Transient Impact of Rituximab in H1N1 Vaccination-associated Narcolepsy With Severe Psychiatric Symptoms.

INTRODUCTION: Narcolepsy type 1 is an organic sleep disorder caused by the destruction of hypocretin producing neurons in hypothalamus. In addition to daytime sleepiness, the spectrum and severity of symptoms are very variable. Psychiatric comorbidity and phenomena resembling psychotic symptoms are also common. Current treatment options for narcolepsy are symptomatic but there are few case reports of positive effect of immunotherapy. We report a very severely affected young boy treated with rituximab (RXB). CASE REPORT: A 12-year-old boy developed narcolepsy after Pandemrix H1N1 vaccination in 2010. He started to express severe psychiatric symptoms shortly after the onset. Cataplexy and sleepiness were devastatingly disabling. Conventional treatments did not have any effect on symptoms so we decided to try RXB, chimeric human monoclonal antibody against CD20 expressed in B lymphocytes. After the first treatment his condition ameliorated dramatically. Unfortunately, the effect lasted only for 2 months. Following attempts did not show any effect. CONCLUSIONS: Effect of RXB on narcolepsy has not been reported before. Remarkable but short-lasting effect of RXB in narcolepsy is intriguing as it could imply that there is still ongoing B cell-mediated autoimmune response possible contributing to symptoms in narcolepsy.

Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland.

BACKGROUND: Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002-2010. METHODS: All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference. FINDINGS: Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002-2009 giving an annual incidence of 0.79 per 100,000 inhabitants (95% confidence interval 0.62-0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12-0.51) per 100,000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100,000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100,000, which equals that in 2002-2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy. INTERPRETATION: A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children.

Analysis of 9p24 and 11p12-13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample.

OBJECTIVE: Autism spectrum disorders (ASD) often show obsessive repetitive symptoms that are characteristic to obsessive-compulsive disorder (OCD). Aberrant glutamate function has been suggested to a risk for both ASDs and OCD. Considering the common metabolic pathway and recent results from association studies both in OCD and ASDs, a question, whether there is common molecular background in ASDs and OCD, was raised. METHODS: Ten single nucleotide polymorphisms (SNPs) at 9p24 and 11p12-p13 containing glutamate transporter genes SLC1A1 and SLC1A2 and their neighboring regions in 175 patients with ASDs and 216 controls of Finnish origin were analyzed using real-time-PCR or direct sequencing. RESULTS: The strongest association was detected with rs1340513 in the JMJD2C gene at 9p24.1 (P=0.007; corrected P=0.011) that is the same SNP associated with infantile autism (P=0.0007) in the autism genome project consortium (2007). No association was detected at 11p12-p13 with ASD. Interestingly, the strongest association in OCD has been found at rs301443 (P=0.000067) residing between SLC1A1 and JMJD2C at 9p24. CONCLUSION: In summary, our results give evidence for a possible common locus for OCD and ASDs at 9p24. We speculate that the area may represent a special candidate region for obsessive repetitive symptoms in ASDs.

Antipyretic agents for preventing recurrences of febrile seizures: randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of different antipyretic agents and their highest recommended doses for preventing febrile seizures. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Five hospitals, each working as the only pediatric hospital in its region. PARTICIPANTS: A total of 231 children who experienced their first febrile seizure between January 1, 1997, and December 31, 2003. The children were observed for 2 years. INTERVENTIONS: All febrile episodes during follow-up were treated first with either rectal diclofenac or placebo. After 8 hours, treatment was continued with oral ibuprofen, acetaminophen, or placebo. MAIN OUTCOME MEASURE: Recurrence of febrile seizures. RESULTS: The children experienced 851 febrile episodes, and 89 of these included a febrile seizure. Febrile seizure recurrences occurred in 54 of the 231 children (23.4%). There were no significant differences between the groups in the main measure of effect, and the effect estimates were similar, as the rate was 23.4% (46 of 197) in those receiving antipyretic agents and 23.5% (8 of 34) in those receiving placebo (difference, 0.2; 95% confidence interval, -12.8 to 17.6; P = .99). Fever was significantly higher during the episodes with seizure than in those without seizure (39.7 degrees C vs 38.9 degrees C; difference, 0.7 degrees C; 95% confidence interval, -0.9 degrees C to -0.6 degrees C; P < .001), and this phenomenon was independent of the medication given. CONCLUSIONS: Antipyretic agents are ineffective for the prevention of recurrences of febrile seizures and for the lowering of body temperature in patients with a febrile episode that leads to a recurrent febrile seizure.

Megalocornea-urticaria pigmentosa syndrome--a new syndrome?

We describe a Finnish boy with megalocornea, urticaria pigmentosa, mild delay in speech and motor development, and slightly dysmorphic facial features. The karyotype and the array-CGH analysis did not reveal any abnormalities. This combination of symptoms has not been reported previously suggesting this might be a new syndrome with an unknown etiology.

Analysis of four neuroligin genes as candidates for autism.

Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with beta-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism.

Visual field constriction in 91 Finnish children treated with vigabatrin.

PURPOSE: To study the prevalence and features of visual field constrictions (VFCs) associated with vigabatrin (VGB) in children. METHODS: A systematic collection of all children with any history of VGB treatment in fifteen Finnish neuropediatric units was performed, and children were included after being able to cooperate reliably in repeated visual field tests by Goldmann kinetic perimetry. This inclusion criterion yielded 91 children (45 boys; 46 girls) between ages 5.6 and 17.9 years. Visual field extent <70 degrees in the temporal meridian was considered abnormal VFC. RESULTS: There was a notable variation in visual field extents between successive test sessions and between different individuals. VFCs <70 degrees were found in repeated test sessions in 17 (18.7%) of 91 children. There was no difference in the ages at the study, the ages at the beginning of treatment, the total duration of the treatment, general cognitive performance, or neuroradiologic findings between the patients with normal visual fields and those with VFC, but the patients with VFC had received a higher total dose of VGB. In linear regression analysis, there were statistically significant inverse correlations between the temporal extent of the visual fields and the total dose and the duration of VGB treatment. The shortest duration of VGB treatment associated with VFC was 15 months, and the lowest total dose 914 g. CONCLUSIONS: Because of a wide variation in normal visual-field test results in children, the prevalence figures of VFCs are highly dependent on the definition of normality. Although our results confirm the previous findings that VFC may occur in children treated with VGB, our study points out the need to reevaluate critically any suspected VFC to avoid misdiagnosis. Nevertheless, our study suggests that the prevalence of VFC may be lower in children than in adults, and that the cumulative dose of VGB or length of VGB therapy may add to the personal predisposition for developing VFC.