Acute and Chronic Kernicterus: MR Imaging Evolution of Globus Pallidus Signal Change during Childhood.

BACKGROUND AND PURPOSE: Despite its rarity in Western countries, kernicterus resulting from severe neonatal hyperbilirubinemia and its associated neurologic consequences still persists. Subtle MR imaging patterns may be overlooked, leading to diagnostic and prognostic uncertainties. The study systematically analyzes MR imaging pattern over time. MATERIALS AND METHODS: A retrospective MR imaging study was conducted in Departments of Pediatric Neurology at the University Children's Hospitals in Leipzig, Germany, or Tübingen, Germany, between 2012 and 2022 in patients who presented beyond the neonatal period suspected of having chronic kernicterus. RESULTS: Eight patients with a total of 15 MR images were identified. The clinical diagnosis of kernicterus was confirmed in all cases on the basis of typical MR imaging findings: Bilateral, diffuse hyperintensity of the globus pallidus was observed in the neonatal period on T1WI (1 MR imaging, at 2 weeks), in infancy on T2WI (4 MR images, at 9-26 months). In children 2 years of age and older, bilateral hyperintensity on T2WI was limited to the borders of the globus pallidus (8 MR images, at 20 months -13 years). Notably, 2 children exhibited normal initial MR imaging findings at 2 months of age. Hence, MR imaging depiction of kernicterus pathology evolves with time, first evident on T1WI, subsequently on T2WI, with a "blind window" during early infancy. The T2WI signal change initially involves the entire globus pallidus and later is limited to the borders. Kernicterus had not been diagnosed in any except 2 patients by previous investigators. CONCLUSIONS: All patients presented with a characteristic clinical history and signs and an evolving MR imaging pattern. Nonetheless, the diagnosis of kernicterus was frequently missed. Abnormalities on later MR images appear to be underrecognized.

Leukodystrophies underlying cryptic spastic paraparesis: frequency and phenotype in 76 patients.

BACKGROUND AND PURPOSE: In chronic progressive spasticity of the legs many rare causes have to be considered, including leukodystrophies due to neurometabolic disorders. To determine the frequency of leukodystrophies and the phenotypic spectrum patients with cryptic spasticity of the legs were screened for underlying neurometabolic abnormalities. METHODS: Seventy-six index patients presenting with adult-onset lower limb spasticity of unknown cause consistent with autosomal recessive inheritance were included in this study. Screening included serum levels of very long chain fatty acids for X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal enzyme activities in leukocytes for metachromatic leukodystrophy, GM1-gangliosidosis, Tay-Sachs, Sandhoff and Krabbe disease. If clinical evidence was indicative of other types of leukodystrophies, additional genetic testing was conducted. Clinical characterization included neurological and psychiatric features and magnetic resonance imaging. RESULTS: Basic screening detected one index patient with metachromatic leukodystrophy, two patients with Krabbe disease and four patients with adrenoleukodystrophy/adrenomyeloneuropathy. Additional genetic testing revealed one patient with vanishing white matter disease. These patients accounted for an overall share of 11% of leukodystrophies. One patient with Krabbe disease and three patients with adrenoleukodystrophy/adrenomyeloneuropathy presented with pure spasticity of the lower limbs, whilst one patient each with Krabbe disease, metachromatic leukodystrophy and adrenoleukodystrophy/adrenomyeloneuropathy showed additional complicating symptoms. CONCLUSIONS: Adult patients presenting with cryptic spasticity of the legs should be screened for underlying X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal disorders, irrespective of the presence of additional complicating symptoms. Leukodystrophies may manifest as late as the sixth decade and hyperintensity of cerebral white matter on magnetic resonance FLAIR images is not obligatory.

Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort.

Metachromatic leukodystrophy (MLD) is a rare inborn error of metabolism leading to severe neurological symptoms and early death. Hematopoietic SCT (HSCT) is considered a treatment option, but results are inconsistent and comparison with natural history is practically missing. We compare a girl with juvenile MLD 10 years after allogeneic HSCT not only with her untreated sister, but also with a large cohort of untreated patients. The girl received HSCT at the age of 5 years when first motor signs appeared. Over 10 years she was stable with respect to her clinical course and gained cognitive abilities. Magnetic resonance imaging (MRI) showed clear regression of white matter changes and magnetic resonance spectroscopy (MRS) demonstrated a reversal of the initial choline increase and N-acetyl-aspartate (NAA) decrease. Only axonal demyelinating neuropathy showed some progression. Her gross motor function and MRI-scores were clearly better compared with her sister and the cohort of untreated patients. Difference to her sister became apparent only 4 years after HSCT. We conclude that HSCT, early in the course of disease, can lead to stabilization of juvenile MLD with a course clearly different from the natural history. HSCT may prevent disease progression, if performed sufficient time before loss of walking, which typically initiates rapid deterioration.

Medical, psychological and intellectual development of 5-year-old children born after intracytoplasmic sperm injection.

BACKGROUND: The neurodevelopmental outcome of children born after intracytoplasmic sperm injection (ICSI) is controversial. PATIENTS AND METHODS: Thus, we compared the medical and developmental outcome at a mean age of 5 years and 6 months of 35 singletons born after an ICSI procedure performed at the Tübingen Medical Center with those of 37 naturally conceived (NC) matched control singletons born at the Tübingen Medical Center. Children with congenital anomalies which could interfere with mental development were excluded, these were reported earlier. Each child was assessed neurologically and physically. Cognitive function was assessed using the Kaufman assessment battery for children (K-ABC). Behaviour was tested using a German behavioural questionnaire for preschoolers (VBV). RESULTS: Medical and cognitive outcome, and behaviour pattern were similar in both groups. Nevertheless, there were sex-related differences in favour of ICSI children: ICSI boys had better social competence than the control boys, while ICSI girls had less emotional problems than the control girls. CONCLUSIONS: Once severe congenital anomalies were excluded, there were no differences in physical and neurodevelopmental outcome of 5-year-old ICSI children compared with controls.With regard to behaviour and emotional development, ICSI children seem to be similar or might be even more stable and socially competent than the control children. As our study is limited by the small sample size, further research is needed to confirm our results.

[2-year follow-up examinations (Bayley II) in infants born at <32 weeks in a German perinatal center]. / 2-Jahres-Nachuntersuchung (Bayley) sehr kleiner Frühgeborener der Jahrgänge 2004-2007: Ergebnisse und Vollständigkeitsanalyse eines Perinatalzentrums.

BACKGROUND: Since 2008, follow-up examinations at 2 years of age with the standardized Bayley II test have become obligatory in Germany for all very low birth weight infants. AIM: We already performed such examinations before 2006. Here, we compared our data and the completeness of our examinations before and after the introduction of the obligatory 2-year follow-up. PATIENTS: From 2004-2007, 372 infants <1500 g or <32 weeks were discharged alive from our center, 19 infants died during their initial hospital stay, 2 after discharge. RESULTS: 271 patients participated in the follow-up examination at age 2 years, with the proportion of participating infants increasing from 64% to 84% after the introduction of obligatory tests. 75% of infants showed a normal development, while 4% had a severe impairment (defined as being blind (1), deaf (1) or having cerebral palsy (6), the CP rate thus being 2%). 49% of infants completed the Bayley test; the mean MDI was 100.3 (SD 10.6). There were no significant qualtitative differences in test results with the introduction of the obligatory test. CONCLUSIONS: The completeness of our follow-up increased over the years. In comparison with international data we found a low rate of severely impaired, deaf or blind VLBW infants.

Metachromatic leukodystrophy--an update.

Metachromatic leukodystrophy (MLD) is a rare lysosomal sphingolipid storage disorder, caused by a deficiency of arylsulfatase A (ASA). It is inherited in an autosomal recessive way, among Caucasians three causing alleles are frequent. Demyelination is the hallmark of MLD. Interest in the disease has increased as therapeutic options such as stem cell transplantation, enzyme replacement and gene therapy are topics of current research. A late-infantile (onset before 3 years of age), a juvenile form (onset before 16 years) and an adult form are usually distinguished. Rapid motor decline is typical for the first and also the second forms, the second may be preceded by cognitive and behavioural problems, which mainly characterize the adult form. There is evidence for a genotype-phenotype correlation: patients homozygous for alleles which do not allow the expression of any enzyme activity (null-allele) suffer from the late infantile form; heterozygosity for a null allele and a non-null allele are more associated with the juvenile form and homozygosity for non-null alleles is more frequent in the most attenuated adult onset form.

Dyskinetic cerebral palsy in Europe: trends in prevalence and severity.

OBJECTIVE: To describe the trends for and severity of dyskinetic cerebral palsy in a European collaborative study between cerebral palsy registers, the Surveillance of Cerebral Palsy in Europe (SCPE). METHODS: The prevalence of dyskinetic cerebral palsy was calculated in children born in 1976-1996. Walking ability, accompanying impairments and perinatal adverse events were analysed. RESULTS: 578 children had dyskinetic cerebral palsy, of whom 70% were born at term. The prevalence per 1000 live births increased from 0.08 in the 1970s to 0.14 in the 1990s. For the 386 children (70%) with a birth weight of > or =2500 g, the increase was significant (0.05 to 0.12). There was a concurrent decrease in neonatal mortality among children with a birth weight of > or =2500 g. Overall, 16% of the children walked without aids, 24% with aids and 59% needed a wheelchair. Severe learning disability was present in 52%, epilepsy in 51% and severe visual and hearing impairment in 19% and 6%, respectively. Accompanying impairments increased with motor severity. In children born in 1991-1996, perinatal adverse events, that is an Apgar score of <5 at 5 min and convulsions before 72 h, had occurred more frequently compared with children with bilateral spastic cerebral palsy (BSCP, n = 4746). Children with dyskinetic cerebral palsy had more severe cognitive and motor impairments than children with BSCP. CONCLUSIONS: The prevalence of dyskinetic cerebral palsy appears to have increased in children with a normal birth weight. They have frequently experienced perinatal adverse events. Most children have a severe motor impairment and several accompanying impairments.

Reorganization of the cerebro-cerebellar network of language production in patients with congenital left-hemispheric brain lesions.

Patients with congenital lesions of the left cerebral hemisphere may reorganize language functions into the right hemisphere. In these patients, language production is represented homotopically to the left-hemispheric language areas. We studied cerebellar activation in five patients with congenital lesions of the left cerebral hemisphere to assess if the language network is reorganized completely in these patients, i.e. including also cerebellar language functions. As compared to a group of controls matched for age, sex, and verbal IQ, the patients recruited an area not in the right but in the left cerebellar hemisphere. The extent of laterality of the cerebellar activation correlated significantly with the laterality of the frontal activation. We suggest that the developing brain reacts to early focal lesions in the left hemisphere with a mirror-image organization of the entire cerebro-cerebellar network engaged in speech production.

(Re-)organization of basal ganglia in congenital hemiparesis with ipsilateral cortico-spinal projections.

In congenital hemiparesis after pre- or perinatally acquired unilateral brain lesions, many patients control their paretic hand via ipsilateral cortico-spinal projections from the contralesional hemisphere. In order to clarify the pattern of basal ganglia activation in case of such a shift of the primary motor cortical representation (M1) of the paretic hand to the contralesional hemisphere, fMRI was performed in eight patients with congenital hemiparesis due to unilateral periventricular white matter lesions and ipsilateral corticospinal projections to the paretic hand (as determined by focal transcranial magnetic stimulation). FMRI during active movements of the paretic hand yielded basal ganglia activation in the ipsilateral (=contralesional) hemisphere, but not in the contralateral (lesioned) hemisphere. Thus, (re-)organization in congenital hemiparesis with ipsilateral cortico-spinal projections includes, in addition to the ipsilateral primary motor cortex (M1), also the ipsilateral basal ganglia - in contrast to the primary somatosensory cortex (S1), which is typically preserved in the affected hemisphere.

[Management of refractory status epilepticus from a neurologic and neuropediatric perspective]. / Management des refraktären Status epilepticus: Eine Bestandsaufnahme aus neurologischer und neuropädiatrischer Sicht.

Status epilepticus is a frequent neurologic emergency that is refractory to benzodiazepines and phenytoin in 60% to 70% of cases. Patients commonly require management in an intensive care unit incorporating aggressive treatment with intravenous anaesthetics. Treatment guidelines commonly comment on initial pharmacologic management in detail, as they can refer to data from randomised controlled trials. In contrast, recommendations for the management of refractory status epilepticus often are sparse, as they rely on data from retrospective or uncontrolled prospective studies only. Since status epilepticus is refractory in every third patient, a critical analysis of the available data and a review focussing on the further management of this condition are urgently needed. The Koenigstein Team, a panel of expert epileptologists and neuropediatricians, discussed at its 31(st) meeting in March 2006 the clinical and experimental aspects and implicit prognostic variables of refractory status epilepticus. Here we present the results of that discussion and state recommendations from a neurologic and neuropediatric perspective for current und future management of refractory status epilepticus.

Increased frequency of severe major anomalies in children conceived by intracytoplasmic sperm injection.

The neurodevelopmental outcome of children born after intracytoplasmic sperm injection (ICSI) is controversial. We compared the medical and developmental outcome of 34 singletons born after ICSI (20 males, 14 females; mean ages of 18 mo and 40 mo [SD 9 mo]; range 2 y 10 mo-4 y 8 mo) with 39 case control studies (21 males, 18 females; mean ages of 18 mo and 40 mo [SD 4 mo]; range 3 y-4 y 1 mo). Each child was assessed physically and tested in three development domains (fine motor, gross motor, and language). Five children born after ICSI versus two control children (p=0.2) had major congenital anomalies (MaCAs). Four children born after ICSI versus no control children had severe MaCAs (p=0.04). These were defined as having a significant impact on development or causing chronic disease: Angelman syndrome (n=1), lissencephaly (n=1), Hanhart syndrome (n=1), and persistent hyperinsulinemic hypoglycaemia of infancy (n=1). Karyotyping in 23 children born after ICSI revealed no abnormalities. An imprinting defect was found in the child with Angelman syndrome. Results of developmental assessment were in all cases normal at the age of 18 months except for the three children with Angelman and Hanhart syndromes, and lissencephaly. At the second assessment, five more children born after ICSI and four control children showed abnormalities in one or more developmental domains. We conclude that there seems to be a higher frequency of severe major anomalies in children born after ICSI. An increased risk for imprinting defects cannot be excluded. If we exclude children with severe MaCAs, the incidence of an abnormal somatic or neurodevelopmental outcome in the fourth year of life in children born after ICSI is similar to that of spontaneously conceived children.

Developing somatosensory projections bypass periventricular brain lesions.

The authors studied four hemiparetic patients with large unilateral periventricular brain lesions acquired during the early third trimester of pregnancy. fMRI and magnetoencephalography demonstrated that the primary somatosensory representation of their paretic hands was nevertheless located in the contralateral rolandic cortex. Thus, outgrowing thalamocortical somatosensory projections had apparently bypassed the lesion to reach their original cortical destination. Such somatosensory projections curving around the lesion were effectively visualized by magnetic resonance diffusion tractography.

Case gender and severity in cerebral palsy varies with intrauterine growth.

BACKGROUND: There is an unexplained excess of cerebral palsy among male babies. There is also variation in the proportion of more severe cases by birth weight. It has recently been shown that the rate of cerebral palsy increases as intrauterine size deviates up or down from an optimum about one standard deviation heavier than population mean weight-for-gestation. AIMS: To determine whether the gender ratio or the severity of cases also varies with intrauterine size. METHODS: A total of 3454 cases of cerebral palsy among single births between 1976 and 1990 with sufficient data to assign case severity (based on intellectual impairment and walking ability) and to compare weight-for-gestation at birth to sex specific fetal growth standards, were aggregated from nine separate registers in five European countries. RESULTS: The greater the degree to which growth deviates either up or down from optimal weight-for-gestation at birth, the higher is the rate of cerebral palsy, the larger is the proportion of male cases, and the more severe is the functional disability. Compared to those with optimum growth the risk of more severe cerebral palsy in male babies is 16 times higher for those with a birth weight below the 3rd centile and four times higher when birth weight is above the 97th centile. In contrast, for mild cerebral palsy in female babies the excess risks at these growth extremes are about half these magnitudes. CONCLUSIONS: Among singleton children with cerebral palsy, abnormal intrauterine size, either small or large, is associated with more severe disability and male sex.

The development of cerebral perfusion in healthy preterm and term neonates.

Quantitative measurement of cerebral blood flow (CBF) volume was performed by sonographic flowmetry of both internal carotid (ICA) and vertebral arteries (VA) in 113 healthy preterm and term infants of 32 - 42 weeks postmenstrual age (PA) in order to delineate the physiological characteristics of brain perfusion in a time period very sensitive to brain injury. Mean CBF volume increased with PA, beginning with 33 +/- 9 ml/min in neonates of 32 - 34 weeks and rising to 45 +/- 10, 58 +/- 13, 69 +/- 14, and 83 +/- 16 ml/min, respectively, in the PA groups of 35 - 36, 37 - 38, 39 - 40 and 41 - 42 weeks. There was no difference in CBF volume between the sexes. The bilateral sum of flow volumes in both ICA and VA rose markedly with PA. The relative contribution of bilateral VA flow volume to total CBF volume was 26 +/- 8 % and remained constant with PA. In addition, we calculated the approximate CBF (ml/100 g brain weight/min) using the brain weights of each child as estimated by means of an equation based on head circumference measurements. Estimated CBF correlated significantly with PA (r = 0.49; p

Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfall in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292 K.

This study describes a diagnostic pitfall in the laboratory diagnosis of patients with sphingomyelinase deficiency (SMD; Niemann-Pick disease types A and B; NPA and NPB), in cases where sphingomyelinase activity was not determined with sphingomyelin as the natural enzymic substrate. Four of 24 SMD patients studied had falsely normal or enhanced activity, when a so-called artificial sphingomyelinase substrate, 2-N-(hexadecanoyl)-amino-4-nitrophenyl phosphorylcholine (HNP), was used, whereas SMD was clear with the sphingomyelin substrate. Those four patients had the Q292 K mutation of the acid sphingomyelinase gene (SMPD1) on at least one allele. Three of the four patients (no data available from one) experienced only late-infantile or juvenile, though distinct, neurological involvement, where learning disabilities, hypo- or areflexia or mild ataxia were initial signs. The laboratory pitfall with HNP substrate, which is used in many laboratories, raises the risk that some SMD patients are overlooked, and it prevents the consideration of a late-manifesting neurological course in some patients as well as the planning of enzyme substitution therapy in non-neurological SMD (NPB) patients. Since classical NPB is very rare, it is suggested that SMD patients with late- or mild-manifesting neurological symptoms should better be assigned to additional SMD subgroups than grouped with NPB.

Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype.

OBJECTIVE: To describe three unrelated children with a distinctive variant of Aicardi-Goutières syndrome (AGS) characterized by microcephaly, severe mental and motor retardation, dyskinesia or spasticity, and occasional seizures. RESULTS: Neuroimaging showed bilateral calcification of basal ganglia and white matter. CSF glucose, protein, cell count, and interferon alpha were normal. Abnormal CSF findings included extremely high neopterin (293 to 814 nmol/L; normal 12 to 30 nmol/L) and biopterin (226 to 416 nmol/L; normal 15 to 40 nmol/L) combined with lowered 5-methyltetrahydrofolate (23 to 48 nmol/L; normal 64 to 182 nmol/L) concentrations in two patients. The absence of pleocytosis and normal CSF interferon alpha was a characteristic finding compared to the classic AGS syndrome. Genetic and enzymatic tests excluded disorders of tetrahydrobiopterin metabolism, including mutation analysis of GTP cyclohydrolase feed-back regulatory protein. CSF investigations in three patients with classic AGS also showed increased pterins and partially lowered folate levels. CONCLUSIONS: Intrathecal overproduction of pterins is the first biochemical abnormality identified in patients with AGS variants. Long-term substitution with folinic acid (2-4 mg/kg/day) resulted in substantial clinical recovery with normalization of CSF folates and pterins in one patient and clinical improvement in another. The underlying defect remains unknown.