Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1.

Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable approximately 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.

Comparison of [18F]FDG-PET, [99mTc]-HMPAO-SPECT, and [123I]-iomazenil-SPECT in localising the epileptogenic cortex.

OBJECTIVES: Firstly, to compare the findings of interictal 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and of single photon emission computed tomography (SPECT) using 99mTc-hexamethyl propylene-amine-oxime (HMPAO) and 123I-iomazenil in localising the epileptogenic cortex in patients who were candidates for epilepsy surgery, but in whom clinical findings, video EEG monitoring (V-EEG), MRI, and neuropsychological evaluations did not give any definite localisation of the seizure onset. Secondly, to assess the ability of these functional methods to help in the decision about the epilepsy surgery. METHODS: Eighteen epileptic patients were studied with FDG-PET and iomazenil-SPECT. HMPAO-SPECT was performed in 11 of these 18 patients. Two references for localisation was used--ictal subdural EEG recordings (S-EEG) and the operated region. RESULTS: Fifteen of 18 patients had localising findings in S-EEG. FDG-PET findings were in accordance with the references in 13 patients and iomazenil-SPECT in nine patients. HMPAO-SPECT visualised the focus less accurately than the two other methods. In three patients S-EEG showed independent bitemporal seizure onset. In these patients FDG-PET showed no lateralisation. However, iomazenil-SPECT showed temporal lobe lateralisation in two of them. CONCLUSION: FDG-PET seemed to localise the epileptogenic cortex more accurately than interictal iomazenil-SPECT in patients with complicated focal epilepsy.

Short-term withdrawal of antiepileptic medication: effects on attention and memory.

INTRODUCTION: The aim of this study was to determine the effect of routine withdrawal of antiepileptic drugs (AEDs) during preoperative evaluation on cognitive functions and also to clarify whether short-term withdrawal of AED would help to lateralize the epileptic focus and to highlight focal dysfunction of memory in patients with temporal lobe epilepsy. MATERIAL & METHODS: Cognitive function was evaluated in 25 patients on full medication and after 1-week during the ongoing AED withdrawal. Six additional patients without AED withdrawal were studied during the same time interval and served as controls. The effect of AED withdrawal on memory tests was evaluated in a subgroup of 11 patients with temporal lobe epilepsy (TLE group). RESULTS: In the TLE group, verbal recurrent-sequences learning tasks deteriorated significantly in patients with left-sided foci during AED withdrawal. In the whole group, attention, concentration and mental flexibility improved both in patients and in controls; the improvement was interpreted as being the result of the practice effect. During AED withdrawal, the number of errors in these tests decreased or remained unchanged. CONCLUSION: We suggest that preoperative neuropsychological testing can be scheduled at any time in patients referred for epilepsy surgery. In patients with temporal lobe epilepsy, the lateralizing results of selective memory tests may be most reliable if the testing is performed during AED withdrawal.

Spectral EEG during short-term discontinuation of antiepileptic medication in partial epilepsy.

The effect of short-term discontinuation of antiepileptic drugs (AEDs) on spectral analysis of EEG background activity (spectral EEG) was studied in patients undergoing preoperative evaluation for epilepsy surgery. We also wished to clarify whether AED discontinuation would provide lateralizing evidence in spectral EEGs of patients with temporal lobe epilepsy (TLE). Spectral EEGs were performed in 15 patients receiving their regular medication regimen and again after a 1-week period during AED withdrawal. A subgroup of 9 patients who had previously undergone temporal lobectomies (TLE group) was studied separately. In this group, we evaluated the effect of preceding seizures on spectral EEG derived from temporal neocortical areas. In all patients, spectral EEG changes were detected even after a short-term AED withdrawal. The total amount of absolute delta activity was reduced and occipital peak frequency and relative alpha activity were increased as compared with baseline values. In TLE patients with habitual seizures occurring < 20 h before the spectral EEG recording, lateralization was correctly identified by the greater amount of absolute delta activity ipsilateral to the epileptogenic focus. Epileptic seizures are accompanied by subtle focal slowing in spectral EEG for a much longer period than has been assumed. In addition, postictal spectral EEG over the temporal lobes may have lateralizing value. Further studies in larger numbers of patients are needed to evaluate the role of spectral EEG in the preoperative evaluation of patients for temporal lobe surgery.

Preoperative EEG predicts memory and selective cognitive functions after temporal lobe surgery.

Preoperative and postoperative cognitive and memory functions, psychiatric outcome, and EEGs were evaluated in 32 epileptic patients who underwent temporal lobe surgery. The presence and location of preoperative slow wave focus in routine EEG predicted memory functions of the non-resected side after surgery. Neuropsychological tests of the function of the frontal lobes also showed improvement. Moreover, psychiatric ratings showed that seizure free patients had significantly less affective symptoms postoperatively than those who were still exhibiting seizures. After temporal lobectomies, successful outcome in postoperative memory functions can be achieved in patients with unilateral slow wave activity in preoperative EEGs. This study suggests a new role for routine EEG in preoperative evaluation of patients with temporal lobe epilepsy.

Lateralization of event-related potentials during discontinuation of antiepileptic medication.

The effect of short-term withdrawal of antiepileptic drugs (AEDs) on auditory event-related potentials (ERPs) was studied in 16 patients undergoing preoperative evaluation for epilepsy surgery. ERPs were performed for all patients during treatment with full medication and after a 1-week period during ongoing tapering of AEDs. To clarify whether AED discontinuation would provide evidence of lateralizing for ERPs, we also studied the subgroup of 9 patients who had already undergone temporal lobectomies (TLE group). In the TLE group, if habitual seizures occurred < 30 h before the ERP recording session, auditory N1 and P3 amplitudes across sphenoidal electrodes were markedly decreased on the side ipsilateral to the epileptic focus. If seizures did not occur, asymmetries in amplitudes were equivocal and not of lateralizing value. In the whole group, midline N1 latencies for standard responses decreased significantly during AED discontinuation. At baseline, long-term habituation of the N1 component for standard responses was attenuated as compared with that of controls. During AED discontinuation, however, enhanced habituation of N1 was observed in TLE patients who did not exhibit seizures before ERP recording.

Sweat gland vacuoles in Unverricht-Lundborg disease: a clue to diagnosis?

There has been no reported pathologic abnormality outside the central nervous system in patients with Unverricht-Lundborg disease (ULD). We report membrane-bound vacuoles with clear contents in eccrine clear cells and dark cells in five of seven patients with ULD, as well as in one clinically unaffected sibling. Vacuoles were not seen in the biopsies of two patients and of eight controls with Lafora's disease. These findings, though not entirely specific, suggest that skin biopsy may serve as a diagnostic aid to give supportive evidence for ULD.

Postoperative EEG and electrocorticography: relation to clinical outcome in patients with temporal lobe surgery.

To evaluate the role of different EEG methods with respect to postoperative clinical follow-up, 32 non-lesionary epilepsy patients who had undergone temporal lobectomy were studied preoperatively and at 2-week, 3-month, and 1-year postoperative follow-up. Routine, sleep, and sphenoidal EEG recordings as well as intraoperative electrocorticography (ECoG) were made for all patients. At 1-year follow-up, the EEGs with sphenoidal electrodes and with sleep deprivation procedure provided important prognostic information; the appearance of seizures was associated with the presence of interictal epileptiform abnormalities in EEG. In the postresection ECoG, however, epileptiform abnormalities were not associated with clinical outcome or with postoperative epileptiform EEG at 1 year. Routine EEG reliably reflects clinical outcome after temporal lobectomy; with sphenoidal electrodes as well as with sleep deprivation procedure, the diagnostic yield can be further improved.

Evaluation of a computerized system for recognition of epileptic activity during long-term EEG recording.

A new method of recognition of epileptic activity using adaptive segmentation in EEG during long-term intensive monitoring was developed in Tampere. The performance of the system was validated and compared to the commercially available discharge recognition system of Gotman. Twelve approximately 30 min EEG segments recorded during intensive monitoring from 6 patients were analysed. On these EEG segments two EEG specialists marked the occurrence of epileptic activity independently. Later they re-evaluated any differences in their scoring. This consensus file was used as a reference in validating the performance of the two computer programs. We found that the program developed in Tampere detected discharge activity more often than the Gotman system. Both systems performed poorly in spike recognition. In the specificity of the recognized segments, the Gotman system was better.

Unverricht-Lundborg disease: absence of nonallelic genetic heterogeneity.

Unverricht-Lundborg disease is a clinically recognizable form of progressive myoclonus epilepsy. Recently, in several families of both Finnish and Mediterranean extraction segregating Unverricht-Lundborg disease, the gene for this disease was linked to the same region of the long arm of chromosome 21. We performed linkage analysis in eight families, including four of neither Baltic nor Mediterranean origin, using a polymorphic (CA)n repeat marker for the human liver-type 6 phosphofructokinase (PFKL) gene, previously mapped to 21q22.3. No recombinations were observed between the disease phenotype and the PFKL marker and a maximum lod score of 5.63 was obtained. These findings confirm tight linkage between PFKL and the gene for Unverricht-Lundborg disease and strongly suggest a lack of nonallelic genetic heterogeneity of the disease.

Ictal recordings of ambulatory cassette EEG with sphenoidal electrodes in temporal lobe epilepsy: comparison with intensive videomonitoring.

Seventy-three seizures in 18 epilepsy patients were studied by analyzing the ictal findings of 8-channel ambulatory EEG (A/EEG) and adjacent 16-channel intensive videomonitoring (IVM). With IVM and A/EEG analysis, accuracy was excellent for determining the lateralization of seizure progression; whereas at seizure onset and post-ictal slowing, accuracy was poor. No false lateralization was found in A/EEG compared with IVM or lateralization according to patient data, and in seizure lateralization the interpretation of A/EEG was discordant in only 3 seizures with IVM analysis. According to our study, ictal 8-channel A/EEG with sphenoidal electrodes is not suitable for localization of temporal lobe foci, but is reliable for lateralization analysis.

Vigabatrin (gamma-vinyl-GABA): neuropathologic evaluation in five patients.

We performed neuropathologic examination of cerebral cortex specimens from 4 patients who underwent epilepsy surgery and the brain of 1 patient who died suddenly. All had severe epilepsy and had received gamma-vinyl-GABA (GVG, vigabatrin) for 3-5.5 years. Neither the surgically resected temporal lobe specimens nor the frontal and temporal lobes autopsy specimens showed abnormal white matter vacuolation.

Clinical picture and long-term course of epileptic seizures that occur during clozapine treatment.

Clozapine is an atypical neuroleptic drug that has proved to be effective in alleviating psychotic symptoms refractory to treatment with standard neuroleptic drugs. In addition to hematological side effects, an increased susceptibility to epileptic seizures during clozapine treatment has previously been described. In this report, we describe the clinical picture and electroencephalographic findings of 12 schizophrenic patients who have had from one to six clozapine-associated epileptic convulsions.

Pre- and postoperative auditory event-related potentials in temporal lobe epilepsy.

We studied auditory event-related potentials (ERPs) in 11 surgically treated patients with intractable temporal lobe epilepsy (TLE) pre- and postoperatively. ERPs through sphenoidal electrodes (Sp1-T3, Sp2-T4) provided clinically relevant and correctly lateralizing electrophysiologic evidence of temporal lobe dysfunction in 9 of 11 patients, confirmed by EEGs, electrocorticograms, neuroradiologic, and neuropsychological results, and clinical follow-up. Lateralizing asymmetries were noted in P300 amplitude, but latencies were prolonged bilaterally. Sphenoidal ERPs might serve as a new functional indicator of temporal lobe dysfunction in patients evaluated for epilepsy surgery.

Magnetoencephalographic localization of epileptic cortex--impact on surgical treatment.

A 24-channel, planar, superconducting quantum interference device gradiometer, sampling a fourth of the head surface over brain tissue, was used to determine the site of an epileptic focus in a 36-year-old woman with intractable complex partial epilepsy. The other presurgical findings appeared divergent: a large arachnoid cyst over the right parietal convexity, dissimilar interictal electroencephalographic patterns, and several neuropsychological dysfunctions. The equivalent current sources of magnetoencephalographic spikes were in the right posterior temporal region of the cortex, 4 cm apart from the cyst. Surgical exploration of the area pinpointed by magnetoencephalography revealed a pachygyric patch of cortex displaying focal discharges on the electrocorticogram. After resection, a dramatic reduction of seizures occurred. The good agreement between electrocorticography and magnetoencephalography warrants future investigation of multichannel magnetoencephalography as a potential alternative to invasive presurgical recordings.

Clinical benefits of scalp EEG studies in intractable seizure disorders.

Intractable seizure disorder is a clinical as well as a diagnostic problem. We evaluated the clinical role of extensive EEGs among patients (n = 64) considered to suffer from intractable paroxysmal neurologic symptoms. By reducing antiepileptic medication, ictal events were recorded in 89% of the cases. From the clinical point of view, intensive EEG-videomonitoring (IVM) was superior to all the other EEG studies. Combined interictal routine EEG (rEEG) and ictal ambulatory EEG (aEEG) findings proved to be surprisingly successful, in some clinical settings equal to IVM. Comprehensive EEG investigations and subsequent treatment in a neurologic ward resulted in proper medication and markedly improved seizure control, confirmed by a prospective clinical follow-up of two years.