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.

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.

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.

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.

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.

Positron emission tomography in two cases of childhood epileptic encephalopathy (Lennox-Gastaut syndrome).

Two patients with childhood epileptic encephalopathy were studied by positron emission tomography before and after corpus callosotomy. Preoperatively, both patients showed in the temporal lobe unilateral hypometabolism that is characteristic of interictal epileptic foci. Postoperatively, the first patient had no seizures by the time of scanning, and his temporal lobe metabolism was bilaterally symmetric. Seizure control in the second patient did not improve by the time of scanning, and unilateral temporal hypometabolism persisted. This finding suggests a temporal lobe focus in two patients with Lennox-Gastaut syndrome.

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.

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.

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.

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.

Utilization of a two-channel, microprocessor-based EEG device for monitoring cognitively vulnerable patients.

Several experiments were conducted to validate the use of a two-channel microprocessor-based electroencephalographic (EEG) device for detecting changes in EEG background rhythm in the clinic or at the bedside. The reliability of background measures in healthy individuals was evaluated by obtaining EEG data on 20 control subjects on two occasions separated by at least 1 day. The sensitivity to an experimental toxic encephalopathy was evaluated using measures of EEG and the Buschke Memory Selective Reminding Test after the administration of scopolamine hydrobromide, 0.86 mg subcutaneously, to three healthy volunteers. Postdrug measures of the EEG showed significant group differences from controls at 1 and 2 hours for relative alpha and relative theta power. The drug-induced change for each individual exceeded the predicted range calculated from data on control subjects. These findings suggest the feasibility and the potential utility of this method. This approach was extended to the elderly with measures on 102 subjects (average age, 85 years) living in an institutional setting. EEG measures in the population were of acceptable reliability and were significantly correlated with Mini-Mental State Examination (MMSE) scores (r = -.375 for theta and .357 for beta). Preliminary findings suggest that this method may detect metabolic encephalopathies in the elderly. The study demonstrates the potential value of this approach and suggests the need for further research.

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.

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.

Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial.

OBJECTIVE: 6002-US-051 was a 12-week, double-blind study evaluating the safety and efficacy of istradefylline, a selective A(2A) adenosine receptor antagonist, as monotherapy in patients with Parkinson's disease (PD). METHODS: Patients with Hoehn-Yahr stages 1-2.5 who had not received dopaminergic drugs in the past 30 days or levodopa for >30 days at anytime were randomized to 40 mg/day istradefylline or placebo. The primary efficacy outcome was the change from Baseline to Endpoint in the Unified Parkinson's Disease Rating Scale (UPDRS) Subscale III score. Safety was assessed by physical examination, laboratory tests, electrocardiograms, and adverse event monitoring. RESULTS: 176 patients comprised the intent-to-treat population. Although istradefylline showed numerically greater improvements in UPDRS Subscale III at each time point and reached statistical significance at Week 2 (LS mean difference = -1.47), it did not show statistically significant improvement from placebo for the primary endpoint (least square [LS] mean difference = -1.11). Similar proportions of patients in each group experienced treatment-emergent adverse events (63% istradefylline, 65% placebo). CONCLUSIONS: Istradefylline, as monotherapy in patients with PD, is safe and well tolerated. However, efficacy in improving motor symptoms in early PD was not statistically demonstrated by this study.

A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease.

BACKGROUND: The safety and efficacy of istradefylline, a selective adenosine A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications. METHODS: Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs). RESULTS: Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20 mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01) for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations. CONCLUSIONS: Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

A direct hepatotoxic effect of valproic acid.

Nine patients treated with valproic acid had low plasma fibrinogen concentration and other liver function abnormalities. Several patients also had a low platelet count and prolonged bleeding time. The abnormal values returned promptly to normal when the drug therapy was discontinued or the dosage reduced. The liver function abnormalities are consistent with a direct, dose-related hepatotoxicity.

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)

Ictal blindness and status epilepticus amauroticus.

Five cases of ictal blindness are presented. All are documented to be ictal by simultaneous EEG monitoring during the period of blindness. In three cases, the blindness was complete; in two, it manifested as a homonymous hemianopia. Three cases (including the two with hemianopia) were secondary to vascular lesions; one case was due to a metastatic lesion; and there was one case of idiopathic epilepsy. Age ranged from 13 to 74 years. In all cases, the blindness was reversible with anticonvulsant therapy. All cases but one lasted from hours to days, meeting a criterion of "status epilepticus amauroticus." In the literature, ictal blindness is seldom reported and even less often documented. Unexplained cortical blindness might represent unrecognized seizure activity more often than is appreciated.

Bicycling movements as a manifestation of complex partial seizures of temporal lobe origin.

Alternating movements of the limbs during a seizure, especially bicycling movements of the legs, are often taken as strong evidence for the psychogenic origin of seizure activity in an adult population. A recent review of pseudoseizure manifestations concluded that alternating limb movements were "highly characteristic of pseudoseizures." We report two adult patients with complex partial seizures of temporal lobe origin, confirmed by ictal video EEG recording, in whom bicycling movements were the prominent ictal manifestation. Bicycling occurred 5-30 s after ictal onset and lasted 15-30 s. Use of video EEG recording continues to increase our understanding of the wide range of behaviors which may occur in the course of an epileptic seizure, particularly complex partial seizures. Few absolute clinical criteria remain to distinguish epileptic seizures from pseudoseizures. These two cases and one other reported case clearly remove bicycling movements from that category.