Hand posture as localizing sign in adult focal epileptic seizures.

OBJECTIVE: The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy. METHODS: In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization. RESULTS: We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ. INTERPRETATION: Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800.

Recovery from emotion recognition impairment after temporal lobectomy.

Mesial temporal lobe epilepsy (MTLE) can be associated with emotion recognition impairment that can be particularly severe in patients with early onset seizures (1-3). Whereas, there is growing evidence that memory and language can improve in seizure-free patients after anterior temporal lobectomy (ATL) (4), the effects of surgery on emotional processing are still unknown. We used functional magnetic resonance imaging (fMRI) to investigate short-term reorganization of networks engaged in facial emotion recognition in MTLE patients. Behavioral and fMRI data were collected from six patients before and after ATL. During the fMRI scan, patients were asked to make a gender decision on fearful and neutral faces. Behavioral data demonstrated that two patients with early onset right MTLE were impaired in fear recognition while fMRI results showed they lacked specific activations for fearful faces. Post-ATL behavioral data showed improved emotion recognition ability, while fMRI demonstrated the recruitment of a functional network for fearful face processing. Our results suggest that ATL elicited brain plasticity mechanisms allowing behavioral and fMRI improvement in emotion recognition.

Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death.

There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene. Functional studies showed that the mutation induces severe loss of function. This observation provides further evidence for a possible link between idiopathic epilepsy and LQTS.

Seizure outcome in surgically treated drug-resistant mesial temporal lobe epilepsy based on the recent histopathological classifications.

OBJECT: The study was performed to investigate the relation between seizure outcome after surgical treatment of mesial temporal lobe epilepsy (MTLE) and pathological findings, classified according to the recently proposed classifications of mesial temporal sclerosis (MTS), granule cell pathology (GCP), focal cortical dysplasia (FCD) and epilepsy-associated low-grade tumors (ELGT). METHODS: The authors analyzed data obtained in 120 consecutive cases involving patients presenting with drug-resistant MTLE, who underwent tailored anteromesial temporal lobe resection, and correlated seizure outcome with pathological findings. They identified 5 histopathological groups: Group 1-ELGT, alone or associated with other lesions (30 cases); Group 2-isolated FCD (17 cases); Group 3-MTS, with or without GCP (28 cases); Group 4-MTS associated with FCD, with or without GCP (37 cases); Group 5-other lesions (8 cases). RESULTS: Engel Class I outcome was observed in 83% of patients with ELGT (Class IA in 63%); in 59% of patients with isolated FCD, with FCD Type II showing a better prognosis than FCD Type I; in 82% of patients with isolated MTS (Class IA in 50%), with MTS Type 1a and MTS Type 1b showing a better prognosis than MTS Type 2 and patients with MTS and GCP having better postsurgical results than those with MTS without GCP. Engel Class I outcome was also achieved in 84% of patients with FCD associated with MTS (Engel Class IA in 62%); also in this group MTS 1a and MTS 1b associated with FCD showed a better prognosis than FCD associated with MTS 2. Finally, Engel Class I was also achieved in 2 patients with vascular malformation and in 1 with a temporal pole encephalocele. CONCLUSIONS: Patients with MTLE and ELGT, MTS, or MTS associated with FCD showed the best postsurgical seizure outcome (Engel Class I in more than 80% of cases), whereas only 63% of patients with isolated FCD achieved the same type of outcome. Interestingly, the analysis of seizure outcome in histopathological subtypes of FCD and of MTS showed different prognoses in the different pathological subgroups, with worse outcomes for atypical MTS, absence of GCP, and isolated FCD Type I.

Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update.

Electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) is an age-related, self-limiting disorder characterised by epilepsy with different seizure types, global or selective neuropsychological regression, motor impairment, and a typical EEG pattern of continuous epileptiform activity for more than 85% of non-rapid eye movement (NREM) sleep. Although the first description of ESES/CSWS dates back to 1971, an agreement about the optimal treatment for this condition is still lacking. ESES/CSWS is rare (incidence is 0.2-0.5% of all childhood epilepsies) and no controlled clinical trials have been conducted to establish the efficacy of different antiepileptic drugs; only uncontrolled studies and case reports are reported in the literature. Treatment options for ESES/CSWS include some antiepileptic drugs (valproic acid, ethosuximide, levetiracetam, and benzodiazepines), steroids, immunoglobulins, the ketogenic diet, and surgery (multiple subpial transections). In this study, the comparative value of each of these treatments is reviewed and a personal therapeutic approach is proposed.

A PTG variant contributes to a milder phenotype in Lafora disease.

Lafora disease is an autosomal recessive form of progressive myoclonus epilepsy with no effective therapy. Although the outcome is always unfavorable, onset of symptoms and progression of the disease may vary. We aimed to identify modifier genes that may contribute to the clinical course of Lafora disease patients with EPM2A or EPM2B mutations. We established a list of 43 genes coding for proteins related to laforin/malin function and/or glycogen metabolism and tested common polymorphisms for possible associations with phenotypic differences using a collection of Lafora disease families. Genotype and haplotype analysis showed that PPP1R3C may be associated with a slow progression of the disease. The PPP1R3C gene encodes protein targeting to glycogen (PTG). Glycogen targeting subunits play a major role in recruiting type 1 protein phosphatase (PP1) to glycogen-enriched cell compartments and in increasing the specific activity of PP1 toward specific glycogenic substrates (glycogen synthase and glycogen phosphorylase). Here, we report a new mutation (c.746A>G, N249S) in the PPP1R3C gene that results in a decreased capacity to induce glycogen synthesis and a reduced interaction with glycogen phosphorylase and laforin, supporting a key role of this mutation in the glycogenic activity of PTG. This variant was found in one of two affected siblings of a Lafora disease family characterized by a remarkable mild course. Our findings suggest that variations in PTG may condition the course of Lafora disease and establish PTG as a potential target for pharmacogenetic and therapeutic approaches.

Seizure-related automatic locomotion triggered by intracerebral electrical stimulation.

We describe the case of an eight-year-old boy, who underwent a video-stereo EEG (SEEG) investigation for the presurgical assessment of drug-resistant epilepsy, related to a right fronto-lateral cortical dysplasia and who became seizure-free after epilepsy surgery. The unexpected finding of the investigations was that intracerebral, high frequency (50 Hz) electrical stimulation (HFS) triggered the emergence of automatic and involuntary forward-backward locomotion during a focal seizure while the boy was standing. This clinical manifestation was different from the chaotic motor activity described during epileptic wanderings. The stimulation of the same fronto-lateral region, while the patient was lying, produced only the subjective sensation that the legs were moving, although there was no physical manifestation of this. Human locomotion is an innate motor behavior that is normally due to the activation of the spinal network for locomotion (central pattern generator). The emergence of different stereotyped motor behaviors during focal epileptic seizures or sleep disorders has recently been interpreted as a release of subcortical central pattern generators (Tassinari et al. 2005). In view of this, we hypothesize that the involuntary and robot-like locomotion of our patient could be the ictal expression of the release of subcortical locomotor CPGs.

Familial epilepsy and developmental dysphasia: description of an Italian pedigree with autosomal dominant inheritance and screening of candidate loci.

PURPOSE: To describe a familial epileptic condition combining a peculiar electro-clinical pattern with developmental language dysfunction in a large Italian kindred. METHODS: We studied the clinical and neurophysiological features of a 4-generation family with 10 affected members (3 deceased). We also analysed in 7 affected and 7 healthy members microsatellite markers for 51 candidate loci for epilepsy, including 42 loci containing ion channel genes expressed in the brain, as well as the SPCH1 and SRPX2 loci. RESULTS: Five of the seven living affected members (aged 20-58 years) had the full phenotype (seizures, EEG epileptiform abnormalities and dysphasia). The language dysfunction was the first symptom, becoming evident since the period of language development and mainly consisting of phonemic and syntactic paraphasias, difficulty of expression and reduced verbal fluency. The seizures had their onset between 2 and 23 years and were reported as epileptic falls (4) associated or not with myoclonic features, absences (3), tonic-clonic (1) and complex partial seizures (1). The seizures were easily controlled by antiepileptic treatment in all patients except one. In the five patients with a good response of seizures to treatment, the EEG tracings showed the coexistence of focal and generalized epileptiform abnormalities; in the refractory patient the interictal EEG demonstrated bilateral asynchronous fronto-temporal paroxysms with left predominance and ictal SEEG recording suggested a multifocal origin of the discharges. MRI of the brain was normal in all patients. Linkage analysis provided negative LOD scores for all the investigated loci. CONCLUSION: We have described a novel familial pattern of epilepsy and developmental dysphasia which is not genetically linked to epilepsy or speech disorder loci, as documented by a candidate-gene linkage approach.

Co-existence of cavernoma and cortical dysplasia in temporal lobe epilepsy.

Cavernomas and cortical dysplasia are well-known causes of partial epilepsy. The association between cavernoma and cortical dysplasia in an epileptic patient has not yet been sufficiently documented. We report a case of long-term, drug-resistant, partial left temporal epilepsy associated with a cavernoma. According to the neurophysiological non-invasive presurgical study, the patient was submitted to a tailored left temporal resection. The histopathological study showed the coexistence of cavernoma and cortical dysplasia. This is an interesting combination of epilepsy-related pathologies that have so far not been documented.

Charles Bonnet syndrome in hemianopia, following antero-mesial temporal lobectomy for drug-resistant epilepsy.

Charles Bonnet syndrome (CBS) is a disorder characterized by the occurrence of complex visual hallucinations in patients with acquired impairment of vision and without psychiatric disorders. In spite of the high incidence of visual field defects following antero-mesial temporal lobectomy for refractory temporal lobe epilepsy, reports of CBS in patients who underwent this surgical procedure are surprisingly rare. We describe a patient operated on for drug-resistant epilepsy. As a result of left antero-mesial temporal resection, she presented right homonymous hemianopia. A few days after surgery, she started complaining of visual hallucinations, such as static or moving "Lilliputian" human figures, or countryside scenes, restricted to the hemianopic field. The patient was fully aware of their fictitious nature. These disturbances disappeared progressively over a few weeks. The incidence of CBS associated with visual field defects following epilepsy surgery might be underestimated. Patients with post-surgical CBS should be reassured that it is not an epileptic phenomenon, and that it has a benign, self-limiting, course which does not usually require treatment.

Lesionectomy in epileptogenic gangliogliomas: seizure outcome and surgical results.

We retrospectively analysed seizure outcome and surgical results in a series of 21 patients with ganglioglioma treated with lesionectomy. The 21 patients (13 males, eight females) had a history of epilepsy longer than 1 year and post-operative follow up of at least 1 year. Information on the duration of the seizures, type and frequency was retrieved from medical records. In all patients, surgery was limited to the tumour. The interval between onset of seizures and surgery ranged from 1 to 35 years (mean 11). Patient age ranged from 6 to 61 years (mean 27.5). Fifteen patients (71.4%) had complex partial seizures and six had simple partial seizures. Secondary generalisation was present in 10 patients (47.6%). Seizure frequency varied from several per day to one per month. Sixteen tumours were temporal (76.1%; 11 temporo-mesial, five temporo-lateral), and five were extratemporal (23.8%). The mean follow-up period was 5.4 years (range: 1.25-10 years). No tumour progression was observed. No patient died during surgery or the post-operative course. Fourteen patients (66.6%) were Engel class I (five temporo-mesial, five temporo-lateral, four extratemporal) and seven (33.3%) were Engel class II. Post-operative complications were observed in six patients (28.6%), two of whom had cerebellar haemorrhage, possibly due to increased transmural venous pressure. In our patients with temporal neocortical and extratemporal ganglioglioma, lesionectomy allowed good seizure control. The unsatisfactory outcome for mesiotemporal gangliogliomas might indicate the need for extensive neurophysiological presurgical evaluation in order to perform tailored surgery. To avoid cerebellar haemorrhage, attention should be paid to those factors involved in transmural venous pressure increases.

Transthyretin RNA profiling in livers from transplanted patients affected by familial amyloidotic polyneuropathy, and identification of a dual transcription start point.

Mutations in the transthyretin (TTR) gene cause familial amyloidotic polyneuropathy (FAP), an autosomal dominant peripheral neuropathy, often associated with cardiomyopathy. Liver transplant currently represents a powerful therapeutic approach for FAP patients, although its efficacy is heavily dependent both on the disease severity and on the cardiac functionality. We have investigated the TTR gene expression searching for tissue-specific additional messengers in human adult and foetal tissues as well as in eight livers from FAP transplanted patients carrying different TTR mutations (Met30, Pro36, Ala47, Arg50, and Gln89). We identified a novel transcript, recognising a different transcription start site. The additional 5'-UTR sequence of this novel transcript contains regulatory boxes possibly highlighting an additional transcription start point. RNA analysis revealed that this region is represented in all foetal/adult tissues analysed. We discussed the implications of this finding which might provide perspectives for better understanding the TTR gene expression.

Ictal grasping: prevalence and characteristics in seizures with different semiology.

PURPOSE: The aim of this study was to investigate ictal grasping (IG), defined as the act of gripping something firmly during focal epileptic seizures, and to evaluate whether it characterizes specific seizure types. METHODS: We analyzed the video-recordings of 694 seizures in 109 consecutive candidates to epilepsy surgery. Seizures with motor manifestations (n = 511) were selected and divided into four semiological groups: (a) frontal "hyperkinetic" seizures (FHS): 30 seizures, 12 patients, (b) frontal lobe seizures (FLS) other than FHS: 228 seizures, 26 patients, (c) temporal lobe seizures (TLS): 194 seizures, 55 patients, (d) extra-frontal/extra-temporal seizures (EF/ETS): 59 seizures, 16 patients. We evaluated IG features by means of video-analysis. RESULTS: IG was observed in 96.7% of FHS (100% of patients), with a mean latency of 3 s, and a mean prevalence of 7.9 IG per seizure, directed to a limited number of surrounding objects or body parts. In 22.4% of FLS (11.5% of patients) 1-3 prolonged IGs were present, with a mean latency of 2 s and mainly directed to a fixed external point. IG was occasionally present in TLS (10.3%, in 20% of patients) and EF/ETS (5.1%, in 12.5% of patients), with longer latencies and without any stereotypy. We did not find a reliable lateralizing value of IG. CONCLUSIONS: Prevalence of IG in FHS was significantly higher than in other seizure groups. In FHS and FLS, IG had shorter latency and stereotyped features, characterizing an automatic ("release"?) behavior. In extra-frontal seizures, IG seemed to be an occasional purposeful movement.

Ictal pattern of EEG and muscular activation in symptomatic infantile spasms: a videopolygraphic and computer analysis.

PURPOSE: To investigate ictal muscular phenomena characterizing symptomatic infantile spasms (ISs) and their relation to ictal EEG. METHODS: Four children with severe encephalopathy, neurologic impairment, and refractory ISs related to different dysplastic lesions, underwent videopolygraphic recordings collecting surface electromyogram (EMG) activity from several cranial and limb muscles to evaluate the pattern of muscular recruitment, duration, and side-to-side asymmetry of ISs. Acquired data were stored for off-line analysis by a computerized polygraphic system. RESULTS: Spasms were characterized by a complex pattern of muscular activation. A constant or rostrocaudal propagation pattern was lacking in all patients. Intervals between the onset of EMG activity in different muscles in each spasm were very long:

Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.

Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.