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.

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.

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.

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.

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.

MRI findings in subacute sclerosing panencephalitis.

Thirty-four MRI studies of 26 patients with subacute sclerosing panencephalitis are reported. Lesions of high signal intensity on T2-weighted images are the most common finding; they frequently involve the periventricular or subcortical white matter. Lesions tend to start in the cortex-subcortical white matter and progress with periventricular white matter involvement and diffuse cerebral atrophy. Pial and parenchymal contrast enhancement, local mass effect of parenchymal lesions, and involvement of the splenic portion of the corpus callosum are not infrequent. Basal ganglia and brainstem lesions were rare in this series. Although cortical and subcortical lesions have some correlation with clinical findings, the extent and location of the periventricular white matter lesions and cerebral atrophy did not reflect the neurologic status in many patients.

Long-term follow-up of patients with subacute sclerosing panencephalitis treated with intraventricular alpha-interferon.

We treated 22 patients with subacute sclerosing panencephalitis (SSPE) with intraventricular alpha-interferon (alpha-IFN) and oral inosiplex between 1986 and 1991. The follow-up for 56 to 108 months demonstrates a higher survival rate in these patients compared with those who did not receive alpha-IFN. However, eight of 11 patients whose condition improved after alpha-IFN treatment and five of five patients whose condition stabilized after alpha-IFN experienced neurologic deterioration 6 to 90 months after treatment; three of 11 and four of five died. The use of inosiplex did not influence the prognosis. Re-administration of the same regimen was not effective in one patient. Treatment-induced remissions in SSPE can be temporary, analogous to spontaneous remissions. Longer treatment with higher doses, or combinations of drugs, may be required.

Intraventricular interferon and oral inosiplex in the treatment of subacute sclerosing panencephalitis.

We treated 22 patients with subacute sclerosing panencephalitis (SSPE) with intraventricular alpha-interferon (IFN) and inosiplex PO and followed them for 2 to 54 months. Three deaths occurred. Clinical improvement, demonstrated by decreasing scores on the Neurological Disability Index, occurred in 11/22 (50%); five patients became stable, and the progression rate of the disease decreased in three. The remission rate was significantly higher than untreated controls from the same institution. Patients who had a slowly progressive disease responded best to treatment. Serious side effects were rare. We recommend intraventricular IFN, combined with oral inosiplex, in the treatment of SSPE.

Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene.

Forty-two missense, truncation, or splice-site mutations of the acetylcholine receptor (AChR) subunit genes have been reported to date in patients with congenital myasthenic syndromes. Here we report a homozygous mutation, epsilon-155G --> A, in the promoter region of the AChR epsilon subunit gene that converts the Ets-binding site of the promoter region from CGGAA to CAGAA. The asymptomatic parents and brother are heterozygous and an affected sister is homozygous for epislon-155G --> A. The Ets-binding site mediates synapse specific expression of the AChR epsilon subunit gene. An identical G-to-A mutation in the mouse Ets-binding site was previously shown to decrease the binding affinity of the Ets-binding site for the GA binding protein, a transactivating factor for the Ets-binding site, and to reduce the synapse specific expression of the epsilon subunit. The decreased synaptic expression of the epsilon subunit readily accounts for the congenital myasthenic phenotype.

Increased muscarinic cholinergic receptor density on CD4+ lymphocytes in progressive multiple sclerosis.

We measured the density and affinity of muscarinic cholinergic receptors (MR) in 29 chronic progressive and ten stable multiple sclerosis (MS) patients and 27 control subjects using [3H]N-methyl-scopolamine. The density of MR on CD4+ lymphocytes was significantly higher in chronic progressive MS (CPMS) than in controls (7.9 +/- 0.7 vs. 4.5 +/- 0.4 fmol/10(6) cells, p less than 0.001). Stable patients did not differ significantly from control subjects. Receptors of the M1 subtype were measured on CD4+ lymphocytes of nine patients and seven controls with the selective antagonist [3H]methylpirenzepine: M1/total receptor ratio was 64.1% in CPMS and 81.2% in controls, suggesting a selective increase of M2-type MR in CPMS. The findings may relate to parasympathetic denervation hypersensitivity of lymphocytes or to lymphocyte activation which is known to be associated with increased MR number.

Increased high affinity beta-adrenergic receptor densities and cyclic AMP responses of CD8 cells in multiple sclerosis.

Beta-adrenergic receptor (beta R) density is increased on suppressor T-cells (Ts) from patients with chronic progressive multiple sclerosis (CPMS). We investigated the contribution of high-affinity (kh) beta R to cAMP responses of nongranular leukocyte subsets from CPMS patients and normal individuals (NL). CD8 beta R density was 1930 receptors/cell in CPMS compared to only 1020 receptors/cell in NL (t(18) = 2.73, P < 0.02). beta R densities on monocytes, B cells, and CD4 cells did not differ between groups. The increased density of beta R on CD8 cells in CPMS was entirely the result of an increase in the number of high affinity receptors. Basal level of cAMP in CD8 lymphocytes were 7.8 pmol/10(6) cells in CPMS and 3.5 pmol/10(6) cells in NL. Isoproterenol stimulation elevated cAMP levels in CD8 cells to 49.9 pmol/10(6) cells in CPMS patients and to 25.7 pmol/10(6) cells in NL (difference after activation: t(18) = 3.23, P < 0.005). No differences between groups were found in cAMP levels of other cell subsets. We also measured circulating catecholamine levels. Supine and standing epinephrine levels were not different between CPMS and NL. Supine norepinephrine (NE) levels were higher in CPMS (411 pg/ml) than in NL (268 pg/ml) (P < 0.03); upon standing, significant increases in NE occurred in both groups to 573 pg/ml in CPMS and to 494 pg/ml in NL. These results extend our previous findings of peripheral sympathetic dysregulation in CPMS and suggest a means whereby Ts function, hypothesized to play a role in the immune pathogenesis of CPMS, may be altered.

Cimetidine as an immunomodulator in subacute sclerosing panencephalitis: a double blind, placebo-controlled study.

Cimetidine, an H2 histamine receptor antagonist, was used in subacute sclerosing panencephalitis patients for its immunomodulatory effect. Patients were randomly assigned to cimetidine (n = 7) and placebo (n = 7) groups. Neurologic disability index, lymphocyte functions, cerebrospinal fluid measles antibodies and IgG index were evaluated before and after 2 months of treatment. The neurologic disability index of the cimetidine group remained stable during the study period whereas the placebo group worsened. There were no differences in the immunologic test results, cerebrospinal fluid measles antibody titers and IgG index of the two groups. This study suggests that cimetidine may have a favorable effect on the clinical progression of subacute sclerosing panencephalitis. Further studies are required to investigate its mechanism of action and the associated changes in immune status.

Subacute sclerosing panencephalitis : diagnosis and drug treatment options.

Subacute sclerosing panencephalitis (SSPE) is a chronic progressive, usually fatal disease of uncertain pathogenesis that is associated with the presence of mutant measles virus in the CNS. The diagnosis is based on clinical criteria and an elevated titre of measles antibodies in the CSF. Electroencephalography, imaging studies and measles antibody synthesis rate in the CSF provide supportive laboratory data. When CSF studies are negative, a brain biopsy is indicated to assess the presence of inclusion bodies, measles virus antigens or viral RNA.Among the many drugs and methods tried in the treatment of SSPE, the highest rate of stabilisation or improvement has been obtained with intraventricular interferon-α (interferon-alfa) and oral inosine pranobex. Further research, including multicentre clinical trials, is warranted to identify more efficient therapeutic regimens.

Juvenile myasthenia: diagnosis and treatment.

Myasthenia in children can be juvenile (autoimmune) or congenital. Juvenile myasthenia (JM) is an autoimmune disorder characterised by fluctuating weakness and fatigue in the ocular, facial, bulbar or limb muscles. Diagnosis is confirmed by electromyography (EMG), single fibre EMG and the patient's clinical response to anticholinesterase medication. Serology is less helpful in children because acetylcholine receptor antibodies, usually positive in adults, are frequently absent in patients with prepubertal onset of the disease. Treatment methods in JM include anticholinesterase drugs, thymectomy and immunomodulatory agents. Plasmapheresis and intravenous immunoglobulin are used in myasthenic crisis. The prognosis of patients with JM is usually good, clinical remission being achieved in the majority of patients with the current treatment methods.

3,4-diaminopyridine in childhood myasthenia: double-blind, placebo-controlled trial.

Eleven patients with congenital and five with juvenile myasthenia gravis, aged 5 to 24 years, were given 3,4-diaminopyridine in a double-blind, placebo-controlled, crossover study. Clinical improvement was observed in 5 of 11 congenital myasthenia patients, and placebo effect, in 3 of 11. Juvenile myasthenia patients did not respond. Single-fiber electromyographic studies did not reveal any changes correlating with the clinical status of the patient. This study demonstrates the importance of double-blind and placebo-controlled studies to determine the effect of 3,4-diaminopyridine in congenital myasthenia. This drug may have different effects on various presynaptic and postsynaptic defects of neuromuscular transmission resulting in congenital myasthenia syndromes.

Beta-interferon plus inosiplex in the treatment of subacute sclerosing panencephalitis.

We treated seven patients with subacute sclerosing panencephalitis with beta-interferon and oral inosiplex for 2 to 15 months. Stabilization or improvement was observed in three patients. The effect of treatment was equivocal in two other patients who became stable. The disease continued its progression in the remaining two patients who died. Treatment shorter than 2 months was not effective. Changes in electroencephalograms (EEG), magnetic resonance images (MRI), or cerebrospinal fluid measles antibody levels did not have a close correlation with clinical course. These results suggest that beta-interferon might be efficient in some patients with subacute sclerosing panencephalitis and justify its trial in larger studies with longer follow-up.

Functional magnetic resonance imaging in children with Asperger's syndrome.

Asperger's syndrome is a pervasive developmental disorder of unknown etiology. We evaluated children with this syndrome (n = 9) and control (n = 8) children by functional magnetic resonance imaging (MRI) during a task involving social judgment. All control and 5 of 9 subjects with Asperger's syndrome showed signal intensity changes in frontal regions. Four patients with Asperger's syndrome, including one case with right frontal dysplasia, had no signal intensity change during the task. In this first functional MRI study of childhood Asperger's syndrome, frontal activation patterns demonstrated some differences between patients and normal subjects. Further studies using other functions frequently impaired in Asperger's syndrome are warranted.

Optic neuropathy in primary antiphospholipid syndrome in childhood.

Neurologic symptoms associated with antiphospholipid antibodies in children include thrombotic events, unilateral movement disorders, or migraine. We present a 7-year-old girl with bilateral optic neuropathy, cerebral white-matter lesions, and antiphospholipid IgM that responded to prednisone and tended to relapse when it was stopped. Remission was obtained under maintenance corticosteroid therapy, and the antiphospholipid antibodies disappeared. This case suggests a role for antiphospholipid antibodies in the pathogenesis of optic neuropathy in childhood.

Interleukin-1beta, interleukin-1 receptor antagonist levels in patients with subacute sclerosing panencephalitis and the effects of different treatment protocols.

Subacute sclerosing panencephalitis is a rare progressive inflammatory disease of the central nervous system caused by a persistent aberrant measles virus infection. Cytokines are polypeptides that regulate immune responses and inflammatory reactions. Interleukin-1beta has been implicated as a central mediator of tissue damage and destruction in a number of central nervous system diseases. Interleukin-1 receptor antagonist could function as an important anti-inflammatory cytokine. We studied interleukin-1beta and interleukin-1 receptor antagonist levels in the cerebrospinal fluids of patients with subacute sclerosing panencephalitis and evaluated the effects of different treatment protocols on these cytokines. Interleukin-1beta and interleukin-1 receptor antagonist levels were measured in 15 patients who had a recent diagnosis of subacute sclerosing panencephalitis (group 1), 6 patients who had been treated with isoprinosine (group 2), 5 patients with intraventricular interferon-alpha (group 3), and 6 patients with interferon-beta (group 4). The results were compared within the groups and also with the results of 10 patients with other neurologic disease (group 5). The interleukin-1beta concentrations in cerebrospinal fluid and sera were all below the detection limits (3.9 pg/mL). Interleukin-1 receptor antagonist levels were not statistically different, except for the group treated with intraventricular interferon-alpha. Interleukin-1 receptor antagonist levels were 170 +/- 52, 175 +/- 58, 1605 +/- 518, 77.5 +/- 24, and 108 +/- 18 pg/mL in groups 1 to 5, respectively. Interleukin-1 receptor antagonist levels and cerebrospinal fluid serum ratios were significantly increased during interferon-alpha treatment. In conclusion, interleukin-1 and interleukin-1 receptor antagonist levels were not elevated in the patients with subacute sclerosing panencephalitis. The only treatment protocol that affects interleukin-1 receptor antagonist levels in cerebrospinal fluid was intraventricular interferon-alpha. Further studies on higher numbers of patients may better document the immunologic status of patients with subacute sclerosing panencephalitis and the effects of different treatment modes.