The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature.

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.

Clusters of cortical spreading depolarizations in a patient with intracerebral hemorrhage: a multimodal neuromonitoring study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Cortical spreading depolarizations (CSDs) increase brain matrix metalloproteinase (MMP)-9 activity leading to perihematomal edema expansion in experimental ICH. METHODS: The purpose of this report is to describe cerebral metabolic changes and brain extracellular MMP-9 levels in a patient with CSDs and perihematomal edema expansion after ICH. RESULTS: We present a 66-year-old male patient with ICH who underwent craniotomy for hematoma evacuation. Multimodal neuromonitoring data of the perihematomal region revealed metabolic distress and increased MMP-9 levels in the brain extracellular fluid during perihematomal edema progression. At the same time, subdural electrocorticography showed clusters of CSDs, which disappeared after ketamine anesthesia on day six. Perihematomal edema regression was associated with decreasing cerebral MMP-9 levels. CONCLUSIONS: This novel association between clusters of CSDs, brain metabolic distress, and increased MMP-9 levels expands our knowledge about secondary brain injury after ICH. The role of ketamine after this devastating disorder needs further studies.

Treatment of epileptic seizures in brain tumors: a critical review.

Epileptic seizures represent a common signal of intracranial tumors, frequently the presenting symptom and the main factor influencing quality of life. Treatment of tumors concentrates on survival; antiepileptic drug (AED) treatment frequently is prescribed in a stereotyped way. A differentiated approach according to epileptic syndromes can improve seizure control and minimize unwarranted AED effects. Prophylactic use of AEDs is to be discouraged in patients without seizures. Acutely provoked seizures do not need long-term medication except for patients with high recurrence risk indicated by distinct EEG patterns, auras, and several other parameters. With chronically repeated seizures (epilepsies), long-term AED treatment is indicated. Non-enzyme-inducing AEDs might be preferred. Valproic acid exerts effects against progression of gliomatous tumors. In low-grade astrocytomas with epilepsy, a comprehensive presurgical epilepsy work-up including EEG-video monitoring is advisable; in static non-progressive tumors, it is mandatory. In these cases, the neurosurgical approach has to include the removal of the seizure-onset zone frequently located outside the lesion.

Idiopathic generalised epilepsy of late onset: a separate nosological entity?

AIM: Seizure onset in idiopathic generalised epilepsies (IGE) is considered to be rare after the second decade of life. The authors aimed to explore age of seizure onset in patients with IGE and compare 'classical' onset to late onset cases. METHODS: Patients with IGE, treated at the outpatient epilepsy clinic (Medical University of Innsbruck, Austria, 1985-2006, n=798) were retrospectively screened. The inclusion criteria were: diagnosis of IGE, more than two follow-up (FU) visits, duration of FU more than 1 year and normal brain imaging. The authors analysed demographic data, age of seizure onset, seizure types, syndromes, neuroimaging and EEG findings, seizure triggers and seizure freedom for 1 and 5 years at last FU. RESULTS: A total of 492 patients (mean age at seizure onset 14.6 years, range 0.1-55, SD 7.9) with IGE were identified: childhood absence epilepsy (n=113, range 1-55, SD 6.5), juvenile absence epilepsy (n=75, range 4-39, SD 5.1), juvenile myoclonic epilepsy (n=112, range 2-39, SD 5.7), and epilepsy with grand mal seizures on awakening (n=192 range 1-52, SD 17.3). Population was stratified into three groups: 28 patients with seizure onset at >30 years, 180 patients between 15 and 30 years and 284 patients <15 years. The distribution of seizure types and epilepsy syndromes differed significantly in a group comparison (p<0.001); seizure outcome and other clinical variables did not differ throughout the groups. CONCLUSION: Apart from age-related onset of seizure types and syndromes with a loose upper limit of onset age, patients with a late onset did not differ from their younger counterparts. These data do not support the view of IGE of late onset as a separate syndrome.

Integration of multimodality imaging and surgical navigation in the management of patients with refractory epilepsy. A pilot study using a new minimally invasive reference and head-fixation system.

OBJECTIVE: To review the experience with a new system (VBH system) for minimally invasive frameless stereotactic guidance, acting as a common platform to provide multimodal image integration and surgical navigation in a consecutive series of 25 patients who underwent surgery for drug-resistant seizures. METHODS: The usefulness of the VBH system for integrating all images to produce one dataset and for intraoperative instrument guidance and navigation was judged semiquantitatively in a three-tiered scale (+, ++, +++). Seizure outcome was classified according to Engel. RESULTS: The presurgical evaluation extended over 21.2 months (mean). A total of 141 registrations of images were performed (mean 5.6 per patient, range: 2 to 16). In 19 (76%) of 25 patients structural data fused with functional data were used for the presurgical workup. Six patients proceeded directly to navigated resection. Nineteen patients (76%) underwent invasive recording, of whom 13 underwent resective surgery. In seven patients (28%) the combination of multimodal image fusion and intra-operative stereotactic guidance was judged "essential" (+++) to remove the epileptogenic zone. Integration of all images to form one dataset was "essential" (+++) for decision making in 15 and "helpful" (++) in 4 patients (overall 76% of patients). Intraoperative use of frameless neuronavigation was "essential" (+++) in ten and "helpful" (++) in all remaining patients. Eighty percent of the patients achieved satisfactory seizure outcome after 1 year. CONCLUSION: The VBH system is a safe and effective non-invasive tool for repetitive imaging, multimodal image fusion and frameless stereotactic surgical navigation in candidates for epilepsy surgery.

Tuberous sclerosis complex with unilateral perisylvian polymicrogyria and contralateral hippocampal sclerosis - a case report.

Malformations of cortical development (MCD) encompass a wide spectrum of brain disorders. Although rare, the combination of certain MCD may occur. We report a rare case of combination of three distinct cerebral pathologies: tuberous sclerosis, polymicrogyria and hippocampal sclerosis in a patient with intractable epilepsy. Ictal EEG and ictal SPECT suggested right perisylvian area as a seizure onset zone. However, on MRI multiple potentially epileptogenic lesions were identified. The neurobiological background of the coexistence of different types of malformations of cortical development remains enigmatic.

Electroclinical and imaging findings in ulegyria and epilepsy: a study on 25 patients.

PURPOSE: Ulegyria refers to cerebral cortex scarring, which results from a perinatal ischaemic brain injury. It presents with a characteristic gyral pattern: small circumvolutions with atrophy at sulci bottom and spared apex. Ulegyria is frequently associated with epilepsy, cerebral palsy and mental disability. We analysed electroclinical and MRI features in patients with ulegyria and epilepsy. PATIENTS AND METHODS: We reviewed 25 patients (14 males/11 females) with ulegyria and epilepsy from the database (about 5000 patients with epilepsy) of our unit. Patients were examined clinically, underwent high resolution MRI, EEG recordings, positron emission tomography, single photon emission computed tomography and neuropsychological testing. Two patients with refractory seizures underwent epilepsy surgery. RESULTS: Mean age of patients was 34 years (5-66) at the reassessment time. The majority (16/25, 64%) had a history of perinatal asphyxia. 15 patients had delayed developmental milestones; 20 had learning disabilities and five patients were severely disabled. Mean age at seizure onset was 4.2 years (1-18). 17 patients (68%) had medically intractable epilepsy. 11 patients (44%) had occipital lobe seizures. The majority (n = 24, 96%) had parieto-occipital lesions on MRI. In 13 patients (52%), ulegyria was bilateral. 12 patients (48%) had hippocampal sclerosis. Two patients underwent epilepsy surgery with an excellent postoperative outcome (Engel class IA and IC). CONCLUSION: Patients with ulegyria often have a history of perinatal asphyxia and present with pharmacoresistant seizures. Their presurgical assessment is complicated because of frequent dual pathology (hippocampal sclerosis) and bilateral lesions.

Unilateral polymicrogyria with ipsilateral cerebral hemiatrophy: a distinct syndrome?

INTRODUCTION: There are sporadic reports of unilateral polymicrogyria with ipsilateral hemiatrophic cerebri associated with epilepsy, focal neurological deficit and mental retardation. The mechanisms which cause this condition are not well understood. The aim of our study was to delineate further, clinical and neuroimaging features of this malformation of cortical development and to explore its possible etiological background. PATIENTS AND METHODS: Four patients (two males and two females), aged from 23 to 31 years (mean age range 27.5 years) were evaluated. Subjects underwent clinical, electrophysiological, neuropsychological and high resolution magnetic resonance imaging assessment. RESULTS: No significant perinatal event or exposure to intrauterine infection was noted. None suffered from birth asphyxia or ischemic injury. The parents of two patients were first cousins. Every subject had delayed developmental milestones, mental disability and congenital, non-progressive, spastic hemiparesis. They had epilepsy with seizure-onset ranging from three months to 17 years (mean 6.8 years); two had intractable seizures. In all patients, unilateral, right-sided polymicrogyria was associated with ipsilateral cerebral hemiatrophy. Polymicrogyria involved mainly anterior perisylvian areas; occipital regions were relatively spared. CONCLUSION: The evaluated patients showed homogenous clinical and neuroimaging characteristics. We support the idea that the disorder could constitute a clinical entity with an underlying genetic cause.

Outcome of adult patients with temporal lobe tumours and medically refractory focal epilepsy.

BACKGROUND: Tumours are a well-recognized cause of medically intractable epilepsies. Tumours represent the primary pathology in 10%-30% of patients undergoing surgical treatment for chronic epilepsy. This study examines the surgical and epileptological outcome of adults with temporal lobe tumoural epilepsy treated within a comprehensive epilepsy surgery programme. METHODS: Between 1999 and 2004, 99 consecutive patients have been operated for intractable temporal lobe epilepsy (TLE). Among these, 14 adult patients exhibited temporal lobe neoplasms associated with TLE. Every patient underwent a comprehensive presurgical evaluation including video-EEG monitoring, MRI, interictal PET scan, ictal SPECT and neuropsychological testing. Surgical strategies were determined in an interdisciplinary seizure conference and tailored to the findings of the presurgical evaluation. All patients were available for follow up at regular intervals after 3, 6, 12 months and yearly thereafter. Epileptological outcome was classified according to Engel [10] and the ILAE (International League Against Epilepsy)/systems [33]. FINDINGS: The surgical procedures performed were temporal lobe resection in 3 patients, extended lesionectomy in 4 and extended lesionectomy with resection of the temporomesial structures in 7. One patient with an astrocytoma grade III underwent a second and third operation for recurrent disease. Histological results: Astrocytoma 5 patients, ganglioglioma/gangliocytoma 5, oligodendroglioma 2, ependymoma 1 and dysembryoplastic neuroepithelial tumour (DNET) 1. Postoperative follow-up was performed after 12-74 months (mean 31). The outcome according to the Engel classification indicated class IA in 9 patients, class IC in 3, and 1 each in classes IIIA and IVA. Epileptological outcome according to the ILAE classification indicated class 1 (12 patients) and class 4 (2 patients). Surgical mortality was zero and mild permanent neurological deficits due to surgery were seen in 2 patients. Postoperatively 3 patients showed a homonymous quadrantanopia. CONCLUSIONS: Patients with drug resistant epilepsy and temporal lobe tumours should undergo evaluation in dedicated epilepsy surgery programmes.

Ictal urinary urge indicates seizure onset in the nondominant temporal lobe.

The authors describe six patients with medically refractory temporal lobe epilepsy whose seizures were characterized by an aura of ictal urinary urge. All seizures originated in the nondominant temporal lobe as evidenced from interictal spikes, ictal EEG, and MRI. Ictal SPECT, which was obtained in two patients, showed a hyperperfusion of the insular cortex, indicating a critical role of the insula for the generation of this symptom. Ictal urinary urge represents a new lateralizing sign indicating a seizure onset in the nondominant temporal lobe.

Asymmetric termination of secondarily generalized tonic-clonic seizures in temporal lobe epilepsy.

In patients with secondarily generalized tonic-clonic seizures (sGTCS) an asymmetric termination of the clonic phase can be observed. The authors systematically analyzed this phenomenon in patients with temporal lobe epilepsy (TLE). Thirty-nine sGTCS from 29 patients with TLE who underwent successful epilepsy surgery were analyzed, in addition to a prospectively collected group of 28 patients with TLE who had 35 sGTCS. The clonic phase of sGTCS did not end synchronously in 65.7% of all patients and in 59.4% of all seizures. In 79.3% to 80% this was ipsilateral to the hemisphere of seizure onset, and there was excellent interobserver agreement.

Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics.

OBJECTIVE: To analyze the clinical features and family history of patients with idiopathic generalized epilepsy (IGE), with pure grand mal (GM), divided into epilepsies with GM occurring exclusively on awakening (GMA) and random GM (RGM). METHODS: We studied retrospectively 98 patients from a large epilepsy outpatient clinic. All patients had a full clinical examination and computed cerebral tomography scans (CCT) or magnetic resonance imaging (MRI) when feasible. We analyzed seizure type, seizure frequency, provocative factors, prognosis, electroencephalography (EEG) findings and family history. RESULTS: Sixty-eight patients had GMA and 30 had RGM. The mean age at seizure onset was 16.6 years (+/-6.3 S.D., range: 5-41) and 16.7 years in those with RGM (+/-7.5 S.D., range: 4-42, NSD). Patients with GMA had a longer course of active epilepsy (median 8.5 years) compared to RGM (median 2 years). Seizure-provoking factors, especially sleep deprivation, were significantly (P=0.001) more common in patients with GMA (52/68, 77%) than in the group with RGM (13/30, 43%). Of all patients, 23% (23/98) reported first degree relatives with seizures or epilepsy. Pure GM was found in 41% (12/29) of affected first degree relatives, other idiopathic generalized epilepsy syndromes were less frequently observed (4/29, 14%). The concordance rate was high within the syndrome - none of the patients with RGM had an affected relative with GMA and vice versa only two of affected relatives of GMA patients had RGM. CONCLUSION: GMA seems to be associated with a longer duration of active epilepsy, a higher relapse rate and a stronger tendency to be precipitated by seizure provoking factors. The different concordance rates between the syndromes suggest a genetically different background.

Childhood febrile convulsions--which factors determine the subsequent epilepsy syndrome? A retrospective study.

To analyze the spectrum of epilepsy syndromes which follow childhood febrile convulsions (FC) and to examine whether retrospective analysis of clinical features of the FC enables discrimination of patients who develop temporal lobe epilepsy (TLE) from those who develop generalized epilepsy (GE). One hundred and thirteen patients with epilepsy and antecedent FC were retrospectively analyzed. We inquired in detail about the clinical characteristics of FC (age, duration, number, focal symptoms) as well as family history, birth history, neurological status, and psychomotor development before onset of FC. Forty five (39.8%) patients had TLE, 41 (36.6%) GE, and 27 (23.9%) had extratemporal epilepsy (ETE). Patients with TLE had a significantly longer duration of FC (P< or =0.001), more often focal features (P< or =0.001), and febrile status epilepticus (P< or =0.001) than patients with GE. Age at FC, Number of FC, family history, birth history and neurological status at FC did not differ between groups. A stepwise discriminant model allowed correct assignment after cross validation in 84.2% to TLE and in 100% to GE. A broad spectrum of epilepsy syndromes follow FC. We found a strong association of prolonged and focal FC with later development of TLE. Short generalized FC were associated with GE.

Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate.

Among a sample of 43 women with epilepsy treated for at least 2 years with valproate (n=22) or other antiepileptic drugs (AEDs) (n=21), polycystic ovary syndrome (PCOS) was diagnosed in three women, two of them were treated with valproate. Although the rate of PCOS and of menstrual disturbances, weight body mass index (BMI) and waist to hip ratio as well as fasting blood glucose levels, fasting insulin, proinsulin and C-peptide values was similar in this small sample of women treated with valproate and other AEDs, valproate exposure was associated with higher androgen levels, higher postprandial (pp) insulin and proinsulin levels, as well as lower cholesterol and low density lipoprotein (LDL) cholesterol levels. The pronounced increase in pp insulin levels during VPA treatment may indicate an effect of the fatty acid derivate VPA on pancreatic islet cells.

Cerebral vasospasm following temporal lobe epilepsy surgery.

OBJECTIVE: Selective amygdalohippocampectomy (AHE) has been associated with postoperative cerebral vasospasm (CVS) in patients with medically intractable temporal lobe epilepsy. The incidence in temporal lobe resection (TLR) is unknown. This retrospective cohort study evaluates the incidence of and risk factors for the development of CVS in patients with TLR and AHE. METHODS: A total of 119 patients were included between 1998 and 2009. All patients were evaluated by standardized preoperative and postoperative transcranial Doppler sonography (TCD) evaluations and neurologic examinations. Postoperative CT scans were evaluated by an independent radiologist and the volume of bleeding within the resection cavity was quantified. RESULTS: Of 107 patients with longitudinal TCD data, 35 (32.7%) developed postoperative CVS. The incidence of CVS did not differ between patients with TLR and AHE. CVS was associated with female gender and a higher bleeding volume in the postoperative CT scan (p = 0.035 and 0.046). Patients with CVS showed a significantly higher incidence of postoperative neurologic signs and symptoms (48.6%) compared to patients without CVS (25%, p = 0.015). The mean length of stay was significantly prolonged in patients with diffuse CVS compared to patients with localized CVS or no CVS (28.8 ± 10.9, 24.2 ± 6.6, and 18.2 ± 6.1 days, p < 0.001). CONCLUSION: CVS is a frequent complication of surgery for temporal lobe epilepsy irrespective of the resection method. Important risk factors for the development of postoperative CVS are female gender and a higher amount of bleeding in the postoperative CT. Patients with CVS more frequently have neurologic signs and symptoms resulting in prolonged hospital stay.

Hippocampal abnormalities in malformations of cortical development: MRI study.

OBJECTIVES: Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities. METHODS: Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 +/- 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%). RESULTS: Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%]). CONCLUSIONS: About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.