Timothy A. Pedley

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.

LGI1 mutations in autosomal dominant partial epilepsy with auditory features

Objectives: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. Methods: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. Results: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. Conclusions: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

The role of transcranial Doppler in confirming brain death: Sensitivity, specificity, and suggestions for performance and interpretation

We performed transcranial Doppler (TCD) examinations on 54 comatose patients over a 1-year period. Of 49 patients with technically adequate TCD examinations, 23 met criteria for determination of brain death by clinical and EEG criteria (21) or clinical criteria alone (2; EEG not performed). A TCD waveform abnormality, consisting of absent or reversed diastolic flow, or small early systolic spikes, in at least 2 intracranial arteries, occurred in 21 brain-dead patients, but in none of the other patients in coma. With appropriate guidelines for performance and interpretation, TCD could be incorporated into institutional protocols as a rapid and convenient alternative to EEG for confirmation of brain death.

Quantitative EEG monitoring for patients with subarachnoid hemorrhage

We evaluated the sensitivity of continuous quantitative EEG in 11 patients with subarachnoid hemorrhage (SAH). We correlated compressed spectral array (CSA) and trend analysis (TA) of total power (1-30 Hz), frequency centroid (1-30 Hz), alpha ratio and percent delta power with clinical and radiological findings. For all ischemic events (n = 11), the most sensitive TA parameter was a change in total power (91%), followed by changes in alpha ratio (64%), frequency centroid (55%), and percent delta (45%). Comparable CSA features were changes in power (44%) and slowing (39%). Total power and frequency varied independently. In 4 cases, EEG findings on TA appeared before clinical changes. Continuous quantitative EEG may be useful for monitoring and predicting ischemia following SAH. TA of individual EEG parameters is more sensitive than CSA, and total power is the most sensitive.

Autosomal dominant partial epilepsy with auditory features: Defining the phenotype

Article abstract The authors previously reported linkage to chromosome 10q22-24 for autosomal dominant partial epilepsy with auditory features. This study describes seizure semiology in the original linkage family in further detail. Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin. Auditory hallucinations, the most striking clinical feature, are useful for identifying new families with this synome.

State‐dependent changes in the N20 component of the median nerve somatosensory evoked potential

Short-latency components of median nerve somatosensory evoked potentials are generally assumed to be unaffected by sleep and level of arousal. We found that sleep prolongs the latency and alters the morphology of the N20 component in normal subjects. These changes may represent differential effects of sleep on various elements contributing to generation of the N20. Failure to control for patient state may degrade the reliability of clinical somatosensory evoked potential testing.

Computerized cranial tomography in cerebral diseases of white matter.

Computerized tomographic scans were performed on 31 patients with primary diseases of the white matter. Among 18 patients with multiple sclerosis, acute lesions were visualized in five, all with symptomatic cerebral hemisphere disease. Characteristic white matter lesions were also demonstrated in adrenoleukodystrophy, spongiform encephalopathy, progressive multifocal leukoencephalopathy, disseminated necrotizing leukoencephalopathy, and an undiagnosed leukoencephalopathy associated with malignancy. Besides identifying white matter abnormalities, the CT scan patterns were often specific enough to help distinguish among the various etiologic possibilities for the abnormalities. Useful diagnostic characteristics included the anatomic distribution of lesions, mass effect, atrophic changes, and enhancement after contrast infusion.

The Predictive Value of Intraoperative Electrocorticography in Resections for Limbic Epilepsy Associated with Mesial Temporal Sclerosis

OBJECTIVE Prior studies on the predictive value of intraoperative electrocorticography (ECoG) have been performed on heterogeneous groups of patients with both temporal and extratemporal interictal spikes, lesional and nonlesional pathological findings, and variably extensive resections by different surgeons. METHODS We performed both pre- and postresection intraoperative ECoG on 29 consecutive patients with medial temporal lobe epilepsy (17 left-sided) who underwent standard nontailored resections by one surgeon (RRG). All patients had only temporal interictal spikes (six bitemporal) and mesial temporal sclerosis diagnosed by preoperative magnetic resonance imaging and confirmed by pathological examination of resected tissue. RESULTS After a mean follow-up of 24.8 months, there were 15 (52%) patients who were seizure-free, 6 (21%) who were seizure-free except for auras, and 8 (28%) who had any seizure after the 1st postoperative month. Fourteen patients (48%) had active interictal discharges outside the area of planned resection revealed by preresection ECoG. Neither the presence of these spikes nor their mean frequency correlated with seizure outcome. Eleven patients (38%) had residual spike discharges after resection, and 18 patients (62%) had new spikes revealed by the postresection ECoG. Neither of these findings nor the mean spike frequency of residual or new spikes related to seizure outcome. Persistent spikes increased in frequency after resection in all outcome groups. CONCLUSIONS Electrocorticographic monitoring of interictal epileptiform activity intraoperatively is not useful in the surgical treatment of patients undergoing standard resection for medial temporal lobe epilepsy with magnetic resonance imaging evidence of mesial temporal sclerosis.

Recognition and Classification of Seizures in Infants

Summary: Purpose: We wished to assess the reliability of the International League Against Epilepsy (ILAE) seizure classification system applied to infantile seizures and to test a proposed new classification.

Propagation patterns of temporal spikes

In standard EEG recordings, spikes appear as single events characterized mainly by the scalp location of the their peak voltage. The signal-to-noise ratio of raw EEG is usually too high to permit more detailed analysis. We used spike averaging to improve the resolution of interictal spikes in 40 patients with temporal lobe epilepsy. Spikes were identified visually in raw, digitally stored EEG. When multiple spike types were present in a patient, they were grouped separately. Spikes were synchronized for averaging by aligning their negative peaks in a designated channel. Sixteen patients demonstrated spike propagation from anterior temporal to posterior temporal electrode locations. Thirty-six patients demonstrated spread of spikes from anterior temporal to fronto-polar electrode sites. While anterior temporal and fronto-polar spikes were often synchronous, fronto-polar spikes followed anterior temporal discharges in 25% of cases and preceded them in 13%. Spike averaging revealed propagation patterns not apparent on visual inspection of raw EEG. We speculate that these patterns may reflect inherent physiological properties of temporal and frontal neuronal circuits, possibly utilized by the epileptogenic process.