Hippocampal expression of heat shock proteins in mesial temporal lobe epilepsy with psychiatric comorbidities and their relation to seizure outcome.

OBJECTIVE: Biologic substrates behind the close association between mesial temporal lobe epilepsy (MTLE) and psychiatric comorbidities are largely unknown. Heat shock protein 70 (HSP70) and HSP90 are ubiquitous molecular chaperones that play important roles in functions from cellular stress response to receptor trafficking control. There are controversial findings regarding HSP expression in epilepsy. Our goal was to examine HSP70 and HSP90 expression within the human hippocampal formation of MTLE patients with and without comorbid major depression and psychosis. In addition, we investigated the possible correlation between HSP expression and seizure outcome. METHODS: MTLE hippocampi of subjects without psychiatric history, MTLE and major depression, and MTLE and interictal psychosis derived from epilepsy surgery and control necropsies were investigated for neuronal densities, HSP70 and HSP90 immunoreactive area. RESULTS: Increased HSP expression in MTLE and decreased HSP expression in MTLE with psychosis cases were detailed. Patients taking fluoxetine showed increased HSP90 expression in CA1, and those taking haloperidol decreased HSP90 in the granular layer and subiculum. MTLE patients with complete seizure remission presented with decreased HSP70 expression in CA4 and subiculum and decreased HSP90 expression in the granular layer. SIGNIFICANCE: The present results provide the first demonstration of HSP expression in human MTLE hippocampal formation with and without psychiatric comorbidities. Distinct HSP70 and HSP90 expression might explain some of the structural and synaptic alterations differentially regulated in MTLE with and without psychiatric comorbidities. Increased HSPs expression in key hippocampal subfields would reflect increased epileptogenicity and poorer outcome of epilepsy surgery.

Psychiatric comorbidity in refractory focal epilepsy: a study of 490 patients.

We studied the prevalence and associated factors of psychiatric comorbidities in 490 patients with refractory focal epilepsy. Of these, 198 (40.4%) patients had psychiatric comorbidity. An Axis I diagnosis was made in 154 patients (31.4%) and an Axis II diagnosis (personality disorder) in another 44 (8.97%) patients. After logistic regression, positive family history of psychiatric comorbidities (O.R.=1.98; 95% CI=1.10-3.58; p=0.023), the presence of Axis II psychiatric comorbidities (O.R.=3.25; 95% CI=1.70-6.22; p<0.0001), and the epileptogenic zone located in mesial temporal lobe structures (O.R.=1.94; 95% CI=1.25-3.03; p=0.003) remained associated with Axis I psychiatric comorbidities. We concluded that a combination of clinical variables and selected structural abnormalities of the central nervous system contributes to the development of psychiatric comorbidities in patients with focal epilepsy.

Do psychiatric comorbidities predict postoperative seizure outcome in temporal lobe epilepsy surgery?

Clinical and demographic presurgical variables may be associated with unfavorable postsurgical neurological outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). However, few reports include preoperative psychiatric disorders as a factor predictive of long-term postsurgical MTLE-HS neurological outcome. We used Engel's criteria to follow 186 postsurgical patients with MTLE-HS for an average of 6 years. DSM-IV criteria and psychiatric comorbidity criteria specific to epilepsy (interictal dysphoric disorder, postictal and interictal psychosis) were used to assess presurgical psychiatric disorders. Kaplan-Meier event-free survival and adjusted hazard ratios were estimated with unconditional logistic regression. Seventy-seven (41.4%) patients had a preoperative Axis I psychiatric diagnosis. Thirty-six patients had depression, 11 interictal dysphoric disorder, 14 interictal psychosis, 6 postictal psychosis, and 10 anxiety disorders. Twenty-three (12.4%) patients had Axis II personality disorders. Regarding seizure outcome, preoperative anxiety disorders (P=0.009) and personality disorders (P=0.003) were positively correlated with Engel class 1B (remaining auras) or higher. These findings emphasize the importance of presurgical psychiatric evaluation, counseling, and postsurgical follow-up of patients with epilepsy and psychiatric disorders.

Occurrence of neoplasms in individuals with congenital, severe GH deficiency from the Itabaianinha kindred.

Growth hormone (GH) and the insulin-like growth factor I (IGF-I) have cell proliferative and differentiation properties. Whether these hormones have a role in mutagenesis is unknown. Nevertheless, severe IGF-I deficiency seems to confer protection against the development of neoplasms. Here, we report five cases of adult patients with severe and congenital isolated GH deficiency (IGHD) due to the c.57+1G>A mutation in the GHRH receptor gene, who developed tumors. Four GH-naïve subjects presented skin tumors: a 42-year-old man with a fibroepithelial polyp, a 53-year-old woman and two men (59 and 56 years old) with epidermoid skin cancers. One of these died from it after three surgeries and radiotherapy. The fifth patient was a 25-year-old woman, who had intermittently received GH replacement therapy (GHRT) from age 11 to 18, who developed an ependymoma extending from the fourth ventricle to the end of the thoracic spine. She underwent three surgical procedures, without obvious evidence of tumor recurrence during the six years follow up. These observations suggest that severe IGHD does not protect completely from development of tumors.

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 Engel's 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.

Surgical treatment of cerebral cysticercosis: long-term results and prognostic factors.

OBJECT: Cysticercosis is the most frequent parasitosis of the central nervous system. Although anticysticercal drugs have proven efficient in some cases, many patients with NCC require palliative, occasionally curative, surgical procedures. The authors analyzed the data and prognostic factors obtained during the follow-up period (range 1-255 months, median 38 months) in 160 patients with cerebral cysticercosis who underwent surgical treatment. METHODS: Different surgical approaches were indicated to control increased intracranial pressure (ICP) in most patients, and some patients had undergone decompressive surgery for local brain lesions. Most patients required more than one surgical procedure. Statistical analysis was performed using the Fisher exact, the log-rank, and the Kruskall-Wallis tests. Survival curves were calculated according the Kaplan-Meier method. The removal of a giant cyst from the parenchyma or cisterns for relief of increased ICP and for chiasm/optic nerve decompression improved most symptoms in patients. The removal of ventricular cysts was effective in the control of increased ICP in most patients. Patients with a ventricular cyst and ependymitis/arachnoiditis required placement of a ventriculoperitoneal (VP) shunt after the cyst was removed. This therapy effectively controlled increased ICP. Patients younger than 40 years of age at the time of treatment and male patients had worse outcomes. The outcome in patients who underwent VP shunt surgery or shunt surgery combined with reservoir implantation was worse than that in those who underwent cyst removal alone. Shunt-related infection was the most frequent complication, and the global mortality rate during the follow-up period was 21.2%. Although both complications were more frequent in the first 2 postoperative years, they occurred at any time. CONCLUSIONS: Long-term prognosis in patients with cerebral cysticercosis who required surgery was not good. Cysts located in the basal cisterns and patient age younger than 40 years were poor prognostic factors.

On the prognostic value of ictal EEG patterns in temporal lobe epilepsy surgery: a cohort study.

PURPOSE: To investigate the prognostic value of ictal scalp EEG patterns in drug-resistant temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) prior to undergoing temporal lobectomy. METHODS: Scalp EEGs of the first seizure recorded during presurgical long-term video-EEG monitoring of 284 patients were reviewed. Patients were divided according to seizure laterality as either unilateral, when the EEG was restricted to one cerebral hemisphere for the entire seizure, or bilateral, when there was involvement of both hemispheres during the seizure. In patients with unilateral hippocampal sclerosis (HS), seizures were subdivided according to the side of initial ictal activity in relation to the side of the HS, as concordant, non-lateralising or contralateral. Postsurgical seizure outcome, according to Engel's classification, was verified at 1, 2, and 5 years after surgery. RESULTS: There was no significant association between ictal EEG characteristics and postsurgical seizure outcome. An Engel I seizure outcome was observed in 87.1% of the patients with unilateral ictal EEGs and in 79.6% of those with bilateral ictal EEGs (p=0.092). CONCLUSION: Analysis of the localisation, morphology, and lateralisation of ictal EEG patterns did not provide prognostic information regarding seizure-free status in patients with MTLE-HS undergoing temporal lobectomy.

Cognitive and surgical outcome in mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis: a cohort study.

BACKGROUND: Where neurocysticercosis (NCC) is endemic, chronic calcified neurocysticercosis (cNCC) can be observed in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS). Considering that both disorders cause recurrent seizures or cognitive impairment, we evaluated if temporal lobectomy is cognitively safe and effective for seizure control in MTLE-HS plus cNCC. METHODS: Retrospective cohort study of neuropsychological profile and surgical outcome of 324 MTLE-HS patients submitted to temporal lobectomy, comparing the results according to the presence or absence of cNCC. FINDINGS: cNCC occurred in 126 (38.9%) of our MTLE-HS patients, a frequency higher than expected, more frequently in women than in men (O.R. = 1.66; 95% C.I. = 1.05-2.61; p = 0.03). Left-side (but not right side) surgery caused impairment in selected neuropsychological tests, but this impairment was not accentuated by the presence of cNCC. Ninety-four (74.6%) patients with MTLE-HS plus cNCC and 153 patients (77.3%) with MTLE-HS alone were Engel class I after surgery (O.R. = 1.16; 95% C.I. = 0.69-1.95; p = 0.58). However, the chances of Engel class IA were significantly lower in MTLE-HS plus cNCC than in patients with MTLE-HS alone (31.7% versus 48.5%; O.R. = 2.02; 95% C.I. = 1.27-3.23; p = 0.003). Patients with MTLE-HS plus cNCC showed higher rates of Engel class ID (15.1% versus 6.6%; O.R. = 2.50; 95% C.I. = 1.20-5.32; p = 0.012). INTERPRETATION: cNCC can be highly prevalent among MTLE-HS patients living in areas where neurocysticercosis is endemic, suggesting a cause-effect relationship between the two diseases. cNCC does not add further risk for cognitive decline after surgery in MTLE-HS patients. The rates of Engel class I outcome were very similar for the two groups; however, MTLE-HS plus cNCC patients achieved Engel IA status less frequently, and Engel ID status more frequently. Temporal lobectomy can be safely performed in most patients with MTLE-HS plus cNCC without affecting cognitive outcome. Long-term surgical seizure control in MTLE-HS plus cNCC is still satisfactory, as long as selected patients remain under medication.

Independent predictors and a prognostic model for surgical outcome in refractory frontal lobe epilepsy.

PURPOSE: Refractory frontal lobe epilepsy (FLE) remains one of the most challenging surgically remediable epilepsy syndromes. Nevertheless, definition of independent predictors and predictive models of postsurgical seizure outcome remains poorly explored in FLE. METHODS: We retrospectively analyzed data from 70 consecutive patients with refractory FLE submitted to surgical treatment at our center from July 1994 to December 2006. Univariate results were submitted to logistic regression models and Cox proportional hazards regression to identify isolated risk factors for poor surgical results and to construct predictive models for surgical outcome in FLE. RESULTS: From 70 patients submitted to surgery, 45 patients (64%) had favorable outcome and 37 (47%) became seizure free. Isolated risk factors for poor surgical outcome are expressed in hazard ratio (H.R.) and were time of epilepsy (H.R.=4.2; 95% C.I.=1.5-11.7; p=0.006), ictal EEG recruiting rhythm (H.R.=2.9; 95% C.I.=1.1-7.7; p=0.033); normal MRI (H.R.=4.8; 95% C.I.=1.4-16.6; p=0.012), and MRI with lesion involving eloquent cortex (H.R.=3.8; 95% C.I.=1.2-12.0; p=0.021). Based on these variables and using a logistic regression model we constructed a model that correctly predicted long-term surgical outcome in up to 80% of patients. CONCLUSION: Among independent risk factors for postsurgical seizure outcome, epilepsy duration is a potentially modifiable factor that could impact surgical outcome in FLE. Early diagnosis, presence of an MRI lesion not involving eloquent cortex, and ictal EEG without recruited rhythm independently predicted favorable outcome in this series.

Utility of ictal single photon emission computed tomography in mesial temporal lobe epilepsy with hippocampal atrophy: a randomized trial.

BACKGROUND: The development of newer diagnostic technologies has reduced the need for invasive electroencephalographic (EEG) studies in identifying the epileptogenic zone, especially in adult patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS). OBJECTIVE: To evaluate ictal single photon emission computed tomography (SPECT) in the evaluation and treatment of patients with MTLE-HS. METHODS: MTLE patients were randomly assigned to those with (SPECT, n = 124) and without ictal SPECT (non-SPECT, n = 116) in an intent-to-treat protocol. Primary end points were the proportion of patients with invasive EEG studies, and those offered surgery. Secondary end points were the length of hospital stay and the proportion of patients with secondarily generalized seizures (SGS) during video-EEG, postsurgical seizure outcome, and hospital cost. RESULTS: The proportion of patients offered surgery was similar in the SPECT (85%) and non-SPECT groups (81%), as well as the proportion that had invasive EEG studies (27% vs 23%). The mean duration of hospital stay was 1 day longer for the SPECT group (P < 0.001). SGS occurred in 51% of the SPECT and 26% of the non-SPECT group (P < 0.001). The cost of the presurgical evaluation was 35% higher for the SPECT compared with the non-SPECT group (P < 0.001). The proportion of patients seizure-free after surgery was similar in the SPECT (59%) compared with non-SPECT group (54%). CONCLUSION: Ictal-SPECT did not add localizing value beyond what was provided by EEG-video telemetry and structural MRI that altered the surgical decision and outcome for MTLE-HS patients. Ictal-SPECT increased hospital stay was associated with increased costs and a higher chance of SGS during video-EEG monitoring. These findings support the notion that a protocol including ictal SPECT is equivalent to one without SPECT in the presurgical evaluation of adult patients with MTLE-HS.

Foramen ovale electrodes can identify a focal seizure onset when surface EEG fails in mesial temporal lobe epilepsy.

PURPOSE: We analyze a series of patients with mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) submitted to presurgical investigation with scalp sphenoidal, followed by foramen ovale electrodes (FO), and, when necessary, with depth temporal electrodes. We sought to evaluate the clinical utility of FO in patients with MTLE-HS. METHODS: We included patients who had phase I investigation with bitemporal independent seizures, nonlateralized ictal onsets, or ictal onset initiating in the side contralateral to the side of hippocampal sclerosis. Patients whose implanted FO failed to demonstrate an unambiguous unilateral ictal onset were later evaluated with depth hippocampal electrodes. RESULTS: Between May 1994 and December 2004, 64 patients met our inclusion criteria: 33 female (51.5%) and 31 male subjects (48.5%). The mean age at enrollment was 37.66+/-10.6 years (range, 12-56 years). The groups with nonlateralized surface ictal EEG onsets and contralateral EEG onsets had a greater chance of lateralization with FO when compared with the group with bilateral independent seizures on surface EEG (p<0.01). Foramen ovale electrodes lateralized the seizures in 60% of patients. Seventy percent of patients became seizure free after temporal lobectomy. Five patients were implanted with depth temporal electrodes after FO video-EEG monitoring. The depth-electrode EEG onsets confirmed the results of FO video-EEG monitoring in all patients, and the surgery was refused. CONCLUSIONS: In MTLE-HS, FO is a reliable method for lateralization of seizures that are not clearly recorded by surface EEGs.

Volumetric evidence of bilateral damage in unilateral mesial temporal lobe epilepsy.

PURPOSE: We sought to analyze the contralateral volumes of the temporal pole, posterior segment of the temporal lobe, amygdala, hippocampus, and parahippocampal gyrus in patients with temporal lobe epilepsy (TLE) due to histologically proven mesial temporal lobe sclerosis (MTLS), seizure free for >or=4 years of postsurgical follow-up. METHODS: Forty-six (23 male) TLE patients, operated on between 1996 and 2001, with histopathologic diagnosis of MTLS, and a postsurgical follow-up of >or=4 years, had their temporal lobe structures manually segmented, measured, and compared with those of 23 normal volunteers, paired as groups for sex, age, and handedness. RESULTS: The mean volumes of the contralateral temporal pole, hippocampus, and parahippocampal gyrus in TLE patients were significantly lower than those in controls. CONCLUSIONS: MRI volumetric data show that the damage in TLE due to MTS may be more widespread and bilateral, even in patients with unilateral TLE by clinical and neurophysiological criteria. Our results are relevant to the discussion of epileptogenic mechanisms in TLE.

Surgically amenable epilepsies in children and adolescents: clinical, imaging, electrophysiological, and post-surgical outcome data.

BACKGROUND AND PURPOSE: A large number of patients with epilepsy in the pediatric population have medically intractable epilepsy. In this age group seizures are usually daily or weekly, and response to antiepileptic therapy is poor, especially for those with neurological abnormalities and symptomatic epilepsies. However, several authors have already demonstrated similarly favorable long-term post-surgical seizure control when comparing pediatric and adult populations. In this article we aim to report the experience of the Ribeirão Preto Epilepsy Surgery Program in pediatric epilepsy surgery. PATIENTS AND METHODS: We analyzed 107 patients with medically intractable epilepsy operated on between July 1994 and December 2002, considering age at surgery, seizure type, pathological findings, and seizure outcome. All data were prospectively collected according to protocols previously approved by the institution ethics committee. RESULTS: We analyzed a total of 115 operations performed in 107 patients. There was no difference in sex distribution. Complex partial seizures occurred in 31.4% of the patients, followed by tonic seizures (25.9%), focal motor seizures (15.4%), and infantile spasms (13.3%). The most common etiologies were cortical developmental abnormalities (25.2%), tumors (16.8%), mesial temporal sclerosis (15.9%), Rasmussen syndrome (6.5%), and tuberous sclerosis (6.5%). Overall post-surgical seizure outcome showed 67.2% of the patients within Engel classes I and II, reaching 75.0% when patients with callosotomies were excluded. CONCLUSIONS: Post-surgical seizure control in the pediatric population is similar to that in adult patients, despite the fact that epilepsies in this age group are more frequently of extratemporal origin, suggesting that surgery should be considered in children as soon as intractability is determined.

Clinical features of patients with posterior cortex epilepsies and predictors of surgical outcome.

PURPOSE: Posterior cortex epilepsies (PCEs) encompass a group of epilepsies originating from the occipital, parietal, or occipital border of the temporal lobe, or from any combination of these regions. When their seizures are refractory to pharmacologic treatment, these patients are usually referred for surgery. The aim of our study was to analyze clinical characteristics of all PCE patients referred for surgery from 1994 to 2003, and to search for predictors of surgical outcome. METHODS: We performed a retrospective analysis of clinical and laboratory data from 81 consecutive refractory PCE patients referred for surgery. Surgical and nonsurgical groups of patients were compared, and detailed analyses of all variables of the surgical cases were performed in the search for predictors of seizure outcome. RESULTS: Risk factors for PCEs included gliosis (34.56%), malformations of cortical development (33.33%), tumors (8.64%), brain trauma (3.70%), Sturge-Weber disease (4.93%), vascular malformations (3.70%), family history of epilepsy (3.70%), history of CNS infections (2.46%), and low IQ (2.46%). Of the 81 patients, 44 were submitted to surgery at the time of the completion of this study. Surgical treatment was highly effective in improving seizures (p<0.001) when compared with previous pharmacologic treatment alone. Twenty-eight (65.11%) patients became seizure free after surgery versus none in the nonsurgical group. Regarding outcome predictors, patients with shorter duration of epilepsy and those without neurologic abnormalities on clinical examination had higher chances of favorable evolution. CONCLUSIONS: Surgical treatment is effective for the treatment of PCEs and superior to pharmacologic therapy alone. In our series, shorter duration of epilepsy and normal neurologic examination were the only independent variables that predicted better surgical outcome.

Glutamate NMDA receptor subunit R1 and GAD mRNA expression in human temporal lobe epilepsy.

1. Molecular mechanisms underlying increased hippocampal excitability in human temporal lobe epilepsy (TLE) are largely unknown. A disturbance of the imbalance between excitatory and inhibitory neurotransmission pathways in the epileptic hippocampus may contribute substantially to a decreased seizure threshold. 2. We have extended the investigation whether TLE is associated with changes in the expression of GAD67 and NMDAR1 by assessing the relative amounts of the mRNAs in human hippocampal samples by means of semiquantitative RT-PCR. The samples included 16 hippocampal slices obtained at surgery from intractable TLE (HS, n = 14; non-HS, n = 2) and 3 postmortem control hippocampi. 3. The ratio for the GAD/NMDAR1 transcripts was significantly higher in TLE cases when compared to the nonepileptic samples. Such findings are mainly a consequence of the increased amounts of GAD mRNA detected in the epileptic hippocampus. Compared with nonepileptic samples, and without correction for neuron losses, the amounts of NMDAR1 mRNA in HS are slightly reduced, and in the non-HS samples they are significantly increased, which is consistent with an increase of NMDAR1 in the hippocampal remaining neurons, as previously reported. 4. Our results also contribute to the indication of GAD67 mRNA upregulation in human TLE. A possible functional implication for the increased GAD mRNA levels could be a mechanism to reduce neuronal hyperexcitability, synchronization, and/or the spread of seizure.