Bhuwan P. Garg

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10−5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Subtypes of ischemic stroke in children and young adults

Specific strategies for primary and secondary stroke prevention in children and young adults can only be recommended once the causes of stroke in these age groups are well described. ICD-9 codes were used to identify children aged 1 to 18 years with acute ischemic stroke. Young adults aged>18 to 45 years were identified from the Indiana University and Northwestern University Young Adults Stroke Registries. Validated criteria were used to subtype ischemic stroke as atherothrombotic (AT), cardioembolic(CE), small-vessel (SV), other determined cause, or unknown cause. Ninety-two children and 116 young adults were identified. Stroke subtypes in children/young adults (percentages) were as follows: AT 0/16 (p< 0.001), CE 15/14 (p = 10), SV 0/3 (p = 0.26), other 49/44 (p = 0.40), and unknown 36/23 (p = 0.04). Children had more prothrombotic causes (25% versus 14%, p = 0.03), and young adults had more dissections (3% versus 15%, p = 0.005). Children aged 15 to 18 years had causes of ischemic stroke more similar to those in young adults. The cause of ischemic stroke is less often identified in children than it is in young adults. Children have more prothrombotic causes of stroke, and adults have more atherothrombotic causes and dissections. Lacunar strokes are rare in both children and young adults. The age of 15 years should be used to separate childhood from young-adult ischemic stroke.

Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy.

The epidermal nevus syndrome (ENS) is a sporadic neurocutaneous disorder that consists of epidermal nevi and congenital anomalies involving the brain and other systems. From among over 60 patients with ENS presenting with neurologic manifestations, we identified 17 who had hemimegalencephaly based on pathologic or radiologic studies. Associated brain and neurologic abnormalities included gyral malformations in 12 of 12, mental retardation in 13 of 14, seizures in 16 of 17 (including 9 with infantile spasms), and contralateral hemiparesis in 7 of 12. All had ipsilateral epidermal nevi of the head, and several had ipsilateral facial hemihypertrophy. We concluded that these abnormalities comprise a recognizable neurologic variant of ENS that we believe represents the full expression of primary brain involvement. Several patients also had evidence of acquired brain lesions such as infarcts, atrophy, porencephaly, and calcifications, which are best explained by prior ischemia or hemorrhage. Given repeated observations of blood vessel anomalies in ENS patients, we hypothesize that underlying vascular dysplasia predisposes to these acquired lesions. The same cause may be invoked to explain the wide variety of neurologic symptoms reported in ENS patients without hemimegalencephaly. While the cause of ENS remains unknown, several observations suggest a somatic mutation.

Cerebral Venous Thrombosis in Children

Cerebral venous thrombosis is an important cause of stroke in children. Understanding the natural history of the disease is essential for rational application of new interventions. We retrospectively identified 31 children with cerebral venous thrombosis confirmed by head computed tomography (4 patients) or by magnetic resonance imaging (27 patients). Risk factors, clinical and radiographic features, and neurologic outcomes were analyzed. There were 21 males and 10 females aged 1 day to 13 years (median 14 days). Nineteen (61%) were neonates. The most common risk factors included mastoiditis, persistent pulmonary hypertension, cardiac malformation, and dehydration. The chief clinical features were seizures, fever, respiratory distress, and lethargy. Fifteen patients had infarctions (8 hemorrhagic, 7 ischemic). Protein C and antithrombin III deficiency were the most common coagulopathies among 14 tested patients. On discharge, 11 patients were normal, 17 had residual deficits, and 2 patients died. Twenty-seven patients were followed from 1 month to 12 years (mean 22 months). At follow-up, 11 patients were normal, and 13 patients had development delay. One had residual hemiparesis and cortical visual impairment. Two had other deficits. Neonatal cerebral venous thrombosis is probably more common than previously thought, and outcomes are worse in this group. All children with cerebral venous thrombosis should be tested for coagulation disorders. (J Child Neurol 2001;16:574-580).

Cerebral Palsy After Perinatal Arterial Ischemic Stroke

The frequency of cerebral palsy, degree of disability, and predictors of disability were assessed in children in a perinatal arterial stroke database. Risk factors were assessed at the univariate level using the Pearson χ2 and Fisher exact test and at the multivariate level using logistic regression analysis. Seventy-six of 111 children with perinatal stroke (68%) had cerebral palsy, most commonly hemiplegic (66/76; 87%). Multivariate analysis of the entire cohort showed both delayed presentation (OR,9.96; 95% CI, 3.10-32.02) and male sex (OR, 2.55; 95% CI, 1.03-6.32) were associated with cerebral palsy. In subgroup multivariate analyses: in children with neonatal presentation, bilateral infarcts were associated with triplegia or quadriplegia (OR, 5.33; 95% CI, 1.28-22.27); in children with unilateral middle cerebral artery infarcts, delayed presentation (OR, 10.60; 95% CI, 2.28-72.92) and large-branch infarction (OR, 8.78; 95% CI, 2.18-43.67) were associated with cerebral palsy. These data will aid physicians in planning long-term rehabilitative care for children with perinatal stroke.

Nonepileptic Seizures in Children

Purpose: To determine if the clinical characteristics of nonepileptic seizures (NES) are different in children younger than 13 years age as compared to adolescents.

Strokes in children due to vertebral artery trauma

Strokes due to vertebral artery lesions are rare in children. We describe three new patients and compare them with the 16 other patients described in the literature. All of these patients are boys. Traumatic vertebral artery lesion at C1–2 level was the most common cause of stroke, and the prognosis for neurologic recovery was good. We suggest that vertebral artery disease be considered in boys with posterior circulation ischemia.

Brain stem auditory, visual and somatosensory evoked potentials in leukodystrophies.

Brain stem auditory (BAERs), visual (VEPs) and somatosensory evoked responses (SEPs) were recorded in 12 patients with Pelizaeus-Merzbacher leukodystrophy (PMD), three with adrenoleukodystrophy (ALD) and three with metachromatic leukodystrophy (MLD). All the 3 evoked responses were abnormal in all patients except normal VEPs and SEPs in a patient with early ALD. In most patients wave I with and without wave II were the only components of the BAERs that remained, subsequent components (waves III-VII) were absent. VEPs were severely altered; either no identifiable response to flash or pattern reversal stimuli could be recorded or the major components were significantly delayed in latency. Short latency SEPs following median nerve stimulation usually showed a normally recorded Erbs potential (N10), but an absence or marked attenuation of cervical (N14) and early scalp components (N19 and P22) or the occurrence of the scalp components with a significant delay. Multimodality evoked responses provide more information regarding the functional integrity of several afferent systems in patients with white matter disorders.

From swelling to sclerosis: Acute change in mesial hippocampus after prolonged febrile seizure

Mesial temporal sclerosis (MTS) has been linked to prolonged febrile seizures. The sequence of changes in the temporal lobe/hippocampus following prolonged febrile seizures and status epilepticus is beginning to be elucidated. We obtained repeated magnetic resonance imaging (MRI) volumetric analysis of the hippocampi in a 23-month-old boy after a prolonged focal febrile seizure. Three days after a prolonged left focal febrile seizure, brain MRI showed increased T2 weighted signal and increased volume (swelling) of the right hippocampus. Repeat MRI 2 months later demonstrated sclerosis of the right hippocampus. Review of the literature shows four other children with prolonged focal seizures associated with the MRI sequence of temporal lobe swelling followed by sclerosis. All had left focal seizures followed by right MTS. Our patient demonstrates a shorter interval for the radiologic development of hippocampal sclerosis compared to other reports.

Ischemic thalamic infarction in children: clinical presentation, etiology, and outcome.

Clinical features of thalamic strokes have not been well delineated in children. Six children with ischemic thalamic infarcts (3 M, 3 F; age range: 21 months to 14 1/2 years) are reported. Three patients had infarction in the thalamoperforate artery territory and all had a decreased level of consciousness and hemiparesis; two of them also had associated ocular motility abnormalities. One patient with left thalamotuberal artery stroke presented with aphasia. Two patients with thalamogeniculate artery infarcts had hemiparesis and involvement of the posterior cerebral artery. Etiologic factors in our patients were: infectious vasculitis, congenital heart disease, migraine, and unknown in 1 patient each and trauma in 2 patients. Follow-up information was available for 5, 4 of whom recovered completely. One patient was left with a neurologic deficit. We conclude that the prognosis of ischemic thalamic strokes in children is relatively good.