Oriano Mecarelli

Behavioral and electrographic patterns induced by systemic administration of kainic acid in developing rats

Abstract Behavioral and electrographic changes induced by systemic injection of 3–6 mg/kg of kainic acid (KA) have been studied during development in 1- to 28-day-old rats. In the first week of life, a few minutes after the administration of the toxin, animals developed motor signs such as scratching movements, hypo- and hyperactivity, loss of postural control, tremors and hyperextension of the limbs. No changes of the electrical cortical and hippocampal activity were detected. Similar, but more accentuated motor signs occur when KA was injected during the second week of postnatal life. In this case, on the electroencephalogram (EEG), bursts of spikes or polispikes localized in the cortex appeared. These bursts became more and more frequent and after only 20 min spread to the hippocampus. No correlation between the electrical and behavioral changes were observed. By the third week of life, in addition to motor signs, systemic kainic acid induced wet dog shakes (WDS) and limbic seizures. These were characterized by rearing, loss of postural control, masticatory movements and forepaw tremors. The EEG was characterized by primary hippocampal discharges that may spread to the cortex. Usually the limbic seizures become more and more frequent, leading to a status epilepticus. In another group of experiments, higher doses of KA (6–12 mg/kg) have been injected in curarized and artificially respirated animals of the same age. During the first days of life (1–7), unlike in the corresponding group of freely moving animals, KA induced sequences of slow spikes localized in the cortex and after 10–20 min spread to the hippocampus. In the following age-groups no differences between the curarized and free moving animals were detected. The different sensitivity of systemic KA to induce limbic seizures in neonatal rats may be related to the immaturity of pre- and post-synaptic glutamergic receptors in the hippocampus. Moreover, a different degree of maturity of cortical versus hippocampal glutamergic receptors may account for the preferential activation of the cortex versus hippocampus during the first period of life.

High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: A case-control study†

Large spontaneous portal‐systemic shunts have been occasionally described in patients with cirrhosis. This study was undertaken to assess the prevalence of portal‐systemic shunts in patients with cirrhosis with recurrent or persistent hepatic encephalopathy (HE) as compared with patients with cirrhosis without HE. Fourteen patients with cirrhosis with recurrent or persistent HE (cases) and 14 patients with cirrhosis without previous or present signs of overt HE matching for age and degree of liver failure (controls) were studied. Each patient underwent neurological assessment and cerebral magnetic resonance (MR) imaging to exclude organic neurological pathological conditions. HE evaluation included psychometric performance (Trail‐Making Test A), electroencephalogram (EEG), mental status examination and grading, arterial, venous, and partial pressure of ammonia determination. The presence of portal‐systemic shunts was assessed by portal venous phase multidetector‐row spiral computed tomography (CT). Large spontaneous portal‐systemic shunts were detected in 10 patients with HE and in only 2 patients without HE (71% vs. 14%; chi square = 9.16; df = 1.0; P = .002). The patients with HE presented ascites (P = .002) and medium/large esophageal varices (P = .02) less frequently than the control group. In conclusion, our study suggests that large spontaneous shunts may often sustain the chronicity of HE; the presence of large shunts should be sought in patients with cirrhosis with recurrent or persistent HE. (HEPATOLOGY 2005;42:1158–1165.)

Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines

By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow‐up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive‐evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short‐latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug‐induced disturbances, non‐convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow‐up period.

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.

Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.

Seizure susceptibility in immature rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate

The administration of the alkylating neurotoxin methylazoxymethanol acetate (MAM) to pregnant rats on day 15 of gestation induces, in the offspring, a marked micrencephaly, characterized by an impaired formation of interneurons at cortical, hippocampal and striatal levels. Since in man developmental CNS malformations are often associated with severe epileptogenic encephalopathies with seizures appearing in the first months or years of life, we have studied the development of kainic-acid- and bicuculline-induced seizures in 15- and 30-day-old rats, prenatally exposed to MAM. Compared to controls, a higher susceptibility to seizures has been found in micrencephalic rats aged 15 days, while no significant differences have been observed in those aged 30 days. It is hypothesized that the cerebral global anatomical dysgenesis caused by MAM underlies the higher seizure susceptibility shown by animals during the first periods of life. Successively, the processes of adjustment occurring between the cerebral regions affected by the neurotoxic action of MAM and the afferent and efferent pathways spared by the substance may re-establish adequate interneuronal relationships and, therefore, a normal convulsive susceptibility.

A DE NOVO LGI1 MUTATION CAUSING IDIOPATHIC PARTIAL EPILEPSY WITH TELEPHONE-INDUCED SEIZURES

Telephone-induced seizures have recently been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone.1 Typical auras consist of auditory or vertiginous symptoms and the inability to speak or understand spoken voices. These features, along with specific EEG ictal findings in one patient, suggest that this condition involves the lateral temporal area.1 Autosomal dominant partial epilepsy with auditory features (ADPEAF; OMIM 600512), or autosomal dominant lateral temporal epilepsy (ADLTE), is a rare familial partial epilepsy syndrome with onset in childhood/adolescence and benign evolution.2,3 The hallmark of the syndrome consists of the presence of typical auditory auras or ictal aphasia in most affected family members, sometimes triggered by environmental sounds and noises. ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 ( LGI1)/Epitempin gene,3,4 the function of which is still unclear. Earlier we described a series of sporadic patients with idiopathic partial epilepsy with auditory features (IPEAF) who were clinically indistinguishable from ADPEAF cases5 …

Bicuculline- and allylglycine-induced epilepsy in developing rats

The development of bicuculline- and allylglycine-induced epilepsy has been studied in developing rats (6 to 30 days old). The results showed that during the first period of life, in both experimental models, the behavioral modifications were atypical and poorly correlated to corresponding epileptic EEG changes. Successively, a gradual evolution of the electroclinical patterns was observed, with similar characteristics in both bicuculline- and allylglycine-treated animals. Only from the 3rd week did electroclinical patterns similar to those of adult animals and more specific for the type of the convulsant agent appear. These data suggest that during the 1st 2 weeks after birth, the level of global cerebral immaturity, rather than the type of the epileptogenic substance, is the prominent element in the characterization of epileptic manifestations. From the 3rd week, the more advanced level of anatomical, biochemical, and neurophysiologic maturation of the CNS allows a more selective involvement of various cerebral structures with subsequent well defined epileptic features.

Past and present public knowledge and attitudes toward epilepsy in Italy.

A nationwide survey was performed in Italy to assess awareness and attitudes of the public about epilepsy. Knowledge about epilepsy, its clinical features, and attitudes towards its social/individual implications were tested in a telephone interview. Included were 819 women and 737 men aged 18+years. 93.4% declared they knew epilepsy, 56.6% knew a person with epilepsy, and 45.1% saw someone seizing. Only 29.2% gave an exact estimate of the prevalence of the disease. 50.4% were unaware of the causes, 56.1% indicated that epilepsy was a psychological/psychiatric disease, 36.5% a form of insanity, and 4.1% an evil spirit possession. Epilepsy was incurable according to 35.5%. Moderate-to-severe restrictions to driving, regular employment, military career, and leisure activities were suggested by 79.8, 57.0, 71.1, and 57.6%. Limitations included marriage and procreation for 46.2 and 38.7%. Knowledge and attitudes varied with education, age and gender. These findings are partly in keeping with other worldwide reports.

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.