P. Pulitano

Clinical, Cognitive, and Neurophysiologic Correlates of Short-Term Treatment with Carbamazepine, Oxcarbazepine, and Levetiracetam in Healthy Volunteers

BACKGROUND The adverse effects of the antiepileptic drugs (AEDs) originally developed are well known, while those of the newer AEDs remain unclear. OBJECTIVE To investigate clinical, cognitive, and neurophysiologic effects of carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. METHODS A double-blind crossover study was conducted in 10 volunteers. Eight-day treatment with carbamazepine, oxcarbazepine, levetiracetam, or placebo was administered in random order. Drug doses were titrated gradually to the daily target doses on day 7: carbamazepine 800 mg, oxcarbazepine 1200 mg, and levetiracetam 1500 mg. At baseline and at the end of each treatment period, participants underwent cognitive and neurophysiologic assessment. A washout period of 14 days between treatment periods was conducted. RESULTS More adverse events were self-reported with carbamazepine (63%) than the other treatments (oxcarbazepine 12%, levetiracetam 20%, placebo 5%; p < 0.001 between the 4 groups). Carbamazepine induced the greatest motor slowing (p = 0.002), followed by oxcarbazepine (p = 0.01). Levetiracetam left baseline motor speed unchanged. All AEDs increased attention span from baseline values as shown on the Stroop test. Quantitative electroencephalogram (EEG) analysis showed that carbamazepine significantly increased the delta–theta power and reduced the frequency of alpha rhythm; oxcarbazepine induced smaller changes than carbamazepine. Levetiracetam did not change any EEG measurements. On color visually evoked potential (VEP) tests, carbamazepine induced a constant slowing of P1 latency, while oxcarbazepine induced changes only after the blue–black pattern. All color VEP measures for volunteers receiving levetiracetam were almost unchanged. CONCLUSIONS After short-term treatment in healthy volunteers, carbamazepine induced major clinical and neurophysiologic changes. Oxcarbazepine was better tolerated than carbamazepine. Levetiracetam interfered least with clinical and neurophysiologic test results.

A questionnaire study on knowledge of and attitudes toward epilepsy in schoolchildren and university students in Rome, Italy

PURPOSE To estimate the knowledge of and attitudes toward epilepsy in schoolchildren and university students in Rome. METHODS We administered a custom-designed questionnaire in Italian on general knowledge, specific knowledge and social impact of epilepsy to a random sample of upper-middle class pupils and university undergraduate students in Rome. RESULTS The young people we studied have a reasonable knowledge of epilepsy: as many as 91% claimed to know something about the disease. Yet only 16% correctly stated the prevalence as being about 1 in 100. Middle-school pupils and university graduates consider epilepsy as an illness from which patients rarely recover and one that creates problems in finding employment. The largest number of correct answers for nearly all the questionnaire items came from university students. CONCLUSIONS These findings suggest that apart from an encouragingly large number of the subjects we studied claim to know something about epilepsy (91% today versus 73% 22 years ago), Italian students still know little about epilepsy. These preliminary data should provide a starting point for a future in-depth population-based survey and information campaigns at schools in the Rome metropolitan area.

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.

EEG patterns and epileptic seizures in acute phase stroke.

Background: The rate of early post-stroke epileptic seizures ranges from 2 to 33%. This wide range is likely due to differences in study design, patient selection and type of neurophysiological monitoring. Electroencephalography (EEG), which is not used in the routine work-up of acute stroke, is the best neurodiagnostic technique for detecting epileptic activity, especially in patients with non-convulsive post-stroke epileptic activity. The aim of this study was to analyze patterns on EEGs performed within 24 h of stroke onset, and to investigate correlations between these patterns and the occurrence of early epileptic seizures and status epilepticus (SE), vascular risk factors, stroke subtypes and short-term outcome. Methods: We prospectively studied 232 patients (mean age 71 ± 12 years; 177 ischemic strokes and 55 hemorrhagic). EEG recording was performed within 24 h from hospitalization. The follow-up lasted 1 week. Results: Fifteen patients (6.5%) had early seizures within 24 h; 10 of these patients had focal SE with or without secondary generalization. EEG revealed sporadic epileptiform focal abnormalities in 10% and periodic lateralized epileptiform discharges (PLEDs) in 6%. SE was recorded in 71.4% of patients with PLEDs. At the multivariate analysis, only early epileptic manifestations (p < 0.001) were independently associated with PLEDs. Conclusions: Our study confirms that seizures are not frequent in the early phase of acute stroke and occur prevalently as focal SE at onset. EEG may help to detect specific patterns, such as PLEDs, that are closely related to early seizures. EEG monitoring should be performed in order to detect purely electrographic seizures.

Clinical and Electroencephalographic Effects of Topiramate in Patients with Epilepsy and Healthy Volunteers

Although topiramate, one of the newer drugs used in treating epilepsy, is effective in reducing seizure frequency and has a wide spectrum of action, it often induces intolerable adverse effects, predominantly related to the central nervous system. Information that would help document adverse reactions early, thus allowing topiramate doses to be adjusted during the drug titration and maintenance phases, could be obtained from electroencephalogram (EEG) studies. We studied the clinical effects and EEG changes induced by topiramate in patients with refractory partial epilepsy receiving the drug as add-on therapy. To exclude effects related to the other drugs and to epilepsy itself, we compared data from patients and healthy volunteers. After receiving topiramate, 22.6% of patients became seizure free and 29% had their seizures reduced by 50% or more. Topiramate nevertheless induced noteworthy adverse reactions, the main problems being sedative and cognitive changes. Also, in healthy volunteers, a single 100-mg dose of topiramate induced mild adverse reactions, mainly affecting concentration and attention, with difficulties in speech and writing. In patients with epilepsy, the EEG changes induced by topiramate consisted of increased delta and theta activities and decreased activity in the rapid bands. This recognizable topiramate-induced EEG pattern was again evident in the healthy volunteers, in whom we also detected a significant reduction in the alpha frequency rhythm. Our results confirm that topiramate needs to be introduced gradually while patients undergo close neuropsychologic and neurophysiologic monitoring to detect adverse sedative and cognitive reactions early. The EEG correlate of these events seems to be increased activity in the slower frequency bands.

Saliva and serum levetiracetam concentrations in patients with epilepsy

Abstract: Although antiepileptic drug (AED) monitoring in saliva may have some clinical applicability, it has not yet come into routine use. The correlation between levetiracetam (LEV) saliva and serum concentrations also remains unclear. To confirm LEV saliva assay as a useful, noninvasive alternative to serum measurement, we investigated the possible correlation between saliva and serum LEV concentrations. Samples of saliva and blood were collected from 30 patients with epilepsy receiving chronic therapy with LEV as monotherapy or add-on therapy, and LEV concentrations were assayed in saliva and serum. Linear regression analyses showed a close correlation between saliva and serum LEV concentrations (r2 = 0.90; P < 0.001). LEV blood and saliva concentrations were linearly related to daily drug doses (r2 = 0.78 and 0.70; P < 0.01). When data were analyzed for subgroups (patients receiving LEV in monotherapy, as add-on therapy with enzyme-inducer AEDs, and as add-on therapy with noninducer or moderate-inducer AEDs), no significant difference was found between saliva and serum LEV concentrations among groups. These preliminary results indicate that LEV, like other AEDs, can be measured in saliva as an alternative to blood-based assays. Saliva LEV collection and assay is a valid noninvasive, more convenient alternative to serum measurement.

Acute Hepatitis Associated with Lamotrigine and Managed with the Molecular Adsorbents Recirculating System (MARS)

Lamotrigine (LTG) has been associated with serious idiosyncratic reactions, including fulminant hepatic failure in children and adults (1–4). Recently Sen et al. (5) proposed treating hepatotoxicity induced by phenytoin (PHT), a drug that is 90% protein bound, by detoxification with the molecular adsorbents recirculating system (MARS). Because this blood-purification system is based on the principle of albumin dialysis, it is especially useful in cases of toxicity induced by highly protein bound drugs. LTG is eliminated primarily by glucuronide conjugation, and its plasma protein binding is 55% (6). We describe a woman with LTG-induced fulminant liver failure who recovered rapidly after MARS treatment.

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine‐rich, glioma‐inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis.

Transcranial Doppler for brain death after decompressive craniectomy: persistence of cerebral blood flow with flat EEG

Dear Editor, Brain death (BD) diagnosis is made based upon clinical criteria—unresponsive coma with absence of brainstem reflexes and persistent apnea—and upon neurophysiologic observation of persistent ‘‘flat EEG.’’ Cerebral circulatory arrest (CCA) must also be assessed with ‘‘ancillary tests,’’ e.g. conventional angiography, transcranial Doppler (TCD), and other neuroimaging techniques, in infants younger than 12 months, when EEG flattening may be related to sedative treatment, and in BD of uncertain origin [1]. CCA may indeed happen both when intracranial pressure (ICP) overrides mean arterial blood pressure (MAP) as well as in diseases affecting cerebral tissue at a cellular level, with ICP not exceeding MAP. TCD is a sensitive, specific, and noninvasive technique to detect CCA in BD by identifying specific patterns [2]. However, it may lead to false-negative results in cases of skull defects (decompressive craniectomy, external drains, and in infants), because in these cases the increase in ICP may partially be compensated for. For these reasons, we recently described the TCD modifications of the CCA patterns in infants with BD, confirming that CCA detection for BD confirmation should be done cautiously in these cases [3]. Here we describe the different TCD findings observed in two adults with BD who were subjected to decompressive craniectomy. Case 1 was a female, 62 years old, with intracerebral right temporo-parietal hemorrhage, middle cerebral artery aneurism rupture. She underwent large right frontotemporal craniectomy and presented with unresponsive coma and flat EEG (Fig. 1). TCD, performed under stable hemodynamic conditions (BP 140/70 mmHg), showed the typical CCA pattern. Short compression of the dural expansion induced a further reduction of the signal, promptly returning to the basal conditions at the end of compression (Fig. 1). Case 2 was female, 56 years old, with a small deep right basal ganglia hemorrhage and aneurysm of the right intracranial internal carotid artery. She was treated with an endovascular procedure. Following sedation withdrawal, 2 days after the procedure, she was conscious but agitated and uncooperative, and she was again sedated. TCD performed under stable hemodynamic conditions (BP 150/ 100 mmHg) (Fig. 2a) showed a very high-resistive pattern with diastolic reduction in both the middle cerebral arteries and expression of elevated ICP, confirmed by invasive

Transcranial Doppler for Brain Death in Infants: The Role of the Fontanelles

Objective: Transcranial Doppler (TCD) is a sensitive technique for circulatory arrest diagnosis in brain death when patterns such as reverberant flow and short systolic spikes are observed. In infants, the nonossified fontanelles compensate for intracranial hypertension. We describe TCD patterns in infants with brain death, different from adults, with the hemodynamic modifications induced by anterior fontanelle compression. Method: TCD was performed in 2 infants with diagnosed brain death admitted to the neonatal intensive care unit. Results: TCD showed a large peak ‘reverberant’ flow, with a high peak systolic velocity and a consistent retrograde component, away from the brain. Compression of the anterior fontanelle induced, at first, a reduction in systolic flow with the subsequent appearance of the characteristic short systolic spikes. Upon compression removal, a brief increase in the systolic flow was observed before the prompt reappearance of the reverberant flow. Conclusion: TCD for brain death diagnosis should be done cautiously in infants. In these cases, reverberating flow may be indicative of circulatory arrest even if with a large peak and with a high peak systolic velocity. Heavy fontanelle compression may reproduce the classical adult TCD patterns of brain death, thus supporting the diagnosis of cerebral circulatory arrest.