Postmarketing studies.
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Anticonvulsants↗
Biomedical subjects
N M Sussman
Publications and source records attributed to N M Sussman.
Dose frequency and dose interval compliance with multiple antiepileptic medications during a controlled clinical trial.
Compliance with medication regimens and clinical trial schedules was evaluated during a study of vigabatrin (VGB), an antiepileptic drug (AED). Medication Event Monitors (MEMS, Aprex Corp., Fremont, CA, U.S.A.) were provided to monitor use of VGB and other AEDs administered to 111 patients at 10 sites. MEMS reports showed the number of doses administered daily, times of doses, and intervals between doses. The 66 patients whose data were evaluable took VGB as prescribed (twice daily, b.i.d.) on 89 +/- 7% of days in the clinical trial (mean 189 +/- 63 days). However, only 66 +/- 24% of doses were taken within the 9-15-h dose interval window for twice-daily dosing, a lower rate than that for dose frequency compliance (p < 0.001). Concomitant medications prescribed b.i.d. (n = 66) (86 +/- 11% dose frequency compliance) were taken at lower rates than VGB (p < 0.02). Interval compliance also was lower for concomitant b.i.d. medications (59 +/- 26%) than for VGB (p < 0.01). Dose frequency compliance for thrice-daily (t.i.d.) medications (n = 36) was 80 +/- 18 and 40 +/- 19% for interval compliance (6-10 h) (both p < 0.0001 vs. VGB). Dose frequency compliance for four times daily (q.i.d.) medications (n = 23) was 80 +/- 23 and 33 +/- 18% for interval compliance (4-8 h) (both p < 0.0001 vs. VGB). Patients at eight sites did not use MEMS properly, often for practical reasons, voiding including of data for 93 medications (32%) because of noncompliance with the study design to monitor compliance.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Effects of differing dosages of vigabatrin (Sabril) on cognitive abilities and quality of life in epilepsy.
Vigabatrin (VGB) prevents seizures by irreversible inhibition of gamma-aminobutyric acid (GABA) transaminase and a resulting increase in GABA levels. We evaluated the cognitive and quality-of-life (QOL) effects of VGB in a double-blinded, add-on, placebo-controlled, parallel group dose-response study of patients with focal epilepsy whose complex partial seizures (CPS) were difficult to control. In a single investigation, patients were randomly assigned to placebo (n = 40), 1 g VGB (n = 36), 3 g VGB (n = 38), or 6 g VGB (n = 32), treated for 12 weeks after a 6-week dose escalation period, and tested at the end of the baseline period and at the end of the treatment period with eight cognitive measures and three tests of mood and adjustment. The patient groups were highly similar at study entry. Results at the end of the study showed substantial relief from seizures. The Digit Cancellation Test showed decreases in performance with increasing doses of VGB. Performance on no other test showed any decrement with increasing dosage. Relief from seizures was not associated with changes on the psychological tests. VGB is a useful antiepileptic drug (AED) that has little impact on tests of either cognitive abilities or QOL, even at a high dose.
Adolescent↗
Use of ex vivo magnetic resonance imaging to detect onset of vigabatrin-induced intramyelinic edema in canine brain.
Vigabatrin (VGB) causes intramyelinic edema (microvacuolation) in brain of dogs and rodent, which has encouraged development of noninvasive methods to monitor for this effect during clinical trials. We report the qualitative ex vivo magnetic resonance imaging (MRI) changes observed in a neuropathology study in dogs to detect time of onset and regression of VGB-induced intramyelinic edema. Beagles were randomly assigned to 18 groups of 6 dogs per group and administered vigabatrin orally (p.o.) at a dose of 300 mg/kg/day (2 males, 2 females) or placebo (1 male, 1 female). Animals were killed and examined at weekly intervals during the 12 weeks of treatment and at 1, 2, 4, 8, 12, and 16 weeks after discontinuation of drug treatment. Myelin microvacuolation in thalamus, hypothalamus, and fornix were noted histologically after 4-5 weeks of treatment. Increases in MRI T2 intensity were observed in hypothalamus after 4 weeks and in thalamus and columns of the fornix after 7 weeks. Both MRI T2 intensity and microvacuolation continued to increase during 12-week VGB treatment. When VGB treatment was discontinued after 12 weeks, both MRI T2 intensity and microvacuolation began to decrease. Sixteen weeks after VGB discontinuation, histopathology had returned to normal and MRI examination demonstrated a marked trend toward reversal of the increased T2 signal intensity. MRI thus has potential as a noninvasive surveillance technique in certain experimental and clinical conditions associated with intramyelinic edema.
Animals↗
Prolactin secretion following repetitive seizures.
We studied serum prolactin levels after 24 seizures occurring in eight subjects. Video-EEG intracranial monitoring confirmed temporal or frontal partial seizures. Seizure type, focus, and duration were similar for seizures with and without significant postictal prolactin elevations. The seizure-free interval (the time between seizures) varied considerably. Seizures occurring after longer seizure-free intervals (31.75 to 240 hours) showed robust prolactin responses. After shorter seizure-free intervals (1.07 to 25.42 hours), prolactin responses were reduced. This suggests that the amount of releasable prolactin is limited, depleted by seizures, or perhaps inhibited by prolactin feedback. Seizure-free intervals should be considered when interpreting prolactin levels.
Adult↗
MRI monitoring of vigabatrin-induced intramyelinic edema in dogs.
Chronic administration of vigabatrin (gamma-vinyl GABA) in dogs produces reversible microvacuolation (intramyelinic edema) in discrete brain regions. Histologic changes are most notable in the columns of the fornix and regions of the hypothalamus, thalamus, optic tract, and hippocampus. In an attempt to image these changes in vivo, we performed high-field MRI on seven treated and four control dogs at baseline and after 15 weeks of dosing with vigabatrin (300 mg/kg/d). All dogs underwent parallel electrophysiologic assessment to determine the effects of vigabatrin on afferent conduction. At 15 weeks, all treated dogs showed increased T2- and decreased T1-weighted signals, with changes from baseline most prominent in the columns of the fornix and to a lesser degree in the surrounding hypothalamus and thalamus. MRIs performed on control dogs were unremarkable. We then perfused a random selection of four treated and two control dogs and imaged their brains ex vivo prior to sectioning. Ex vivo imaging confirmed the in vivo findings and strongly correlated with both electrophysiologic and subsequent histopathologic findings. Imaging was repeated in the surviving dogs 5 and 12 weeks after discontinuation of dosing. Signal abnormalities in the treated dogs progressively diminished during recovery, paralleling the electrophysiologic and histopathologic results. These findings demonstrate that MRI can detect signal changes anatomically congruent with vigabatrin-induced intramyelinic edema and suggest that MRI may provide a useful noninvasive tool for monitoring patients during clinical trials.
4-Aminobutyrate Transaminase↗
Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers.
The pharmacokinetics of vigabatrin were investigated after single and multiple oral doses in two groups of 24 healthy male volunteers. Vigabatrin was well tolerated by the volunteers; headache was the most frequently reported adverse event. There were no clinically remarkable changes in serum chemistry, urinalysis, or hematology attributable to vigabatrin. For the single-dose study, a stepwise linear contrast method was used to assess dose proportionality. The results showed that vigabatrin exhibited dose linear pharmacokinetics after single oral doses ranging from 0.5 to 4.0 g. Slight changes in the terminal phase half-life and renal clearance were evident in the higher dosage groups. These changes with increasing dose of vigabatrin were relatively minor and not considered to be clinically important. Evaluation of the multiple-dose pharmacokinetics indicated that vigabatrin exhibited dose linearity over the range of 0.5 to 2.0 g administered every 12 hours. The terminal phase half-life and renal clearance of vigabatrin during multiple dosing were consistent with that after single doses. During multiple dosing, steady-state concentrations of vigabatrin were reached on the second day of dosing, and drug accumulation was minimal.
Administration, Oral↗
Evaluation of the effects of vigabatrin on cognitive abilities and quality of life in epilepsy.
We evaluated the psychological effects of the antiepilepsy drug vigabatrin in a randomized multicenter double-blind placebo-controlled parallel group study that compared 3 grams oral vigabatrin with placebo as daily add-on therapy in patients with focal epilepsy whose complex partial seizures were difficult to control. Testing at baseline and after 12 weeks of vigabatrin (n = 83) or placebo (n = 85) used eight measures of cognitive abilities and three of mood and adjustment. The vigabatrin and placebo groups were highly similar at entry into the study. At the end of the study, there were no differences between the vigabatrin and placebo groups on any cognitive variable or on any measure of mood and adjustment. Analysis of the results related to relief from seizures demonstrated only chance findings. In a similar manner, there were no relationships between vigabatrin serum levels at the end of the study and changes on measures of abilities and adjustment. Vigabatrin appears to be a useful antiepilepsy drug with little impact upon tests of either cognitive abilities or quality of life.
Adaptation, Psychological↗
European investigational antiepilepsy drug trials.
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Anticonvulsants↗
Presurgical electroencephalographic patterns and outcome from anterior temporal lobectomy.
We reviewed data from 48 patients after anterior temporal lobe resection for medically intractable epilepsy. All had ictal electro-encephalographic (EEG) evidence of unilateral temporal lobe onset. Depth electrodes were used in 19 patients. Successful surgical outcome correlated significantly with factors that suggested a temporal lobe focus, particularly in the interictal scalp EEG. The most successful outcome occurred in patients with well-localized unilateral interictal temporal spikes (100% improved). The group with well-localized bilateral temporal spikes also did well (76% improved). Patients with extratemporal spread of the interictal spike on scalp EEG, either unilaterally or bilaterally, did less well. Only one third improved, despite extensive extracranial and intracranial monitoring, when indicated. The interictal scalp EEG may be the only EEG necessary for the presurgical evaluation of selected patients with intractable temporal lobe epilepsy.
Adolescent↗
Effects of high-dose gamma-vinyl GABA (vigabatrin) administration on visual and somatosensory evoked potentials in dogs.
gamma-Vinyl GABA (GVG, vigabatrin) is a GABA transaminase-inhibiting antiepileptic agent. In dogs, chronic GVG administration produces reversible microvacuolation (intramyelinic edema) in discrete brain regions and slowing in central afferent transmission as measured by somatosensory evoked potentials (SEPs). Because this microvacuolation is especially prominent in the optic tract, this study tested the sensitivity of visual evoked potentials (VEPs) to GVG-induced changes in conduction. We also replicated the earlier SEP findings. Eight beagles received daily oral vigabatrin at the maximum tolerated dose (300 mg/kg/day); four were placebo controls. Cortical VEPs and SEPs were recorded using scalp needle electrodes at baseline and every 2 weeks throughout treatment. One treatment dog died at 2 weeks. The remainder showed an increase in central latencies beginning at 6 weeks, attaining significance (p < 0.05) at 8 and 10 weeks for SEPs and VEPs, respectively. No changes occurred in peripheral or spinal conduction in treated dogs, or in any measure in control dogs. Three GVG and two control dogs were followed after drug was withdrawn; both VEP and SEP measures returned to baseline values within 5 weeks. These findings support the use of VEPs and SEPs to monitor patients receiving vigabatrin therapy.
Aminocaproates↗
Memory deficits before and after temporal lobectomy: effect of laterality and age of onset.
Laterality and age of onset effects on semantic and figural memory were evaluated in 30 right-handed, left speech dominant (amobarbital test) patients with epilepsy before and after temporal lobectomy. There were no effects of focus on WAIS-R IQ scores. Early onset (less than or equal to 5 years) was associated with lower IQ and memory (WMS). Left Temporal (LT) patients showed worse semantic than figural memory preoperatively. Unexpectedly, early onset LT had marked postoperative decline of figural memory, whereas late onset LT patients showed the previously reported worsening of semantic memory. Right Temporal (RT) lobectomy patients, in contrast, improved in both semantic and figural memory regardless of age of onset. A "crowding effect" was suggested by the decline in figural memory following surgery in the early onset LT patients who remained stable or improved in semantic memory. Results indicate the need to incorporate age of onset of seizures into laterality models of memory function following unilateral temporal-hippocampal resection.
Adult↗
Initial experience with SPECT imaging of the brain using I-123 p-iodoamphetamine in focal epilepsy.
Nineteen patients with complex partial seizures refractory to medical treatment were examined with routine electroencephalography (EEG), video EEG monitoring, computed tomography or magnetic resonance imaging, neuropsychological tests and interictal single photon emission computed tomography (SPECT) with I-123 iodoamphetamine (INT). In 18 patients, SPECT identified areas of focal reduction in tracer uptake that correlated with the epileptogenic focus identified on the EEG. In addition, SPECT disclosed other areas of neurologic dysfunction as elicited on neuropsychological tests. Thus, IMP SPECT is a useful tool for localizing epileptogenic foci and their associated dynamic deficits.
Adolescent↗
Contralateral and ipsilateral control of fingers following callosotomy.
The extent of ipsilateral control of the distal limbs is not documented. In this experiment visuo-motor control of fingers was investigated in two callosotomy patients. A substantial amount of ipsilateral control was evident, especially for the left hand fingers. Ipsilateral control of the right hand was evident for the thumb and index fingers, but not for the other fingers. Left hand fingers did not vary significantly in degree of ipsilateral control.
Adult↗
Magnetic resonance imaging after corpus callosotomy.
Magnetic resonance imaging (MRI) can visualize the extent of corpus callosotomy performed for medically intractable epilepsy not amenable to focal surgery. Five patients underwent complete callosotomy and one an anterior callosotomy, aged 19 to 24 years, 21 to 53 months (prior to scanning). T1 images showed complete absence of the callosal shadow in five cases and visualization of the genu and splenium in the sixth case. T2-weighted pulse sequence spin-echo MRI showed intense image throughout the region of the entire callosum in the two cases with the longest postoperative course. The two middle cases showed intense T2 signal from the splenium, and the two latest showed no increase in T2 signal. We believe the increase in T2 signal in the transected callosum may represent an in vivo example of anisomorphic gliosis. T1 images demonstrate the anatomic extent of transection, while T2 images demonstrate the chemical and pathophysiologic sequence of transection. Thus, MRI is the imaging test of choice to evaluate callosotomy patients.
Adolescent↗
Computed EEG topography in epilepsy.
Computed EEG Topography (CET) of 74 cases of epilepsy demonstrates the potential utility of this method beyond that of the analog EEG for the quantification and localization of regions of epileptogenesis. For the detection and localization of focal epilepsy, CET was equal to or better than the EEG in 77 p. 100 of cases and provided more evidence of focal abnormality in 8.5 p. 100. The topography of spectral power and of early and late, extravisual, components of the averaged evoked potential to flash were abnormal in the region of interictal spike activity.
Adolescent↗
Hemispheric control of the writing hand: the effect of callosotomy in a left-hander.
We report a case of a left-hander with left hemispheric language. After callosotomy, he could use the left hand to write only random letters and digits, and he became right-handed for writing. Therefore, writing by left-handers with left hemispheric language dominance may be accomplished by transcallosal transmission of the linguistic content from the left hemisphere to the right.
Adult↗
Mutism as a consequence of callosotomy.
Transient mutism has been reported following commissurotomy and callosotomy. The cause for this mutism is unknown. A case of mutism following callosotomy is presented, and the preoperative and postoperative data on neurological, physiological, and psychological functioning are discussed. The data suggest that the mutism is not caused by general intellectual deterioration, cortical lesion, or peripheral damage affecting speech production. The syndrome may result from severing interhemispheric connections in cases where both hemispheres are required for speech production.
Adult↗