Migraine and the development of additional psychiatric and pain disorders in the transition from adolescence to adulthood

Introduction: The transition from childhood to adolescence and from adolescence to adulthood are vulnerable phases in life. In these phases, late or insufficient treatment of diseases may lead to chronification and favor development of additional disorders. In adolescents, migraine often has a highly negative impact on school performance and everyday life. The hypothesis of the present study was that adolescents with migraine have a higher risk for developing additional disorders such as psychiatric disorders or other pain syndromes in the course of the disease. Materials and methods: In this study, we analyzed health insurance data of 56,597 German adolescents at the age of 15 years in the year 2006. By using the International Classification of Diseases (ICD 10), we determined a group with migraine diagnosis in the year 2006 and a control group without any headache diagnosis in 2006. We then compared both groups regarding the development of additional disorders (based on the ICD 10) during the following 10 years (2007 to 2016). Results: Adolescents with migraine had a 2.1 fold higher risk than persons without migraine diagnosis to develop an additional affective or mood disorder, a 1.8 fold higher risk to obtain neurotic, stress-related and somatoform disorders, a 1.8 fold higher risk to subsequently suffer from behavioral syndromes, a 1.6 higher risk to get back pain and a 1.5 fold higher risk for irritable bowel syndrome during the next 10 years. Conclusion: Adolescents with migraine are at risk for developing additional disorders later. Considering and addressing the patient’s risks and potential medical and psychosocial problems might improve the long-term outcome significantly

Migräne im Kindes- und Jugendalter — Ausblick auf innovative Behandlungsansätze im Rahmen multimodaler Therapiekonzepte

Although migraine is a~relevant health issue in children and adolescents, clinical care and research are still underrepresented and underfunded in this field. Quality of life can be significantly reduced when living with frequent episodes of pain. Due to the high level of vulnerability of the developing brain during adolescence, the risk of chronification and persistence into adulthood is high. In this narrative review, we describe the corner stones of a~patient-centered, multimodular treatment regimen. Further, an update on the pathophysiology of migraine is given considering the concept of a~periodically oscillating functional state of the brain in migraine patients (\textquotedblmigraine is a~brain state\textquotedbl). Besides central mechanisms, muscular structures with the symptoms of muscular pain, tenderness, or myofascial trigger points play an important role. Against this background, the currently available nonpharmacological and innovative neuromodulating approaches are presented focusing on the method of repetitive peripheral magnetic stimulation.Die Migräne ist auch im Kindes- und Jugendalter ein häufiges, aber in klinischer Versorgung und Wissenschaft oft unterrepräsentiertes Krankheitsbild. Gerade im Kindes- und Jugendalter bestehen relevante Einschränkungen der Lebensqualität durch das (häufige) Schmerzerfahren. Bedingt durch die entwicklungsspezifisch hohe Vulnerabilität des adoleszenten Gehirns besteht ein hohes Chronifizierungs- und Persistenzrisiko bis ins Erwachsenenalter hinein. In diesem Beitrag werden die Bestandteile eines patientenzentrierten, multimodalen Therapiekonzepts dargestellt. Darüber hinaus werden die aktuellsten Erkenntnisse zu den pathophysiologischen Grundlagen der Migräneerkrankung beleuchtet, nach denen Migräne durch einen sich phasenweise verändernden Funktionszustand des Gehirns entsteht (Stichwort: „migraine is a brain state“). Auch periphere Komponenten wie Muskelschmerzen, -verspannungen und -triggerpunkte spielen eine wichtige Rolle. Vor diesem Hintergrund werden nichtpharmakologische innovative Therapieansätze vorgestellt, die auf dem Prinzip der Neuromodulation beruhen, mit Fokus auf der repetitiven peripheren Magnetstimulation

J Med Genet

was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of -related neurodevelopmental disorder. We collected detailed phenotypes of an international cohort of individuals (n=17) with variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. We confirm the role of in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration

Prevalence, predictors and outcome of an infection with Plasmodium falciparum in infants in an holoendemic area in Ghana

Die Malaria stellt weiterhin eine der Hauptursachen für die Mortalität bei Kleinkindern in Afrika südlich der Sahara dar. Ziel der vorliegenden Arbeit war es, Prävalenz, Prädiktoren und Folgen einer Infektion mit Plasmodium falciparum bei Säuglingen in einem holoendemischen Malariagebiet in Ghana näher zu untersuchen. Bei 136 Kindern erfolgte in den ersten 28 Lebenswochen monatlich eine klinische, hämatologische und parasitologische Untersuchung. Eine Infektion mit P. falciparum wurde vor Ort mittels Mikroskopie und immunchromatographischem Schnelltest diagnostiziert. Zur Erfassung submikroskopischer Infektionen mit P. falciparum wurde am Institut für Tropenmedizin Berlin eine Polymerase-Ketten-Reaktion (PCR) durchgeführt. Als Infektion wurde der Nachweis von Plasmodien durch die PCR definiert. Eine Malaria wurde definiert als Fieber und mikroskopisch positivem Parasitennachweis. Eine Anämie wurde als Hb < 10 bzw. < 11 g/dl definiert. Eine Infektion mit P. falciparum konnte bei 39,7 % der Kinder diagnostiziert werden. Eine klinisch-manifeste Malaria war dagegen mit 15,4 % deutlich seltener. Eine konnatale Malaria wurde nicht beobachtet. Mit 4 Wochen waren 1,5 % der Kinder infiziert und mit 28 Wochen 31 % der Kinder. Das mittlere Alter bei der Erstinfektion lag bei 17 Wochen. Eine plazentare Infektion mit P. falciparum konnte bei 55,9 % der Schwangeren diagnostiziert werden. Sie war signifikant mit einer Infektion der Kinder im ersten halben Lebensjahr assoziiert. Insgesamt hatten 52,4 % der Kinder eine Anämie im ersten halben Lebensjahr. Die Anämie war signifikant mit einer gleichzeitig bestehenden Infektion mit P. falciparum assoziiert. Die mittlere Hämoglobindifferenz zwischen den infizierten und den nicht-infizierten Kindern betrug 1,1 g/dl. In der multivariaten Analyse mittels logistischer Regression wurden folgende Risikofaktoren für eine Anämie mit 6 Monaten ermittelt: Eisenmangel (odds ratio (OR): 4,3; 95% Konfidenzintervall: 1,5-12,2), eine aktuelle Infektion mit P. falciparum (OR: 3,5 (1,2-10,1)), sowie eine mikroskopisch nachweisbare plazentare Infektion der Mutter bei der Geburt (OR: 3,0 (1,0-9,1)). Die genauen Pathomechanismen der Malaria-assoziierten Anämie wie die Hämolyse infizierter Erythrozyten, der Abbau nicht-infizierter Erythrozyten und die Dyserythropoese sind dabei unzureichend verstanden. Kontrovers diskutiert wird der Einfluss asymptomatischer Parasitämien und submikroskopischer Infektionen in der Entstehung der Malaria-assoziierten Anämie. Zur Klärung der klinischen Folgen asymptomatischer Parasitämien und milder bis moderater Anämien auf die kognitive und die motorische Entwicklung bei Säuglingen und Kleinkindern sind weitere Längsschnittstudien erforderlich.Malaria continues to be a major health problem in sub-Saharan Africa. Especially the mortality among children less then 5 years of age is still very high. In a longitudinal study among 136 children in Ghana we determined prevalence, predictors and outcome of an infection with Plasmodium falciparum. The follow-up was for 28 weeks including a clinical, hematology and parasitology examination every month. Plasmodium falciparum was detected by microscopy, histidine-rich-protein-2 (HRP2) capture test and PCR (polymerase chain reaction). Infection with Plasmodium falciparum was defined as a positive PCR. Malaria was defined as fever and the microscopically confirmation of P. falciparum. Anemia was defined as Hb < 10 mg/dl or < 11 mg/dl. An infection with P. falciparum could be found in 39,7 % of the children. Malaria was observed in 15,4 % of the patients. Non of the patients revealed a connatal Malaria. 1,5 % of the 4 weeks old infants and 31 % of the half-year old children were infected. The mean age of initial infection was 17 weeks. A placental infection with P. falciparum was diagnosed in 55,9 % of the pregnant women and it was significant associated with an infection in the first half-year of life. 52,4 % of the children were anemic after 6 months of life. Anemia and concomitant infection with P. falciparum showed statistical significance. The difference between the mean hemoglobine values of infected and non-infected children was 1,1 g/dl. In a multivariance analysis via logistic regression model, following risk factors of anemia were detected: iron deficiency (odds ratio (OR): 4,3; 95% confidence interval (CI): 1,5-12,2), an concomitant infection with P. falciparum (OR: 4,3; CI: 1,5-12,2), a via microscopy detected placental infection of the mother (OR: 3,0; CI: 1,0-9,1). The exact pathophysiology of the malaria-related anemia like hemolysis, degradation of non-infected erythrocytes and dyserythropoesis is still not understood completely. The influence of asymptomatical parasitemia and submicroscopic infection in the pathogenesis of malaria associated anemia is controversial discussed. To detect the clinical outcome of asymptomatical parasitemias and mild to moderate anemias in cognitive and motoric development of infants and children, more clinical studies are necessar

Burden of disease and lifestyle habits in adolescents and young adults prone to frequent episodic migraine: A secondary comparative analysis

The objective of this study was to assess the burden of disease and prevalence of lifestyle factors for adolescents and young adults with frequent episodic migraine. We conducted a secondary comparative analysis of data collected during two previous studies. Inclusion criteria for this analysis were age 15-35~years, 15 to 44 migraine episodes within 12~weeks, and completeness of Migraine Disability Assessment and lifestyle questionnaire data. Datasets of 37 adults (median age interquartile range: 25 6) and 27 adolescents (median age interquartile range: 15 1) were analyzed. 81{\%} (n = 30) of adults reported severe disability (16{\%} n = 3 of adolescents; p 0.05). This study underlines the importance of educating adolescents and young adults with migraine about lifestyle habits that are likely to interfere with the condition

Repetitive Neuromuscular Magnetic Stimulation for Pediatric Headache Disorders: Muscular Effects and Factors Affecting Level of Response

Repetitive neuromuscular magnetic stimulation (rNMS) for pediatric headache disorders is feasible, safe, and alleviates headache symptoms. This study assesses muscular effects and factors affecting response to rNMS. A retrospective chart review included children with headaches receiving six rNMS sessions targeting the upper trapezius muscles. Pressure pain thresholds (PPT) were measured before and after rNMS, and at 3-month follow-up (FU). Mean headache frequency, duration, and intensity within the last 3 months were documented. In 20 patients (14.1 ± 2.7 years), PPT significantly increased from pre- to post-treatment (p < 0.001) sustaining until FU. PPT changes significantly differed between primary headache and post-traumatic headache (PTH) (p = 0.019–0.026). Change in headache frequency was significantly higher in patients with than without neck pain (p = 0.032). A total of 60% of patients with neck pain responded to rNMS (≥25%), while 20% of patients without neck pain responded (p = 0.048). 60% of patients receiving rNMS twice a week were responders, while 33% of patients receiving rNMS less or more frequently responded to treatment, respectively. Alleviation of muscular hyperalgesia was demonstrated sustaining for 3 months, which was emphasized in PTH. The rNMS sessions may positively modulate headache symptoms regardless of headache diagnosis. Patients with neck pain profit explicitly well. Two rNMS sessions per week led to the highest reduction in headache frequency

Neuromodulation in Pediatric Migraine using Repetitive Neuromuscular Magnetic Stimulation: A Feasibility Study

Migraine has a relevant impact on pediatric health. Non-pharmacological modalities for its management are urgently needed. This study assessed the safety, feasibility, acceptance, and efficacy of repetitive neuromuscular magnetic stimulation (rNMS) in pediatric migraine. A total of 13 patients with migraine, ≥6 headache days during baseline, and ≥1 myofascial trigger point in the upper trapezius muscles (UTM) received six rNMS sessions within 3 weeks. Headache frequency, intensity, and medication intake were monitored using headache calendars; headache-related impairment and quality of life were measured using PedMIDAS and KINDL questionnaires. Muscular involvement was assessed using pressure pain thresholds (PPT). Adherence yielded 100%. In 82% of all rNMS sessions, no side effects occurred. All participants would recommend rNMS and would repeat it. Headache frequency, medication intake, and PedMIDAS scores decreased from baseline to follow-up (FU), trending towards statistical significance (p = 0.089; p = 0.081, p = 0.055). A total of 7 patients were classified as responders, with a ≥25% relative reduction in headache frequency. PPT above the UTM significantly increased from pre- to post-assessment, which sustained until FU (p = 0.015 and 0.026, respectively). rNMS was safe, feasible, well-accepted, and beneficial on the muscular level. The potential to reduce headache-related symptoms together with PPT changes of the targeted UTM may underscore the interplay of peripheral and central mechanisms conceptualized within the trigemino-cervical complex

Correction to: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency (Genetics in Medicine, (2021), 23, 9, (1705-1714), 10.1038/s41436-021-01194-x)

Unfortunately the funding information was not given. Funding is as follows: This work was funded by the ERA PerMed project PerMiM (Austrian Science Fund FWF, I4704-B) to S.B.W. This study was supported by a “Sonata Bis 5” grant of the National Science Center Poland (2015/18/E/NZ1/00673) to S.Z. and D.M

Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency

Purpose: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. Methods: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. Results: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. Conclusion: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1

ARF1-related disorder: phenotypic and molecular spectrum.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration