Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases.

Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood-onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.

A de novo mutation in the ß-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and ß-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.

Microdeletion 5q14.3 and anomalies of brain development.

5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern.

Cerebral hemiatrophy associated with hippocampal sclerosis following a single prolonged febrile seizure.

The etiological relation of prolonged febrile seizures with hippocampal sclerosis and cerebral hemiatrophy is controversial. Causal relationship is mainly adopted from retrospective statistical analysis and data from epilepsy surgery. We report a 17-month-old boy who had a prolonged febrile seizure with a transient postictal flaccid hemiparesis and anisocoria. Family history was unremarkable. Magnetic resonance imaging (MRI) revealed abnormal results in the right hippocampal area where diffusion-weighted sequences showed increased signal intensity consistent with acute neuronal edema. Repeat MRI 5 months later demonstrated sclerosis and atrophy of the right hippocampus in association with an increased T2-weighted signal and atrophy of the right frontal, temporal, and parietal lobe. In addition, 18-fluorodeoxyglucose positron emission tomography and 99mTc-ECD single-photon emission computed tomography revealed glucose hypometabolism and decreased perfusion in the right hemisphere, respectively. A final MRI, 12 months following the seizure, was widely unchanged. Interestingly, during a follow-up of 42 weeks, only minor motor deficits were observed. This case uniquely presents the acute onset of hippocampal sclerosis and, consecutively, cerebral hemiatrophy after a single febrile seizure. This suggests that a single prolonged febrile seizure may cause global morphological changes of the brain, not only affecting hippocampal formation.

Life-long increase of substantia nigra hyperechogenicity in transcranial sonography.

Transcranial ultrasound of the substantia nigra (SN) shows a distinct hyperechogenicity in the majority of patients with Parkinson's disease. Recent studies indicate a larger area of hyperechogenicity in elderly healthy adult subjects. The present study aimed to determine the size of the SN hyperechogenicity and of the mesencephalic brainstem in children and adults without evidence of movement disorders. The areas of echogenicity in the substantia nigra (aSN) and the area of the ipsilateral midbrain (aMid) were assessed in 121 healthy infants and children as well as in 64 healthy adults. Furthermore, the ratio of aSN and aMid was calculated (S/M ratio). We found a positive correlation between age and aSN and between age and the S/M ratio. The values for aSN and S/M ratio were smaller in infants and children compared to healthy adults (aSNmax 0.06+/-0.05 cm2 vs. 0.13+/-0.08 cm2). The aSN and S/M ratio grew with increasing age in an almost linear progression. The increase of SN hyperechogenicity over time suggests that the biological process underlying this ultrasound finding may be more dynamic and possibly progressive than previously thought.

Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/microl (median 5 cells/microl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).

Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region.

Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor.

Lyme disease with lymphocytic meningitis, trigeminal palsy and silent thalamic lesion.

We describe a follow-up in a 15-year-old boy with neuroborreliosis diagnosed by clinical symptoms, CSF and serum analysis. MRI revealed a thalamic lesion and an enhancement of the right trigeminal nerve clinically associated with mild hypasthesia in the right maxillary region. Both, clinical symptoms and radiological findings disappeared within 2 months after treatment. Borrelia burgdorferi specific IgM and IgG in CSF and IgG in serum became negative between 6 and 12 months after diagnosis. We show that neuroborreliosis at an early stage may present only with moderate neurological deficits and that at this stage MRI reveals distinct cerebral lesions which might even precede clinical manifestation. Thus, early diagnosis and treatment of neuroborreliosis may prevent persistent neurologic lesions.

Familial megalencephaly with dilated Virchow-Robin spaces in magnetic resonance imaging: an autosomal recessive trait?

We report the unusual occurrence of progressive megalencephaly and dilated periventricular cystic Virchow-Robin spaces on magnetic resonance imaging in two siblings of a Turkish family. Both affected children in addition presented with psychomotor retardation. Since the index patients were of different gender and their parents were consanguineous, this constellation of findings is suggestive of an autosomal recessive trait.

Do Glut1 (glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?

In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (PED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of KD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role.

Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease.

Alexander disease (AD) is a rare genetic disorder of the central nervous system due to a dysfunction of astrocytes. The most common infantile form presents as a progressive leukodystrophy with macrocephalus. Recently, heterozygous de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP) have been demonstrated to be associated with AD. We used localized proton magnetic resonance spectroscopy (MRS) to assess metabolic abnormalities in grey and white matter, basal ganglia, and cerebellum of 4 patients with infantile AD and GFAP mutations. Strongly elevated concentrations of myo-inositol in conjunction with normal or increased choline-containing compounds in all regions investigated point to astrocytosis and demyelination. Neuroaxonal degeneration, as reflected by a reduction of N-acetylaspartate, was most pronounced in cerebral and cerebellar white matter. The accumulation of lactate in affected white matter is in line with infiltrating macrophages. Metabolic alterations demonstrated by in vivo proton MRS are in excellent agreement with known neuropathological features of AD.

New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum.

BACKGROUND AND PURPOSE: Leukoencephalopathies of unknown origin constitute a considerable problem in child neurology. The purpose of our ongoing study of the subject was to define new disease entities among them by using primarily MR imaging pattern recognition. METHODS: We identified seven unrelated patients with a distinct MR imaging pattern consisting of hypomyelination and atrophy of the basal ganglia (neostriatum) and cerebellum (H-ABC). We reviewed the clinical, MR imaging, MR spectroscopic, and laboratory data. RESULTS: Clinically, the patients' diseases were characterized by variably disturbed early development followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacity was variably affected, but it appeared to be relatively preserved. Parents were not related, and none of their siblings were affected. No metabolic defect was found. Follow-up MR imaging demonstrated atrophy of the cerebral white matter, neostriatum, and cerebellum, which was most pronounced in the most clinically severe cases. Single-voxel proton MR spectroscopic results were normal in the parietal cortex. In the cerebral white matter, myo-inositol and creatine levels were elevated; this finding was compatible with gliosis. N-acetylaspartate and choline levels were normal, suggesting that neither axonal loss nor active demyelination occurred. Proton MR spectroscopic imaging revealed relatively decreased N-acetylaspartate levels in the frontal region. CONCLUSION: The uniform and highly characteristic MR imaging findings, in combination with the similarities in the clinical findings, provide evidence of a distinct nosologic entity. The acronym H-ABC is offered to indicate patients sharing these clinical and MR imaging features.

Frontoethmoidal encephalocele with ocular leakage of cerebrospinal fluid. Case report.

The authors present the case of a 2-year-old boy who was born with a small bulging mass in the middle frontonasal area and hypertelorism. In the neonatal period he suffered from a continuous lacrimal secretion mistaken for recurrent conjunctivitis. Cranial computerized tomography scanning and magnetic resonance imaging revealed a frontoethmoidal encephalocele associated with an ocular leakage of cerebrospinal fluid. One-stage repair of the encephalocele, along with correction of hypertelorism and bone grafting of the forehead, was performed with good result. During a 2-year follow-up period no neurological deficits appeared.

Multiphasic disseminated encephalomyelitis associated with streptococcal infection.

Multiphasic disseminated encephalomyelitis (MDEM) is a rare peculiar diagnosis which is defined as acute demyelinating central nervous system disease with relapses occurring only within 4 weeks of initial manifestation. This report describes the case of a 6-year-old boy with MDEM diagnosed by clinical findings and magnetic resonance imaging. The disease had a biphasic evolution, and with a second course of high-dose corticosteroids a complete recovery without further relapse was obtained during the following 18 months. Serological evidence of streptococcal infection as specific trigger for MDEM was given. Thus this report raises the question whether an additional penicillin prophylaxis could be valuable for prevention of streptococcus-associated MDEM relapses.

Isolated unilateral cortical oedema and complex partial seizures in association with coxsackievirus B infection.

A unilateral cortical oedema in association with coxsackievirus B infection is reported. A 10-year-old girl presented with right hemiparesis and complex partial seizures. The cerebral MRI showed a unique pattern of isolated unilateral cortical oedema sparing the white matter with intravascular gadolinium enhancement of the left hemispheric sulcal veins. With anticonvulsant medication, the patient recovered within two weeks and MRI abnormalities were completely resolved after four weeks, whereas the EEG left hemispheric slowing showed delayed normalisation over the following five months.

Unmet health care needs and impact on families with children with disabilities in Germany.

OBJECTIVES: We sought to determine the independent effect of unmet health needs on family burden, in addition to the effects of functional impairment and parental care load, in children and adolescents with disabilities. METHODS: We conducted a cross-sectional survey of 273 families with children with disabilities using ambulatory services at an academic children's hospital in Germany. We measured family burden using a translated version of the Impact on Family Scale (FABEL). Independent variables were unmet health needs in 4 areas (medical care, care coordination, health education, and psychosocial services), level of functional disability, and nursing care load at home. Control variables included the child's age and gender, maternal employment status, and parental educational attainment. RESULTS: Most children had complex health conditions such as brain injury, congenital malformations, metabolic disease, myopathies, and brain tumors. Nearly half of families (44.6%) received home nursing cash benefits, indicating high care load. Parents reported most unmet needs in the areas of psychosocial counseling (17.2%) and care coordination (8.1%). After controlling for sociodemographic factors, unmet health needs predicted family burden independently of type (mental retardation or mobility impairment) and number of disabilities and nursing care load. Although only a few parents reported lack of medical services, this factor also contributed significantly to family burden. Multivariate analysis with these variables explained 45% of the variance in impact on the family. CONCLUSIONS: Addressing unmet health needs may alleviate the impact of caring for a child with a disability. Further studies are needed to show more definitively that families can benefit from integrated services including psychosocial counseling.

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

Beneficial prenatal levodopa therapy in autosomal recessive guanosine triphosphate cyclohydrolase 1 deficiency.

OBJECTIVE: To report the first prenatal dopaminergic replacement therapy in autosomal recessive (AR) guanosine triphosphate cyclohydrolase 1 (GTPCH) deficiency without hyperphenylalaninemia. DESIGN: Case reports, literature review, and video presentation. SETTING: University of Lübeck, Lübeck, Germany. PATIENTS: Two boys from a consanguineous family. MAIN OUTCOME MEASURES: Physical and mental development as a function of replacement initiation. RESULTS: The older sibling presented with typical features of AR GTPCH deficiency due to a homozygous mutation in the GCH1 gene with proven pathogenicity. Levodopa treatment was initiated at age 10 months and resulted in a distinct motor improvement. However, mental development was delayed. In the younger sibling, prenatal replacement therapy was initiated after a prenatal diagnosis of AR GTPCH deficiency was made. At age 17 months, both motor and mental development were normal for his age. CONCLUSIONS: This report highlights the importance of an early diagnosis, including prenatal diagnosis, of complex dopa-responsive extrapyramidal syndromes. Prenatally initiated dopaminergic replacement therapy is beneficial and thus justified in AR GTPCH deficiency, allowing prevention of significant impairment of mental abilities.

Operative and technical complications of vagus nerve stimulator implantation.

BACKGROUND: The treatment of refractory epilepsy by vagus nerve stimulation (VNS) is a well-established therapy option for patients not suitable for epilepsy surgery and therapy refractory depressions. OBJECTIVE: To analyze surgical and technical complications after implantation of left-sided VNS in patients with therapy-refractory epilepsy and depression. METHODS: One hundred five patients receiving a VNS or VNS-related operations (n = 118) from 1999 to 2008 were investigated retrospectively. RESULTS: At the time of operation, 84 patients were younger than 18 years, with a mean age of 10.5 years. Twenty (19%) patients had technical problems or complications. In 6 (5.7%) patients these problems were caused by the operation. The device was removed in 8 cases. The range of surgically and technically induced complications included electrode fractures, early and late onset of deep wound infections, transient vocal cord palsy, cardiac arrhythmia under test stimulation, electrode malfunction, and posttraumatic dysfunction of the stimulator. CONCLUSION: VNS therapy is combined with a wide spread of possible complications. Technical problems are to be expected, including electrode fracture, dislocation, and generator malfunction. The major complication in younger patients is the electrode fracture, which might be induced by growth during adolescence. Surgically induced complications of VNS implantation are comparably low. Cardiac symptoms and recurrent nerve palsy need to be taken into consideration.

Right-sided vagus nerve stimulation in humans: an effective therapy?

Vagus nerve stimulation (VNS) is an additive treatment option for refractory epilepsy. The electrode is placed on the cervical trunk of the left vagus nerve. In patients who are not suitable for left-sided vagus nerve stimulation (L-VNS) right-sided vagus nerve stimulation (R-VNS) may be as effective. In animal models epilepsy is sufficiently suppressed by R-VNS. In a 16 years old boy suffering from medically refractory psychomotoric seizures with secondary generalisation, L-VNS reduced the frequency of generalized seizures. A deep wound infection required the removal of the system eight weeks later. Cicatrisation did not allow preparation of the left vagus nerve, therefore we implanted R-VNS with sufficient seizure suppression. However, compared to L-VNS, the effect occurred months later and cardiac symptoms were induced by stimulation of the right vagus nerve. R-VNS seems to be an effective and alternative therapy in selected patients responding to L-VNS where a left-sided reimplantation is not possible. Placement and adjustment of the device should be performed under ECG control. Further studies are necessary to compare the efficacy of L-VNS and R-VNS.