Congenital muscular dystrophy, white-matter abnormalities, and neuronal migration disorders: the expanding concept

The congenital muscular dystrophies are a heterogeneous, recessively inherited group of disorders that have been subclassified on the basis of clinical central nervous system involvement. We report two children with "pure" congenital muscular dystrophy, one merosin negative and one merosin positive with extensive white matter and occipital cortical neuromigration abnormalities on magnetic resonance imaging (MRI). The first patient (merosin-negative congenital muscular dystrophy) presented with hypotonia and weakness in the neonatal period and subsequently was found to have a leukoencephalopathy and occipital cortical dysplasia on magnetic resonance imaging. The second patient presented with developmental delay without definite weakness. Initial investigations revealed a leukoencephalopathy and cortical dysplasia, but the patient subsequently was shown to have merosin-positive congenital muscular dystrophy. These patients illustrate that white-matter changes are not specific for merosin-negative congenital muscular dystrophy alone and that extensive cortical abnormality can be found in both groups of patients. In addition, our second patient illustrates a nonmuscular mode of congenital muscular dystrophy presentation that should be considered in patients with a "nonprogressive leukodystrophy."     

Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings

Seventeen patients with cortical dysplasia who had surgical resection for medically intractable partial epilepsy were studied. Compared with two groups of surgically treated patients with intractable epilepsy due to tumour (n = 20) and mesial temporal sclerosis (n = 40), patients with cortical dysplasia showed significantly more frequent extratemporal lesions, more frequent non-epileptiform EEG abnormalities and less favourable surgical outcome for seizure control. Patients with cortical dysplasia were younger at onset of seizures and had a lower detection rate of CT abnormalities compared with the tumour group, and lower IQ compared with the mesial temporal sclerosis group. MRI was abnormal in five of seven patients. Six patients became seizure-free or almost seizure-free but eight did not experience relief of seizures. Surgical outcome related to the extent of pathology but not to the histological abnormality. Lesions outside the temporal and frontal lobes were correlated with poor surgical outcome, as were generalised interictal EEG abnormalities, which may reflect extensive or multiple lesions. Ictal intracranial recordings were not useful for presurgical evaluation of cortical dysplasia.     

MR of the normal neonatal brain: assessment of deep structures

BACKGROUND AND PURPOSE: Recent work has shown that up to 50% of patients with congenital muscular dystrophies (CMDs) have abnormalities of the brain that can be detected by brain MR imaging. We attempted to determine whether brain MR imaging is useful for the diagnosis and classification of patients with CMDs. METHODS: The brain MR studies of 12 patients with biopsy-proved CMDs were reviewed retrospectively. Using information available in the literature regarding associated brain anomalies as a guide, an attempt was made to classify the patients in terms of "pure" CMD, CMD with occipital agyria, Fukuyama CMD, muscle-eye-brain disease, or Walker-Warburg syndrome. RESULTS: All the patients were easily classified into one of four groups: pure CMD (four patients), Fukuyama CMD (four patients), muscle-eye-brain disease (two patients), or Walker-Warburg syndrome (two patients). Patients with pure CMD had diffuse central cerebral hypomyelination with mild pontine and cerebellar hypoplasia. Patients with Fukuyama CMD had diffuse central cerebral hypomyelination, cerebellar polymicrogyria (with or without cysts), frontal polymicrogyria, a variable degree of hypoplasia of the pons and cerebellar vermis, and a variable occipital cobblestone cortex. Patients with muscle-eye-brain disease had cerebellar polymicrogyria (with or without cysts), absence of the septum pellucidum, diffuse cerebral cortical dysplasia, pontine and cerebellar vermian hypoplasia, patchy hypomyelination, and variable callosal hypogenesis and hydrocephalus. Patients with Walker-Warburg syndrome had diffuse cerebral cobblestone cortex, absence of cerebral and cerebellar myelin, cerebellar polymicrogyria (with or without cysts), pontine and cerebellar vermal hypoplasia, hydrocephalus, and variable callosal hypogenesis. CONCLUSION: MR imaging shows distinctive brain anomalies that allows patients with CMD to be classified into four distinct groups that are consistent with known disorders.     

Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules

PURPOSE: To investigate the significance of cortical pathology of tonic spasms in patients with tuberous sclerosis. METHODS: The subjects were 38 patients with epilepsy associated with tuberous sclerosis. We analyzed ictal EEGs of tonic spasms and partial seizures by means of video-EEG monitoring for a total of 763 tonic spasms in 20 patients and 107 partial seizures in 15 patients. We also investigated the relation between partial seizures and magnetic resonance imaging (MRI) findings of these patients. RESULTS: Ictal EEG patterns of tonic spasms were divided into generalized and focal patterns. Thirteen patients had only generalized patterns, whereas seven had both patterns. In five patients who had focal ictal patterns of tonic spasms and partial seizures, the location of focal patterns corresponded with the location of onset of partial seizures. Focal discharges were seen immediately before, after, and in the middle of tonic spasms in series in 13 patients. The location of focal discharges also corresponded with the location of the onset of partial seizures in 10 of the 13 patients. Regarding partial seizures, four patients had multiple active epileptogenic foci during the same period, and two others had shifting epileptogenic foci with increasing age. CONCLUSIONS: These findings indicate that cortical pathology plays an important role in the occurrence not only of partial seizures but also of tonic spasms in patients with tuberous sclerosis.     

Latest tests for prostatic neoplasia

Neurofibromatosis 1 is a common, genetically transmitted neurodevelopmental disorder with a high potential to cause subcortical focal brain lesions. Although seizures occasionally complicate neurofibromatosis 1, they have not been characterized adequately in the disease. Other phacomatoses with attendant subcortical focal brain lesions have been associated with an evolution from generalized to focal-onset epilepsy. This evolution may be related to the cortical dysplasias that also appear in such disorders. Cortical dysplasias, although occasionally found in neurofibromatosis 1 epileptic patients, are not as frequent as in other phacomatoses. The authors retrospectively screened 499 neurofibromatosis 1 patients for the prevalence and etiology of seizures, their response to therapy, and the evolution of seizure type over time. The prevalence of epileptic seizures (4.2%) was about twice the prevalence in the general population. There were no significant cortical dysplasias identified radiographically nor was there a relationship among the presence of subcortical focal brain lesions and seizure type, response to treatment, or evolution of epilepsy in the neurofibromatosis 1 population. The authors' data do not suggest an ontogeny of epilepsy in neurofibromatosis 1 that is different from the general epileptic population.     

Bilateral neuropathologic changes in a child with hemimegalencephaly

Evaluation of a 7-month-old girl with developmental delay and intractable seizures revealed hemispheric asymmetry and an enlarged right cerebral hemisphere. Because of a history of seizures refractory to medical therapy, she was admitted for right hemispherectomy, but died of complications of surgery. Postmortem brain examination revealed asymmetric enlargement of the right cerebral hemisphere but no gross abnormalities in the left hemisphere. Microscopic examination demonstrated bilateral neuropathologic changes consistent with severe cortical dysplasia in the right cerebral hemisphere and mild cortical dysplasia in the left. Although white matter abnormalities in the unaffected hemisphere have been reported in hemimegalencephaly, bilateral cortical abnormalities, not reported previously in patients with hemimegalencephaly, may account for the varied clinical outcome with medical therapy or after hemispherectomy.     

Immunocytochemical investigation on dysplastic human tissue from epileptic patients

In this report we describe three patients with developmental cortical abnormalities (generally referred as cortical dysplasia), revealed by MRI and operated on for intractable epilepsy. Tissue, removed for strictly therapeutic reasons, was defined as the epileptogenic area by electroclinical data and stereo EEG (SEEG) recordings. Tissue samples were processed initially for histology, and selected sections were further processed for immunocytochemical investigation in order to determine whether the region of cortical dysplasia was co-extensive with the epileptogenic area. In two patients with nodular heterotopia, disorganized aggregates of neurons (as revealed by neuronal cytoskeletal markers) were found within the nodules. Both pyramidal and local circuit neurons were present in the nodules, but no reactive gliosis was present. When nodules reached the cortex, the cortical layers were disrupted. In the patient with localized cortical dysplasia, a complete disorganization of the cortical lamination was found, and numerous neurons were also present in the white matter. Disoriented pyramidal neurons weakly labelled with cytoskeletal neuronal markers were also present but no cytomegalic cells were found. One of the patients with nodular heterotopia underwent only partial resection of both the 'epileptogenic area' and of the lesion; this patient still presents with seizures. The other patient with nodular heterotopia is seizure-free after a complete lesionectomy and excision of the epileptogenic area. The third patient, with focal cortical dysplasia, had two surgeries; she became seizure-free only after the excision of the epileptogenic area detected by SEEG recording. The present data suggest that the dysplastic areas identified by MRI should not be considered as the only place of origin of the ictal discharges. From the neuropathological point of view, the focal cortical dysplasia can be considered as a pure form of migrational disorder. However, the presence of large aggregates of neurons interspersed within the white matter, in the subcortical nodular heterotopia, suggests that a defect of neuronal migration could be associated with an exuberant production of neuroblasts and/or a disruption of mechanisms for naturally occurring cell death.     

Histological change of keratinocyte in full-thickness skin autograft and its effect on hyperpigmentation of the graft

OBJECTIVES: To investigate the frequency of ECG abnormalities suggestive of myocardial ischaemia in patients with severe drug resistant epilepsy and without any indication of previous cardiac disease, assuming that these changes may be of significance for the group of epileptic patients with sudden unexpected death. MATERIAL AND METHODS: Twelve patients with medically intractable epilepsy were investigated with simultaneous long ECG and EEG recordings while attending either epilepsy surgery investigational procedures or the investigational programme for diagnostic purposes, and one while having an episode of status epilepticus. RESULTS: The ECG recording failed in 1 patient. This patient had chest pain and minor yet morphologically conspicuous changes in the ECG, suggestive of myocardial infarction. He died in heart arrest. Eight epilepsy patients had episodes of ST segment depression in the ECG, many of which coincided with video- and EEG documented epileptic seizures. Two patients experiencing simple partial seizures and 1 patient experiencing absence seizures had no ST segment depressions in the ECG. One patient had an episode of status epilepticus secondary to brain damage and no ST segment deviation was seen during the ECG recording which continued until 3 h before the patient died. CONCLUSION: Patients with severe drug resistant epilepsy have episodes of ST segment changes, some of which are closely related to epileptic seizures. Further studies are needed to confirm the present results and to investigate the nature of these changes and document the effect of prophylactic treatment with cardioactive drugs to reduce the risk of sudden death.     

Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients

BACKGROUND: Seizures in patients with tuberous sclerosis complex (TSC) are often intractable to antiepileptic medications and searching investigation may provide evidence that surgical treatment can be considered. OBJECTIVE: To review the results of investigation and surgical therapy, a treatment modality not generally considered in patients with medically refractory seizures and TSC. METHODS: We report 18 patients (9 male) with TSC who underwent surgical treatment of medically refractory epilepsy. Twelve patients had a well-localized epileptogenic lesion and were treated by lesionectomy or focal resection. Resections were: 7 frontal, 4 temporal, 1 frontotemporal, 1 occipital, and 1 frontoparietal. Four patients underwent more than one operation. Six patients had corpus callosotomy (CC). RESULTS: Follow-up ranged from 1 month to 47 years. Outcome of the patients treated by resection was excellent in 7 (5 were seizure-free and 2 had auras only), good in 1, fair in 3, and 1 was lost to follow-up. Best outcome was obtained in patients who had focal seizures and good imaging and EEG correlation, although they might have multiple seizure types, other imaging abnormalities, and multifocal or generalized EEG findings. When there was no such correlation, CC was found to be an option as five patients had at least some improvement and only one showed no change. CONCLUSION: Surgical treatment of patients with TSC and intractable epilepsy is most effective when a single tuber or epileptogenic area can be identified as the source of seizures and resected. This may be possible even when other tubers or diffuse EEG abnormalities are present. In patients with unlocalizable epileptic abnormalities, palliation may be obtained by CC.     

Kabuki make-up syndrome associated with West syndrome

A Japanese boy with Kabuki make-up syndrome associated with West syndrome is reported. He developed periodic tonic spasms at 6 months of age while his electro-encephalogram also revealed hypsarrhythmia. Although only a few previously reported cases of Kabuki make-up syndrome have been associated with epilepsy, it is likely that epileptic seizures are another primary feature of Kabuki make-up syndrome.     

Molecular characterization of a dual endothelin-1/Angiotensin II receptor

Clinical neurophysiologic studies have an important role in the diagnosis and management of the patient with epilepsy. Epilepsy is a clinical diagnosis and the EEG is an important adjunct used to differentiate epileptic seizures from nonepileptic events, refine the diagnosis of epilepsy into specific seizure types and epileptic syndromes, and provide a measure of brain function. The value of the EEG is highly dependent on the clinical context in which it is being applied. In some epilepsies the interictal EEG may be diagnostic whereas in others an ictal recording may be necessary to obtain a specific diagnosis. Both the interictal and ictal EEG characteristics vary with specific seizure types and epilepsies and are described in detail in this review. The usefulness of the EEG in the management of epilepsy and in aiding in the decision to discontinue antiepileptic therapy is also discussed.     

Epilepsy and disorders of cortical development in children with congenital cytomegalovirus infection

INTRODUCTION: Neuroimaging and experimental studies have related cytomegalovirus (CMV) to certain neuronal migration disorders. MATERIAL AND METHODS: To define the electroclinical picture of children with epilepsy associated with disorders of cortical development (DCD) and congenital CMV infection, we conducted a clinical, electroencephalographic and neuroradiological study of 10 children with this condition. RESULTS: Eighty per cent of them had dismorphic traits, or malformations outside CNS. All showed other neuroradiological signs (cerebral calcification, white matter damage, porencephaly). Six patients with bihemispheric DCD (agyria-pachigyria, 2; 'poligyria', 1; schizencephaly, 1; bilateral opercular DCD, 2) showed: Tetraparesis, severe or profound mental deficiency, early onset epilepsy (mean age at onset: 11 months) with spasms, tonic seizures, partial seizures, and multifocal paroxysms or unusual diffuse sharp Alfa-Beta EEG activity. One child developed Epilepsia Partialis Continua. Children with bilateral opercular DCD evolved to a continuous spike and wave (SW) electrical status during wakefulness and sleep, linked to a worsening of psychomotor derangement. Four patients with unilateral hemispheric DCD (pachigyric or 'poligyric') showed: Congenital hemiparesis, mild intellectual deficiency, motor seizures (orofacial, hemiclonic, generalized) beginning in the third year of live, atypical absences with focal phenomena, frequent focal rhythmic SW discharges during wakefulness, and continuous SW status during sleep (CSWS). CONCLUSIONS: A wide spectrum of DCD due to congenital CMV infection is documented. Characteristic electroclinical pictures related to the extent and topographical distribution of the DCD are recognized, which may lead to an appropriate diagnosis and prognosis.     

Predictive factors of early seizures after acute cerebrovascular disease

BACKGROUND AND PURPOSE: Seizures within the first 48 hours of a first stroke or transient ischemic attack (TIA) are an independent prognostic factor for in-hospital mortality. The aim of this study was to determine predictive factors of early seizures in first-ever stroke patients. METHODS: Data of 1220 first-ever stroke patients admitted consecutively to an acute stroke unit of a 450-bed teaching hospital between January 1986 and December 1993 were collected from a stroke registry. Demographic, anamnestic, clinical, neurological, and neuroimaging variables in the seizure and nonseizure group were compared using the t test and the chi 2 test. The independent predictive value of each variable on the development of early seizures was assessed with a logistic regression analysis. RESULTS: Early epileptic seizures were diagnosed in 29 patients (2.4%). Seizures were significantly more frequent in patients with hemorrhagic stroke (4.3%) than in those with ischemic stroke (2%). Patients with seizures were significantly younger and significantly more likely to have acute confusional state, cortical involvement, large stroke, and involvement of the parietal, frontal, occipital, and temporal lobes than patients without seizures. The in-hospital mortality rate was 37.9% in the seizure group and 14.4% in the nonseizure group (P < .0005). After multivariate analysis, only cortical involvement (odds ratio of 6.01) and acute agitated confusional state (odds ratio of 4.44) were independent clinical factors for developing epileptic seizures. CONCLUSIONS: Cortical involvement in the neuroimaging studies and agitated acute confusional state at the onset of stroke were independent predictive factors of early seizures in first-ever stroke patients. The efficacy of anticonvulsant drugs in the prophylactic control of seizures should be assessed in prospective, randomized, double-blind clinical trials conducted in the subgroup of patients with the highest risk of developing epileptic seizures.     

Parietal and occipital lobe epilepsy: a review

There has been considerable recent interest in frontal lobe epileptic syndromes, and less attention paid to occipital and parietal epilepsies. The occipital and parietal lobes have arbitrary anatomical borders. The prinicpal seizure symptomatology includes somatosensory (paresthetic, painful, thermal, sexual, apraxia, disturbances of body image); visual (amaurotic, elementary and complex hallucinations, illusions) and other phenomena (anosognosia, apraxia, acalculia, alexia, aphemia, confusional states, gustatory, vertiginous, adversive, oculoclonic and eyelid flutter). The seizure symptoms are of varying localizing and lateralizing value and seizure discharges may spread rapidly and perceived symptoms may reflect secondary spread rather than the primary site of seizure onset. Recognized parietal and occipital epilepsy syndromes include benign epilepsy of childhood with centrotemporal spikes, benign epilepsy of childhood with parietal evoked spikes, benign occipital epilepsy of childhood, migraine/epilepsy syndromes, and epilepsy with bilateral occipital calcification. In addition, occipital and parietal epilepsy may be on the basis of any underlying structural lesion. There is frequently a poor correlation between clinical and EEG features. MRI and functional imaging often reveals underlying pathology. There have been no specific trials of different antiepileptic drugs for occipital and parietal seizures. Surgical treatment has its place, with attention to the risk of causing a fixed neurological deficit.     

Changes of laminin beta 2 chain expression in congenital muscular dystrophy

We studied the distribution of laminin beta 2 chain in the skeletal muscle basement membrane of 16 patients with congenital muscular dystrophy (CMD) by immunohistochemistry. A dramatic reduction in the laminin beta 2 staining was observed in four patients with classical merosin-negative CMD. A moderate reduction of laminin beta 2 labelling was observed in four patients with partial merosin deficiency and two patients with merosin-positive CMD. Two patients with merosin-positive CMD had no apparent changes in the expression of laminin beta 2. In three patients and one fetus diagnosed as Walker-Warburg syndrome (WWS) the laminin beta 2 pattern was similar to normal controls. We conclude that a primary deficiency in the laminin alpha 2 chain may lead to a vast or moderate reduction in the laminin beta 2 chain in the skeletal muscle membrane.     

Reading-induced epilepsy: three new cases

INTRODUCTION: Primary epilepsy of reading is a rare syndrome in which patients present with mandibular myoclonia when reading texts. Seizures are also frequently provoked by other stimuli. Occasionally they may be followed by generalized tonic-clonic seizures. CLINICAL CASES: We present the clinical features and electroencephalographs of three patients with epilepsy of reading, one of them also had seizures when playing chess and after doing arithmetic and the third after reading music. Treatment with valproic acid and clonazepam completely controlled the seizures in all three patients. In two cases we saw epileptiform activity on EEG whilst they were reading, although the basal EEG was normal. CONCLUSIONS: We believe that epilepsy of reading is under-diagnosed and emphasize the importance of careful questioning of epileptic patients as to factors which may precipitate the seizures. In view of the social problems which may arise, early recognition of the syndrome is important for the patient.     

Epileptiform electroencephalographic patterns

Electroencephalography (EEG) is the most useful test for assessment of patients with epilepsy. It can help establish the diagnosis of epilepsy and determine the type of seizure disorder and its site of origin. Epileptiform abnormalities in the EEG tracing may be focal or generalized. The main types of focal epileptiform discharges arise from the temporal, frontal, occipital, centroparietal, centrotemporal, and midline regions of the brain. Generalized epileptiform discharges consist of the 3-Hz spike-and-wave, slow spike-and-wave, atypical spike-and-wave, paroxysmal fast activity, and hypsarrhythmic patterns. Status epilepticus is manifested by continuous epileptiform discharges or recurrent seizure activity without interim recovery, which can occur in a generalized or focal manner. Benign epileptiform variants unassociated with seizures can also be present in the EEG. Included in this category are the "14 & 6" positive bursts, small sharp spikes, wicket waves, 6-Hz spike-and-wave discharges, and rhythmic temporal theta activity. The EEG findings should be interpreted in the context of the overall clinical picture.     

Twenty-four-hour ambulatory EEG monitoring in infantile spasms

Twenty-four-hour ambulatory EEG (AEEG) recordings were performed in 74 infants with West Syndrome (WS) who had not received corticosteroids before the recording. EEG analysis was performed visually for interictal background activity as well as for ictal events: spasms (isolated or in clusters) and other seizures either generalized or partial. Six hundred fifty-four seizures were recorded in 67 patients. Partial seizures (PS) were noted in 31 infants (51% of symptomatic WS cases, 33% of cryptogenic WS cases). In 14 patients, PS were immediately followed by a cluster of spasms consisting of a single ictal event. Patients with PS had an asymmetrical interictal background activity in 85% of cases, with no return to hypsarrhythmia between spasms in a given cluster. AEEG is a reliable method to detect and analyze ictal events in infants with WS. In this population, patients with unfavorable outcome of both epilepsy and psychomotor development have PS. Therefore, the existence of PS may contribute to etiologic diagnosis and prognostic evaluation.