Synthetic MRI in Neurofibromatosis Type 1.

BACKGROUND AND PURPOSE: Synthetic MRI enables the generation of various contrast-weighted images and quantitative data in a reasonable scanning time. We aimed to use synthetic MRI to assess the detection and underlying tissue characteristics of focal areas of signal intensity and normal-appearing brain parenchyma and morphometric alterations in the brains of patients with neurofibromatosis type 1. MATERIALS AND METHODS: Conventional MR imaging and synthetic MRI were prospectively obtained from 19 patients with neurofibromatosis type 1 and 18 healthy controls. Two neuroradiologists independently evaluated focal areas of signal intensity on both conventional MR imaging and synthetic MRI. Additionally, automatically segmented volume calculations of the brain in both groups and quantitative analysis of myelin, including the focal areas of signal intensity and normal-appearing brain parenchyma, of patients with neurofibromatosis type 1 were performed using synthetic MRI. RESULTS: The comparison of conventional MR imaging and synthetic MRI showed good correlation in the supratentorial region of the brain (κ = 0.82-1). Automatically segmented brain parenchymal volume, intracranial volume, and GM volumes were significantly increased in the patients with neurofibromatosis type 1 (P < .05). The myelin-correlated compound, myelin fraction volume, WM fraction volume, transverse relaxation rate, and longitudinal relaxation rate values were significantly decreased in focal areas of signal intensity on myelin and WM maps (P < .001); however, GM, GM fraction volume, and proton density values were significantly increased on the GM map (P < .001). CONCLUSIONS: Synthetic MRI is a potential tool for the assessment of morphometric and tissue alterations as well as the detection of focal areas of signal intensity in patients with neurofibromatosis type 1 in a reasonable scan time.

Pediatric headache and neuroimaging: experience of two tertiary centers.

INTRODUCTION: Headache is a frequent complaint in children and adolescents. Decision-making for neuroimaging should take into account the cost and the need for sedation in young children. AIM: To evaluate the yield of MRI in pediatric headache patients seen in two large tertiary hospitals. METHODS: Data were retrospectively collected from patient records (n = 613) and neuroimaging reports. Headache was classified according to International Headache Society guidelines. RESULTS: There were 346 children with imaging studies (MRI n = 281, CT n = 65). Of patients who had at least one MRI study, 29% demonstrated an abnormal finding. Findings altering the management were obtained in 21 (7%) patients: the majority (n = 17, 80%) had headache for less than 3 months. On the other hand, four patients with headache longer than 3 months (19%) and 12 patients with normal neurological examination (57%) had significant MRI results affecting management. None of the children in whom the diagnosis of migraine could be made on clinical grounds (n = 40) had a significant MRI finding. CONCLUSION: Neuroimaging should be performed selectively in children with headache seen in pediatric neurology clinics, especially in headache of short duration (< 3 months) and features atypical for migraine. A normal neurological examination should not reassure the clinician.

Subacute sclerosing panencephalitis and immune thrombocytopenia: More than a coincidence?

Subacute sclerosing panencephalitis (SSPE) is a progressive disease caused by persistent measles virus (MV). It has an incidence of 0.4-2.0/million in Turkey. Immune thrombocytopenia (ITP) is a bleeding disorder whose estimated incidence is 4.2/100.000 person/years in the pediatric age group. We observed three cases with ITP in our cohort of 315 pediatric SSPE cases, an incidence higher than coincidentally expected in the general population. We hypothesize an association between SSPE and ITP. Our three cases had measles 1-2 years before the onset of ITP and 8-10 years before first symptoms of SSPE. A common immunogenetic background creating susceptibility to infection and autoimmunity might play a role. Alternatively, chronic antigenic stimulation by the MV leading to synthesis of cross-reacting antibodies against platelets, or treatment of ITP with immunoglobulins or steroids might affect or alter the development and manifestation of SSPE. The co-occurrence of these two disorders of viral and immune pathogenesis may draw attention to similar observations and provide clues for their mechanisms.

The effect of parental age on NF1 patients in Turkey.

Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, and its clinical presentations are highly variable. NF1 is caused by mutations in the NF1 gene, and 50% of NF1 cases are sporadic, which occur in the absence of a family history of the disease and usually result from a new mutation in the germline of a parent. Advanced paternal age may increase the risk for germinal NF1 mutations; however, some dominant conditions, including neurofibromatosis, have shown a lesser association with paternal age, although there are conflicting reports in the literature. We investigated the effects of paternal and maternal age in 241 NF1 patients (121 sporadic and 120 familial cases) who were seen in Hacettepe hospital, a reference center for genetic diseases in Turkey. For statistical analysis, Spearman's and Chi-square tests were used. In this study, we evaluated paternal and maternal age at birth in sporadic and familial cases of NF1. We also compared the effect of parental age on the appearance and coexistence of various NF1 symptoms. There were no significant statistical differences between paternal age and coexistence of the NF1 symptoms. However, a slightly negative correlation was observed between paternal age and the coexistence of NF1 symptoms in familial cases (p < 0.05). We did not find strong evidence for the effect of parental age on the clinical severity of NF1.

Milestones of language development in Turkish children.

OBJECTIVES: Language delays are common in childhood, may be associated with delays in other areas of development, and can affect school performance. Various tests designed for general developmental screening or specifically for language are used to assess developmental status in preschool children. Knowledge of the probabilities of normal developmental milestones may simplify detection of problems and delays. The aim of this study was to determine the milestones of language development in Turkish children. PATIENTS AND METHODS: We assessed data from application of the Denver II Developmental Screening Test's Turkish standardization to 1,993 children, 976 (49.0%) boys and 1,017 (51.0%) girls aged 0.6-82.0 months. We used binary logistic regression to analyze the predicted probability of accomplishing the language items on the Denver II Developmental Screening Test. RESULTS: We determined the sequence of assessed language items and the ages associated with accomplishing those items, as well as the ages at which 25, 50, 75, and 100% of children passed the items. Language items followed a sequential route. Graphs had polynomial slopes. CONCLUSION: Curves for normal development allow detection of aberrations in the predicted course of language development, and may facilitate earlier diagnosis of delays in language.

Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders affecting approximately 1/3500 individuals in all ethnic groups. It is characterized by cutaneous and plexiform neurofibromas, café-au-lait spots, Lisch nodules, freckling in axillary and inguinal regions, optic gliomas and an increased risk of malignancy. The mutation rate of NF1 is one of the highest known for human disorders: approximately 50% of all affected individuals carry de novo mutations. Detection of disease causing mutations in the NF1 gene allows presymptomatic and prenatal diagnosis, but is complex and time-consuming due to the large size of the gene, the existence of pseudogenes, the lack of clustering of the mutations in a particular region of the gene, and the variability of clinical findings. Because the time for investigations in prenatal diagnosis is restricted, detection of disease-associated NF1 alleles is more rapid and useful especially for familial cases. Therefore, genetic diagnosis of NF1 is frequently performed by linkage analysis. In our laboratory, 37 families were characterized with this method, of which two requested prenatal diagnosis. One fetus was found to be under NF1 risk. However, parents elected to continue pregnancy: the child is now 2.5 years old and has NF1 features. The phenotypic variability and the absence of genotype-phenotype correlation create difficulties in reproductive decisions for NF1 families, underlining the importance of appropriate counseling and detailed discussion of possible outcomes before genetic testing of the fetus.

Assessment of citrullinated myelin by 1H-MR spectroscopy in early-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Myelin instability and citrullinated myelin basic protein have been demonstrated in the brains of patients with chronic and fulminating forms of multiple sclerosis (MS). Our aim was to trace citrulline in the brains of patients with early-onset MS by using proton MR spectroscopy ((1)H-MR spectroscopy). MATERIALS AND METHODS: A short-echo single-voxel (1)H-MR spectroscopy by using the point-resolved proton spectroscopy sequence was performed in 27 patients with MS and 23 healthy subjects. Voxels of interest were chronic demyelinating lesions (CDLs, n = 25) and normal-appearing white matter (NAWM, n = 25) on T2-weighted imaging, and when available in patients with MS, enhancing demyelinating lesions (EDLs, n = 8). Frontal white matter (WM) was studied in control subjects. N-acetylaspartate, choline, and myo-inositol (mIns)-creatine (Cr) ratios and the presence of a citrulline peak were noted. RESULTS: Citrulline peaks were more frequently observed in patients with MS than in control subjects (P = .035), located in the NAWM in 8/25 (32%), in CDLs in 7/25 (28%), and in EDLs of 1/8 (12.5%) patients with MS. The presence of citrulline and measured metabolite/Cr ratios was not related to age at imaging, age at disease onset, duration of disease, or number of relapses. There was no significant metabolic difference between the NAWM of patients with MS and the WM of the control subjects. mIns/Cr was significantly greater in CDLs compared with the NAWM of patients with MS and the WM of healthy subjects. CONCLUSIONS: Citrulline was more frequently identified in the brains of patients with early-onset MS than in healthy subjects by (1)H-MR spectroscopy, suggesting an association of increased citrullination of myelin proteins with demyelinating diseases.

L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings.

L-2-Hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a rare autosomal recessive neurodegenerative disorder characterized by psychomotor delay, cerebellar and extrapyramidal signs and subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement. Mutations in the gene L2HGDH ( C14ORF160/DURANIN/) have been identified as causative for L-2-HGA. A feature disproportionally associated with L-2-HGA is the development of malignant brain tumors. In our cohort of 40 patients with L-2-HGA, two developed medulloblastoma and glioblastoma multiforme during the course of the disease. Two missense mutations in two patients were identified in the L2HGDH gene in exon 3 (c.292C-->T) and in exon 7 (c.887T-->A). Both mutations were present in the homozygous state. Serial MR imaging findings as well as MR spectroscopy imaging is reported in a patient who developed glioblastoma multiforme.

Urinary epidermal and insulin-like growth factor excretion in autistic children.

Growth factors have been implicated in the pathogenesis of autism. We have investigated daily urinary excretion of insulin-like growth factor-1 (IGF-1), epidermal growth factor, and insulin-like growth factor binding protein-3 in autistic children (n=34, age 2-5 years) and age-matched control children (n=29). The mean urinary IGF-1 level was lower in the autism group than the control group (p=0.03). Height was normal. These findings suggest altered IGF-1 metabolism in young autistic children. The cause-effect relationship should be examined by longitudinal studies and insulin-like growth factor provocation tests.

Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.

Diffusion-weighted imaging findings in juvenile metachromatic leukodystrophy.

Magnetic resonance (MR) imaging has an important role in the diagnosis of metachromatic leukodystrophy (MLD). We report diffusion-weighted MR imaging (DWI) findings of four cases of juvenile type MLD. DWI showed restricted diffusion lines with greater areas of increased diffusion in three patients and widespread increased diffusion in one patient. This variability in DWI findings can be related to the histological stage of the disease at the time of imaging, ranging from intracellular metachromatic material accumulation to breakdown of myelin membranes.

Beta-sarcoglycan gene mutations in Turkey.

The term limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that, at the outset, affect primarily the muscles of the hip and shoulder girdle. Limb-girdle muscular dystrophy is genetically heterogeneous comprising autosomal dominant (types LGMD 1A-1E) as well as autosomal recessive forms (types LGMD 2A-2J known). A subgroup among the autosomal recessive forms comprises the sarcoglycanopathies (LGMD2C-2F), caused by mutations in the gamma (gamma-SG), alpha (alpha-SG), beta (beta-SG) and delta (delta-SG) sarcoglycan genes, respectively. The sarcoglycans form the sarcoglycan complex, part of the dystrophin-associated glycoproteins. Mutations in the beta-SG gene causes LGMD2E. Disease severity, in this form, varies from mild to severe phenotypes depending on the individual mutation. Homozygous missense mutations in critical locations may result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane and a phenotype as severe as null mutations. In the present study, through screening 80 unrelated LGMD2 families, we identified 13 families with LGMD2E. Mutations in the beta-SG gene were identified in 12 patients from nine families. One of these patients carried a previously reported truncating mutation (Q11X), while the other 11 carried novel missense/rameshift mutations (M1L, V89M, I92T, I92S, 739insA), some of which were seen in more than one patient and may, therefore, be more common in the Turkish population.

Acute disseminated encephalomyelitis in children: outcome and prognosis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is the most common demyelinating disorder of childhood. Its clinical features, prognosis and treatment vary in different reports. OBJECTIVES: To examine a series of children with ADEM for clinical findings, course, recurrences, and possible variables affecting outcome. METHODS: Multicentric data collected from 7 tertiary referral centers were registered and evaluated in a central database in 1990 - 2001 for clinical, laboratory, and MRI features. Course and prognosis were assessed in patients with at least 12 months' follow-up. RESULTS: Forty-six patients were evaluated. Median age at onset was 8 years, M/F ratio, 1.7/1. Most common symptoms and signs pertained to the motor system and consciousness. Of 39 children with 12 months' follow-up, 71 % recovered completely. Thirteen (33 %) children had relapses. Patients who had more than one relapse (n = 4) presented with new symptoms at each attack. Treatment with high-dose methylprednisolone was associated with complete recovery, and tapering over more than 3 weeks, with a lower rate of relapses. MRI lesions could persist even in asymptomatic patients; in particular, periventricular lesions tended to disappear later than others. CONCLUSIONS: Complete clinical recovery is common and serious complications are rare in childhood ADEM, but the rate of relapses is considerable. Clinical picture at first relapse may help to identify patients likely to experience multiple relapses. The timing and duration of steroid treatment affects outcome.

Apoptosis in the developing human brain: a preliminary study of the frontal region.

BACKGROUND: Natural cell death due to apoptotic mechanisms has been described in various species. Relatively few studies examined this process in humans. AIM: To investigate the distribution of apoptosis in fetal brain tissue. DESIGN: We examined apoptosis in the frontal region of human fetal brain by the TUNEL method in nine fetuses with no neurological conditions, gestational age 14-26 weeks, and three fetuses with structural anomalies of the nervous system (lumbar meningomyeloceles, n=2, hydrocephalus, n=1). RESULTS: In normal fetuses, TUNEL-positive cells were most concentrated in the intermediate zone (IZ) and between 18 and 22 weeks of gestation; cortical apoptosis was not prominent. The fetus with hydrocephalus had increased numbers of TUNEL-positive cells while those with neural tube defects did not differ from normals. CONCLUSION: The definition of normally occurring apoptosis may provide a basis for further studies directed at central nervous system (CNS) malformations.

Changing epidemiological features of subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a chronic central nervous (CNS) system infection caused by measles virus. Because changing immunization practices affect the epidemiology of measles and consequently SSPE, we examined the epidemiological data of our SSPE registry. MATERIALS AND METHODS: Age of onset, age at onset of measles, duration of Latent period and immunization status were examined in cases recorded at the SSPE Registry Center in Turkey between 1975 and 1999. RESULTS: Age of onset diminished from 13 years before 1994 to 7.6 years after 1995; age at onset of measles declined from 29 months to 20 months and the Latent interval from 9.9 years to 5.9 years. Age at onset of measles and immunization status did not directly affect the duration of the Latent period. CONCLUSION: Although its incidence has decreased in Turkey, SSPE has been seen at younger ages in recent years. This change cannot be attributed solely to younger age at onset of measles. Factors affecting the duration of the Latent period should be investigated further.

Tumor necrosis factor-alpha gene polymorphisms in children with multiple sclerosis.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine implicated in the pathogenesis of infectious and autoimmune disorders including multiple sclerosis (MS). Childhood-onset MS presents some clinical and laboratory features differing from adult disease. We studied TNF-alpha - 238 G-->A and - 308 G-->A polymorphisms in 24 patients with childhood-onset MS using PCR-RFLP and compared them with healthy control subjects from the same population (n = 93). The genotypes and allele frequencies were not different between patient and control groups (p = 0.348, 95 %CI, 0.28 - 1.92, chi(2) = 0.10 and p = 0.797, 95 %CI, 0.312 - 2.285, chi(2) = 0.20 for - 238 and - 308 alleles, respectively). Although the size of the study group is small, these results do not support a role for TNF-alpha gene polymorphisms in susceptibility to MS in children.