Vagus Nerve Stimulation for Treatment of Partial Seizures: 3. Long-Term Follow-Up on First 67 Patients Exiting a Controlled Study

Summary: Vagus nerve stimulation (VNS) has demonstrated a significant anticonvulsant effect in preclinicalstudies, in pilot studies in humans, and in the acute phaseof a multicenter, double-blinded, randomized study. After completion of a 14–week, blinded, randomized study, with 31 receiving high (therapeutic) VNS and 36 receiving low (less or noneffective) VNS, 67 patients elected tocontinue in an open extension phase. During the extension phase, all 67 patients received high VNS. Seizurefrequency during the 3-month treatment blocks was compared with a 12–week baseline. For both groups, all periods of high VNS demonstrated a significant decrease inseizure frequency (p < 0.01 level) as compared with baseline. For the 16–18–month period of VNS, data wereavailable for 26 of the 31 patients randomized to highVNS. This group achieved a 52.0% mean seizure frequency percentage réduction as compared with baseline. For those converted from low to high VNS, data wereavailable for 24 of the 36 patients at the 16–18-month timeperiod. This group reported a mean seizure frequency percentage reduction of 38.1% as compared with baseline. No significant change in the safetyhde effect profilewas reported during longterm followup. The previouslyreported side effects of hoarsenesslvoice change, coughing, and paresthesia (sensation in neck and jaw) continued to occur during VNS. These side effects were well tolerated. During the follow-up period, 1 patient died of thrombotic thrombocytopenic purpura (TTP) and 5 patients discontinued treatment because of unsatisfactory efficacy.     

Vagus Nerve Stimulation for Treatment of Partial Seizures: 1. A Controlled Study of Effect on Seizures

Summary: Vagus nerve stimulation (VNS) was shown to reduce seizure frequency in refractory epilepsy patients in two pilot studies. Based on these results, a multicenter, prospectively randomized, parallel, double-blind study of patients with refractory partial seizures was initiated. After a 12–week baseline period, identical vagus nerve stimulators were implanted and patients randomized to either a high or low 14–week VNS treatment paradigm. The primary objective was to demonstrate that high VNS (therapeutic parameters) was more effective in reducing partial seizure frequency than was low VNS (less or noneffective parameters). Patients continued receiving antiepileptic drugs (AEDs) with plasma concentrations held constant throughout the study. We report results of the first 67 patients to exit the 14-week acute phase. After 14 weeks of VNS, 31 patients receiving high VNS experienced a mean seizure frequency percentage reduction of 30.9%, which was statistically significant as compared with the mean seizure frequency percentage reduction of 11.3% in 36 patients receiving low VNS (p = 0.029, t test; p = 0.036, Wilcoxon rank-sum test). In addition to the significant intra group p-values, mean seizure frequency percentage change reached statistical significance for high VNS (p < 0.001) but not low VNS (p = 0.072) as compared with baseline. Twelve of 31 (38.7%) patients receiving high VNS achieved at least 50% reduction in seizure frequency whereas 7 of 36 (19.4%) patients receiving low VNS experienced at least 50% reduction after 14 weeks. The implant procedure and VNS therapy were well tolerated. Our study confirmed the effectiveness of VNS as treatment for epilepsy patients with refractorypartial seizures.     

Double-Blind Study of Gabapentin in the Treatment of Partial Seizures

Forty-three patients completed a double-blind, placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period, after which they were randomly allocated to receive either a placebo or 900 or 1,200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1,200 mg, in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.     

Remission of Seizures and Relapse in Patients with Epilepsy

In a longitudinal study of patients with epilepsy in Rochester, Minnesota, we found that the probability of being in remission (at least 5 consecutive years seizure-free, and continuing) at 20 years after diagnosis was 70%. The rates for remission we encountered were generally higher than those previously reported. We believe that the better prognosis in our series results from inclusion of all incidence cases in a defined population, beginning at the initial diagnosis of epilepsy. Prognosis for remission of epilepsy is poor in patients with associated neurologic dysfunction identified from birth. Patients with idiopathic seizures and survivors of postnatally acquired epilepsy have better prospects for eventual remission. The probability of remission is highest in patients with generalized-onset seizures diagnosed before 10 years of age. Prognosis is less favorable for those with partial complex seizures and adult-onset epilepsy.     

Systematic Testing of Medical Intractability for Carbamazepine, Phenytoin, and Phenobarbital or Primidone in Monotherapy for Patients Considered for Epilepsy Surgery

Summary: Purpose: To assess medical intractability in patients considered for restrictive epilepsy surgery.
Methods: Seventy-four patients received single drug treatment with carbamazepine (CBZ), phenytoin (PHT), and either phenobarbital (PB) or primidone (PRM). Medical intractability was established if seizure control was not obtained despite maximum tolerable doses of the drug. In all, 120 single drug treatments were administered with the drugs that has not been administered at maximal doses in monotherapy before the study.
Results: Complete seizure control was not achieved in any patient. However, 7 patients (9.5%) had significant seizure reduction of at least 80%. In 4 patients, only the third antiepileptic drug (AED) proved effective.
Conclusion: The poor result of AED monotherapy in our patients may be attributed to the patients'long-standing chronic epilepsies and high seizure frequencies. Our findings suggest that despite the failure of one or two major AEDs in controlling seizures completely, further single drug treatment may still improve the quality of life in some patients who are candidates for epilepsy surgery.     

Follow-Up of 146 Children with Epilepsy after Withdrawal of Antiepileptic Therapy

The relapse rate after discontinuation of antiepileptic drug treatment was investigated in 146 children with epilepsy, in whom medication was withdrawn according to a predesigned protocol, after a seizure-free period of at least 2 years and normalization of the EEG. The cumulative probability of remaining seizure-free in this series was 74.5%. Three-quarters of the relapses occurred during the withdrawal period and in the 2 years thereafter. From multivariate analysis, the factors indicating a significantly higher relapse risk were seizures with a known cause and female sex. In primary generalized epilepsy, no factor significantly increased the likelihood of a recurrence. In partial epilepsy, significant factors predictive of recurrence were the presence of a neurological deficit (focal neurological signs and/or mental retardation), female sex, a positive family history for epilepsy, and the number of drugs necessary for control of the seizures. The present results are compared with the available literature data. It is argued that using multivariate analysis after elimination of EEG variables uncovers significant clinical predictive factors that in other studies may have remained hidden. Finally, it is argued that statistical analysis may be used to enable the clinician to predict the likelihood of recurrence in individual children with a given set of relevant predictive factors.     

Relief of Seizures from a Predominantly Posterior Temporal Tumor with Anterior Temporal Lobectomy

We report the relief of intractable complex partial seizures in a patient with a posteromesial temporal lobe hamartoma after anterior temporal lobectomy, despite minimal tumor removal. We suggest that the key to successful treatment is the mainly medial, or limbic, location of the tumor, which apparently requires anterior limbic structures for full clinical expression of seizures. We conclude that excision anterior to a posterior temporal lesion can result in seizure relief and that a medial tumor location may be important for successful treatment.     

Effects of Antiepileptic Drugs on Sperm Motility of Normal Controls and Epileptic Patients with Long-Term Therapy

The in vitro effects of four antiepileptic drugs (AEDs) on human sperm motility were studied with a transmembrane migration method. Sperm motility of epileptic patients receiving chronic AED therapy was also investigated. Sperm motility was measured immediately after semen had been mixed with AED and after a 2-h preincubation at 37 degrees C. Both in vitro and in vivo studies demonstrated that AEDs inhibited sperm motility. When the drug effect was evaluated after the semen-AED mixture had been preincubated for 2 h, sperm motility was inhibited to 50% of control at concentrations of 1.59, 4.23, and 5.00 mM for phenytoin, carbamazepine, and valproate, respectively. Both with and without preincubation, phenobarbital, even up to 12.92 mM, did not inhibit the motility to less than 50% of the control. In the in vivo study, poor sperm motility was noted in epileptic patients with long-term AED therapy despite serum levels within the therapeutic range. Shorter duration of activity of spermatozoa was also observed in these patients. Interference with sperm membrane function by AEDs may be the underlying mechanism.     

Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study of the Effects of Monotherapy on the Long-Term Course of Epilepsy

Summary: A cohort of 280 previously untreated epilepsy subjects (159 men and 121 women aged 2–81 years) recruited in 14 Italian centers were treated with antiepileptic drug (AED) monotherapy and followed for a median period of 48 months to investigate the rates of seizure remission (i.e., complete control), in general and with reference to various prognostic factors. The cumulative probability of achieving 1-year remission was 62% by 1 year after onset of treatment, 81% by 2 years, 92% by 3 years, and 98% by 5 years. The corresponding figures for 2- and 3-year remission at 5 years were 92 and 78%, respectively. Sixty-two patients (22.1%) had no remission period with monotherapy. Remission rates were significantly lower among patients with two or more seizure types and were inversely correlated to the number of seizures before treatment. The rate of seizure relapses during the first year of follow-up appear to correlate to the risk of developing refractory epilepsy (i.e., with no remission).     

Vagus Nerve Stimulation for Treatment of Partial Seizures: 2. Safety,Side Effects,and Tolerability

Summary: Vagus nerve stimulation (VNS) significantly reduces the frequency of partial seizures in refractory epilepsy patients. We examined the serious adverse events, side effects, and tolerability as they relate to the surgical implant procedure and the stimulating device.We also reviewed potential drug interactions, device out-put complications, and impact of the therapy on overallhealth status. We analyzed the first 67 patients to exit theacute phase of the EO3 VNS trial comparing high (therapeutic) VNS to low (less or noneffective) VNS. Datawere collected from case report forms used at each of thefour visits during the 12-week baseline and at each of thefour visits during the 14-week randomized phase of the trial. No significant complications were reported as a re-sult of the implant procedure. Serious adverse events in-cluded 1 patient who experienced direct current to thevagus nerve owing to generator malfunction resulting inleft vocal cord paralysis and withdrawal of the patientfrom the study. No clinically significant effects on vitalsigns, cardiac function, or gastric function were detected. Side effects associated with VNS in the high group werehoarseness (35.5%), coughing (13.9%), and throat pain(12.9%). In the low group, only hoarseness (13.9%) andthroat pain (13.9%) were associated with VNS. Theseeffects generally were not considered clinically significantand occurred primarily during the stimulation pulses. Nopatients discontinued VNS therapy during the acutephase because of side effects associated with normal stimulation. Except for the one instance of a short circuitin the system resulting in a direct current, stimulatingsystem complications were minor, limited to programming, unscheduled stimulation, and high lead impedance.Patients, investigators, and patient companions rated patients receiving high stimulation as more “improved” than those receiving low stimulation in regards to overallhealth status. Antiepileptic drug (AED) plasma concentrations were not affected by VNS. The implant procedure, stimulating system, and therapy proved safe andtolerable during the study. The high percentage (67 of 68)of patients completing the study reflects patient acceptance and tolerability of this mode of therapy.     

Effect of Long-Term Anticonvulsant Therapy on Glucose Metabolism in Humans

This study was undertaken to evaluate the effect of anticonvulsants on glucose metabolism in humans. Tissue sensitivity to insulin (euglycemic clamp technique) and liver microsomal enzyme activity (oral antipyrine test) were measured in six subjects with epilepsy plus type 1 diabetes mellitus. They had received anticonvulsant drugs for greater than 8 years. Three groups--type 1 diabetics, persons with epilepsy, and healthy subjects--matched for sex, and weight, served as controls. Glucose disposal rate (M) was faster in subjects on anticonvulsant therapy as compared with the corresponding control group (p less than 0.01) and in nondiabetics as compared with diabetics (p less than 0.001). Antipyrine metabolism was rapid among patients on anticonvulsants and high normal in diabetics. Liver microsomal enzyme activity and glucose metabolism were related among diabetic (r = 0.593) and nondiabetic (r = 0.649) groups, respectively. Anticonvulsants with liver microsomal enzyme-inducing properties appear to enhance insulin sensitivity. These findings may serve to understand the long-term effect of anticonvulsants on glucose metabolism in humans.     

Long-Term Follow-Up of Stereotactic Lesionectomy in Partial Epilepsy: Predictive Factors and Electroencephalographic Results

We performed an extended follow-up study assessing the efficacy of stereotactic lesionectomy in 23 patients with foreign-tissue lesions and intractable partial epilepsy. Sixteen lesions involved functional or eloquent cortex as determined by anatomic localization. By definition, the surgical objective in these patients was excision of the lesion, and not the surrounding cerebral cortex. The mean duration of follow-up was 48.5 months (range 26-69 months). Seventeen patients (74%) had a significant reduction in seizures (greater than or equal to 90%) after lesionectomy. Thirteen patients (56%) had a class I operative outcome (seizure-free, single seizure episode, or auras only). Five of these patients were successfully discontinued from antiepileptic drug (AED) therapy. Patients with temporal lobe lesions were statistically less likely to be rendered seizure-free (p less than 0.05). Age at operation, duration of epilepsy, and underlying pathology were not significant predictors of seizure outcome. The anatomic distribution of extracranial EEG recorded epileptiform activity did not appear to be an important determinant of outcome. The absence of interictal epileptiform activity in the 3-month postoperative EEG correlated with a significant reduction in seizures. Long-term follow-up indicates that lesionectomy may be effective in select patients with medically refractory partial seizure disorders.     

Double-Blind, Placebo-Controlled Trial of Topiramate as Add-on Therapy in Patients with Refractory Partial Seizures

Summary: In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM) with placebo as addon therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b. i. d.)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients were randomized to each treatment group. In the intent-to-treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo-treated patients and 43% of the patients treated with TPM experienced 250% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75–100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentation, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefithisk ratio of TPM in resistant partial epilepsy.     

Long-Term Evaluation of Vigabatrin (Gamma Vinyl GABA) in Epilepsy

Summary: In studies spanning more than 5 years, more than 1,100 patients with epilepsy have been treated with vigabatrin (gamma vinyl GABA, GVG). Sixty-two patients with partial seizures with secondary generalization took part in this trial: 41 patients continued in the trial after 19 months of treatment. After 36 months, the median percentage of baseline seizures was <20%. GVG is a very potent antiepileptic drug. It is well tolerated in humans. The side effects are few. Skin rash and other allergic reactions have rarely been seen. Tolerance to the sedative effect is in contrast to the lack of tolerance to the anti-epileptic effect.     

Clonazepam in the Treatment of Epilepsy. A Clinical Long-Term Follow-Up Study

Sixty-eight patients with various types of epileptic seizures have been treated with clonazepam (Rivotril®). Fifty-four patients could be evaluated. In 44 patients, clonazepam was used as a supplement to insufficient previous medication. Ten patients received clonazepam alone. The mean duration of treatment was 2 years and 7 months. Thirty-three patients are still on clonazepam, with a mean duration of treatment of 3 years and 4 months. In 34 patients (63%) a reduction of more than 50% was seen in the seizure frequency of the only type suffered by a patient, or of one of several types. No significant decrease in antiepileptic potency with time was observed. Medication was withdrawn in a total of 21 of the 54 patients because of freedom from seizures (2 patients), lack of effect (7 patients), increased frequency of seizures (3 patients), or lack of cooperation and/or side-effects (3 patients). In 5 patients, the drug may have provoked new types of epileptic seizure. This long-term follow-up study seems to substantiate the favorable antiepileptic properties of clonazepam.     

Juvenile Myoclonic Epilepsy: Long-Term Response to Therapy

Summary: Data from 50 patients with juvenile myoclonic epilepsy (JME) were analyzed retrospectively to assess the response to drug therapy–long-term seizure control, relapse rates, and confounding factors in seizure recurrence. Valproate is the only available antiepileptic drug that has been shown to be effective in controlling the generalized seizure components of JME–myoclonic, tonoclonic, and absence seizures–without significant side effects. Data were collected using the EpiMonitor software and represented case follow-up from 2 months to 9 years. Forty-three patients (86%) were seizure free for at least 1 year; 25 patients (50%) relapsed at some point during follow-up. Relapses were precipitated most frequently by fatigue, noncompliance, stress, sleep deprivation, and alcohol consumption. With accurate diagnosis and appropriate therapy, seizures in JME can be adequately controlled, although JME is a chronic disorder that may require lifelong therapy. To minimize relapse, patient management must also focus on patient lifestyle to eliminate or control lifestyle-associated precipitants of seizure relapse.     

Antiepileptic Drug Treatment After Temporal Lobe Epilepsy Surgery: A Randomized Study Comparing Carbamazepine and Polytherapy

Temporal lobectomy is an effective treatment in selected patients with medically intractable temporal lobe epilepsy (TLE). Postoperative antiepileptic drug (AED) treatment guidelines have not been established, and patients are often treated with polytherapy postoperatively. We prospectively randomized 40 patients undergoing temporal lobectomy to monotherapy with carbamazepine (CBZ, 20) or to continuation of their presurgical polytherapy (20) to assess the efficacy and safety of each regimen during the first year after operation. No significant differences between groups were noted with respect to seizure recurrence rate and type or time of recurrence. Patients in the polytherapy group had a 30% incidence of drug-related side effects as compared with only 10% in the CBZ group. These results suggest that after temporal lobectomy for intractable epilepsy, patients can be safely treated with CBZ monotherapy and that treatment with multiple AEDs is not necessary.     

Comparing the Cognitive Effects of Phenytoin and Carbamazepine in Long-Term Monotherapy: A Two-Year Follow-Up

Summary: We compared the cognitive effects of randomly prescribed phenytoin (PHT) and carbamazepine (CBZ) therapy on newly diagnosed patients with epilepsy in a 2–year parallel group follow-up study. Fifteen patients were receiving PHT and 16 were receiving CBZ. Neuropsychological assessements were conducted before the treatment and after 6 and 24 months of steady-state drug therapy. Differential effects of PHT and CBZ during follow-up were observed in 3 of 32 measurements. PHT appeared to have negative effects on visually guided motor speed of both hands. In addition, the performance of the PHT group as compared with the CBZ group developed less positively in one visual memory task. The development of mood, as measured by Profile of Mood States (POMS), was quite similar in both drug groups; Tension, Depression, and Bewilderment decreased and Vigor increased during the follow-up. The results suggest that the long-term effects of PHT as compared with thoseof CBZ on cognition are few and restricted mainly to some visually guided motor functions. The effects of PHT on cerebellar function as a possible mechanism for these changes is discussed.     

Temporal Neocorticectomy in Management of Intractable Epilepsy: Long-Term Outcome and Predictive Factors

We report the results of a long-term follow-up study of 50 patients who underwent removal of temporal neocortex with preservation of deeper limbic structures as surgical therapy for intractable temporal lobe epilepsy. The follow-up period ranged from 3 to 15 years. Preoperative EEG investigations were based on interictal discharges alone. Three factors were predictive of a good outcome: (a) A clear unilateral anterior-midtemporal focus (p less than 0.01), (b) stereotypical onset of temporal lobe seizure (p less than 0.005), and (c) greater volume of tissue removed at operation (p less than 0.05). Overall results showed that 62% of patients experienced an outcome of "cure" or "almost cure," as classified according to a modified version of Crandall's criteria (Crandall's I and II). Those who experienced a significant reduction in seizures but who continued to have intractable epilepsy (Crandall's III) were not considered to have had a good result. Overall outcome compares favorably with other that of centers using different surgical approaches and indicates that neocorticectomy is a suitable procedure in a highly selected population even when limited resources are available.