Américo C. Sakamoto

Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy

Objective: Sodium-coupled transporters remove extracellular neurotransmitters and alterations in their function could enhance or suppress synaptic transmission and seizures. This study determined hippocampal gamma-aminobutyric acid (GABA) and glutamate transporter immunoreactivity (IR) in temporal lobe epilepsy (TLE) patients. Methods: Hippocampal sclerosis (HS) patients (n = 25) and non-HS cases (mass lesion and cryptogenic; n = 20) were compared with nonseizure autopsies (n = 8). Hippocampal sections were studied for neuron densities along with IR for glutamate decarboxylase (GAD; presynaptic GABA terminals), GABA transporter-1 (GAT-1; presynaptic GABA transporter), GAT-3 (astrocytic GABA transporter), excitatory amino acid transporter 3 (EAAT3; postsynaptic glutamate transporter), and EAAT2-1 (glial glutamate transporters). Results: Compared with autopsies, non-HS cases with similar neuron counts showed: 1) increased GAD IR gray values (GV) in the fascia dentata outer molecular layer (OML), hilus, and stratum radiatum; 2) increased GAT-1 OML GVs; 3) increased astrocytic GAT-3 GVs in the hilus and Ammon’s horn; and 4) no IR differences for EAAT3-1. HS patients with decreased neuron densities demonstrated: 1) increased OML and inner molecular layer GAD puncta; 2) decreased GAT-1 puncta relative to GAD in the stratum granulosum and pyramidale; 3) increased GAT-1 OML GVs; 4) decreased GAT-3 GVs; 5) increased EAAT3 IR on remaining granule cells and pyramids; 6) decreased glial EAAT2 GVs in the hilus and CA1 stratum radiatum associated with neuron loss; and 7) increased glial EAAT1 GVs in CA2/3 stratum radiatum. Conclusions: Hippocampal GABA and glutamate transporter IR differ in TLE patients compared with autopsies. These data support the hypothesis that excitatory and inhibitory neurotransmission and seizure susceptibility could be altered by neuronal and glial transporters in TLE patients.

Cellular prion protein: on the road for functions

Cellular prion (PrPc) is a plasma membrane glycosyphosphatidylinositol‐anchored protein present in neurons but also in other cell types. Protein conservation among species suggests that PrPc may have important physiological roles. Cellular and molecular approaches have established several novel features of the regulation of PrPc expression, cellular trafficking as well as its participation in copper uptake, protection against oxidative stress, cell adhesion, differentiation, signaling and cell survival. It is therefore likely that PrPc plays pleiotropic roles in neuronal and non‐neuronal cells, and as such the loss of function of PrPc may be an important component of various diseases.

Nasu-Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy—PLOSL): A Dementia Associated with Bone Cystic Lesions. From Clinical to Genetic and Molecular Aspects

The authors review the clinical, radiological, electrophysiological, pathological, and molecular aspects of Nasu–Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy or PLOSL). Nasu-Hakola disease is a unique disease characterized by multiple bone cysts associated with a peculiar form of neurodegeneration that leads to dementia and precocious death usually during the fifth decade of life. The diagnosis can be established on the basis of clinical and radiological findings. Recently, molecular analysis of affected families revealed mutations in the DAP12 (TYROBP) or TREM2 genes, providing an interesting example how mutations in two different subunits of a multi-subunit receptor complex result in an identical human disease phenotype. The association of PLOSL with mutations in the DAP12 or TREM2 genes has led to improved diagnosis of affected individuals. Also, the possible roles of the DAP12/TREM2 signaling pathway in microglia and osteoclasts in humans are just beginning to be elucidated. Some aspects of this peculiar signaling pathway are discussed here.

Serial EEG during human status epilepticus Evidence for PLED as an ictal pattern

Objective: To analyze the relationship between periodic lateralized epileptiform discharges (PLED) and status epilepticus (SE), to evaluate the relationship between mortality and periodic patterns, and to determine whether a stereotypic sequence of EEG patterns exists during human SE. Methods: The authors performed a prospective clinical and electrographic study comprising 62 episodes of SE, 55 patients, and 254 ictal/postictal EEG recordings. Serial daily EEG were obtained in all cases. Results: Partial SE was the predominant clinical type. Four distinct ictal EEG patterns were identified: intermittent EEG seizures (IES), merging EEG seizures (MES), continuous ictal discharges (CID), and periodic epileptiform discharges (PED) which could be lateralized (PLED) or bilateral (PBED). IES was the most common ictal pattern. In the same record, only one combination of ictal patterns was observed corresponding to an association of PLED or PBED and MES pattern. Serial EEG demonstrated that approximately one-third of SE resolved before the second EEG, another one-third persisted and maintained the same ictal pattern throughout the entire evolution, and the final one-third showed variable ictal EEG patterns. PLED were also unequivocally associated with epileptic seizures, and in some patients were the initial ictal pattern. Conclusion: PLED can be an ictal pattern; and, in contrast to previous observations, no stereotyped sequence of ictal EEG patterns was found. PLED/PBED were not a terminal ictal pattern in every case, and outcome was more related to age and etiology than to specific ictal EEG patterns.

Self-perception of factors that precipitate or inhibit seizures in juvenile myoclonic epilepsy

PURPOSE To assess self-perception of factors that precipitate or inhibit seizures in patients with juvenile myoclonic epilepsy (JME). PATIENTS AND METHODS Thirty-six males and 39 females with JME and mean age of 25.8+/-8.7 years were analysed. All patients completed a standardized questionnaire to assess for the presence or absence of precipitant or inhibitory factors for their seizures in a face-to-face interview. These data were statistically analysed through logistic and linear regression models and Phi coefficient. RESULTS Ninety-two percent of the patients identified at least one precipitating factor (PF). In order of frequency the following PFs were recorded: stress (83%), sleep deprivation (77%), specific thoughts/mental concentration (23%), performance of hand activities and complex finger movements (20%), flashing lights and playing games (15%), speaking out in public (11%) and alcohol intake (11%), reading (7%), calculating and writing (5%), playing musical instruments (4%), drawing (3%), and specific types of music (1%). Menstrual cycle was the third most important PF in the women (33%). Although PFs were easily recognized, 77% of the patients stated that they were unable to avoid the occurrence of the seizures. CONCLUSIONS Structured questionnaire is useful in stimulating patients to self-report seizure precipitants. Patients with higher education and uncontrolled seizures identified them more easily. The presence of a significant number of uncommon PFs, such as mental and motor hand tasks, considered uncommon for other epileptic syndromes, suggests that the role of these factors may be under-recognized in JME.

Calcified neurocysticercotic lesions and postsurgery seizure control in temporal lobe epilepsy

Background: Several studies suggest that neurocysticercosis is the main cause of symptomatic epilepsy in developing countries. In such areas, calcified cysticercotic lesions (CCL) are frequently found in patients with complex partial seizures associated with hippocampal sclerosis (HS). The authors studied whether there are clinical and pathologic differences between HS patients with and without CCL. Methods: The authors determined the clinical and pathologic findings of 30 patients with HS and compared them with 32 patients with HS + CCL. Hippocampi from both groups were measured for fascia dentata Timm staining and cell density in hippocampal subfields. Results: In the HS + CCL group, single or multiple CCL were found in all lobes with no lobar predominance. An initial precipitating event occurred in 83.3% of HS and in 62.5% of HS + CCL. First complex partial seizure occurred at 10.1 years in HS and at 11.9 years in HS + CCL. No significant differences were found for fascia dentata Timm staining and hippocampal cell densities. Good postsurgery outcome (Engel I classification) did not differ between groups, with this result occurring in 76.6% of patients with HS and 81.2% of patients with HS + CCL. Conclusions: The presence of CCL does not influence the clinical and pathologic profile of patients with hippocampal atrophy. Clinical histories and postsurgical outcomes were similar to those of patients with classic HS, suggesting that the CCL is probably, in this set of patients, a coincidental pathology and does not have a role in epileptogenesis.–1491

Hyperventilation Revisited: Physiological Effects and Efficacy on Focal Seizure Activation in the Era of Video‐EEG Monitoring

Summary:  Purpose: Hyperventilation is an activation method that provokes physiological slowing of brain rhythms, interictal discharges, and seizures, especially in generalized idiopathic epilepsies. In this study we assessed its effectiveness in inducing focal seizures during video‐EEG monitoring.

Increased hippocampal AMPA and NMDA receptor subunit immunoreactivity in temporal lobe epilepsy patients

This study determined if hippocampal AMPA and NMDA subunit immunoreactivity (IR) in temporal lobe epilepsy patients was increased compared with nonseizure autopsies. Hippocampi from hippocampal sclerosis patients (HS; n=26) and nonsclerosis cases (non-HS; n=12) were compared with autopsies (n=6) and studied for GluRl, GluR2/3, NMDAR1, and NMDAR2 IR gray values (GV) along with fascia dentata and Ammons horn neuron densities. Compared with autopsies, non-HS cases with similar neuron densities and HS patients with decreased neuron densities showed: (a) Increased GluRl GVs in the fascia dentata molecular layer; (b) increased NMDAR1 GVs in the CA3-1 stratum radiatum and greater IR within pyramids; and (c) increased GluR2/3 and NMDAR2 GVs throughout all hippocampal subfields. Furthermore, HS patients showed that relative to the outer molecular layer; (a) GluRl GV differences were decreased in the CA4/hiIar region and CA1 stratum radiatum compared with autopsies; and (b) NMDAR2 GV differences were increased in the inner molecular layer compared with non-HS cases. In temporal lobe seizure patients, these results indicate that AMPA and NMDA receptor subunit IR was increased in HS and non-HS hippocampi compared with nonseizure autopsies. In humans, these findings support the hypothesis that glutamate receptor subunits are increased in association with chronic temporal lobe seizures, which may enhance excitatory neurotransmission and seizure susceptibility.

Seizure outcome after surgery for epilepsy due to focal cortical dysplastic lesions

Neocortical development is a highly complex process encompassing cellular proliferation, neuronal migration and cortical organization. At any time this process can be interrupted or modified by genetic or acquired factors causing malformations of cortical development (MCD). Epileptic seizures are the most common type of clinical manifestation, besides developmental delay and focal neurological deficits. Seizures due to MCD are frequently pharmacoresistant, especially those associated to focal cortical dysplasia (FCD). Surgical therapy results have been reported since 1971, however, currently available data from surgical series are still limited, mainly due to small number of patients, distinct selection of candidates and surgical strategies, variable pathological diagnosis and inadequate follow-up. This study addresses the possibilities of seizure relief following resection of focal cortical dysplasia, and the impact of presurgical evaluation, extent of resection and pathological findings on surgical outcome. We included 41 patients, 22 adults and 19 children and adolescents, with medically intractable seizures operated on from 1996 to 2002. All were submitted to standardized presurgical evaluation including high-resolution MRI, Video-EEG monitoring and ictal SPECT. Post-surgical seizure outcome was classified according to Engels schema. Univariate and multivariate analysis were performed. Fifteen patients had temporal and 26 extratemporal epilepsies. Of the total 26 patients (63.4%) reached seizure-free status post-operatively. There was no correlation between outcome and age at surgery, duration of epilepsy, frequency of seizures, and pathological findings. There was, however, a clear correlation with topography of FCD (temporal versus extratemporal) and regional ictal EEG onset, on univariate as well as multivariate analysis.

Epilepsies associated with hippocampal sclerosis.

Hippocampal sclerosis (HS) is considered the most frequent neuropathological finding in patients with mesial temporal lobe epilepsy (MTLE). Hippocampal specimens of pharmacoresistant MTLE patients that underwent epilepsy surgery for seizure control reveal the characteristic pattern of segmental neuronal cell loss and concomitant astrogliosis. However, classification issues of hippocampal lesion patterns have been a matter of intense debate. International consensus classification has only recently provided significant progress for comparisons of neurosurgical and clinic-pathological series between different centers. The respective four-tiered classification system of the International League Against Epilepsy subdivides HS into three types and includes a term of “gliosis only, no-HS”. Future studies will be necessary to investigate whether each of these subtypes of HS may be related to different etiological factors or with postoperative memory and seizure outcome. Molecular studies have provided potential deeper insights into the pathogenesis of HS and MTLE on the basis of epilepsy-surgical hippocampal specimens and corresponding animal models. These include channelopathies, activation of NMDA receptors, and other conditions related to Ca2+ influx into neurons, the imbalance of Ca2+—binding proteins, acquired channelopathies that increase neuronal excitability, paraneoplastic and non-paraneoplastic inflammatory events, and epigenetic regulation promoting or facilitating hippocampal epileptogenesis. Genetic predisposition for HS is clearly suggested by the high incidence of family history in patients with HS, and by familial MTLE with HS. So far, it is clear that HS is multifactorial and there is no individual pathogenic factor either necessary or sufficient to generate this intriguing histopathological condition. The obvious variety of pathogenetic combinations underlying HS may explain the multitude of clinical presentations, different responses to clinical and surgical treatment. We believe that the stratification of neuropathological patterns can help to characterize specific clinic-pathological entities and predict the postsurgical seizure control in an improved fashion.