Sleep-related epilepsy in a Long-Evans hooded rat model of depression.

INTRODUCTION: Neonatal treatment with clomipramine (CLI) has been shown to have reliable behavioral and biological changes that mimic major symptomatic and biochemical changes found in depression. This paper further explores a common feature of depression, the comorbidity of seizure activity and depressive behaviors in this mode. METHODS: Rat pups were neonatally treated with 40 mg/kg/day of CLI from postnatal day 8 through 21. In adulthood, they were instrumented with electroencephalographic (EEG) and electromyographic (EMG) electrodes for 24 h of polysomnogram (PSG) recordings. PSG data were analyzed for: (1) sleep-wake cycle; (2) spectral power; and (3) epileptiform activity, including NREM-to-REM transition (NRT) bursts. RESULTS: Neonatal treatment with CLI reliably produces enhanced levels of REM (p < 0.01) and reduced sexual activity (p < 0.05). Theta power was enhanced during NREM sleep in the CLI group (p = 0.02). CLI-treated animals experienced increased frequency at the NRT (p < 0.01), as well as additional epileptiform activity of continuous (CTS; p < 0.05) and petite-continuous (P-CTS; p < 0.01) types, across the sleep-wake cycle. There is a strong temporal correlation with increased REM sleep duration, increased frequency of NRT bursts, and increased theta power during NREM sleep in CLI-treated animals. DISCUSSION: Neonatal CLI-treated animals experienced significantly more epileptiform activity as a whole, in addition to comorbid features of depression in adulthood. Neonatal exposure to CLI will not only produce depressive phenotype but may also enhance risk for epilepsy in some individuals. This warrants further investigation into currently acceptable medicinal use in humans.

5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases.

PURPOSE: 5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5-FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy. PATIENTS AND METHODS: None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis. RESULTS: Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients. CONCLUSION: These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future.

Nicotine-induced dystonic arousal complex in a mouse line harboring a human autosomal-dominant nocturnal frontal lobe epilepsy mutation.

We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the alpha4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1-2 mg/kg) elicit a novel behavior termed the dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is an additional component of the DAC. Similar to attacks in ADNFLE, the DAC can be partially suppressed by the sodium channel blocker carbamazepine or by pre-exposure to a very low dose of nicotine (0.1 mg/kg). The DAC is centrally mediated, genetically highly penetrant, and, surprisingly, not associated with overt ictal electrical activity as assessed by (1) epidural or frontal lobe depth-electrode electroencephalography or (2) hippocampal c-fos-regulated gene expression. Heterozygous knock-in mice are partially protected from nicotine-induced seizures. The noncompetitive antagonist mecamylamine does not suppress the DAC, although it suppresses high-dose nicotine-induced wild-type-like seizures. Experiments on agonist-induced 86Rb+ and neurotransmitter efflux from synaptosomes and on alpha4S248Fbeta2 receptors expressed in oocytes confirm that the S248F mutation confers resistance to mecamylamine blockade. Genetic background, gender, and mutant gene expression levels modulate expression of the DAC phenotype in mice. The S248F mouse thus appears to provide a model for the paroxysmal dystonic element of ADNFLE semiology. Our model complements what is seen in other ADNFLE animal models. Together, these mice cover the spectrum of behavioral and electrographic events seen in the human condition.

Frontal nonconvulsive status epilepticus associated with high-dose tiagabine therapy in a child with familial bilateral perisylvian polymicrogyria.

PURPOSE: Antiepileptic drugs are known to exacerbate absence and myoclonic seizures, especially in patients with idiopathic generalized epilepsies. Exacerbation of nonconvulsive generalized seizures in patients with partial epilepsy is less common. Recently, however, a number of cases of putative generalized nonconvulsive status epilepticus (NCSE) or NCSE without further specification have been reported in patients with chronic partial epilepsy treated with the gamma-aminobutyric acid reuptake inhibitor tiagabine. Although complex partial status epilepticus during tiagabine therapy has also been reported, possible precipitation of NCSE specifically associated with frontal lobe discharges does not appear to have been recognized. In this communication, we describe the case of a boy with familial bilateral perisylvian polymicrogyria who developed frontal NCSE after being stabilized on high-dose tiagabine METHODS: A 12-year-old boy with familial bilateral perisylvian polymicrogyria, mental retardation, and refractory partial seizures was administered tiagabine in addition to sodium valproate. The tiagabine dosage was increased gradually up to 10 mg t.i.d. (1 mg/kg per day), resulting in complete seizure control. RESULTS: After 1 week on maintenance treatment, seizures were completely controlled, but the child developed hypoactivity, decreased reactivity, and affective detachment. An EEG recording revealed subcontinuous sharp-wave discharges with irregular runs of atypical spike-wave complexes over the anterior regions of both hemispheres, consistent with a diagnosis of frontal NCSE. A reduction in tiagabine dosage to 15 mg/day led to complete regression of the behavioral and affective changes and to disappearance of the subcontinuous EEG discharges. CONCLUSIONS: Although tiagabine-induced NCSE has been described previously, particularly in patients with preexisting spike-wave abnormalities, this is the first report that identifies its potential role in the precipitation of frontal NCSE.

Propagation of acute seizure activities observed by local cerebral glucose metabolism.

We studied the propagation of acute focal seizure activities in animals by means of the [14C]deoxyglucose method. Seizures were induced unilaterally by injecting penicillin in the neocortical area 4 and area 9 in the monkey, and by injecting kainic acid in the hippocampus of the rat and in the ventral posterolateral thalamic nucleus of the cat. The earliest and the most consistent propagation was the one to the target structures of the primary focus, mediated through the "preferential" projection pathways. At a more advanced stage, the propagation to the immediately adjoining brain regions occurred, followed by the secondary propagation to the target structures of the adjoining regions. Propagation to the contralateral homologous structure was not a major one at the early stage unless the structure of the primary focus had its own commissural connections.