Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder prevalent in Japan, characterized by cobblestone lissencephaly and dystrophic changes in skeletal muscle, resulting in mental retardation, epilepsy and motor impairment. FCMD patients in Japan carry at least one copy of an ancestral founder mutation, a 3 kb insertion in a 3'-untranslated region, that results in a reduction in fukutin mRNA levels. We analyzed 35 patients with FCMD and found 18 patients carried a homozygous founder mutation (homozygotes) and 17 a combined heterozygous between founder mutation and a nonsense or missense mutation (heterozygotes). During an average follow-up of over 10 years, 61% of homozygotes and 82% of heterozygotes developed febrile or afebrile seizures. The ages at onset of febrile and afebrile seizures on average were 5.4 and 4.6 years, respectively, in homozygotes and 3.6 and 3.7 years, respectively, in heterozygotes. Repeated seizures were treated with antiepileptic drugs. While all homozygotes showed good seizure control, four heterozygotes had intractable seizures. Mutations other than the 3 kb insertion were identified in seven of 12 heterozygotes examined. Five patients with a nonsense mutation in exon 3 and one with a missense mutation in exon 5 had a severe phenotype and some showed intractable seizures. On the other hand, one with a nonsense mutation in exon 8 had only one febrile seizure. It was concluded mutational analysis of the FCMD gene could predict seizure prognosis. Heterozygotes usually developed seizures earlier than homozygotes and some heterozygotes showed intractable seizures. Mutational analysis other than of the 3 kb insertion may also help to predict seizure prognosis.     

The Risk of Nonfebrile Seizures in Children Who Have Experienced Febrile Convulsions

Abstract: (1) The frequency of development of nonfebrile seizures in 116 children who had experienced at least one febrile convulsion and were followed for more than five to eight years was 4.3% (5 cases). Of these, three cases had prolonged generalized convulsions of the clonic or tonic-clonic type and two had brief generalized fits of the tonic-clonic type. (2) The risk factors identified as nonfebrile seizures after febrile convulsions were the preexisting neurological abnormality or developmental retardation, focal features and more than a 10-minute duration of the first febrile convulsions, and abnormal paroxysmal discharges at the initial interictal EEG recordings.     

A case of Fukuyama-type congenital muscular dystrophy with a very mild mental deficit

A boy had the clinical features of congenital muscular dystrophy with a very mild mental deficit. A muscle biopsy at one year of age showed the typical findings of Fukuyama-type congenital muscular dystrophy, including selective loss of immunoreactions for alpha dystroglycan. Magnetic resonance imaging showed no findings suggestive of migration disorders. The diagnosis of Fukuyama-type congenital muscular dystrophy was confirmed by a molecular assay at 8 years of age, and his haplotype analysis was heterozygous. At 9 years of age, his FIQ on the Wechsler Scale for Children revealed 69, while his IQ on the Tanaka Binnet scale of intelligence was 97. In this report the relationship between mild clinical condition of the studied case and its genotype is discussed.     

Congenital muscular dystrophy with central nervous system involvement: case report

A case of a mediterranean boy with congenital muscular dystrophy (CMD) and central nervous system (CNS) involvement with mild intellectual impairment and seizures is reported. Muscular dystrophy involved both skeletal and mimic muscles, and histological findings were consistent with a congenital dystrophy. EEG recordings showed generalized and localized paroxysmal activities. CT scan demonstrated low-density periventricular areas. Ophthalmoplegia was also observed. A literature review disclosed that in some western cases of CMD plus CNS involvement, cranial muscles other than mimic muscles may be involved.     

Broader clinical spectrum of Fukuyama-type congenital muscular dystrophy manifested by haplotype analysis

Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease are clinically similar autosomal-recessive diseases, characterized by congenital muscular dystrophy, cobblestone lissencephaly, and eye anomalies. The classification of these disorders remains controversial. We analyzed five patients with congenital muscular dystrophy from four families who had severe eye and brain anomalies, such as retinal dysplasia and hydrocephalus, using polymorphic microsatellite markers flanking the Fukuyama-type congenital muscular dystrophy locus on chromosome 9q31. All patients were heterozygous for the Fukuyama muscular dystrophy founder haplotype with 3-kb insertion. In three cases, the other chromosome without the 3-kb insertion exhibited the same haplotype with a nonsense mutation on exon 3 of the Fukuyama gene. Thus, these three patients were compound heterozygotes for the condition. Severe eye anomalies such as retinal dysplasia or detachment and hydrocephalus could be included in the clinical spectrum of Fukuyama muscular dystrophy. The clinical spectrum of this disease is much broader than previously presumed.     

Generalized absence seizures with 10-15 Hz fast discharges.

OBJECTIVE: To report clinical and EEG features in 5 adults with unusual, fast rhythmic discharges accompanying absence seizures. DESIGN AND METHODS: The 5 patients presented with uncontrolled seizures. All had EEG-video monitoring with recorded seizures. Video seizures were reviewed and ictal as well as interictal epileptiform activity was analyzed. The patients were followed up after appropriate therapy for a minimum of 6 months. RESULTS: There were 3 women and two men, with a mean age of 37 years (range: 23-59). Two patients had onset of absence seizures in childhood, one in adolescence and two after age 20. All patients also had generalized tonic-clonic seizures. Ictal EEG recordings showed generalized spike and wave (SW) discharges of variable dominant frequencies (2.5-6 Hz) and intermingled 10-15 Hz generalized rhythmic discharges which also occurred in isolation or as the dominant activity. Interictal recordings showed similar but shorter 2.5-6 Hz generalized SW discharges. The background activity was normal in 3 patients and mildly slow in two who had very frequent absence seizures during the recording period. Four patients became seizure free and one had 75% improvement on appropriate antiabsence therapy. CONCLUSIONS: The fast 10-15 Hz rhythmic discharges that we report appear to occur mostly in adult patients with absence, as well as, generalized tonic-clonic seizures. They can occur in isolation or be embedded in more typical SW discharges accompanying typical absence seizures. Their presence does not imply a poor prognosis for seizure control.     

Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness

OBJECTIVE: The fukutin gene (FKTN) is the causative gene for Fukuyama-type congenital muscular dystrophy, characterized by rather homogeneous clinical features of severe muscle wasting and hypotonia from early infancy with mental retardation. In contrast with the severe dystrophic involvement of skeletal muscle, cardiac insufficiency is quite rare. Fukuyama-type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of alpha-dystroglycan, an indispensable molecule for intra-extra cell membrane linkage. METHODS: Protein and functional analyses of alpha-dystroglycan and mutation screening of FKTN and other associated genes were performed. RESULTS: Surprisingly, we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old. Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of alpha-dystroglycan and reduced laminin binding ability. One cardiac muscle that underwent biopsy showed altered glycosylation of alpha-dystroglycan similar to that observed in a Fukuyama-type congenital muscular dystrophy patient. INTERPRETATION: FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy.     

Epilepsy in patients with advanced Fukuyama congenital muscular dystrophy

BackgroundRecent advances in respiratory management have improved survival for patients with Fukuyama congenital muscular dystrophy (FCMD), characterized by congenital muscular dystrophy and brain malformation. Previous studies reported that more than half of patients exhibit seizures in childhood. However, little is known about epilepsy after childhood.MethodsTo elucidate the long-term clinical course of epilepsy, we retrospectively reviewed all medical records in nine patients (6 males, mean age 20.7 years) with FCMD diagnosed between 1981 and 2019.ResultsThe follow-up periods ranged from 6 to 30 years (mean 18.4 years). A total of 75 EEG recordings were available from nine patients. In some patients, EEGs were normal during early childhood but tended to show paroxysmal discharges with age. Overall, epileptic seizures were observed in six patients. Except for one presenting with afebrile seizure at one year of age, the remaining five patients developed epilepsy between 13 and 22 years of age. The most common seizure type was focal impaired awareness seizure. After adolescence, four patients exhibited status epilepticus. Their convulsive movements of the seizures became less prominent with progression of the disease. At the last evaluation, most patients (5/6) had uncontrolled seizures.ConclusionsDespite presence of distinct brain malformation, epileptic seizures may develop after childhood in FCMD patients. Our experience suggests that clinicians should be careful not to overlook epileptic seizures, especially in advanced-stage patients who had profound muscle weakness.     

Push-pull perfusion of pentylenetetrazol in the brain stem of 'encéphale isolé' cats

Nine 'encéphale isolé' cats had 'push-pull' perfusions of pentylenetetrazol (PTZ) in various loci of the brain stem, while the EEG from the right and left motor cortices, EMG from neck muscles, ocular movements and clinical changes were recorded. Perfusions in the rostral MRF induced bilateral rhythmic paroxysmal EEG discharges and myoclonic twitching of neck and head, more prominent in the muscles contralateral to the perfused side. PTZ in the caudal MRF induced tonic-clonic paroxysmal EEG discharges and EMG seizures, similar to those seen when PTZ is injected systemically. Perfusion in the PRF induced EEG spindle bursts, muscular hypotonia and myosis. When perfusion in the MRF inducing rhythmic paroxysmal EEG discharges and myoclonic twitching was followed by perfusion in the PRF, the EEG discharges were not modified, but the myoclonic movements were abolished. Perfusions outside the MRF and PRF did not produce obvious changes other than tonic gaze deviation to the contralateral side or nystagmus. The results suggest that PTZ has a differential effect in various structures of the CNS, producing primary generalized convulsive seizures when acting directly on the MRF.     

Fukuyama type congenital muscular dystrophy as a natural model of childhood epilepsy.

Fukuyama type Congenital Muscular Dystrophy, inherited autosomal-recessively, is characterized by muscular dystrophy associated with severe mental retardation and epileptic convulsions. By examining 56 cases, followed for more than three years, 75 EEG records from 40 patients and visual evoked potentials from 11 patients with reference to autopsied materials, the authors aimed at clarifying the causative relationship between congenital central nervous system (CNS) lesions and childhood epilepsy. In 36 out of 56 cases diffuse epileptic seizures were observed with onset at 1.64 +/- 1.01 years average. In 32/36 cases seizures developed before 3 years of age. In 51/75 EEGs focal paroxysmal discharges (FPD), fronto-contro-parietal in younger and centro-occipital in older cases, were observed. Abnormal basic activities (ABA), diffuse-alpha-activity and/or abundant or extreme spindles, were observed more often in older than younger cases. The incidence of FPD was similar between convulsive and non-convulsive cases, but ABA predominated in the former, VEP revealed abnormal findings in 64% of 11 cases examined. Of the CNS pathology, consisting of cerebral and cerebellar gyral abnormalities and a hypoplastic corticospinal tract, the gyral lesions (verrucous polymicrogyria with adhesions of adjacent gyri and cellular disarrangement) were thought to be lesions causing epilepsy. Cortical nonprogressive gyral lesions occurring around the second trimester could cause FPD and clinical diffuse epileptic seizures develop with other factors concerned with ABA.     

Clinical and EEG studies on complex partial seizure in children

In 18 (40%) of 45 patients with CPS, paroxysmal discharges were hard to be found on their interictal EEG examinations. These patients were, however, not different from the other 27 patients with paroxysmal discharges on EEG as for the onset, prognosis for attack, complication of generalized tonic-clonic seizure and febrile convulsion, family history and adaptation to society.     

Clinical and electroencephalographic findings prior to the onset of juvenile myoclonic epilepsy: A case series

The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike–wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike–waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.     

Is cerebral arteritis the cause of the Landau-Kleffner syndrome? Four cases in childhood with angiographic study.

Four children with Landau-Kleffner syndrome were studied over a six year period. They presented with acquired aphasia, epilepsy, and focal or generalized EEG discharges which were exacerbated during sleep. In addition, cerebral angiography demonstrated isolated arteritis of some branches of the carotid arteries in all cases. Computed tomographic and magnetic resonance images were normal. Nicardipine in a dose of 1 to 2 mg/kg/day, added to conventional anticonvulsant drugs provided effective supplementary control of seizures, of paroxysmal EEG discharges, and of language and behavioural disturbances, even several years after the onset of the disorder and in patients whose response to other medications, including steroids, had been poor. Interruption of nicardipine administration was followed by relapse of the language disorder. Repeat angiography was performed in all four patients and showed recanalization of obstructed vessels in two cases. Focal cerebral vasculitis may be the pathogenesis of the Landau-Kleffner syndrome and calcium channel blockers such as nicardipine may be effective and specific therapy.     

Primary generalized epilepsy during infancy and early childhood

The present study delineates a benign generalized epileptic disorder during infancy and early childhood similar to the well-defined syndrome of primary generalized epilepsy in adolescence. The inclusion criteria for the study required infants under the age of 4 years mainly presenting with generalized nonfebrile seizures, requiring corroboration with generalized epileptic discharges on electroencephalograms (EEGs); an unremarkable pregnancy, labor, and perinatal course; a favorable response to antiepilepsy drugs, preferably monotherapy; and a normal cognitive outcome. The clinical features of seizures, EEG correlates, response to medications, developmental outcome, and family history were analyzed. Twenty-five infants fulfilled the inclusion criteria, presenting at ages 4 to 36 months (mean 17 months) with recurrent generalized clonic seizures, which were commonly short-lived, lasting up to 5 minutes; two infants also had status epilepticus. Fourteen infants (56%) had accompanying febrile seizures, which preceded the nonfebrile seizures in 10 of them. A positive family history of seizures was found in 8 (32%) patients. Analysis of the EEG showed generalized epileptiform discharges in the form of 3 to 4 Hz spike-wave and normal background activity in 21 patients (84%), with a photosensitive response induced in 3 children. A larger group of 18 infants promptly responded to therapy, mainly valproic acid, which was terminated after 2 years, along with EEG normalization and no recurrence of seizures. A smaller group of 7 patients require prolonged therapy that keeps them seizure free; the EEG remains paroxysmal, and the seizures could recur when treatment is discontinued. All patients are presently seizure free within a follow-up period of 1.5 to 14 years. Their cognition is normal, but 12 patients have short attention and concentration spans, impulsiveness, and learning difficulties. As such, the data presented here delineate an idiopathic generalized epileptic disorder during infancy with a benign course, a rapid response to therapy, and preservation of cognitive skills that may be added to the current classification of the epileptic syndromes.     

Merosin-negative congenital muscular dystrophy,occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families

We report clinical, EEG and neuroimaging findings of three patients in two Italian families with merosin-negative congenital muscular dystrophy (CMD), drug-resistant occipital epilepsy, diffuse persistent cerebral white matter changes and focal cortical dysplasia. Clinical and epilepsy histories, EEG and neuroimaging findings were very similar in all patients. Seizures started in childhood and mainly consisted of periodic spasms, a particular type of partial seizure characterized by clusters of epileptic spasms. The motor expression of the spasms was very mild so that they had been frequently missed or misinterpreted as non-convulsive generalized absence seizures. Interictal EEG showed occipital spike-waves and bilateral synchronous slow spike-wave discharges. Ictal EEG showed prolonged periodic sequences of slow waves with associated fast rhythm complexes, characteristic of periodic spasms. Two patients had normal intelligence, one patient presented moderate mental retardation. Focal cortical dysplasia in the posterior areas of the brain, in addition to marked diffuse white matter alterations, was detected in the magnetic resonance images of all patients. Findings in these patients indicate that in merosin-negative CMD brain involvement can include cortical dysplasia, in addition to white matter changes. In such cases the brain damage can lead to a childhood-onset localization-related symptomatic occipital epilepsy. Epileptic seizures and cortical dysplasia can be, however, difficult to detect in CMD. The clinical semiology of epileptic seizures may in fact be modified because of muscular weakness. This implies that epilepsy may be misdiagnosed or even missed and EEG-polymyographic recordings may be necessary to identify it. Similarly, cortical dysplasia may be very localized and visible by neuroimaging only if it is carefully investigated on the basis of epileptological and EEG-polymyographic findings.     

Effect of sagittal transections of the brain stem tegmentum on alumina cream-induced focal motor seizures in cats

The effect of extensive and circumscribed sagittal transections of the brain stem tegmentum on types B (epilepsia partialis continua) and C (contradversive tonic-clonic seizures) alumina cream-induced focal motor seizures in cats was investigated. The neurological abnormalities of cats with transections and differences in the EEG-EMG patterns of types B and C seizures between operated and intact animals were statistically analyzed. Animals with either extensive or superior central nucleus transections showed bilateral neglect and internuclear palsy syndromes, no tonic type C seizures (contradversion), and a significant decrease in electromyogram multiple-unit activity (EMG MUA) from 0 to 10 s or more after the onset of EEG paroxysmal tonic-clonic discharges. Animals with rostral transections showed a unilateral neglect and internuclear palsy or ataxic syndromes with a concomitant partial reduction of contradversive seizures and a significant decrease in EMG MUA from 0 to 5 s or less after the onset of EEG tonic-clonic discharges; those with dorsal and caudal transections showed a transient neglect and insomniac syndromes with no differences in contradversion and EMG MUA at the onset of EEG tonic-clonic discharges in relation to intacts. Experimental and intact animals showed neither differences in types C and B EEG patterns nor in EMG MUA at the end of type C EEG tonic-clonic discharges and type B EEG spikes. These results support the idea that tonic and clonic muscular seizures are due to epileptic impulses originating in the cerebral cortex and mediated at the level of the brain stem by different pathways.     

Rudimentary spike-wave complexes in children during drowsiness

This study consists of the investigation of the anamnestic and electroclinical features of 37 children who showed paroxysmal activity on EEG during drowsiness. This activity is composed of generalized slow high-voltage waves with intermixed spikes and sharp waves (Rudimentary Spike-Wave complexes). All the children had suffered from febrile convulsions, with none of them developing epileptic syndromes during the 3 years following the onset of the study. We point out the diagnostic value of RSW as well as the necessity of careful monitoring of the waking-drowsy state during EEG in children with febrile convulsions.     

EEG Changes and Seizure Exacerbation in Young Children Treated with Carbamazepine

Summary: Carbamazepine (CBZ) has been reported to exacerbate some seizure types in children. We studied the correlation between CBZ-associated EEG changes and seizure exacerbation in 59 children aged <6 years treated with CBZ. All patients had EEGs before and after initiation of treatment; initial EEGs were not significantly different among the patients. In 33 children (56%), the subsequent EEGs were either unchanged or improved or demonstrated minor changes (Group I), and excellent to complete seizure control was achieved in 67% of patients. In 26 children (44%), the EEG became significantly more abnormal and was characterized predominantly by new appearance of generalized spikelpolyspike-and-wave discharges (group 11). The majority of these patients (65%) experienced seizure exacerbation (p <0.001). For group I, symptomatic partial epilepsy, idiopathic focal epilepsy, and complex febrile seizures were significantly more common; in group 11, cryptogenic seizure disorders were more common (p < 0.005). Children in group I were more likely to remain on CBZ or to be weaned from medication after successful treatment, whereas children in group II required additional medication(s) or complete discontinuation of CBZ. Our results suggest that new appearance of generalized paroxysmal discharges after treatment is highly correlated with seizure exacerbation or suboptimal control as well as with adverse outcome. Conversely, absence of significant EEG deterioration on CBZ is usually associated with good seizure control.     

Seizure Prognosis in Long-Stay Mentally Subnormal Epileptic Patients: Interrater EEG and Clinical Studies

Summary: Two groups of long-stay mentally subnormal epileptic patients, those with a chronically high seizure frequency and those who had become seizure-free, were studied for clinical and EEG factors relating to the prognosis of seizures. The mean period of observation was 20 and 22 years, respectively. All patients had a detailed clinical examination including psychometric testing, and for each, two EEG records were selected for blind semi-quantitative interrater analysis: an admission EEG and an EEG obtained within 6 months of the start of the study. Early onset of seizures, a high initìal seizure frequency, multiple seizure types, upper motor neuron signs, and severe mental retardation characterized the seizure group. Significant admission EEG findings in this group included an absence of posterior dominant rhythmic activity, generalized delta activity, and frequent generalized paroxysmal discharges.
Results of a linear discriminant analysis confirm that the admission EEG and clinical findings provide a basis for predicting outcome with a reliability on the order of 80%.     

Early-Childhood Progressive Myoclonus Epilepsy Presenting as Partial Seizures in Dentatorubral-Pallidoluysian Atrophy

Summary: Purpose: We explored the characteristics of epileptic seizures of progressive myoclonus epilepsy (PME) in 2 brothers with dentatorubral-pallidoluysian atrophy (DRPLA).
Methods: We obtained the case history of the siblings and ictal and interictal EEGs. Postmortem examination or demonstration of elongated CAG repeat in the gene for DRPLA was used to confirm the diagnosis.
Results: Two Japanese siblings developed PME characterized by versive or himiclonic seizures with or without secondarily generalized tonic-clonic convulsions. The elder brother regressed mentally and exhibited increasing spasticity after age 1 year. Myoclonus and seizures developed at age 4 years. The younger brother had shown psychomotor retardation before age 4 years, when he began to deteriorate further neurologically as the elder brother had. He also developed myoclonus and seizures at that age. Seizures in both patients remained partial until their deaths at ages 19 and 15 years, respectively. Ictal EEG verified partial onset of seizure evolving to generalized tonic-clonic seizure (GTCS). Interictal EEGs showed multifocal paroxysmal discharges with little or no diffuse paroxysms. Postmortem examination or genetic study confirmed the diagnosis of DRPLA.
Conclusions: Seizures of patients with DRPLA may present as partial seizures in children with early-onset PME.