Discontinuation of levetiracetam because of behavioral side effects: a case-control study.

BACKGROUND: Levetiracetam (LEV) is a recently approved anticonvulsant with proven efficacy and safety in the treatment of partial seizures. LEV may cause behavioral abnormalities that can be severe and require discontinuation of this drug. Risk factors for discontinuing LEV have not been established. OBJECTIVE: To determine incidence of behavioral abnormalities severe enough to require discontinuation of LEV and identify risk factors for such behavioral abnormalities. METHODS: All patients treated with LEV at MINCEP between January 2000 and February 2002 constituted the study population (n = 553). Patients who had discontinued LEV for behavioral reasons were selected as index cases. Case controls were patients starting LEV immediately after the index case. Potential risk factors for LEV discontinuation included age, gender, cognitive function, history of psychiatric diagnosis, epilepsy syndrome, number of antiepileptic drugs, titration rate, maximum dose of LEV, and LEV level at maximum dose. RESULTS: Thirty-eight patients (6.9%) discontinued LEV because of behavioral abnormalities. Variables associated with LEV discontinuation included faster titration rate to maximal dose, history of a psychiatric disorder, and diagnosis of symptomatic generalized epilepsy. Patients who discontinued LEV owing to behavioral reasons had significantly lower maximum LEV doses than controls. CONCLUSIONS: This study identified variables associated with discontinuation of LEV due to behavioral abnormalities. Slower titration of LEV should be considered in those patients at higher risk of discontinuing LEV for behavioral reasons.

Intracranial electrophysiologic studies.

The presurgical evaluation of patients with medically refractory epilepsy begins with a thorough noninvasive approach, including ictal monitoring with scalp recording technique. The concept of convergence of evidence is used to determine the adequacy of the noninvasive localization. A variety of intracranial electrophysiologic studies can be employed when the noninvasive evaluation is insufficient. Intracranial studies are used for precise identification of eloquent cortex. The ultimate lines of resection are then designed to include as much of the epileptogenic zone as possible, while excluding areas of eloquent cortical function.

8-12 Hz rhythmic oscillations in human motor cortex during two-dimensional arm movements: evidence for representation of kinematic parameters.

Direct cortical recordings were taken from 12 patients with implanted subdural electrode arrays during performance of a 2-dimensional, multi-joint, visually guided arm movement task. Task-related changes in the amplitude of the motor cortex 8-12 Hz surface local field oscillations were evaluated for the encoding of direction and amplitude of movement in the 6 patients in whom no epileptogenic or ECoG background abnormalities were detected over the motor-sensory cortical areas under the recording electrode array. The topography, time of onset and duration of these responses were evaluated in the context of motor cortex somatotopy, as defined by cortical stimulation delivered through the electrode array. Multi-joint arm movements were accompanied by a decrease in the power of the 8-12 Hz frequency components of the ECoG signal. These power changes were spatially distributed over the upper extremity, motor-sensory representation. Movement amplitude influenced the magnitude, duration, and extent of the spatial distribution of ECoG power changes in the 8-12 Hz band. These effects occurred predominantly over cortical areas corresponding to the upper extremity motor-sensory representations. Direction of movement had a weaker influence on the 8-12 Hz frequency components of the ECoG over the upper extremity motor-sensory representations, but influenced the patterns of 8-12 Hz ECoG response on adjacent cortical regions. These results show that the amplitude of surface electrical oscillations generated over the rolandic cortex are correlated with the kinematics of multi-joint arm movements. These changes in the ECoG signal appear to reflect shifts in the functional state of neuronal ensembles involved in the initiation and execution of motor tasks.

Progressive myoclonus epilepsy treated with zonisamide.

Two patients with progressive myoclonus epilepsy of the Unverricht-Lundborg type and with intractable seizures in spite of standard anticonvulsant regimens were treated with zonisamide. After zonisamide therapy was initiated, both had a marked decrease in seizure frequency and significant improvement of functioning. Serum zonisamide concentrations were 43 and 27 micrograms/ml, respectively, with doses of 8.8 and 10.5 mg/kg/d. Both patients also continue to receive valproic acid and a benzodiazepine.

Selection of adult patients for surgical treatment of epilepsy.

The ideal treatment for epilepsy would produce complete control without toxicity and without side effects. The physician would like to have surgical therapy as an option for those patients who are not completely free of seizures and for those who are free of seizures but suffer toxic side effects. Surgery for epilepsy has now become an option that should be considered along with various medical treatment options. The success rates have increased and the complication rates decreased dramatically at those centers performing surgery on a substantial number of cases a year. Patients with complex partial seizures with a clear-cut unilateral temporal lobe focus and highly stereotyped seizures are by far the best candidates for surgery. In the hands of several major epilepsy programs significant improvement in seizure frequency is achieved in greater than 90 per cent of patients. Patients with sudden drop attacks or uncontrolled generalized tonic-clonic seizures can benefit from section of the corpus callosum. Good results are seen in 85 per cent of the cases.

Diagnostic difficulties and treatment implications.

Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.

Psychogenic seizures.

Psychogenic seizures occur in a heterogeneous population and are varied in their expression and etiology. Patients with psychogenic seizures form a significant percentage of patients presenting with "epilepsy"--especially the group intractable to treatment. Intensive neurodiagnostic monitoring of ictal events and the classification of patients into clinically useful subgroups are important tools in approaching this disorder.

Behavior disorders related to epilepsy.

This chapter discusses episodic behavioral disorders that may be mistaken for seizures, but which are not caused by a primary disturbance of excitation and inhibition among neurons. Three major topics are discussed: hysterical or pseudoseizures, episodic aggression, and episodic psychosis. The development of techniques of simultaneously recording a video picture of behavior and the EEG has ushered in a new era in the analysis of patients with hysterical or pseudoseizures. Combined video/EEG monitoring is of proven effectiveness in making the distinction. Patients commonly suffer from both true and pseudoseizures, therefore it is often necessary for the patient to be seen in a special epilepsy center where anticonvulsants can be slowly withdrawn and both types of seizures documented. Detailed psychosocial evaluation is necessary to understand the behavior in the context of the patient's life. Intensive monitoring techniques have also been useful in dealing with the question of episodic behavioral disturbance. Episodic aggression is very difficult to study and the problem largely remains open.

Value of computed tomographic scan in the evaluation of adult patients after their first seizure.

The role of the computed tomographic (CT) scan in evaluating adults after their first seizure(s) was determined by reviewing the hospital records of 148 patients studied within 30 days of their ictus. Patients with alcohol or drug intoxication or withdrawal or with known brain tumor, craniotomy, or open skull fracture were excluded. Type of seizure; neurological, CT, and electroencephalographic findings; final diagnosis; and hospital outcome were cross correlated. The cause of seizure was established in 71 patients (48%); a structural lesion was identified by CT in 55 (37%), and 16 (11%) had metabolic seizures. CT findings agreed with the results of neurological examination 82% of the time. Structural lesions (including three tumors) were found by CT in 14 patients (15%) with nonfocal findings and in 12 (22%) of those with generalized electroencephalographic abnormalities. Our findings are similar to those reported in adult epileptics and lead us to conclude that the CT scan is a valuable aid in establishing the cause of seizures and in disclosing early lesions.

Corpus callosotomy: clinical and electroencephalographic effects.

Six persons (five male, one female), 15-41 years of age (mean, 23 years), with medically intractable epilepsy for 7-35 years (mean, 15 years) underwent total corpus callosum section (anterior commissure to posterior commissure) for treatment of seizures resulting in falls and injuries. Preoperative EEGs demonstrated two or more morphologically distinct interictal discharges, at least one of which was generalized. Generalized ictal EEG discharges were documented in all cases to account for the clinical seizures resulting in injury. A comparison of generalized epileptiform discharges in comparable states of arousal pre- and postoperatively demonstrated a statistically significant (p less than 0.05) reduction of generalized discharges after surgery. Postoperative observation periods have ranged from 10 to 30 months (mean, 17.6 months) and have documented a statistically significant (p less than 0.05) decrease in the number of falling seizures (means: preoperative, 23.2 seizures/month; postoperative, 0.7 seizures/month). A statistically significant difference in pre- and postoperative total (generalized and focal) interictal discharges was not demonstrated. Long-term, clinically apparent complications of surgery did not occur in our patients. Thus, sectioning of the corpus callosum interrupts generalized epileptiform discharges (as documented by the postoperative EEG) and usually results in a significant decrease in generalized seizures.

Routine EEG vs. intensive monitoring in the evaluation of intractable epilepsy.

Appropriate treatment of patients with intractable seizures requires precise identification of the type (or types) of seizure the patient experiences and correlation of this information with data from electroencephalography localizing the focus of the seizure in the brain. For such patients, the technique of "intensive monitoring" has gained rapid acceptance in the past several years as the investigative method of choice.Intensive monitoring usually entails prolonged electroencephalographic recording with simultaneous videotaping of the patient. Another common technique is prolonged monitoring of the patient's electroencephalogram (EEG) by radiotelemetry, during which time the patient is closely observed by trained personnel for suspected seizures.To compare the quality of information obtained from intensive monitoring with that from careful routine electroencephalography, the authors reviewed the medical records of 100 consecutive patients who had received both kinds of study after being referred for treatment in the special Epilepsy Treatment Unit of the University of Minnesota's Comprehensive Epilepsy Program (CEP).Success of each method was defined by ability to record an actual seizure. The routine EEG examination recorded actual seizures in 7 percent of patients in the study. With video EEG, following careful withdrawal of anticonvulsant drugs, seizures were recorded in 70 percent of patients. Telemetered EEG recorded seizure activity in 50 percent of those patients for whom the other two methods had failed to detect seizures.Intensive monitoring revealed that 60 percent of patients for whom the routine EEG study had recorded only one seizure type actually suffered from two or more types. Clinical diagnosis was changed in 84 percent of the patients. In this study, intensive monitoring was found to be far superior to the routine EEG examination as an aid to precise diagnosis of intractable seizure disorders.

Compressed spectral array patterns following cardiopulmonary arrest. A preliminary report.

Continuous taped EEG recordings were made following resuscitation in 18 survivors of cardiopulmonary arrest. These taped data were processed, using Bickford's method of compressed spectral array, and four distinctive patterns were recognized. These patterns correlated significantly with eventual outcome of these patients, suggesting that processed EEG information can provide important prognostic information for such patients.

Clinical evaluation of a depth electroencephalography electrode.

Stereo depth electroencephalography (EEG) is of proven benefit in lateralizing and localizing seizure origin in select cases of epilepsy. There are potential hazards and technical considerations inherent with depth EEG, however, that have limited the general applicability of this technique. A new depth EEG electrode with materials and design features that facilitate safe insertion and artifact-free recording has been developed. The design features and technique for inserting the electrode are described. The electrode was evaluated during 2600 hours of implantation and recording in seven patients. With the use of stereotactic techniques, the electrode could be positioned accurately within precise anatomical landmarks such as the amygdaloid nucleus and the hippocampus. After insertion, no hemorrhage or edema was detected along the electrode tracts by third generation computed tomographic scanning. There was no evidence of pyrogenicity or infection. Electrode migration was not observed. A large electrical field could be sampled because of the relatively large surface of the cylindrical depth electrode contacts.

Machine detection of spike-wave activity in the EEG and its accuracy compared with visual interpretation.

Machine detection of epileptiform activity in the EEG is useful in seizure monitoring because of its inherent consistency and the rapid data reduction it can provide. Devices based on a few detection criteria have lacked reliability of detection and those with more complex algorithms have sacrificed operating speed and portability. This paper describes a largely analog device which detects irregular as well as classic spike and wave activity. It is portable and it can process the accelerated playback of 24 h tape recorders as well as real-time EEG. It recognizes spikes by their shape and waves by their frequency. It makes inter-channel comparisons to identify trains of bilateral synchronous spikes, generalized waves, and coincidence of spikes and waves and furnishes a limited description of each event in terms of these characteristics. The device was tested against the judgment of 3 experienced and certified electroencephalographers in 18 h of EEG containing 769 bursts of spike-wave activity from 6 patients. It detected 96.5% of the consensus spike and wave activity (i.e., activity identified by all 3 electroencephalographers). Only 0.56% of the machine's detections were false positives (i.e., activity identified by none of the electroencephalographers), though the false positive rate was higher in the presence of chewing artifact. It measured burst duration with an average error of 0.43 sec/burst. While reader-machine agreement varied somewhat by patient, in general, the machine disagreed with the consensus no more than the readers disagreed with each other. In a second reading session after 6 months, the amount of activity identified by the readers changed by an amount ranging from 2.4% to 57% while the machine was consistent within a few tenths of 1%. Hence, this paper demonstrates that by implementing a multi-criteria detection algorithm in special purpose circuitry, a cost-effective solution to the problem of reliable machine detection of spike and wave activity can be obtained.

Rapid and slow release phenytoin in epileptic patients at steady state: comparative plasma levels and toxicity.

Phenytoin plasma level and toxicity data were compared in a three-way crossover study performed in 18 patients at steady state. Formulations compared were a rapid and a slow release capsule and an oral solution. Plasma concentration-time integrals and maximum plasma phenytoin levels were significantly greater for the rapid release capsule and solution than for the slow release capsule. The incidence of nystagmus and toxicity did not differ for the three treatments, but the occurrence of mental symptoms was more frequent for the oral solution, possibly because of the solvent used in this formulation.