Cerebral Dysgenesis Research Articles

Etiologic yield of cerebral palsy: a contemporary case series

Cerebral palsy is an established symptom complex that results from heterogeneous etiologies. Our understanding of the relative contribution of underlying etiologies to the occurrence of cerebral palsy is largely derived from studies lacking systematic neurologic evaluation or the application of contemporary imaging modalities. Throughout a 10-year inclusive period, the case records of all consecutive patients diagnosed with cerebral palsy in a single pediatric neurology practice were reviewed with reference to clinical features and diagnostic yield. A total of 217 cases of cerebral palsy were identified (129 male, 88 female): 77 (35.5%) spastic quadriplegic, 68 (31.3%) spastic hemiplegic, 39 (18%) spastic diplegic, five (2.7%) spastic monoplegic, 12 (5.5%) mixed, 12 (5.5%) ataxic-hypotonic, two (0.9%) dyskinetic, two (0.9%) Worster-Drought syndrome. Overall etiologic yield was 82.0%, varying according to type of cerebral palsy: 50% dyskinetic, 59% diplegia, 80% monoplegia, 80.9% hemiplegia, 90.9% quadriplegia, 91.7% ataxic hypotonia, and 100% mixed/Woster-Drought. The top five etiologic entities identified were periventricular leukomalacia, 24.9%; intrapartum asphyxia, 21.7%; cerebral dysgenesis, 17.1%; intracranial hemorrhage, 12.9%; and vascular, 9.7%. Although a single etiology was apparent in 144 (66.4%) of the cases, multiple etiologies were believed to be contributory in 34 (15.6%) of the cases. The etiologic profile varied according to such features as the type of cerebral palsy, gestational age, and the source (high-risk neonatal population or not) of the patients. Features of the child’s cerebral palsy, such as microcephaly, neonatal difficulties, prior or coexisting epilepsy, and high-risk source, were found to be predictive of eventual etiologic yield. This contemporary evaluation of cerebral palsy etiologic yield suggests that it is much higher than previously reported and varies, depending on key clinical features.

Clinical and Diagnostic Profile of Agenesis of the Corpus Callosum

This study reports the clinical profile, etiologies identified, and outcomes for a consecutive series of children with partial or complete agenesis of the corpus callosum. Children with agenesis of the corpus callosum were identified in a comprehensive computerized database of all patients seen in a single pediatric neurology practice over an 11-year interval. Medical records were then systematically reviewed. Twenty-four children with agenesis of the corpus callosum were identified of a total of 6911 children in the database (0.35%). Fifteen were male (62.5%); 9 (37.5%) had presented antenatally, 6 (25%) neonatally, and 9 (37.5%) postneonatally. Eight (33.3%) were microcephalic, 12 (50%) were dysmorphic, 11 (45.8%) had coexisting epilepsy, and 9 (37.5%) had a cerebral palsy variant. Investigations revealed an etiology in 11 (45.8%): 3 chromosomal abnormality, 3 metabolic disorder, 3 cerebral dysgenesis, and 2 genetic syndromes (Aicardi, Andermann). Outcomes identified included normal or mild developmental delay in 7 (29.2%) and moderate-severe developmental delay in the remaining 17 (70.8%). Factors predictive of successful etiologic determination on bivariate analysis included moderate-severe developmental delay or associated cerebral dysgenesis. Factors predictive of eventual developmental outcome included microcephaly, coexisting epilepsy, cerebral palsy, or cerebral dysgenesis. A spectrum of clinical presentations, underlying etiology, and developmental outcome is thus apparent in children with agenesis of the corpus callosum. An underlying etiology can be identified in slightly less than half of cases, and a normal or mildly delayed outcome is apparent in slightly less than a third. Factors predictive of identifying an underlying etiology or eventual outcome can be identified.

X-linked hydrocephalus: a novel missense mutation in the L1CAM gene

X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.

Neuropathological analysis of an adult case of the Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CDLS) is a rare multisystemic malformative syndrome of uncertain etiology characterized by severe psychomotor and mental retardation. Here we report the neuropathological analysis of a 35-year-old patient who displayed the classical clinical symptomatology of CDLS. A congenital dysgenesis of the brain was evident including abnormal convolution patterns of the cerebral gyri, frontal lobe hypoplasia and focal lack of myelination in layers V and VI of the left temporal cortex. In addition, there were vascular scars in the CA2-3 region of the left hippocampus and in the right parietal cortex as well as a few neurofibrillary tangles in the CA fields of the hippocampus and in the entorhinal cortex. In contrast to previous reports, there were no midline cerebral dysgenesis and no ectopic neuron formations in the present case. Neuronal loss and gliosis were also absent in all cortical and subcortical areas. Our observations suggest that the main neurodevelopmental deficits in CDLS occur during the late phase of gestation. Conversely, early neurodegenerative changes are not characteristic of CDLS. In the light of previous studies in younger CDLS patients, the vascular and degenerative lesions observed in the present case may be secondary to his severe congenital heart abnormalities and self-injury behavior, respectively.

CHOLESTEROL AND DEVELOPMENT: THE RSH ("SMITH-LEMLI-OPITZ") SYNDROME AND RELATED CONDITIONS

The half-century of lipophobia in the United States may be abating with some return of sanity on the discussion of health and dietary fat [Taubes, 2001]. The youngest victims of this collective, decades long madness are those infants deprived for one reason or another of breast milk. They are unable to speak for themselves at a time of greatest need for cholesterol during growth, the most critical period of myelination of central and peripheral nervous system, formation of bone and bile, and of every steroid hormone. Some of the commercial formulas they are fed contain only 1 or 2 mg of cholesterol per 100 g edible portion contrasted with almost 14 mg in breast milk. One can only hope that the confidence in their endogenous ability to synthesize sufficient amounts of cholesterol is not misplaced. Pediatric pathology has learned that when this endogenous ability fails during embryogenesis on the basis of mutations in the postsqualene biosynthesis of cholesterol, a startling variety of developmental pathology may present itself ranging from lethal forms of "idiopathic" hydrops, microcephaly with cerebral dysgenesis and dysmyelinization, agenesis of corpus callosum, cerebellar vermis dysgenesis, cataracts, cleft palate, many different forms of congenital heart defect, pyloric stenosis and/or Hirschsprung dysganglionosis, adrenal (cortical) insufficiency, cholestatic liver disease, limb malformations, and genital ambiguity in genetic males. Population genetic considerations suggest a hypothetical birth prevalence of the RSH (so-called Smith-Lemli-Opitz) syndrome, the commonest of these Garrodian errors of cholesterol biosynthesis, of 1/2500; since only about 1/15,000 to 1/20,000 homozygotes are liveborn and biochemically confirmed, over 80% prenatal or perinatal mortality must occur and deserves the most discerning of services from birth attendants, perinatologists, neonatologists, and fetal/pediatric pathologists. An easy, reliable, economical biochemical test for the presence of 7-dehydrocholesterol is available and the commonest mutation, the IVS8-1G &#77 C mutation, is quickly and reliably tested for molecularly. Thus, the successful diagnosis, even after death, will contribute substantially to correct genetic counseling, carrier detection, prenatal diagnosis, and treatment in those known to be affected prenatally and planned to be liveborn. Thus, developmental pathology plays an integral, vital role in preventive medicine.

Expression of calbindin D-28k and parvalbumin in cerebral cortical dysgenesis induced by administration of ethylnitrosourea to rats at the stage of neurogenesis.

It has been reported that transplacental administration of ethylnitrosourea (ENU), which is cytotoxic immediately after administration, to rat fetuses at the neurogenesis stage induces dysgenesis of the cerebral cortex, characterized by neuronal sparseness and architectural irregularity. In the present study, we examined the topographic distribution of neurons containing 5-bromo-2-deoxyuridine (BrdU), and those containing calbindin D-28k (CaBP) and parvalbumin (PV), most of latter two are considered to be interneurons located in particular layers of the normal cerebral cortex in rats with experimentally induced cerebral cortical dysgenesis. Pregnant Wistar albino rats were given a single transplacental administration of ENU on embryonic day 16, followed 4, 8, 16, 24, 36, or 48 h later by a single intraperitoneal injection of BrdU. The pups were killed 10 weeks after birth. In the normal cerebral cortex, BrdU-immunopositive neurons showed an inside-out pattern according to the time of BrdU injection, whereas in ENU-treated rats the topographic localization of the BrdU-immunopositive neurons was irregular and the inside-out pattern was disrupted. Although the number of CaBP- and PV-immunopositive neurons was lower in ENU-treated animals, no topographic difference was evident between the normal and the dysgenetic cerebral cortices. These findings indicate that the expression of CaBP and PV in the neurons of the rat cerebral cortex is extrinsic, and depends on the position of the neurons rather than on the time of their formation or on genetic control. This suggests the existence of re-regulation of the expression of CaBP and PV in the developing brain, which may be one of the effective mechanisms by which the cerebral cortex can maintain its normal function in spite of cytoarchitectural abnormality.

Neuroimaging abnormalities in children with an apparent first unprovoked seizure

Objective: To determine the incidence and type of neuroimaging abnormalities in children presenting with a first seizure. Methods: In a prospective observational study, 411 children with a first afebrile seizure were seen between 1983 and 1992. Imaging studies were performed in 218 (53%). For this analysis we examined the most sensitive neuroimaging study performed which included 159 computed tomography scans and 59 magnetic resonance imagings (MRI). Results: Four children were found to have lesions requiring intervention (brain tumor in two, neurocysticercosis in two). The remaining 407 were enrolled in a follow-up study of children with a first unprovoked seizure. After a mean follow-up of >10 years, none have developed clinical evidence of a tumor. In these 411 children, 45 (21%) of 218 imaging studies were abnormal. The most common abnormalities were focal encephalomalacia ( n=16) and cerebral dysgenesis ( n=11). Although children with partial seizures were more likely to be imaged (64%) than children with generalized seizures (43%) ( P<0.001), the fraction of abnormal imaging studies was similar in both groups. Six children with a normal neurological examination who were initially classified as cryptogenic were subsequently found to have errors of cerebral migration on MRI. The incidence of lesions requiring acute intervention in children presenting with a first seizure is low. A significant proportion will have neuroimaging abnormalities particularly on MRI. Conclusions: Neuroimaging should be considered in any child with a first seizure who does not have an idiopathic form of epilepsy.

Horner syndrome associated with implantation of a vagus nerve stimulator

PURPOSE: To report a case of Horner syndrome that occurred after implantation of a vagus nerve stimulator. METHODS: Case report. RESULTS: A 6-year-old female with cerebral dysgenesis and intractable partial seizures presented with Horner syndrome after vagus nerve stimulator implantation. CONCLUSION: Horner syndrome can occur as a result of the vagus nerve stimulator implant procedure and should be included as one of its possible surgical complications.

Epilepsy surgery in children with developmental disabilities

Surgery for treatment of medically uncontrolled epilepsy in children is now widely accepted with reported outcomes similar to those in adults. Epilepsy is reported in 8.8% to 32% of children with mental retardation (MR) and in up to half of children with severe retardation. There has been concern that patients with low IQ will experience unsatisfactory outcomes from epilepsy surgery and not achieve good seizure control. It is appropriate to reassess the prior bias against resective epilepsy surgery in children with MR in view of the changing criteria for potential candidacy for epilepsy surgery in infants and young children. There are three prerequisites for epilepsy surgery: (1) the epilepsy must be medically intractable; (2) the surgery must be feasible, that is, the epileptogenic zone can identified and safely resected; and (3) there is high likelihood of a satisfactory outcome as regards both the epilepsy and the patient's functional status. Patients with MR may have diffuse cerebral dysfunction and diffuse or multifocal epileptogenic regions. Appropriate patient selection is made possible through use of current technology that allows identification of lesions or areas of cerebral dysgenesis, aiding in identification of localized areas of epileptogenesis. Results from various series of patients with MR who have undergone resective surgery for epilepsy have shown that with careful presurgical evaluations, outcomes are similar between patients with normal IQ scores and those with low scores. Surgical protocols specifically for patients with MR and intractable epilepsy are required, including careful definition of desired outcomes.

Etiologic yield of subspecialists' evaluation of young children with global developmental delay

To determine the etiologic yield of subspecialists' evaluation of young children with global developmental delay. In addition, variables that may predict finding an underlying etiology were also identified. All children <5 years of age, referred over an 18-month period to subspecialty services for initial evaluation of a suspected developmental delay, were prospectively enrolled. Diagnostic yield was ascertained after the completion of clinical assessments and laboratory investigations requested by the evaluating physician. Ninety-nine children (71 boys) were found to have global developmental delay; 96% had a mild or moderate delay documented. An etiologic diagnosis was determined in 44. Four diagnoses (cerebral dysgenesis, hypoxic-ischemic encephalopathy, toxin exposure, chromosomal abnormalities) accounted for 34 of 44 (77%) of the diagnoses made. The presence of co-existing autistic traits was associated with significantly decreased diagnostic yield (0/19 vs 44/80, P <.0001), whereas specific historical features (eg, family history, toxin exposure, and perinatal difficulty; 23/32 vs 21/67, P =.0002) and findings on physical examination (eg, dysmorphology, microcephaly, and focal motor findings; 35/48 vs 9/51, P <.0001) were significantly associated with identifying a diagnosis. Multiple logistic regression analysis identified antenatal toxin exposure, microcephaly, focal motor findings, and the absence of autistic traits as significant predictor variables for the identification of an etiology. An etiologic diagnosis is often possible in the young child with global developmental delay, particularly in the absence of autistic features. Etiologic yield is augmented by presence of specific findings on history or physical examination on initial assessment.

Neonatal Seizures

Neonatal Seizures

Autosomal recessive syndrome due to amazing consanguinity

We report on a patient with a syndrome of MR/MCA who was the product of a highly consanguineous family. The patient was the result of a union between a man and his daughter. The daughter was in turn the product of a mating between the man and his mother. Major findings include: severe psychomotor and mental retardation, microcephaly with cerebral dysgenesis and cerebellar hypoplasia, delayed visual development, seizures, early hypotonia and late hypertonia; short stature and failure to thrive, early swallowing incoordination with aspiration pneumonias; dysmorphic face with striking hypertelorism, upslanting palpebral fissures and dysplastic, asymmetric, low-set ears; wide set nipples, sacral dimple, right inguinal hernia, hypospadias, cryptorchidism, overlapping fingers, and rocker-bottom feet. At onset of puberty, he developed severe scoliosis with secondary pulmonary restriction. He died at age 14 secondary to post-operative sepsis. Chromosomal and metabolic studies were normal. Although this patient presents some features of other syndromes (such as the Opitz-GBBB syndrome), the severity and peculiarity of his phenotype suggests a new, probably private, autosomal recessive disorder due to homozygosity for one or more loci.

Clinical correlations of occipital epileptiform discharges in children.

To determine the frequency of different causes of occipital epileptiform discharges (OEDs) in children and to analyze the EEG features that help predict epilepsy type and prognosis. We identified children with OEDs in the absence of other focal discharges using an EEG database at our center; the presence of generalized spike-wave discharges (GSW) or slowing was not an exclusion criterion. Diagnosis, neurologic status, seizure semiology, and seizure remission status were recorded. Of 90 patients with OEDs, 50 (56%) had symptomatic seizures (18 with cerebral palsy, 11 with cerebral dysgenesis, 8 with genetic abnormalities); 31 (34%) had idiopathic seizures, including 6 with benign childhood epilepsy with occipital paroxysms (BCEOP), 8 (9%) had no seizures; and 1 (1%) had febrile seizures. Only two reported ictal visual symptoms. Eighty-seven percent with background slowing had symptomatic seizures, and 87% with normal backgrounds had idiopathic seizures (p < 0.001). Of 72 children with seizures and adequate follow-up, 28 of 45 (62%) with a normal background experienced seizure remission compared with 10 of 27 (37%) with background slowing (p = 0.04). Twenty of 81 patients with epilepsy had GSW. Twelve (60%) of the 20 GSW-positive patients had idiopathic epilepsy compared with 19 of 61 (31%) without GSW (p = 0.02). Most epilepsy in referred children with OEDs is symptomatic; syndromes such as BCEOP are rare. Visual ictal symptoms are rare. The presence of GSW or a normal background rhythm correlates with idiopathic seizures and a better prognosis.

Developmental anomalies of the brain in mental retardation

Intuitively it is understood that persons with mental retardation must have 'something' different about the structure and organization of the central nervous system. In the past, defining what that something might be was usually a high cost, low yield endeavour. Recent advances in neuroimaging techniques have greatly enhanced our ability to identify structural changes in CNS development that correlate closely with the patient's neurodevelopmental abnormalities.In this article we review the most common identifiable developmental CNS anomalies seen in patients with mental retardation.We describe both overt (gross) malformations and the more recently appreciated'subtle markers of cerebral dysgenesis'.For selected conditions we also discuss recent insights into the etiologic and pathogenetic basis of the condition from many of the exciting new developments in molecular biology.

Dipstick Diagnosis of Neonatal Seizure Disorder

A dipstick test strip (Sulfistix) showing elevated urinary sulfite concentrations (400 mg/l) was used in diagnosis of molybdenum cofactor deficiency (MCD), an inborn errror of metabolism, in a male infant presenting with convulsions and cerebral dysgenesis at birth and followed for 3 years at the Klinik fur Kinder und Jugendmedizin, St Marlenhospital, Vechta, Germany.

Mechanisms of cerebral dysgenesis.

Cerebral dysgeneses are increasingly recognized by modern neuroimaging techniques in association with a large variety of pathologies such as epilepsy, learning disabilities, mental retardation, and some psychiatric disorders. Although the mechanisms of these brain dysmorphogeneses are still mostly unknown, the discovery of genes responsible for cerebral dysgeneses and the analysis of relevant animal models have allowed the identification of a few pathophysiologic pathways. This review focuses on some of these recently described molecular mechanisms of cerebral dysgenesis.

Is the underlying cause of epilepsy a major prognostic factor for recurrence?

We investigated the prognostic value of the type of epilepsies and epileptic syndromes for seizure recurrence. In patients with partial epilepsy, we focused on the prognostic value of any structural brain abnormality and of the location of the epileptogenic region. A total of 2,200 adult outpatients were included in a hospital-based observational survey, with a follow-up of 1 to 7 years. Twenty-two percent of the patients exhibited generalized epilepsy, 62% partial epilepsy, and 16% undetermined epilepsy. Seizure control (>1 year without seizure) was achieved in 82% of patients who had idiopathic generalized epilepsy, 35% of those with symptomatic partial epilepsy, 45% of those with cryptogenic partial epilepsy, and 11% of those with partial epilepsy associated with hippocampal sclerosis (HS). Temporal lobe epilepsy (TLE) was the most refractory partial epilepsy, with only 20% of such patients remaining seizure free, compared with 36% of extra-TLE patients. In partial epilepsy, HS, cerebral dysgenesis, and dual pathology (HS and another lesion) were associated with a low rate of seizure-free patients (11%, 24%, and 3%, respectively). No significant difference in seizure control was found between patients with extra-TLE and those with TLE and no HS. In adults, partial epilepsy is more difficult to treat than idiopathic generalized epilepsy. In patients who have partial epilepsy, the location of the epileptogenic zone does not seem to be a determining factor. Brain abnormalities--especially HS, either alone or associated with another lesion--are a major prognostic factor.

In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review.

Certain developmental abnormalities of the cerebral cortex are closely associated with epilepsy in humans. Exposure of fetal rats to external gamma-irradiation produces diffuse cortical dysplasia and neuronal heterotopia. These abnormalities are the result of radiation-induced cell death coupled with continued cortical development in an altered cellular environment. In vivo electroencephalography studies in these animals have revealed an increased propensity for electrographic seizures in the presence of the sedating agents, acepromazine and xylazine. In vitro neocortical slices containing dysplastic cortex demonstrate enhanced excitability, as compared to control neocortex, when inhibition that is mediated by the A-type gamma-amino butyric acid receptor is blocked with bicuculline methiodide. In utero irradiation of rats produces structural changes that mimic some aspects of cerebral dysgenesis in humans and results in physiologic changes that increase the animals' propensity for seizures. Similarities and differences between the animal model and the human syndromes are discussed.

Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes.

In patients with idiopathic generalized epilepsy (IGE), visual inspection of routine MRI is normal. However, pathological studies have shown microdysgenesis in grey and white matter in a large percentage of autopsies from cases of IGE. Recently, widespread structural changes not evident on visual inspection of high resolution MRI have been shown using quantitative MRI in patients with apparently focal cerebral dysgenesis. We sought to determine whether similar quantitative changes might be present in patients with IGE, reflecting possible underlying structural abnormalities. Twenty patients with juvenile myoclonic epilepsy, 10 patients each with childhood absence epilepsy and juvenile absence epilepsy, five patients with tonic-clonic seizures on awakening and 30 control subjects had T1-weighted volume acquisition MRI scans on a 1.5T GE scanner. The cerebral hemispheres were segmented semi-automatically, allowing the comparison of normalized cortical and subcortical matter volumes between groups, and investigation of the regional distribution of cortical and subcortical matter in individual subjects. Patients with IGE had significantly larger cortical grey matter volumes than control subjects. Significant abnormalities of the regional distribution of cerebral grey and subcortical matter were found in eight out of 20 patients with juvenile myoclonic epilepsy, one out of 10 patients with childhood absence epilepsy, four out of 10 patients with juvenile absence epilepsy and two out of five patients with tonic-clonic seizures on awakening, but in none of the 30 control subjects. Using MRI-segmentation, we identified widespread cerebral structural changes in patients with various IGE syndromes. Quantitative MRI supports the existence of structural abnormalities in patients with IGE.

Similar brain spect findings in subclinical and clinical seizures in two neonates with hemimegalencephaly

Brain single-photon emission computed tomography (SPECT) findings during clinical and subclinical seizures were compared in two neonates with hemimegalencephaly. Interictal and ictal brain SPECT were performed in two neonates. The ictal studies were performed during a clinical seizure in one neonate and during a subclinical seizure in another neonate. They revealed similar focal hemispheric hyperperfusion at the electroencephalographic seizure foci in both cases. The similar perfusion patterns imply that clinical and subclinical seizures place similar metabolic demands on the cerebral tissue involved in the generation of electroencephalographic seizures in neonates with cerebral dysgenesis and suggest that clinical and subclinical seizures should be treated similarly in this population.