Lamotrigine High-Dose Tolerability and Safety in Patients with Epilepsy: A Double-Blind, Placebo-Controlled, Eleven-Week Study

Summary: Purpose: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice-daily (b.i.d.) dosage regimen of 700 mg/day larnotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses 500 mg/day in patients receiving concomitant enzyme-inducing antiepileptic drugs (AEDs). Methods: Twelve adult male epileptic patients treated with enzyme-inducing AEDs received 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). For 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients received regimens of 500, 600, and 700 mg/day for 1 week each. Controls received matching placebo in the same sequence. At study end, dosages were tapered in 2 weeks. Follow-up evaluations were made 7 days later. Results: Five LTG patients tolerated 700 mg/day for 1 week. LTG was reduced to 600 mg/day in a patient with mild diplopia and to 500 mg/day in a patient with mild oscillopsia and diplopia. One patient discontinued 300-mg/day therapy with a moderately intense diffuse papular skin rash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity and occurred in 50–75% of patients in both groups (except for diplopia, occurring only with LTG). Concomitant AED plasma concentrations were not markedly changed by LTG. LTG pharmacokinetics were linear over the range of 500–700 mg/day. Conclusions: LTG doses 700 mg/day can be tolerated in patients receiving concomitant enzyme-inducing AEDs.     

Evolution of Lennox-Gastaut Syndrome: A Long-Term Longitudinal Study

Summary: In 102 patients with Lennox-Gastaut syndrome (LGS) observed for an average of 16 years (range, 10–20 years), 12 of the patients worked normally, 36 worked part-time or at a sheltered workshop, and most of the remaining 54 were under home care or institutionalization. LGS evolved from West syndrome or from unspecified epilepsies, or as the primary form, mostly in childhood and rarely in adolescence or adulthood. At the worst stage, there were diverse types of generalized seizures, slow spike-and-wave EEG complexes, fast rhythms, and multiple spike-and-wave complexes. Mental subnormality progressively worsened. Characteristic symptoms of LGS continued in one third of patients, and various abortive forms of LGS were seen in the other two thirds, although LGS did not evolve into a localization-related epilepsy during the survey period. The evolution of seizure and EEG epileptic discharges suggests that LGS has a characteristic clinical course as it progresses. The persistent generalized tonic seizures of various magnitude over a long time in the vast majority of patients indicate that the brainstem rather than the cortical mantle is involved as the seat of seizure-generating mechanisms in LGS.     

Hemicranial Volume Deficits in Patients with Temporal Lobe Epilepsy With and Without Hippocampal Sclerosis

Summary: Purpose: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippocampus. Hippocampal sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements.
Methods: We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippocampal volume (HCV), and T₂relaxometry. MRI results were compared with histological findings in the resected temporal lobe.
Results: Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p <0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p ≥ 0.004). Unilateral hippocampal atrophy and increased T, value were found in 71% of patients with HS, and bilaterally normal HCV and T, value were found in 67% of patients without HS.
Conclusions: The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippocampi.     

The diagnostic value of the short sleep EEG and other provocative methods following sleep deprivation

Summary One hundred and eighty-five EEGs recorded after deprivation of sleep for 24h were evaluated. Valuable diagnostic information was found in 59% of the EEG recordings; 24% of the EEGs contained seizure activity. The duration of the stages of sleep and the frequency of seizure activity, paroxysmal sharp wave groups and localizing findings were analyzed. The sleep stages A to C (based on the Loomis scale) were reached for about equal duration by an EEG recording of 30–40 min; sleep stage D was reached only shortly and stage E was not observed. Pathological EEG findings appeared for the most part in the sleep stages A and B. Localized findings were pronounced in stage C. No significant differences pertaining to the occurrence and form of EEG patterns were found between patient groups with primary generalized seizures, psychomotor seizures or those with unclarified disturbances of consciousness. The combination of the short sleep EEG following 24h of sleep deprivation with subsequent use of the additional provocative methods of hyperventilation, photostimulation and hydration, yielded, in all, new information in 50% of the patients. Each of these additional methods contributed nearly equally to this information.

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Zusammenfassung Es wurden 185 EEGs nach 24h Schlafentzug ausgewertet. Hiervon enthielten 110 EEGs (59%) diagnostisch weiterführende Befunde. In 24% fand sich Krampfaktivität. Es wurden die Dauer der Schlafstadien, die Häufigkeit des Auftretens von Krampfaktivität, paroxysmalen Steilwellengruppen und Lokalbefunden analysiert. Die Schlaftiefen A bis C (nach Loomis) wurden während einer EEG-Ableitung von 30–40 min gleichmäßig lang, Stadium D nur kurz, Stadium E nicht erreicht. Pathologische EEG-Befunde traten überwiegend in den Schlafstadien A und B auf. Lokalbefunde fanden sich besonders im Stadium C. Zwischen den Patientengruppen mit primär generalisierten Anfällen, psychomotorischen Anfällen sowie Zuständen ungeklärter Bewußtseinsstörung fand sich kein signifikanter Unterschied hinsichtlich Auftreten und Ausprägung der EEG-Veränderungen. Die regelmäßig durchgeführte Hyperventilation und Fotostimulation und die Flüssigkeitsbelastung, die nur bei negativen Vorbefunden zusätzlich durchgeführt wurde, ergaben zusammen in 50% eine neue Information.

     

Effect of daily saline, drug or blank injections on the susceptibility to the convulsant effect of drugs.

The daily intraperitoneal injection to rats of doses of metrazol (30 mg/Kg), strychnin sulfate (1 mg/Kg) or picrotoxin (1.2 mg/Kg) that were initially subconvulsant, caused after a number of days which varied with the drug, clonic convulsions in a high percentage of the animals. However, after 18 daily injections of saline there was a similar increase of seizure susceptibility to the 3 drugs. The daily handling of rats as for injection, either followed or not by actual abdominal pricking (blank injection), had a similar though less pronounced effect. In animals that were housed in the same room where the others were tested, but which were not handled, the above mentioned doses of metrazol, strychnine and picrotoxin had no convulsant effect. These results indicate that the procedure of submitting rats to daily intraperitoneal injections is not as unconsequential as is usually thought to be, and that it may induce neurological changes.     

Lack of protection by pyridoxine or hydrazine pretreatment against monosodium L-glutamate-induced seizures.

Pretreatment of rats with hydrazine (100 mg/kg), a compound which raises brain gamma-aminobutyric acid (GAGA) 175 percent in 12 hr was not able to prevent the occurrence of seizures induced by monosodium L-glutamate (MSG). Pyridoxine (50 mg/kg) the cofactor essential in the conversion of glutamate to GABA, also failed to prevent convulsions induced by parenteral MSG administration. It is concluded that the mechanism of action of MSG-induced seizures is neither by decreasing brain GABA levels or interfering with the pyridoxine cofactor.     

Toxocara canis and lead alter consummatory behavior in mice

Ingestion of palatable and unpalatable solutions was measured in adult mice to which had been administered the common parasite of the dog, Toxocara canis alone, or in combination with lead. In addition, response to hot plate and susceptibility to electroconvulsive seizure were also measured. Results from the palatability test indicated that either lead or Toxocara may alter the mouse's mode of interacting with its environment. However, the two agents in combination interacted in their effects on consummatory behavior. Results from the hot plate and ECS measures were less clear with respect to how lead and/or Toxocara influence temperature reactivity and seizure susceptibility. Histological examination of the CNS in parasite infected animals revealed Wallerian Type degeneration of fiber pathways including the corpus callosum, olfactory tract, and cerebellar penduncles.     

内源性血红素氧合酶-一氧化碳体系对反复热性惊厥脑损伤的影响

目的探讨内源性血红素氧合酶(HO)—一氧化碳(CO)系统对反复热性惊厥(febrile seizures,FS)脑损伤的影响。方法21日龄SD大鼠24只,随机分为3组：对照组、FS组和FS 锌原卟啉Ⅸ(ZnPPⅨ)组。采用热水浴诱导大鼠FS,隔日诱导1次,共诱导10次。用双波长分光光度计间接测定大鼠血浆中CO含量;记录大鼠惊厥强度、潜伏期、持续时间及惊厥时的肛温;HE染色观察海马神经元形态学改变;电镜观察海马神经元超微结构的改变;尼氏染色对海马神经元进行半定量计数分析。结果反复FS后,血浆CO含量明显高于对照组,FS ZnPPⅨ组血浆CO含量较FS组低,与对照组比较无统计学意义;随着惊厥次数的增加,FS组大鼠惊厥持续时间呈延长趋势,FS ZnPPⅨ组大鼠惊厥潜伏期呈缩短趋势,惊厥持续时间较FS组长,惊厥强度和惊厥时的肛温两组差异无统计学意义;反复FS后,光镜和电镜下均发现海马神经元出现损伤改变,ZnPPⅨ的干预加重了神经元的损伤;反复FS后未见海马神经元的丢失,ZnPPⅨ的干预导致了神经元的显著丢失。结论内源性HO-CO系统对反复FS脑损伤发挥着重要的保护作用。     

Photic- and pattern-induced seizures: expert consensus of the Epilepsy Foundation of America Working Group

PURPOSE: In August, 2004, the Epilepsy Foundation of America convened a workshop to begin to develop an expert consensus on photosensitive seizures. METHODS: Literature and data were reviewed, and consensus was derived from discussion. RESULTS: A flash is a potential hazard if it has luminance >or=20 cd/m2, occurs at a frequency of >or=3 Hz, and occupies a solid visual angle of >or=0.006 steradians (approximately 10% of the central visual field or 25% of screen area at typical viewing distances). A transition to or from saturated red also is considered a risk. A pattern with the potential for provoking seizures contains clearly discernible stripes, numbering more than five light-dark pairs of stripes in any orientation. When the light-dark stripes of any pattern collectively subtend at the eye from the minimal-expected viewing distance a solid angle of >0.006 steradians, the luminance of the lightest stripe is >50 cd/m2, and the pattern is presented for >or=0.5 s, then the pattern should display no more than five light-dark pairs of stripes, if the stripes change direction, oscillate, flash, or reverse in contrast; if the pattern is unchanging or smoothly drifting in one direction, no more than eight stripes. These principles are easier to apply in the case of fixed media, for example, a prerecorded TV show, which can be analyzed frame-by-frame, as compared with interactive media. CONCLUSIONS: A consensus view of stimuli likely to provoke visually evoked seizures can be developed.     

Pharmacologic evidence for abnormal thalamocortical functioning in GABA receptor beta3 subunit-deficient mice, a model of Angelman syndrome

PURPOSE: gamma-Aminobutyric acid receptor (GABA(A)r) subunit beta3-deficient mice model Angelman syndrome by displaying impaired learning, abnormal EEG with interictal spikes and slowing, myoclonus, and convulsions. The beta3-subunit deficiency causes a failure of intrathalamic reticular nucleus inhibition, leading to abnormally synchronized thalamocortical oscillations. We postulated that this pathophysiology underlies the abnormal cortical EEG and triggers interictal spikes and seizures, but extrathalamic regions also contribute to interictal spikes and seizures, so that the EEG slowing should reveal an absence-like response profile, whereas spikes and seizures have dual responsiveness to absence and partial-seizure drugs. METHODS: Recording electrodes were implanted over the parietal cortices of wild-type, heterozygotes, and homozygous null mice. In each experiment, EEG was recorded for 45 min, either drug or vehicle administered, and EEG recorded for another 3 h. Each EEG was scored for slow-wave activity, interictal spikes, and seizures by a reader blinded to treatments. RESULTS: Interictal spiking and percentage of time in EEG slowing in heterozygotes were increased by the proabsence drug baclofen (GABA(B)-receptor agonist), whereas CGP 35348 (GABA(B)-receptor antagonist) had the opposite effect. The antiabsence drug ethosuximide markedly suppressed EEG slowing and interictal spiking in heterozygote and null mice. Broad-spectrum clonazepam and valproate were more effective on interictal spiking than on EEG slowing, and fosphenytoin suppressed only interictal spiking. CONCLUSIONS: The results suggest that this model of Angelman syndrome, although not expressing typical absence seizures, is characterized by hypersynchronous thalamocortical oscillations that possess absence-like pharmacologic responsiveness and promote EEG slowing, interictal spikes, and convulsive seizures.