Topiramate dose effects on cognition: a randomized double-blind study.

BACKGROUND: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. OBJECTIVE: To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). METHODS: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. RESULTS: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. CONCLUSIONS: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

A pilot study of topiramate in childhood absence epilepsy.

OBJECTIVE: Evaluate the antiepileptic effect of topiramate monotherapy in childhood absence epilepsy (CAE). MATERIALS AND METHODS: Childhood absence epilepsy patients aged 4-9 years were initiated with topiramate 15 or 25 mg/day, which was titrated upwards until patients were free of absence seizures. The primary efficacy outcome was seizure-free rates after a 12-week maintenance period. RESULTS: The study was terminated early due to lack of efficacy after enrollment of 12 patients. Four patients completed the study; two became clinically seizure-free, but without a significant reduction in the number of electrographic seizures. Six patients discontinued for lack of efficacy, none due to adverse events (AEs). Mean reduction in seizure count was seen on Days 22 (P = 0.0391) and 36 (P = 0.0156) and percentage of days with seizures decreased from baseline. Most AEs were mild. CONCLUSIONS: Although well-tolerated, this pilot study did not demonstrate an antiepileptic effect of topiramate monotherapy for treatment of CAE.

Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse.

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo-controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.

Weight change and clinical markers of cardiovascular disease risk during preventive treatment of migraine.

Migraine, particularly migraine with aura, and increased body weight are independent risk factors for cardiovascular disease (CVD). The association of weight change and clinical markers of CVD risk was evaluated in subjects participating in a randomized double-blind, parallel-group study of migraine-preventive treatment comparing 100 mg/day of topiramate and amitriptyline. Individuals from both treatment groups were pooled and stratified into three groups. The 'major weight gain' group gained > or = 5% of their baseline body weight at the conclusion of the study; the 'major weight loss' group lost > or = 5% of their baseline body weight. The third group had < 5% of weight change. The influence of weight change in headache outcomes, as well as in markers of CVD (blood pressure, cholesterol, C-reactive protein), was assessed using analysis of covariance. Of 331 subjects, 52 (16%) experienced major weight gain and 56 (17%) experienced major weight loss. Weight change was not associated with differential efficacy for the treatment of headache. However, contrasted with those with major weight loss, those who gained weight experienced elevations in mean diastolic blood pressure (+2.5 vs. -1.2 mmHg), heart rate (+7.6 vs. -1.3 beats per minute), glycosylated haemoglobin (+0.09% vs. -0.04%), total cholesterol (+6.4 vs. -6.3 mg/dl), low-density lipoprotein cholesterol (+7.0 vs. -4.4 mg/dl) and triglycerides (+15.3 vs. -10.4 mg/dl) and an increase in high-sensitivity C-reactive protein (+1.8 vs. -1.9 mg/l). Both groups experienced decreases in systolic blood pressure (-4.0 vs. -1.3 mmHg) and high-density lipoprotein cholesterol (-3.7 vs. -0.8 mg/dl). Increased weight during migraine treatment is not associated with poor headache treatment outcomes, but is associated with deterioration of CVD risk markers.

Topiramate in essential tremor: a double-blind, placebo-controlled trial.

BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients. CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Differential cognitive and behavioral effects of topiramate and valproate.

OBJECTIVE: Cognitive effects have been reported during topiramate (TPM) treatment, but effects relative to standard antiepileptic drugs are unclear. METHODS: The authors compared TPM and valproate (VPA) added to carbamazepine (CBZ) in adults with partial seizures. A comprehensive neuropsychological test battery including cognitive, mood, and quality of life measures was used in this multicenter, randomized, double-blind study. After a 4-week baseline, study drug was titrated over 8 weeks to target dosages of 400 mg/d TPM, 2,250 mg/d VPA, or placebo and then maintained for an additional 12 weeks. The neuropsychological test battery was administered at baseline and at the end of titration and maintenance periods. RESULTS: Slightly more patients on TPM dropped out. Neuropsychological data at all three test periods were available for 62 patients. At the end of maintenance, effects of TPM and VPA were comparable, except for two variables (Symbol Digit Modalities Test and Controlled Oral Word Association Test), in which TPM had greater negative effects relative to VPA. The statistical differences appeared to be due in large part to a small subset of patients who were more negatively affected by TPM. Cognitive effects of TPM relative to VPA were greater at the end of titration than at the end of maintenance. CONCLUSIONS: With adjunctive therapy at moderate dose escalation rate, the cognitive effects of TPM are slightly worse overall than VPA in patients who tolerate therapy over several months.

Seizures in special populations. Children, the elderly, and patients with coexistent medical illness.

Epilepsy management may need to be modified in certain patient groups. The management of epilepsy in all age-groups, and particularly in children, may be best approached from a disease-based model that recognizes specific epilepsy syndromes. Accurate diagnosis of pediatric epilepsy syndromes allows the physician to improve medication selection, estimate duration of treatment, and counsel patients and family members about aggravating factors and prognosis. Epilepsy management in elderly patients requires knowledge of age-related changes in the metabolism and protein binding of anticonvulsants and how these changes affect use of particular antiepileptic drugs. Concurrent medical illness, especially renal and hepatic disease, may alter drug distribution, metabolism, and excretion in some patients. In addition, a number of medications used to treat coexistent medical or psychiatric illness are associated with seizure provocation. Knowledge of these factors can improve epilepsy management in special patient populations.

Stump pressure, electroencephalographic changes, and the contralateral carotid artery: another look at selective shunting.

BACKGROUND: Selective shunting during carotid endarterectomy is associated with the lowest operative stroke rate; therefore, patient selection for carotid shunting is critical. Electroencephalography (EEG) can detect ischemic brain cell dysfunction before irreversible injury. The carotid stump back pressure (CSP) has been inconsistent in determining the need for shunting, and contralateral carotid disease has had a variable impact. The purpose of this study was to evaluate CSP and operative EEG changes, and to determine the effect of contralateral carotid artery disease on determining the need for carotid shunting. METHODS: In 140 consecutive carotid procedures, operative EEG and CSP were monitored, and contralateral carotid disease was documented. The carotid stump pressure/mean arterial pressure index (CSP/MAP) was also calculated to determine if this was a better indicator of the need for shunting than the CSP alone. RESULTS: There was a 58% incidence of EEG changes when the CSP was < or = 25 mm Hg, 32% with a CSP of 26 to 50 mm Hg, and 4% with a CSP > 50 mm Hg. There was a 43% incidence of EEG changes and lower CSP among patients with a contralateral occlusion, both of which were significantly different from patients with a patent contralateral carotid artery. Three patients with CSP > 50 mm Hg had EEG changes, but none had a contralateral occlusion. Two patients had permanent neurologic deficits, and 2 had transient deficits. Excluding combined procedures, operative stroke rate was 0.8%. CONCLUSIONS: A CSP of < 50 mm Hg achieved a sensitivity of 89% in patients who developed ischemic EEG changes during carotid clamping, and a pressure > 50 mm Hg had a negative predictive value of 96%. However, a CSP of < 50 mm Hg had a positive predictive value of only 36%. Neither the addition of the status of the contralateral carotid artery or the calculation of the CSP/MAP improved the sensitivity of the CSP in determining the need for shunting. Operative EEG monitoring remains the most sensitive guide to carotid shunting in patients undergoing carotid endarterectomy under general anesthesia.

Electroencephalographic sleep patterns in post-anoxic stupor and coma.

We analyzed EEGs performed over a 6-month period on patients with impaired consciousness following acute hypoxia or anoxia. There were 17 EEGs performed on 14 patients. Nine of the 17 records contained spindle activity. Spindles were present in 6/8 EEGs in stuporous patients, in 3/9 EEGs in comatose patients, in 6/10 patients who eventually died, and in 3/3 patients who regained consciousness. When spindle activity or background reactivity were absent, outcome was poor, ie, death or a persistent vegetative state. The presence of EEG spindle activity after hypoxic or anoxic injury did not indicate a favorable prognosis, but the absence of spindles or EEG background reactivity was associated with a poor outcome.

Parietal lobe lesional epilepsy: electroclinical correlation and operative outcome.

We retrospectively studied ictal behavior, extracranial EEG, and operative outcome in 10 consecutive patients with intractable partial epilepsy of presumed parietal lobe origin who received a lesionectomy, i.e., resection of the neuroimaging-identified abnormality, at the Mayo Clinic. Nine patients had a pathologically verified foreign-tissue lesion, e.g., tumor or vascular malformation, and 1 patient had gliosis. All patients with foreign-tissue lesions were rendered seizure-free. The patient with gliosis experienced a reduction in seizure tendency. There were no operative complications. The most common seizure type was a simple partial seizure with visual, motor, or sensory symptoms (n = 8). Complex partial seizures (n = 5) and secondarily generalized tonic-clonic seizures (GTC, n = 2) were also observed. The ictal behavior was often nonspecific although useful in identifying lateralization of the epileptogenic zone. Extracranial interictal and ictal EEG changes were unreliable markers of the parietal lobe origin of seizure activity. Lesionectomy without chronic intracranial monitoring or functional mapping may be an effective and safe alternative surgical procedure in patients with partial epilepsy related to parietal lobe lesions.

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.

Bilateral periodic lateralized epileptiform discharges in Mycoplasma encephalitis.

Status epilepticus and prolonged coma developed in two patients with respiratory tract infections caused by Mycoplasma pneumoniae. Serial electroencephalography initially revealed bilateral, independent, periodic, lateralized epileptiform discharges. This pattern was replaced several days later by other electroencephalographic abnormalities.

Clinical and electrophysiological assessments in ALS patients.

Since the relationships between traditional assessments in ALS patients have not been defined, three clinical and four electrophysiological assessments were performed in a cross-sectional study of 87 ALS patients. The clinical assessments produced Norris ALS scores, muscle strength scores and illness durations (DUR). The electrophysiological assessments produced scores for motor unit interference pattern, denervation potentials, compound muscle action potential, and fasciculations. The individual muscle scores were averaged to produce mean scores, and Spearman rank correlations were performed on the mean scores. The association between Norris ALS and mean muscle strength (MMS) scores is significant (p less than .001, rs = 0.84), and these scores are significantly correlated with mean interference pattern (0.77, 0.82), mean denervation potential (-0.63, -0.70), and mean compound muscle action potential scores (0.55, 0.60), respectively. Correlations between IP and DP scores (-0.71), IP and CMAP scores (0.62), and DP and CMAP (-0.56) scores are also significant. Scatterplots of the data and regression lines suggest linear relationships between each of these assessments. Illness duration and fasciculation scores are not strongly correlated (rs less than 0.55) with any of the other clinical or electrophysiological assessments.