Nicola Pietrafusa

Claustrum damage and refractory status epilepticus following febrile illness

Objective: To characterize the clinical, EEG, and brain imaging findings in an adult case series of patients with de novo refractory status epilepticus (SE) occurring after a febrile illness. Methods: A retrospective study (2010–2013) was undertaken with the following inclusion criteria: (1) previously healthy adults with refractory SE; (2) seizure onset 0–21 days after a febrile illness; (3) lacking evidence of infectious agents in CSF; (4) no history of seizures (febrile or afebrile) or previous or concomitant neurologic disorder. Results: Among 155 refractory SE cases observed in the study period, 6 patients (17–35 years old) fulfilled the inclusion criteria. Confusion and stupor were the most common symptoms at disease onset, followed after a few days by acute repeated seizures that were uncountable in all but one. Seizures consisted of focal motor/myoclonic phenomena with subsequent generalization. Antiepileptic drugs failed in every patient to control seizures, with all participants requiring intensive care unit admission. Barbiturate coma with burst-suppression pattern was applied in 4 out of 6 patients for 5–14 days. One participant died in the acute phase. In each patient, we observed a reversible bilateral claustrum MRI hyperintensity on T2-weighted sequences, without restricted diffusion, time-related with SE. All patients had negative multiple neural antibodies testing. Four out of 5 surviving patients developed chronic epilepsy. Conclusions: This is a hypothesis-generating study of a preliminary nature supporting the role of the claustrum in postfebrile de novo SE; future prospective studies are needed to delineate the specificity of this condition, its pathogenesis, and the etiology.

PCDH19-related epilepsy and Dravet Syndrome: Face-off between two early-onset epilepsies with fever sensitivity.

Aim of this study is to compare PCDH19-related epilepsy and Dravet Syndrome (DS) in order to find out differences between these two infantile epilepsies with fever sensitivity. We retrospectively reviewed the medical records of 15 patients with PCDH19-related epilepsy and 19 with DS. Comparisons were performed with Fishers exact test or Students t-test. Females prevailed in PCDH19-related epilepsy. Epilepsy onset was earlier in DS (5.0+2.1 vs 11.2+7.0months; p<0.05). The second seizure/cluster occurred after a longer latency in PCDH19-related epilepsy rather than in DS (10.1±13.6 vs 2.2±2.1months; p<0.05). Seizures were mainly single and prolonged seizures in DS, and brief and clustered in PCDH19-related epilepsy. Myoclonic and clonic seizures have been found only in DS. Other types of seizures were found in both epilepsies with a prevalence of GTCS and atypical absences in DS, and focal motor and hypomotor seizures in PCDH19-related epilepsy. Seizures with affective symptoms have been confirmed to be typical of PCDH19-related epilepsy. Status Epilepticus equally occurred in both groups. Photosensitivity was detected only in DS. No differences were found about the presence of intellectual disabilities and behavioral disturbances. We were able to find out some distinctive features, which could address the diagnosis towards DS or PCDH19-related epilepsy, since first manifestation. These considerations suggest to definitively considering PCDH19 gene as cause of a proper epileptic phenotype.

Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy

Nicotinic acetylcholine receptor genes are involved mainly in nocturnal frontal epilepsy. Despite extensive studies, to date, the α2 subunit did not show a strong association with this peculiar epileptic phenotype. We report CHRNA2 missense mutation in a family with benign familial infantile seizures (BFIS). TrueSeq Custom Amplicon (TSCA) sequencing approach was used to screen 10 ion channel genes in patients with idiopathic epilepsies. TSCA revealed a heterozygous single‐nucleotide substitution in CHRNA2 gene (c.1126 C>T; p. Arg376Trp) that segregated in a family with BFIS; based on bio‐informatics inspection, the change was predicted to be pathogenic. The investigated family includes parents and their three daughters. In affected individuals, seizures started between 6 and 24 months of age. Seizures were mainly in cluster and well‐controlled. Outcome was good in all subjects. Even if nicotinic acetylcholine receptor genes are traditionally associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), this single‐family description can open new possibilities in the genetic diagnosis, molecular characterization, and management of CHRNA2‐related epilepsy. The pathogenic conversion of arginine 376 to tryptophan alters all of these interactions in the cytoplasmic domain, never reported to be involved in epileptogenic mechanism. Further functional tests will be necessary to strongly relate CHRNA2 mutation with BFIS phenotype.

Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease

This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes.

Vigabatrin efficacy in GPR56-associated polymicrogyria: The role of GABAA receptor pathway

To the Editors: G protein–coupled receptor 56 (GPR56) gene mutations are responsible for the syndromic condition known as bilateral frontal and frontoparietal cortical malformation (BFPP). The main clinical features of BFPP include severe mental retardation, developmental delay, and epilepsy, often presenting as Lennox-Gastaut syndrome. Although there is some evidence of the pathogenesis of BFPP, the pathophysiology of the resulting epilepsy is poorly understood. Localized freezing in neonatal mice brain is currently used as an experimental model mimicking the histologic characteristics of a human four-layered polymicrogyria. This model documented a widespread functional disruption of c-aminobutyric acid A receptors (GABAARs) revealing a downregulation of GABAAR sub-units. 6 We observed four female patients from two families with consanguineous parents. All of them presented with BFPP due to GPR56 mutations. Mutations in 16q12.2–21 were identified [C.1453C>T and C.1693C>T]. All patients presented with tonic and secondarily generalized seizures. Epileptic spasms occurred in half of them. All patients had drugresistant epilepsy, gait impairment, and intellectual disability. All treatments were ineffective, including benzodiazepines and barbiturates. Vigabatrin was introduced at a median age of 8.8 years old (range 7.2–8.9). We observed a median seizure reduction of 75% (range 25–100%) after vigabatrin introduction. This effect persisted all over the follow-up (median 15 months, range 6–72). The Clinical Global Impression (CGI) test administered to parents revealed an overall improvement (one case “very much improved”, two cases “much improved”, one case “minimal improved”). In addition, parents reported an increase of attention in three patients. The functional disruption of GABAAR sub-units could be the biologic mechanism involved in epileptogenesis, and in the specific sensitivity to vigabatrin in patients with BFPP. The evidence linking epilepsy with dysfunction of GABAergic inhibition is well documented, and GABAAR is a major target of antiepileptic drugs (AEDs). Functional studies demonstrated that the sub-unit composition of GABAAR determines its electrophysiologic and pharmacologic properties. In our patients, different drugs active on the GABA pathway were used: benzodiazepines (clobazam and clonazepam) and barbiturates (phenobarbital) failed. The function of GABAARs can be modulated through the allosteric site, or directly activated through the orthosteric site. Vigabatrin increases the availability of GABA in synaptic space (inhibition of the GABA catabolism), and might be effective through the direct activation of the orthosteric site. Loss-of-function of allosteric sites, caused by downregulation of GABAARs sub-units, might be an explanation for the inefficacy of other GABA agents tested. The selectivity of benzodiazepine responsiveness of GABAARs is determined by specific alpha subunits (those abnormally expressed in the animal model of polymicrogyria). Similarly, the main antiseizure mechanism of barbiturates is likely the allosteric effect on GABAARs: some evidence related with beta sub-units. One similar model is stiripentol effectiveness in Dravet syndrome: positive modulation by stiripentol was most effective on GABAARs containing an alpha-3 subunit, those characteristics of the immature brain. GABAARs are established targets for AEDs, but data regarding the specificity of AEDs in different syndromes are lacking. Our report suggests that also in rare diseases, a better knowledge of the AED’s mechanism of action and the understanding of the disease pathophysiology could allow a tailored treatment.

Peri-ictal water drinking: a rare automatic behaviour in temporal lobe epilepsy

Peri-ictal water drinking (PIWD) has been reported as the action of drinking during or within two minutes of an electroclinical seizure. It is considered a peri-ictal vegetative symptom, evident both during childhood and adulthood epilepsy. The aim of this paper was to describe the clinical and electroencephalographic features of two new adult subjects suffering from symptomatic temporal lobe epilepsy with episodes of PIWD recorded by VIDEO-EEG and to review literature data in order to better define this peculiar event during seizures, a rare and probably underestimated semiological sign. To date, 51 cases with focal epilepsy and seizures associated with PIWD have been reported. All patients presented with temporal lobe epilepsy. All cases but one had symptomatic epilepsy. Most of the patients had an involvement of the right hemisphere. Water drinking was reported as an ictal sign in the majority of patients, and less frequently was reported as postictal. We believe that PIWD might be considered a rare automatic behaviour, like other automatisms. Automatisms are more frequently described in patients with temporal lobe epilepsy. PIWD was reported also to have lateralizing significance in the non-dominant temporal lobe, however, because of its rarity, this finding remains unclear.