Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine.

OBJECTIVE: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1. METHODS: A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. RESULTS: Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 µg/mL, reference range 1.3-5.0 µg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10-18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval -1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. CONCLUSION: Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. CLINICAL TRIALS REGISTRATION: Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.

Gait instability in valproate-treated patients: Call to measure ammonia levels.

OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

Impending status epilepticus and anxiety in a pregnant woman treated with levetiracetam.

Levetiracetam (LEV) has been considered to undergo no significant change in bioavailability during pregnancy; however, it was recently demonstrated to display modifications leading to a drop in its serum level. We describe a patient who displayed impending status epilepticus following a fall in her LEV level during the first trimester. The oral LEV dosage was increased, and phenytoin and benzodiazepines were transiently prescribed. She experienced severe anxiety and an unbearable fear over the deleterious consequences for her baby despite repeated, reassuring explanations. Her anxiety was so strong that she aborted electively shortly after leaving the hospital. This observation emphasizes the need for LEV level monitoring during pregnancy to prevent unexpected seizure relapses. The rapid increase in levetiracetam dosage in parallel with the loss of seizure control is suspected of facilitating the induction of significant psychiatric changes.

Thrombophilia interpretation in childhood stroke: a cautionary tale.

Several authors have reported a link between childhood stroke and inherited thrombophilia in recent years. The impact of such a relationship on management and outcome is yet to be determined, as is the potential cost-benefit ratio associated with the performance of thrombophilic screening in children presenting with ischemic stroke. We present a case that highlights the need for clinical and radiologic examinations to remain the definitive criteria used to diagnose stroke in children. The diagnosis should not be influenced by the finding of a thrombophilic marker.

Serum prolactin levels are elevated also after pseudo-epileptic seizures.

The aim of the study was to evaluate the sensitivity, specificity and the predictive values of repeated serum prolactin measurements in relation to epileptic seizures versus pseudoseizures. The method used was prospective measuring of serum prolactin from blood samples drawn (1) 15 min after seizure and (2) 2 hr after the first sample. Two parameters were used: the absolute maximal level; and the relative rise in blood level. In the study 38 had epilepsy (simple or complex partial seizures with or without secondary generalisation); and 20 had pseudo-epileptic seizures. In all cases, the diagnoses were made independent of the prolactin levels. In 30/38 (79%) of epilepsy patients and 17/20 (85%) of pseudoseizure patients, the diagnoses were corroborated by intensive EEG monitoring (video or cassette telemetry). There was a statistically significant rise in prolactin levels in both groups (p < 0.0001 and < 0.02, respectively), and also a significant difference between the two groups. However, repeated measurements in a number of patients (epilepsy: mean 1.5 measurements; pseudo; mean 2.1) showed also considerable intra-patient variations. The sensitivity for the maximal rise in pseudoseizures (5.5x) was only 20% and the negative predictive value 40%. For the cut-off in absolute level (1025 microU/ml), the corresponding figures were 34% and 44%, respectively. The rather limited discriminative power of prolactin measurements makes it of questionable value in discerning between epileptic and pseudo-epileptic seizures.

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.

Serum prolactin response to repetitive epileptic seizures.

We measured postictal prolactin (PRL) levels during repetitive seizures in 14 patients (10 men and 4 women) suffering from epilepsy with focal and/or secondarily generalized seizures. Between two and six seizures occurred per patient (mean 2.7). The interveral between seizures was 15 min and 8 h 40 min (mean 3 h 32 min). Five of the 14 patients showed a marked postictal PRL rise after each seizure (i.e. concentrations above 700 microU/ml for women, 500 microU/ml for men). In the remaining 9 patients there was no detectable rise in PRL. A decrease in PRL did not occur in any of the 14 patients. In those patients who had shown a marked PRL increase after the first seizure, the PRL continued to rise in subsequent seizures. Unlike previous investigations, these results show that repetitive epileptic seizures are not necessarily followed by a decrease in postictal PRL levels. A decrease in PRL response is known to occur if there is progression to status epilepticus.

[Rise in serum prolactin concentration after frontal lobe seizures. Possibilities in differential diagnosis of psychogenic seizures]. / Anstieg der Serum-Prolactinkonzentration nach Frontallappenanfällen. Möglichkeit zur Differentialdiagnose psychogener Anfälle.

The prolactin concentration profile over 24 hours was determined in three men, aged 19, 27 and 43 years, who suffered from treatment-resistant complex-partial and (or) grand mal seizures of frontal lobe origin. All three patients were examined in the course of preoperative epilepsy diagnosis, the seizures being classified by video-EEG recordings, including subdural and sphenoidal foramen ovale electrodes. Seizures were recorded in all three patients (4 grand mal; 2 complex-partial), each of them followed by a rise in serum prolactin concentration (over 700 microU/ml). These findings contradict the theory that prolactin concentration rises only after temporal, not after frontal seizures. Knowing the postseizure serum prolactin concentration may help to distinguish frontal epileptic from psychogenic seizures.