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Bilateral posterior agyria-pachygyria and epilepsy
Abstract
We analyzed the electroclinical findings in two patients with bilateral posterior agyria-pachygyria. Both patients presented with mental retardation, mild motor deficit and epilepsy. The electroclinical findings were characterized by frequent tonic or atonic generalized seizures with occasionally simple or complex partial seizures. Interictal electroencephalography (EEG) showed occipital spikes and diffuse polyspike-wave paroxysms predominantly in the posterior region. Ictal EEG showed diffuse 10-11 Hz activity. Cerebral magnetic resonance imagings (MRIs) showed thickened cortex in the parieto-occipital lobes, bilaterally and symmetrically. The volume of underlying white matter appeared reduced, and the overlying subarachnoid spaces were enlarged. The occipital horns were dilated. These findings were compatible with agyria-pachygyria of the posterior portions of the brain. In conclusion, in patients with mental retardation, mild motor deficit and epilepsy characterized by tonic or atonic generalized seizures, interictal EEG with diffuse polyspike-wave paroxysms predominantly in posterior region, posterior focal epileptilorm abnormalities and ictal diffuse 10-11 Hz activity, bilateral parieto-occipital agyria-pachygyria should be considered as a possible etiology. Magnetic resonance image is the best neuroradiological study to identify this disorder of cortical development.
Patients with malformations of cortical development (MCD) present with a wide spectrum of clinical manifestations ranging from asymptomatic cases to those with epilepsy and developmental problems. Clinical presentation of MCD is variable and depends on the affected cortical area. While severe malformations can be recognized with definite developmental retardation and early-onset recurrent seizures, mild malformations are usually identified at any age, mostly during evaluation following a seizure. With the help of high resolution neuroradiological imaging techniques, there has been an increase in the number of cortical developmental lesions. The etiology in many MCDs is unknown. It is possibly a general response of the developing brain to genetic and environmental factors. Alterations during neuronal proliferation, migration and organization stages of the developing brain constitute the basis of these malformations. During the developmental stages, intervening genetic and prenatal environmental factors may contribute to the development of malformations. Nevertheless, in the majority of cases the cause is unknown.
Malformations of cortical development (MCD) form a spectrum of lesions produced by insult to the developing neocortex. Clinical presentation and electrophysiologic findings of MCD are variable and depend on the affected cortical area. We evaluated epilepsy, EEG, and response to antiepileptic treatment in patients with MCD with respect to the neuroimaging findings. We studied 101 patients, ranging between 1 month and 19 years of age. Fifty-four patients were diagnosed with polymicrogyria (PMG), 23 patients with lissencephaly, 12 patients with schizencephaly, and 12 patients with heterotopia. With regards to epilepsy and seizure type, 72/101 (71.3%) patients had epilepsy, and 62/101 (61.4%) patients presented with seizures. Overall, 32.7% of patients had generalized seizures, and 25.7% had complex partial seizures. Mean age at the onset of seizures was 2.7 +/- 3.4 years. The onset of epilepsy tended to be younger in patients with lissencephaly and older in patients with heterotopias. Of the cases, 79.2% had abnormal EEG (56.3% with epileptiform abnormality, 22.9% with non-epileptiform abnormality). EEG was abnormal in 44.9% (13/29) of the cases without epilepsy. EEG showed bilateral synchronous and diffuse epileptiform discharges in 90% of patients with lissencephaly. Patients with schizencephaly had mostly focal epileptiform discharges. Heterotopia cases had a high rate of EEG abnormalities (72.7%). Patients with PMG had epileptiform abnormality in 59.5% of the cases. Patients with heterotopias and PMG achieved better seizure control in comparison with the other groups. In conclusion, epilepsy is the most common problem in MCD. Epilepsy and EEG findings of patients with MCD are variable and seem to be correlated with the extent of cortical involvement.
Subcortical band heterotopia (SBH) are bilateral and symmetric ribbons of gray matter found in the central white matter between the cortex and the ventricular surface, which comprises the less severe end of the lissencephaly (agyriapachygyriaband) spectrum of malformations. Mutations in DCX (also known as XLIS ) have previously been described in females with SBH. We have now identified mutations in either the DCX or LIS1 gene in three of 11 boys studied, demonstrating for the first time that mutations of either DCX or LIS1 can cause SBH or mixed pachygyria - SBH (PCH-SBH) in males. All three changes detected are missense mutations, predicted to be of germline origin. They include a missense mutation in exon 4 of DCX in a boy with PCH-SBH (R78H), a different missense mutation in exon 4 of DCX in a boy with mild SBH and in his mildly affected mother (R89G) and a missense mutation in exon 6 of LIS1 in a boy with SBH (S169P). The missense mutations probably account for the less severe brain malformations, although other patients with missense mutations in the same exons have had diffuse lissencephaly. Therefore, it appears likely that the effect of the specific amino acid change on the protein determines the severity of the phenotype, with some mutations enabling residual protein function and allowing normal migration in a larger proportion of neurons. However, we expect that somatic mosaic mutations of both LIS1 and DCX will also prove to be an important mechanism in causing SBH in males.
1. FETAL AND NEONATAL NEUROLOGY ( Linda de Vries ). 2. MALFORMATIONS OF THE CENTRAL NERVOUS SYSTEM ( Jean Aicardi ). 3. NEUROCUTANEOUS DISEASES AND SYNDROMES ( Jean Aicardi ). 4. NEUROLGOICAL AND BEHAVIOURAL ASPECTS OF GENETIC ABNORMALITIES AND DYSMORPHIC SYNDROMES ( Christopherg Gillberg, Jean Aicardi and Martin Bax ). 5. OSSEOUS MALFORMATIONS OF THE SKULL AND CERVICAL VERTEBRAE ( Jean Aicardi ). 6. HYDROCEPHALUS AND NON-TRAUMATIC PERICEREBRAL COLLECTIONS ( Jean Aicardi ). 7. CEREBRAL PALSY ( Ingeborg Krageloh-Mann and Martin Bax ). 8. METABOLIC DISEASES ( Helene Ogier and Folker Hanefeld ). 9. HEREDODEGENERATIVE CENTRAL NERVOUS SYSTEM DISORDERS ( Jean Aicardi and Folker Hanefeld ). 10. INFECTIOUS DISEASES ( Hermione Lyall and Cheryl Hemin gway). 11. PARAINFECTIOUS AND OTHER INFLAMMATORY DISORDERS OF NEUROLOGICAL ORIGIN ( Folker Hanefeld and Jean Aicardi ). 12. ACCIDENTAL AND NON-ACCIDENTAL INJURIES BY PHYSICAL AGENTS AND TOXIC AGENTS ( Keith Brown and Robert Minns ). 13. TUMOURS OF THE CENTRAL NERVOUS SYSTEM AND OTHER SPACE-OCCUPYING LEASIONS ( Jean Aicardi ). 14. CEREBROVASCULAR DISORDERS ( Jean Aicardi ). 15. EPILEPSY AND OTHER SEIZURE DISORDERS ( Alexis Arzimanoglou ). 16. PAROXYSMAL DISORDERS OTHER THAN EPILEPSY ( Jean Aicardi ). 17. DISORDERS OF OCULOMOTOR AND VISUAL SYSTEMS ( Matsuba Carey and Jean Aicardi ). 18. HEARING IMPAIRMENT ( Anne O'Hare ). 19. NEUROMUSCULAR DISEASES ( Jean Aicardi ). 20. DISORDERS OF THE PERIPHERAL NERVES ( Robert Ouvrier ). 21. MUSCLE DISORDERS ( Kathryn North and Lloyd Shield ). 22. NEUROLOGICAL MANIFESTATIONS OF SYSTEMC DISEASES ( Jean Aicardi ). 23. MENTAL AND BEHAVIOURAL DEVELOPMENT ( Christopher Gillberg and Martin Bax ).
Twenty-one Dutch patients were the subject of an extensive study into lissencephaly type I. One hundred and fourteen EEG's of these patients were studied. The EEG's were compared to 52 EEG's recorded from 21 patients with an atypical cortical dysplasia and to a control group consisting of 882 EEG's recorded from 823 patients for various reasons. The EEG's in the lissencephaly patients showed the following patterns significantly more often:
(a) generalized fast activity (8-18/s) with an amplitude higher than 50 µV,
(c) sharp- and slow-wave complexes with an amplitude higher than 500 µV,
(d) an alternating pattern consisting of bursts of sharp waves alternating with periods of electrocerebral depression.
Ninety-five percent of the lissencephaly patients showed pattern (a) or (c) or both compared to only 5 % of the patients with an atypical cortical dysplasia and 0.4% in the controls.
The SSEP's recorded in ten patients after stimulation of the median nerve were abnormal in all.
EEG and evoked potentials appear to be valuable examinations in the (differential) diagnosis of lissencephaly type I.
We report clinical, cytogenetic, and molecular studies in 65 patients with isolated lissencephaly sequence (ILS). All had type I lissencephaly of varying severity and a grossly normal cerebellum. Some had additional brain abnormalities. Facial appearance was essentially normal. All had severe to profound mental retardation, seizures, hypotonia that evolved into spasticity, and feeding difficulties. Clinical and laboratory studies demonstrated etiologic heterogeneity. Molecular studies detected microdeletions in chromosome band 17p13.3 in six of 44 patients tested, confirming that deletion of all or part of this "critical region" is the cause of ILS in some cases. There were slightly larger deletions in the same region in a majority of patients with Miller-Dieker syndrome. One patient had an apparently balanced, de novo reciprocal translocation with breakpoints at Xq22 and 2p25. Four sibs from two families had a new, autosomal recessive syndrome of ILS with neonatal death. Other causes supported by clinical observations include autosomal recessive inheritance, intrauterine infection, and intrauterine perfusion failure. Those ILS probands in whom no etiology could be established had 41 sibs of whom three were affected, giving an empiric recurrence risk of 7%.
Fifteen cases of lissencephaly were studied and the literature reviewed. The authors concluded that the clinical findings of lissencepaly infancy are not‐specific, consisting of development delay and hypotonia. While the CT scan establishes the diagnosis, it may also be strongly suggested by an EEG showing ‘major fast dysrhythmia’, characterized by abnormally rapid, very high‐voltage activity, predominantly in the alpha and beta frequency bands. Some possible mechanisms for this highly suggestive EEG pattern are proposed.
RÉSUMÉ
Lissencéphalie (agyrie‐pachygyrie): données cliniques et études EEG en serie
Quinze cas de lissencálie ont étéétudies, avec une analyse de la littérature. Les auteurs concluent que les données cliniques de la lissencéphalie durant l'enfance ne sont pas spécifiques, consistent en un retard de développement et une hypotonic Tandis que la tomodensitométrie fait le diagnostic, celui‐ci peut étre aussi fortement suggéré par un EEG montrant “une dysrhytmie majeure rapide”, caracterisee par une activite anormalement rapide, de trés haut voltage, prédominant dans les bandes de fréquence alpha et béta. Quelques mécanismes possibles pour ces particularités EEG hautement suggestives sont proposés.
ZUSAMMENFASSUNG
Lissencephalie (Agyrie‐Pachygyrie): Klinische Befunde und fortlaufende EEG Untersuchungen
15 Fälle mit Lissencephalie wurden untersucht und die Literatur wurde gesichtet. Die Autoren sind der Meinung, daß die klinischen Befunde der Lissencephalie im Kindesalter unspezifisch sind, sie bestehen in Entwicklungsverzögerung und Hypotonie. Obwohl die Diagnose durch das Computertomogramm gesichert wird, kann sie doch mit großer Wahrscheinlichkeit durch ein EEG mit vorwiegend hochfrequenter Arrhythmie, charakterisiert durch abnorm schnelle, sehr hohe Amplituden, vorwiegend in den Alpha und Beta Frequenzen, gestellt werden. Es werden einige mögliche Vorgänge für dieses höchst verdächtige EEG Muster diskutiert.
RESUMEN
Lisencefaiia (agiria‐paquigiria): hallazgos cli'nicos y estudios EEG seriados
Se estudiaron quince casos de lisencefaiia y se revisó la literatura. Los autores concluyen que los hallazgos clinicos de la lisencefaiia en la lactancia no son especificos y consisten en retraso en el desarrollo e hipotonia. Si bien la TAC establece el diagnostico, puede ser también sospechado por el EEG que muestra una disritmia rápida mayor, caracterizada por una actividad anormalmente rapida con voltaje muy alto, con predominio en las bandas de frecuencia alfa y beta. Se proponen algunos posibles mecanismos para este tipo de EEG tan sugestivo.
Neuronal migration disorders are a group of malformations of the brain which primarily affect development of the cerebral cortex. The best known of these is lissencephaly (smooth brain). Most types result from incomplete neuronal migration to the cortex during the third and fourth months of gestation. In this review, we describe and illustrate the different types of neuronal migration disorders. We also review the many different genetic syndromes associated with neuronal migration disorders.
Over 25 syndromes with lissencephaly or other neuronal migration disorders have been described. Among them are syndromes with several different patterns of inheritance including chromosomal or new mutation autosomal dominant, autosomal recessive, X-linked and unknown. Genetic counseling thus differs greatly between syndromes. The genes responsible for several of the lissencephaly syndromes have been mapped. X-linked lissencephaly has tentatively been mapped to chromosome Xq22 based on observation of a single X-autosomal translocation in a girl. Both Miller-Dieker syndrome and isolated lissencephaly sequence (in many patients) were mapped to chromosome 17p13.3 by detection of deletions and other structural chromosome rearrangements. Fukuyama congenital muscular dystrophy was mapped to chromosome 9q31-33 by homozygosity mapping.
We describe two brothers with mental retardation and refractory epilepsy. MRI revealed symmetrical agyria-pachygyria of the temporo-occipito-parietal regions, areas of deeply infolded polymicrogyric parietal cortex, and dilated occipital horns (colpocephaly). The stereotyped clinical, EEG, and MRI findings suggest that this may be a distinct inherited condition and imply that agyria-pachygyria with polymicrogyria is not always sporadic.
NEUROLOGY 1995;45: 150-153
Classical lissencephaly or "smooth brain" is a human brain malformation that consists of diffuse agyria and pachygyria. Two genes associated with classical lissencephaly have recently been cloned-LIS1 from chromosome 17p13.3 and XLIS (also called DCX) from Xq22.3-q23.
We performed genotype-phenotype analysis in children with lissencephaly associated with mutations of different genes.
We compared the phenotype, especially brain imaging studies, in a series of 48 children with lissencephaly, including 12 with Miller-Dieker syndrome (MDS), which is associated with large deletions of LIS1 and other genes in the region, 24 with isolated lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with isolated lissencephaly sequence caused by XLIS mutations.
We found consistent differences in the gyral patterns, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly in individuals with XLIS mutations. Thus, mutations of LIS1 are associated with a posterior-to-anterior gradient of lissencephaly, whereas mutations of XLIS are associated with an anterior-to-posterior gradient. We also confirmed differences in severity between MDS and ILS17. Hypoplasia of the cerebellar vermis proved to be more common with XLIS mutations.
It is often possible to predict the gene mutation from careful review of brain imaging studies.
Although once thought to be rare, malformations of cortical development are being increasingly recognized as the underlying cause of developmental delay in children and of epilepsy in children and young adults. Advances in neuroimaging and developmental neurobiology have created the tools by which these important malformations have been investigated. Through a symbiotic type of relationship, these investigations, and the search for a better understanding of these malformations, have led to advances in neuroimaging techniques and better understanding of both normal and abnormal brain development. In this review, the most common malformations or cortical development associated with epilepsy are discussed in regard to their clinical manifestations, classification, imaging appearance and basic neurobiology.
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