New Techniques in Magnetic Resonance and Epilepsy

Summary: Developments in magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon emission tomography (SPECT) have opened new opportunities for noninvasive brain investigation. Functional imaging methods involving noninvasive MRI and minimally invasive PET and SPECT are available that allow investigation of brain abnormality in intractable epilepsy patients. Noninvasive techniques enable the investigation of many aspects of the underlying neuropathologic basis of intractable seizures and of the relationship of functional abnormalities both to structural abnormalities and to the seizure focus. New MRI techniques demonstrate the structure of the brain in fine detail (especially the hippocampus), provide information about the underlying metabolism of brain regions, and demonstrate functional activity of the brain with high spatial and temporal resolution. The clinical impact of this noninvasive information cannot be overstated and these techniques provide indispensable information to neurologists specializing in epi-leptology. The proper use and interpretation of the findings provided by these new technologies will be a major challenge to epilepsy programs in the next few years.     

Cerebral Arteriovenous Malformations and Epilepsy: Factors in the Development of Epilepsy

Sixty-one patients of a population of 343 with cerebral arteriovenous malformations (AVMs) were diagnosed with seizures. Their AVMs were larger (p less than 0.02) and more frequently superficial (p less than 0.05) as compared with the AVMs of patients who were diagnosed with haemorrhage. The factors influencing the development of denovo seizures in patients with diagnosed AVMs were surgical treatment, a presentation with haemorrhage, and age at diagnosis.     

Assessment and Selection of Candidates for Surgical Treatment of Epilepsy

Summary: A variety of surgical strategies are available to deal with intractable epilepsy. These are resective operations, consisting of the removal of a focus or a discrete lesion, gross removal of malfunctioning brain, and functional operations consisting of division of the pathways of propagation or of an epileptic neuronal aggregate. A method of assessment for surgery involves investigation managed in phases, with the patient either being refused surgery, offered surgery or proceeding to the next phase. The place of the common modalities of investigation, e.g., clinical data, brain imaging, neurophysiological investigation, and neuropsychological assessment have a role in this phased management.     

Juvenile Myoclonic Epilepsy: Factors of Error Involved in the Diagnosis and Treatment

Juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, has a distinct clinical and electroencephalographic profile. Often JME is not recognized, with serious consequences on the sufferers. We examined factors contributing to the missed diagnosis even in an epilepsy clinic. Of 70 JME patients, 66 (91.4%) were not diagnosed on referral and 22 (33%) were not initially recognized in the epilepsy clinic. The correct diagnosis was established after a mean of 8.3 +/- 5.5 years from disease onset and an interval of 17.7 +/- 10.4 months from first evaluation in the epilepsy clinic. Myoclonic jerks, the hallmark of the disease, were not usually reported by patients. Similarly, relevant questioning may not be included in the history. Absence seizures antedating jerks by many years, myoclonic jerks reported as unilateral, generalized tonic-clonic seizures occurring during sleep and focal EEG abnormalities are other factors contributing to not recognizing JME. Our study reemphasizes the need to have not only a correct seizure diagnosis but also a correct epilepsy-disease diagnosis.     

Benign Partial Epilepsy with Affective Symptoms: Hyperkinetic Behavior During Interictal Periods

Summary: We report a 4-year-old boy with benign partial epilepsy (BPE) with affective symptoms associated with hyperkinetic behavior during interictal periods. He had had hypermobility and restlessness since about age 3. At 4 years, 6 months, he developed episodes consisting of an expression of terror without complete loss of consciousness. Although we first suspected an acute psychic problem, the ictal EEG was abnormal. After carbamazepine (CBZ) therapy, the frequency of the attacks decreased dramatically and the hyperkinetic behavior gradually diminished.     

Vascular Cognitive Impairment: Disease Mechanisms and Therapeutic Implications

The prevalence of vascular cognitive impairment (VCI) is likely to increase as the population ages and cardiovascular disease survival improves. We provide an overview of the definition and disease mechanisms of VCI and present a systematic literature review of the current evidence for the pharmacologic and nonpharmacologic therapies used to treat the VCI symptoms of cognitive dysfunction or to modify VCI through primary and secondary prevention. The Cochrane Database of Systematic Reviews was searched from 2005 to October 2010 using the keywords “vascular dementia” or “vascular cognitive impairment and therapy.” MEDLINE was searched for English-language articles published within the last 10 years using the combined Medical Subject Headings (MeSH) “therapeutics and dementia,” “vascular” or “vascular cognitive impairment.” Although cholinesterase inhibitors and memantine produce small cognitive improvements in patients with VCI, these drugs do not improve global clinical outcomes and have adverse effects and costs. Selective serotonin reuptake inhibitors and dihydropyridine calcium channel blockers may improve short-term cognitive function in patients with VCI. Anti-hypertensive therapy with an ACE inhibitor-based regimen and statins may prevent the major subtype of VCI known as poststroke cognitive decline. Clinical and effectiveness studies with long-term follow-up are needed to determine the benefits and risks of pharmacologic and nonpharmacologic therapies to prevent and treat VCI. Given its growing health, social, and economic burden, the prevention and treatment of VCI are critical priorities for clinical care and research.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-011-0047-z) contains supplementary material, which is available to authorized users.     

Epilepsy with Continuous Spike-Waves During Slow Sleep and Its Treatment

Five children with epilepsy with "continuous spike-waves during slow sleep" (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age, (b) the occurrence of several types of seizure (i.e., partial motor, generalized motor, and atypical absence), and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (greater than 95%), diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide, ESM) and clonazepam (CZP), the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.     

Progressive Myoclonus Epilepsies: Clinical and Genetic Aspects

The progressive myoclonus epilepsies (PMEs) are a group of rare genetic disorders previously shrouded in nosological confusion. Recent advances have clarified the features of these disorders and provided a rational approach to diagnosis. The major causes of PME are now known to be Unverricht—Lundborg disease, myoclonus epilepsy ragged-red fiber (MERRF) syndrome, Lafora disease, neuronal ceroid lipofuscinoses, and sialidoses. Over the past 3 years, a series of molecular genetic findings have further refined the understanding of the PMEs. The specific mutation responsible for many cases of MERRF has been identified, and the genes for Unverricht—Lundborg disease and for juvenile neuronal ceroid lipofuscinosis have been linked to chromosomes 21 and 16, respectively. Although the PMEs are among the rarest of the inherited epilepsies, because of molecular genetic discoveries they may soon be the best understood at the neurobiologic level.     

Cellular Mechanisms of Epilepsy and Potential New Treatment Strategies

Summary: Over the last 15 years, neurobiologists have begun to unravel the cellular mechanisms that underlie epileptiform activity. Such investigations have two main objectives: (I) to develop new methods for treating, "curing" or preventing epilepsy; and (2) to learn more about the normal functioning of the human brain at the cellular/ molecular and the neurological/psychological levels by analyzing abnormal brain functioning. The electroencephalogram (EEG) spike is a marker for the hyperexcitable cortex and arises in or near an area with a high epileptogenic potential. The depolarizing shift (DS) that underlies the interictal discharge (ID) appears to be generated by a combination of excitatory synaptic currents and intrinsic voltagedependent membrane currents. The hyperpolarization that follows the DS (post-DS HP) limits ID duration, determines ID frequency, and prevents ID deterioration into seizures. The disappearance of the post-DS HP in some models is related to the onset of seizures and the spread of epileptifonn activity. During the transition to seizures , the usually self-limited ID spreads in time and anatomical space. Several processes may intervene in the pathophysioogical dysfunction. These include enhancing GABA-mediated inhibition, dampening NMDA-mediated excitability, interfering with specific Ca²⁺ currents in central neurons, and perhaps stimulating "gating" pathways.     

Long-Term EEG-Video-Audio Monitoring: Detection of Partial Epileptic Seizures and Psychogenic Episodes by 24-Hour EEG Record Review

Twenty-seven patients with medically refractory paroxysmal disorders underwent EEG-video-audio (EVA) monitoring in an inpatient neurology-neurosurgery unit over 1-15 (mean 8.9) days. Fast visual review of all EEG records (5,784 h) and subsequent analysis of synchronized EVA patterns demonstrated a total of 208 partial epileptic seizures (ES) in 12 individuals and 87 psychogenic episodes (PE) in 15 subjects. Clinical ES lasted 83.3 s on the average and were most frequent from day 7 to 9 of monitoring (42.3%) and during sleep (56.4%). PE were longer in duration (mean 724.5 s), most numerous during the first 2 days of monitoring (41.4%), and occurred exclusively during wakefulness. Subjects with PE signaled (by pressing on a push button) more events (35.6%) than did the individuals with ES (27.9%). Multiple observers raised the proportion of alarms to 69.0% of PE compared to 39.9% of ES. Following the alarm, nurses reached the patients' bedside within a brief time (mean 22.2 s). To differentiate partial ES from PE or to establish the association of these disorders, EVA monitoring is best performed around the clock over a period of 1-2 weeks. The limited number of paroxysmal events, especially ES, signaled by the patients should be considered when designing studies of the effectiveness of pharmacologic, surgical, and other treatments.     

Vascular Determinants of Epilepsy: The Rotterdam Study

Summary: Purpose: To investigate the relation between vascular determinants and epilepsy in an elderly population. Methods: This is a cross-sectional, community-based, case-control study. The total study population was comprised of 4,944 subjects, 65 of whom had epilepsy which conformed to International League Against Epilepsy (ILAE) criteria. Vascular determinants that were evaluated included a history of stroke or myocardial infarction, peripheral vascular disease, hypertension, serum total cholesterol and left ventricular hypertrophy. Multivariate logistic regression analysis was used to calculate prevalence odds ratios (OR), adjusted for age and gender, as a measure of the strength of the associations. Results: A history of stroke was strongly associated with lifetime epilepsy (OR 3.3; 95% CI [Confidence Interval] 1.3–8.5), as well as with late-onset epilepsy (OR 3.1; 95% CI 0.9–10.6). All vascular determinants were associated with lifetime epilepsy and late-onset epilepsy, with odds ratios >1. When stroke patients were excluded, the odds ratios were statistically significant for the relationships between total cholesterol and late-onset epilepsy (OR 1.3, 95% CI 1.O–1.6) and left ventricular hypertrophy and late-onset epilepsy (OR 2.9, 95% CI 1.0–8.6). Furthermore, presence of any of these vascular indicators was twice as common among subjects with late–onset epilepsy as compared with subjects without epilepsy (OR 2.0, 95% CI 0.9–4.2), and this was statistically significant when stroke patients were excluded (OR 2.1, 95% CI 1.04.7). Conclusions: These results suggest that there may be a relationship between vascular factors and the risk of late–onset epilepsy, apart from the relationship that exists through clinically overt stroke.     

Clinical and EEG Asymmetries in Juvenile Myoclonic Epilepsy

Summary: We reviewed records of 85 patients with juvenile myoclonic epilepsy (JME) for significant asymmetries in clinical seizures or the EEG. We noted asymmetries in 26 of 85 patients (30.6%). Only 2 patients had both clinical and EEG asymmetries; 12 had clinical asymmetries and 12 had EEG asymmetries exclusively. Analysis of patients with and without asymmetries showed no statistically significant differences in comparisons of sex, age at seizure onset, family history of epilepsy, seizure type, or response to treatment. The delay in diagnosis was greater in JME patients with asymmetries (9.5 years) than in JME patients with no asymmetries (7.5 years), but this difference was not statistically significant. Fourteen of the 26 patients with asymmetries (53.8%) were initially misdiagnosed as having partial seizures. Asymmetries in JME patients are not only common, but are also a frequent cause of misdiagnosis.     

Basic Mechanisms of Epilepsy: Targets for Therapeutic Intervention

Summary: Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage-dependent calcium currents and inhibition of GABA_B receptor-mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure-provoking mechanisms and to enhance the brain's natural protective mechanisms.     

Radiosurgical Techniques and Clinical Outcomes of Gamma Knife Radiosurgery for Brainstem Arteriovenous Malformations

Objective

Brainstem arteriovenous malformation (AVM) is rare and radiosurgical management is complicated by the sensitivity of the adjacent neurological structures. Complete obliteration of the nidus is not always possible. We describe over 20 years of radiosurgical procedures for brainstem AVMs, focusing on clinical outcomes and radiosurgical techniques.

Methods

Between 1992 and 2011, the authors performed gamma knife radiosurgery (GKRS) in 464 cerebral AVMs. Twenty-nine of the 464 patients (6.3%) reviewed had brainstem AVMs. This series included sixteen males and thirteen females with a mean age of 30.7 years (range : 5-71 years). The symptoms that led to diagnoses were as follows : an altered mentality (5 patients, 17.3%), motor weakness (10 patients, 34.5%), cranial nerve symptoms (3 patients, 10.3%), headache (6 patients, 20.7%), dizziness (3 patients, 10.3%), and seizures (2 patients, 6.9%). Two patients had undergone a previous nidus resection, and three patients had undergone a previous embolization. Twenty-four patients underwent only GKRS. With respect to the nidus type and blood flow, the ratio of compact type to diffuse type and high flow to low flow were 17 : 12 and 16 : 13, respectively. In this series, 24 patients (82.8%) had a prior hemorrhage. The mean target volume was 1.7 cm³ (range 0.1-11.3 cm³). The mean maximal and marginal radiation doses were 38.5 Gy (range 28.6-43.6 Gy) and 23.4 Gy (range 18-27 Gy), and the mean isodose profile was 61.3% (range 50-70%).

Results

Twenty-four patients had brainstem AVMs and were followed for more than 3 years. Obliteration of the AVMs was eventually documented in 17 patients (70.8%) over a mean follow-up period of 77.5 months (range 36-216 months). With respect to nidus type and blood flow, the obliteration rate of compact types (75%) was higher than that of diffuse types (66.7%), and the obliteration rate of low flow AVMs (76.9%) was higher than that of high flow AVMs (63.6%) (p<0.05). Two patients (6.9%) with three hemorrhagic events suffered a hemorrhage during the follow-up period. The annual bleeding rate of AVM after GKRS was 1.95% per year. No adverse radiation effects or delayed cystic formations were found.

Conclusion

GKRS has an important clinical role in treatment of brainstem AVMs, which carry excessive surgical risks. Angiographic features and radiosurgical techniques using a lower maximal dose with higher isodose profiles are important for lesion obliteration and the avoidance of complications.     

Benign Partial Epilepsy with Centrotemporal (or Rolandic) Spikes and Brain Lesion

We describe three patients with benign partial epilepsy with centrotemporal spikes (BECT) in association with proven brain lesion (agenesis of the corpus callosum, lipoma of the corpus callosum, and congenital toxoplasmosis, respectively). The age of onset, the ictal signs, the interictal electroencephalographic findings and the favorable outcome of epilepsy even after withdrawal of drug therapy led to the diagnosis of BECT although organic brain lesions were present. In such cases, the epilepsy should not be ascribed to the lesions but should be considered benign even though fortuitiously associated with brain lesions.     

Occipital Lobe Developmental Malformations and Epilepsy: Clinical Spectrum, Treatment, and Outcome

Summary: Purpose : Cortical developmental malformations (CDM) are increasingly recognized in association with epilepsy. We describe 10 patients (age range 14–35 years) with symptomatic occipital lobe epilepsy and CDM.
Methods : Neurologic, neuroophthalmologic and electro-physiologic studies were performed. Patients had MRI, SPECT, and in some cases intracranial EEG investigators.
Results : Mean age of seizure onset was 8 years. We noted strong correlations between the presence of visual auras, the scalp EEG pattern, and the subtype of underlying pathology. Magnetic resonance imaging (MRI) showed CDM in all patients, with polymicrogyria and focal dysplasia being the most frequent malformations. Despite the presence of occipital lobe structural malformations in all patients, visual field deficits were present in only 2. Those who underwent cortical resections were seizure–free or showed major improvement at a mean follow–up of 3.5 years.
Conclusions : Intracranial stimulation studies and the low frequency of pre- and postoperative deficits suggest that some degree of cortical visual reorganization may occur in patients with occipital lobe malformations. Occipital lobe CDM should be sought as a cause of symptomatic occipital lobe epilepsy even though they may become symptomatic after childhood.     

Mesial Temporal Lobe Epilepsy: Clinical Features and Seizure Mechanism

Summary: To study the clinical features of mesial temporal lobe epilepsy, 24 cases were selected based on two criteria: (a) the origin of seizure was localized to the mesiotemporal region on phase 2 monitoring, and (b) a class 1 or 2 postoperative result was obtained after selective mesiotemporal resection. A history of febrile convulsion, particularly in the form of status epilepticus, seems to be a prognostic factor. As for presurgical evaluation, electroencephalography (EEG), magnetic resonance imaging (MRI), magnetoencephalography (MEG), and ictal single-photon emission-computed tomography (SPECT) are important tests. Recording of spontaneous seizures by means of intracranial electrodes is the most reliable for diagnosis. Ammon's horn sclerosis and mesial temporal sclerosis are the most frequent pathologic findings. The seizure mechanism was studied by means of depth EEG recordings and ictal SPECT. The hippocampal formation is more responsible than the amygdala for the origin of seizures. Preferential pathways for seizure spread may be the fornix and stria terminalis, amygdalofugal fibers, and uncinate fasciculus. The concept of mesial temporal lobe epilepsy is valid for selecting medically refractory but surgically remediable patients for surgical treatment.     

Effect of Epilepsy and Sleep Deprivation on the Rate of Benign Epileptiform Transients of Sleep

Seventy-eight individuals with EEG records containing benign epileptiform transients of sleep (BETS) were identified among 7,400 records reviewed in our laboratory in a 6-year period. The records contained no other abnormality in 51 patients (65%). Genuine epileptiform discharges were found in the records of 19 patients; 14 had a history of epilepsy. Thirty-five patients (45%) had a proven history of epilepsy with antiepileptic drug (AED) therapy. In the records of these patients, the mean number of BETS per unit of time was significantly higher (11.88 +/- 2) than in the record of the rest of the laboratory population with BETS (6.89 +/- 0.9) (p less than 0.02). Among five conventional surface montages, ipsilateral ear referential montage (IERM) showed a significantly higher number of BETS per unit of time than did any other surface montage used in the study. Thirty-nine records (50%) were performed after sleep deprivation (SD). When only IERM was considered, SD records showed a significantly higher number of BETS per unit of time (7.36 +/- 1.1) than did non-SD records (3.89 +/- 0.69) (p less than 0.01). Our findings support the general consensus that individual BETS may be normal variants, but a high occurrence of BETS in the record should raise suspicion of underlying epilepsy.     

Epilepsy and the Electroencephalogram in Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic Atrophy (the PEHO Syndrome)

Summary: Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome) is an apparently autosomal recessive disorder manifested by infantile spasms, severe hypotonia, and early arrest of psychomotor development. Subcutaneous edema in the limbs, typical facial features, and blindness with optic atrophy are also present. Neuropathologic and radiographic studies show progressive brain atrophy, which is accentuated infratentorially. We recorded 85 EEGs from 10 patients between the ages of 3 weeks and 12.7 years; follow-up ranged from 7 months to 12.1 years. The infantile spasms were preceded by other neurological symp- toms in all patients. Seven of nine patients showed focal or generalized epileptiform activity or abnormal EEG background. All patients developed hypsarrhythmia, first recorded between 3 and 11 months of age, that was resistant to therapy with ACTH and antiepileptic drugs. After the hypsarrhythmia disappeared, five patients showed slow spike-wave activity generally seen in the Lennox-Gastaut syndrome, and three patients showed background EEG abnormality with generalized or diffuse paroxysmal activity. There were no specific EEG features that could help in the diagnosis of PEHO. The PEHO syndrome should be borne in mind in the diagnostic work-up of patients with infantile spasms, so that potentially harmful treatment can be avoided, and the parents can be counseled about the inheritability of the disorder.