Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

Ictal cognitive assessment of partial seizures and pseudoseizures.

BACKGROUND: Previous studies suggest that responsiveness is impaired during complex partial seizures (CPS) and pseudoseizures (PS); however, to our knowledge, there has been no systematic comparison using both response and memory testing. OBJECTIVE: To compare CPS with PS using ictal cognitive assessment (ICA) of responsiveness and memory. PATIENTS AND METHODS: We used a nonautomated method of ICA by bedside observers, consisting of family members and staff, during video electroencephalographic monitoring to test responsiveness and memory during the ictal phase in 245 events. We assessed the adequacy of testing and compared the testing results in 31 patients during CPS and 13 patients during PS. RESULTS: The ictal presentation of a command was successful in 58% of the events. The ictal presentation of at least 2 memory items with testing for recall after orientation was adequate in 57% of events. Impaired responsiveness was shown during both CPS and PS. However, some response was detected during 48% of PS compared with 18% of CPS (P<.01). Memory items were recalled during 63% of PS but during only 4% of CPS (P<.001). The International Classification of Epileptic Seizures remained useful, but in 11 events (8%), distinguishing complex from simple partial seizures was difficult. Recall of various types of stimuli (aural-verbal vs visual-pictorial) during ICA did not correlate with the side or location of the seizure focus, but this may have been confounded by the rarity of any memory recall during CPS. CONCLUSIONS: Ictal cognitive assessment by bedside observers is practical and provides the interaction necessary for properly classifying seizures; ICA, especially memory, may help to distinguish CPS from PS.

Abnormal sensory evoked potentials in amyotrophic lateral sclerosis.

We have reviewed sensory evoked potential (EP) findings in 17 patients with amyotrophic lateral sclerosis (ALS). Somatosensory EPs were abnormal in 7 of 16 patients after lower-extremity stimulation and in 2 of 16 patients after upper-extremity stimulation. Brainstem auditory EP abnormalities were found in 2 of 12 patients. No abnormalities were noted on pattern reversal visual EPs in 12 patients. Overall, 47% of all ALS patients studied had at least one EP abnormality. EP evidence of CNS sensory dysfunction in ALS is more frequent than that noted clinically or pathologically and offers further support to previous observations of sensory system involvement in ALS.

Intraoperative brainstem auditory evoked potentials: significant decrease in postoperative morbidity.

Evoked potentials are commonly used for intraoperative monitoring of neural tissue under surgical threat despite the lack of unequivocal evidence demonstrating its effectiveness in preventing neural injury. This study retrospectively compares the auditory morbidity of posterior fossa microvascular decompressive surgery before and after the introduction of intraoperative brainstem auditory evoked potentials (BAEPs). All patients underwent a similar operative procedure performed by a single surgeon. The two groups were comparable with regards to age, sex, and indications for surgery. In the nonmonitored group, auditory morbidity had not declined with increasing experience of the surgeon. Ten of 152 patients (6.6%) suffered a profound hearing loss in the nonmonitored group. In the monitored group, none of 70 patients suffered a profound hearing loss. We attribute this significant decline (p = 0.02) in morbidity to the introduction of intraoperative BAEPs. We believe this to be the first demonstration of a significant decrease in operative morbidity directly associated with the use of intraoperative evoked potential monitoring.

Neologistic speech automatisms during complex partial seizures.

There are no documented cases of seizures causing reiterative neologistic speech automatisms. We report an 18-year-old right-handed woman with stereotypic ictal speech automatisms characterized by phonemic jargon and reiterative neologisms. Video-EEG during the reiterative neologisms demonstrated rhythmic delta activity, which was most prominent in the left posterior temporal region. At surgery, there was an arteriovenous malformation impinging on the left supramarginal gyrus and the posterior portion of the superior temporal gyrus. Though intelligible speech automatisms can result from seizure foci in either hemisphere, neologistic speech automatisms may implicate a focus in the language-dominant hemisphere.

Accuracy and interobserver reliability of scalp ictal EEG.

We studied the accuracy and reliability of scalp ictal EEG in 137 complex partial seizures (119 temporal and 18 extratemporal) in 35 patients in whom we knew the correct site of seizure origin because all patients had been seizure-free for more than 2 years after seizure surgery. Three electroencephalographers independently determined side of seizure origin based on activity at onset of electrographic seizure (ASO), rhythmic theta and alpha (RTA), postictal findings (PIF), and the electrographic seizure as a whole. When all seizures were analyzed, including those with generalized features or obscured by artifact, we determined side of seizure onset correctly in 76% to 83% of temporal seizures and 47% to 65% of extratemporal seizures. In most of the remainder, a lateralization judgment was impossible. When analysis was confined to those seizures in which lateralization was possible, we correctly lateralized 93% to 99% of temporal seizures and 89% to 100% of extratemporal seizures. Interobserver reliability was excellent. RTA and PIF were more accurate than ASO. RTA was significantly more common in temporal seizures. Our data indicate that lateralization by scalp EEG is highly accurate and reliable.

Seizure onset from periventricular nodular heterotopias: depth-electrode study.

The association between gray matter heterotopias and seizures is well established; whether seizures originate from these lesions is not known. We evaluated three patients with intractable complex partial seizures and periventricular nodular heterotopias (PNHs) with video-EEG monitoring with multiple depth electrodes, including placement in the PNH, to determine whether seizures originate from the PNH. In two of the three patients, all seizures arose from the PNH as low-voltage beta activity. In the third patient, 80% arose from the hippocampi and 20% from the heterotopia. PNHs may serve as an epileptogenic focus in patients with intractable epilepsy.

Clinical and electrographic manifestations of lesional neocortical temporal lobe epilepsy.

To determine whether lesional neocortical temporal lobe epilepsy (NTLE) can be differentiated from mesial temporal lobe epilepsy (MTLE) during the noninvasive presurgical evaluation, we compared the historical features, seizure symptomatology, and surface EEG of 8 patients seizure free after neocortical temporal resection with preservation of mesial structures and 20 patients after anterior temporal lobectomy for MTLE. Seizure symptomatology of 107 seizures (28 NTLE, 79 MTLE) was analyzed. One hundred one ictal EEGs (19 NTLE, 82 MTLE) were reviewed for activity at seizure onset; presence, distribution, and frequency of lateralized rhythmic activity (LRA); and distribution of postictal slowing. Seizure symptomatology and EEG data were compared between groups, and sensitivity, specificity, and positive and negative predictive values were determined for variables that differed significantly. Multiple logistic regression was used to determine whether patients could be correctly classified as having MTLE or NTLE. MTLE patients were younger at onset of habitual seizures and more likely to have a prior history of febrile seizures, CNS infection, perinatal complications, or head injury. NTLE seizures lacked features commonly exhibited in MTLE, including automatisms, contralateral dystonia, searching head movements, body shifting, hyperventilation, and postictal cough or sigh. NTLE ictal EEG recordings demonstrated lower mean frequency of LRA that frequently had a hemispheric distribution, whereas LRA in MTLE seizures was maximal over the ipsilateral temporal region. We conclude that it may be possible to differentiate lesional NTLE from MTLE on the basis of historical features, seizure symptomatology, and ictal surface EEG recordings. This may assist in the identification of patients with medically refractory nonlesional NTLE who frequently require intracranial monitoring and more extensive or tailored resections.

Treatment of radiation-induced nervous system injury with heparin and warfarin.

When radiation is used to treat nervous system cancer, exposure of adjacent normal nervous system tissue is unavoidable, and radiation-induced injury may occur. Acute injury is usually mild and transient, but late forms of radiation-induced nervous system injury are usually progressive and debilitating. Treatment with corticosteroids, surgery, and antioxidants is often ineffective. We treated 11 patients with late radiation-induced nervous system injuries (eight with cerebral radionecrosis, one with a myelopathy, and two with plexopathies, all unresponsive to dexamethasone and prednisone) with full anticoagulation. Some recovery of function occurred in five of the eight patients with cerebral radionecrosis, and all the patients with myelopathy or plexopathy. Anticoagulation was continued for 3 to 6 months. In one patient with cerebral radionecrosis, symptoms recurred after discontinuation of anticoagulation and disappeared again after reinstitution of treatment. We hypothesize that anticoagulation may arrest and reverse small-vessel endothelial injury--the fundamental lesion of radiation necrosis--and produce clinical improvement in some patients.

Migratory leptomeningeal inflammation with relapsing polychondritis.

We report a case of relapsing polychondritis with focal sensorimotor seizures, aseptic meningitis, and migratory leptomeningeal enhancement on contrast MRI. These abnormalities on imaging studies correlated accurately with laterality of the patient's seizures, facilitating early aggressive management of his neurologic symptoms.

Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis.

OBJECTIVE: To determine seizure outcome and its predictors in patients with medically refractory temporal lobe epilepsy (TLE) after temporal lobectomy (TL). BACKGROUND: TL is the most common surgical procedure performed in adolescents and adults for the treatment of medically refractory TLE. Seizure outcome has been reported extensively during the first few postoperative years, but little is known beyond that time. METHODS: The authors analyzed seizure outcome in 79 patients who underwent TL for epilepsy at the Duke University Medical Center from 1962 through 1984. Patients with less than 2 years of follow-up and degenerative disorders were excluded. Predictors of seizure outcome were analyzed using Kaplan-Meier survival analyses. RESULTS: The mean follow-up was 14 years (range, 2.1 to 33.6 years). Using Engel's classification, 65% of patients were class I, 15% were class II, 11% were class III, and 9% were class IV. At least one postoperative seizure occurred in 55% of subjects. The majority of recurrences (86%) took place within 2 years of surgery. Later recurrences tended not to lead to medical intractability. Higher monthly preoperative seizure frequency was associated with poor seizure outcome. A seizure-free state at 2 years was found to be a better predictor of long-term outcome than the 6-, 12-, and 18-month landmarks. CONCLUSIONS: TL provides sustained, long-term benefit in patients with medically refractory TLE. Seizure-free status at 2 years from the time of surgery is predictive of long-term remission.

Anterior temporal lobectomy for complex partial seizures: evaluation, results, and long-term follow-up in 100 cases.

We report evaluation and results in 100 patients who had undergone anterior temporal lobectomy for intractable complex partial seizures. Average follow-up was 9.0 years (range, 2 to 21 years). In the 2nd postoperative year, 63% were seizure free, 16% were significantly improved, and 21% were considered not significantly improved. Mean number of seizures in the last group was 27% of preoperative levels. Surgical results did not change significantly in subsequent postoperative years; good outcomes tended to persist over the longer term. We also examined the utility of continuous depth electrode monitoring in the evaluation of patients with independent bitemporal interictal epileptiform activity. Despite limited numbers of subjects in this category, there was a trend toward improved surgical outcome when such subjects were evaluated with depth electrodes.

Temporal lobe hypometabolism on PET: predictor of seizure control after temporal lobectomy.

To investigate the relationship of temporal lobe hypometabolism demonstrated on PET to surgical outcome and underlying pathology, we reviewed 30 consecutive epilepsy patients who underwent interictal PET studies with 18F fluorodeoxyglucose before temporal lobectomy. Two interpreters blindly reviewed the PET studies and graded them for degree, extent, and location of temporal lobe hypometabolism. Pathologic analysis of en bloc resected tissue showed mesial temporal sclerosis (n = 22), astrocytoma (n = 2), and no pathologic diagnosis (n = 6). Outcome (24 to 40 months' follow-up) was rated as seizure-free (21 patients), significantly improved (five patients), and not significantly improved (four patients). Both the degree and extent of the temporal lobe hypometabolism demonstrated on PET were strongly associated with subsequent seizure control. Pathologic findings, however, did not correlate with degree of PET hypometabolism or subsequent outcome. These data demonstrate that in patients judged to have temporal lobe epilepsy, the presence of temporal lobe hypometabolism is associated with a positive outcome after ipsilateral temporal lobectomy.

X-linked malformations of neuronal migration.

Malformations of neuronal migration such as lissencephaly (agyria-pachygyria spectrum) are well-known causes of mental retardation and epilepsy that are often genetic. For example, isolated lissencephaly sequence and Miller-Dieker syndrome are caused by deletions involving a lissencephaly gene in chromosome 17p13.3, while many other malformation syndromes have autosomal recessive inheritance. In this paper, we review evidence supporting the existence of two distinct X-linked malformations of neuronal migration. X-linked lissencephaly and subcortical band heterotopia (XLIS) presents with sporadic or familial mental retardation and epilepsy. The brain malformation varies from classical lissencephaly, which is observed in males, to subcortical band heterotopia, which is observed primarily in females. The XLIS gene is located in chromosome Xq22.3 based on the breakpoint of an X-autosomal translocation. Bilateral periventricular nodular heterotopia (BPNH) usually presents with sporadic or familial epilepsy with normal intelligence, primarily in females, although we have evaluated two boys with BPNH and severe mental retardation. The gene for BPNH has been mapped to chromosome Xq28 based on linkage studies in multiplex families and observation of a subtle structural abnormality in one of the boys with BPNH and severe mental retardation.

Use of in vivo desensitization to treat a patient's claustrophobic response to nasal CPAP.

Continuous positive airway pressure (CPAP) has proven to be a safe, effective treatment for sleep apnea patients. However, many patients display claustrophobic reactions to the CPAP nasal mask and cannot tolerate this treatment. The current report describes the successful application of in vivo desensitization with a male apnea patient who initially failed CPAP therapy due to his claustrophobia. Over the course of treatment, the patient became able to tolerate using his CPAP device throughout his nocturnal sleep periods. Moreover, follow-up visits scheduled 6 months and again at 6 1/2 years after behavioral treatment showed that the patient continued to use CPAP on a regular basis. It is concluded that in vivo desensitization therapy may be useful in assisting claustrophobic patients to tolerate nasal CPAP. Results are discussed in view of the specific features of the case presented, and future applications of this behavioral procedure are encouraged.

Does cognitive-behavioral insomnia therapy alter dysfunctional beliefs about sleep?

STUDY OBJECTIVES: This study was conducted to exam the degree to which cognitive-behavioral insomnia therapy (CBT) reduces dysfunctional beliefs about sleep and to determine if such cognitive changes correlate with sleep improvements. DESIGN: The study used a double-blind, placebo-controlled design in which participants were randomized to CBT, progressive muscle relaxation training or a sham behavioral intervention. Each treatment was provided in 6 weekly, 30-60-minute individual therapy sessions. SETTING: The sleep disorders center of a large university medical center. PARTICIPANTS: Seventy-five individuals (ages 40 to 80 years of age) who met strict criteria for persistent primary sleep-maintenance insomnia were enrolled in this trial. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants completed the Dysfunctional Beliefs and Attitudes About Sleep (DBAS) Scale, as well as other assessment procedures before treatment, shortly after treatment, and at a six-month follow-up. Items composing a factor-analytically derived DBAS short form (DBAS-SF) were then used to compare treatment groups across time points. Results showed CBT produced larger changes on the DBAS-SF than did the other treatments, and these changes endured through the follow-up period. Moreover, these cognitive changes were correlated with improvements noted on both objective and subjective measures of insomnia symptoms, particularly within the CBT group. CONCLUSIONS: CBT is effective for reducing dysfunctional beliefs about sleep and such changes are associated with other positive outcomes in insomnia treatment.

Periodic limb movement variability in older DIMS patients across consecutive nights of home monitoring.

Older difficulty initiating and/or maintaining sleep (DIMS) patients who met criteria for periodic limb movement disorder (PLMD) were monitored for three consecutive nights in their homes using ambulatory polysomnography (PSG). Correlational analyses of the group data suggested little night-to-night variability in either movement indices or movement-related arousal indices for this sample. However, within-subjects comparisons suggested considerable variability in these indices and other sleep measures across nights. Nevertheless, for most subjects, the variability noted for these indices appeared to have little effect on PLMD severity classification or clinical treatment decisions derived from blind examinations of PSGs. Further, the initial PSG study generally led to a representative severity classification and clinical decision. Additional research is needed to determine the generalizability of these results to younger subjects, patients with complaints of excessive somnolence and other methods of home PSG monitoring.

Polysomnographic assessment of DIMS: empirical evaluation of its diagnostic value.

This investigation examined the diagnostic value of polysomnography (PSG) for evaluating disorders of initiating and maintaining sleep (DIMS). The sample consisted of 100 outpatients who presented to the Duke Sleep Disorders Center with a complaint of chronic insomnia. All patients were given comprehensive medical, psychiatric, behavioral, and ambulatory PSG evaluations. Sleep disorder diagnoses were assigned using the criteria of the Association of Sleep Disorders Centers. Overall, PSG yielded important diagnostic information in 65% of the sample: 34% were given a primary sleep disorder diagnosis that was heavily dependent on PSG data [periodic movements of sleep (PMS) = 25%, apnea = 3%, and subjective insomnia = 6%]; 15% were given a secondary diagnosis of one of these three disorders; and PSG ruled out suspected PMS in 9% and sleep apnea in 7% of the sample. Patients greater than 40 years of age had a significantly higher rate of positive PSG findings than younger patients. Using only the clinical exam, two experienced sleep clinicians were able to predict only 14 of 25 PMS cases and one of three cases of sleep apnea. Based on these data, we suggest using PSG routinely with older insomniacs and with younger patients who fail initial treatment.

MR imaging in patients with temporal lobe seizures: correlation of results with pathologic findings.

Thirty-nine consecutive patients with medically intractable complex partial seizures were studied with electroencephalography and MR imaging to localize an epileptogenic focus for temporal lobectomy. The patients were divided into three groups on the basis of pathologic findings after lobectomy: Group 1 comprised 13 patients with neoplasms, hamartomas, or cysts; group 2 comprised 13 patients with moderate and severe mesial temporal sclerosis (one patient was included in both groups 1 and 2); and group 3 comprised 14 patients who underwent aspiration lobectomy, which yielded limited tissue for pathologic study so no pathologic diagnosis was made. The majority of the patients in group 3 were assumed to have mesial temporal sclerosis. Abnormal MR signal in the temporal lobe on T2-weighted images was graded as minimal increase (1+), intermediate or moderate increase (2+), and very significant increase (3+). An abnormal signal was demonstrated in 26 (67%) of the 39 patients. In group 1, the tumor/cyst subgroup, an abnormal signal was seen in all 13 patients. Most had 3+ signal. There was increased signal in eight (62%) of 13 patients in group 2 and in six (43%) of 14 patients in group 3. This study suggests that MR can detect almost all tumors and a significant number of mesial temporal sclerosis lesions in individuals with complex partial seizures. On the basis of this small series, individuals who exhibit significant signal (3+) can be expected to have neoplasms, hamartomas, or cysts, and patients who exhibit minimal signal (1+) will usually have mesial temporal sclerosis.

Lamotrigine-induced blepharospasm.

Movement disorders such as tremor and ataxia occur commonly during therapy with antiepileptic drugs (AEDs). Dystonias, however, are rare. Blepharospasm, although reported with neuroleptic agents, has never been reported with AEDs. Our patient developed blepharospasm during therapy with lamotrigine.