus associated with extensive neuronal degeneration. When administered immediately after the KA infusion, baclofen (5 mg/kg i.p.) protected five of six animals against the development of status epilepticus and did not alter the behavioral expression of the residual discrete electrographic seizures. Phenobarbital (40 mg/kg i.p.) given 15 min before KA also prevented the development of status epilepticus in five of six rats, but blocked the behavioral expression of the residual electrographic seizures. In two of five additional rats, baclofen prevented or reversed status epilepticus when administered 50 to 60 min after the end of the KA infusion. The ability of these drugs to prevent KA-induced neuronal degeneration correlated with their anticonvulsant action.

Comparison of seizures and brain lesions produced by intracerebroventricular kainic acid and bicuculline methiodide.

Intracerebroventricular kainic acid produces in rats brain lesions similar to Ammon's horn sclerosis in humans. To test the hypothesis that these lesions result indirectly from prolonged seizure activity and not from a direct action of kainic acid on the neurons that are destroyed, the effects of intracerebroventricular kainic acid and bicuculline methiodide were compared. Although bicuculline methiodide seizures differed dramatically from kainic acid seizures, both electrographically and behaviorally, the resulting brain lesions were similar for a given total limbic seizure duration. These results, in combination with other data, support the view that lesions made by intracerebroventricular administration of convulsants are indeed caused by prolonged limbic seizures. The total duration of seizure activity appears to be one important variable.

Gabapentin for the treatment of spasticity in patients with spinal cord injury.

Our serendipitous observations suggested that some patients with spasticity appeared to have improved following the administration of the anticonvulsant drug gabapentin. As some patients with spasticity are either refractory to or intolerant of established medical treatments, we conducted this study to investigate the effect of gabapentin on spasticity in patients with spinal cord injury. Twenty-five patients with spinal cord injury and spasticity received oral gabapentin (2400 mg over 48 h) in a randomized, double blind, placebo-controlled crossover study. We assessed responses by measuring the Ashworth spasticity scale, muscle stretch reflexes, presence of clonus and reflex response to noxious stimuli. Patient ratings were obtained using a Likert Scale. Administration of gabapentin, but not placebo, was associated with an 11% reduction in spasticity as measured by the Ashworth Scale (P = 0.04) and by a 20% reduction in the Likert Scale (P = 0.0013). Significant changes were not obtained for the other measures. The data obtained suggest that gabapentin may be useful in the management of spasticity associated with spinal cord injury.