Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.

BACKGROUND AND OBJECTIVE: PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands. METHODS: PRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed. RESULTS: PRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic. DISCUSSION: PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.

Pediatric vs. Adult Prodrome and Postdrome: A Window on Migraine Pathophysiology?

Few studies have been conducted on the prodromal and postdromal phases of the migraine attack in children and adolescents. Using a questionnaire, we found that 67% of 103 children and adolescents with migraine reported at least one prodromal symptom, with a mean number per subject of 1.8 (median 2.2). The most frequently reported prodromal symptoms were face changes, fatigue and irritability. In pediatric patients selected as having prodrome, fatigue, mood change and neck stiffness were the most frequently reported prodromal symptoms. Using a different design, Laurell et al. found that 71% of 137 pediatric patients reported at least one prodromal symptom with a mean number per subject of 1.9 ± 2.0. Studying postdrome was fraught with unexpected difficulties as our preliminary research showed. Patients reported 2 groups of symptoms occurring during the resolution phase of the headache: symptoms whose onset was before headache cessation and were persisting after it, and symptoms whose onset was after headache cessation. We referred to the former as persistent symptoms and to the latter as true postdromes. Ninety-one per cent of patients reported persistent symptoms, with a mean of 6.0 and a median of 2, asthenia, pallor, cognitive difficulties, anorexia, somnolence, and nausea being the more frequently reported. True postdromes were reported by 82% of patients, with a mean of 2.6 and a median of 2, thirst, somnolence, visual disturbances, food craving, paraesthesias, and ocular pain being the most frequent reported. Interestingly, several prodromal and postdromal symptoms are also encountered during the aura classic and/or accompany the headache phase. Functional imaging in migraine has showed that the activations in areas such as hypothalamus or brainstem may begin before headache onset and/or persist after headache relief. Thus, one may wonder whether prodromal and postdromal symptoms may indicate the involvement of the limbic system, dopaminergic pathways, the hypothalamus and the brainstem. Differences between children, adolescents and adults might contribute to the understanding of migraine neurobiology.

Postdrome symptoms in pediatric migraine: A questionnaire retrospective study by phone in 100 patients.

Background No study dedicated to postdrome symptoms of migraine attacks is available in children and adolescents. Objective To study the resolution phase of the migraine attack in children and adolescents. Methods 100 children and adolescents with ICHD-3 beta migraine without and/or with typical aura were included. Each patient, and one of her/his parents, were interviewed by phone about the postdrome phrase of their last six months' migraine attacks. They were specifically instructed to distinguish symptoms that had begun before and went on after migraine headache cessation (referred to as persistent symptoms), and symptoms whose onset was strictly after headache cessation (referred to as true postdromes). Results 91% of patients reported persistent symptoms, with a mean of 2.9 and a median of 2; asthenia, cognitive difficulties, pallor, cognitive slowing, anorexia, somnolence, and nausea were the most frequently reported. They lasted less than 12 h in 71% of patients. True postdromes were reported by 82% of patients, with a mean of 2.6 and a median of 2; thirst, somnolence, visual disturbances, food craving, paraesthesias, and ocular pain being the most frequently reported. They lasted less than 12 h in 94% of patients. Conclusions This study showed that children and adolescents with migraine had both frequent persistent symptoms and true postdromes. Both were notably different from those reported in adults.

Experts' opinion about the primary headache diagnostic criteria of the ICHD-3rd edition beta in children and adolescents.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. RESULTS: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. RESULTS: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.

Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy.

INTRODUCTION: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families. METHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing. RESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families. CONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.

Trigger Factors in Childhood Migraine: A Prospective Clinic-Based Study From North of France.

The objective was to study the prevalence and characterization of pediatric migraine triggers and to compare results to this retrospective study. A total of 101 pediatric patients with ICHD-II migraine with and/or without aura were instructed to prospectively complete a diary dealing with attacks triggers for a 3-month period. Each subject reported at least 1 trigger (range: 1-14) with a total number of 532 attacks and a median per subject of 3. Lack of sleep (51.4%), stress (44.6%), warm climate (41.9%), noise (32.4%), and excitation (29.7%) were the most frequently reported. The delay between trigger exposure and attack onset was between 0 and 3 hours in 67.6% of attacks. This prospective study confirmed the findings of the authors' previous study, with the exception that number of triggers was smaller, probably due to recall bias. The 4 most frequent triggers (lack of sleep, stress, hot weather, and noise) were identical in both studies.

Stability of Pediatric Migraine Subtype After a 5-year Follow-Up.

The study assessed the 5-year follow-up outcome and possible prognostic factors of migraine subtypes with onset in childhood or adolescence. A total of 343 patients meeting the International Classification of Headache Disorders (ICHD)-II criteria for migraine without aura (MO), migraine with aura (MA), or both MO+MA (ie, 1.1, 1.2) were contacted by phone and underwent structured follow-up headache interviews. Of the original sample patients, 22.7% were headache-free at follow-up, 14.1% had a transformed headache diagnosis (tension-type headache: 8.2%, chronic daily headache: 5.8%), and 63.3% still had migraine fulfilling the criteria for ICHD-II 1.1. or 1.2, but those who were still migraineurs at follow-up were older at baseline (respectively 12.93, 9.99, and 11.02 years for MO, MA and MO+MA, P = .0005). The probability of having the same migraine subtype diagnosis at baseline and at 5-year follow-up was 55.2%, 95.1%, and 31.1% for ICHD-II 1.1, 1.2, and both 1.1 and 1.2, respectively.

Further delineation of eye manifestations in homozygous 15q13.3 microdeletions including TRPM1: a differential diagnosis of ceroid lipofuscinosis.

The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the "b" wave was smaller than the "a" wave after a dark adapted pupil and bright flash in all patients. Clear genotype-phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis.

A patient with myoclonic epilepsy in infancy followed by myoclonic astatic epilepsy.

Myoclonic epilepsy in infancy (MEI) is a primary generalized epilepsy. According to the literature, the outcome of MEI is usually benign. Here we report a patient who developed myoclonic astatic epilepsy at age four, having been seizure free without antiepileptic drug treatment for 2 years after his recovery from MEI. At age four, a video-EEG-recording showed frequent head nodding (atonic seizures) and myoclonic astatic seizures associated with diffuse spikes or polyspikes and waves. The interictal EEG revealed frequent bursts of generalized 100-200 µV, 2-4 Hz spike-and-slow-wave complexes. Despite a general favorable outcome, more severe epilepsy syndromes may develop after MEI, and mental retardation is sometimes observed. Our case and the previous literature suggest that epilepsies following on from MEI often involve myoclonic seizures.

The prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents.

The prevalence and characterization of migraine triggers have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined trigger factors in a clinic-based population. In 102 children and adolescents fulfilling the Second Edition of The International Headache Classification criteria for paediatric migraine, at least one migraine trigger was reported by the patient and/or was the parents' interpretation in 100% of patients. The mean number of migraine triggers reported per subject was 7. Mean time elapsed between exposure to a trigger factor and attack onset was comprised between 0 and 3 h in 88 patients (86%). The most common individual trigger was stress (75.5% of patients), followed by lack of sleep (69.6%), warm climate (68.6%) and video games (64.7%). Stress was also the most frequently reported migraine trigger always associated with attacks (24.5%). In conclusion, trigger factors were frequently reported by children and adolescents with migraine and stress was the most frequent.

Childhood periodic syndromes.

This review focuses on so-called "periodic syndromes of childhood that are precursors to migraine," as included in the second edition of the International Classification of Headache Disorders. Presentation is characterized by an episodic pattern and intervals of complete health. Benign paroxysmal torticollis is characterized by recurrent episodes of head tilt, secondary to cervical dystonia, with onset between ages 2-8 months. Benign paroxysmal vertigo presents as sudden attacks of vertigo lasting seconds to minutes, accompanied by an inability to stand without support, between ages 2-4 years. Cyclic vomiting syndrome is distinguished by its unique intensity of vomiting, affecting quality of life, whereas abdominal migraine presents as episodic abdominal pain occurring in the absence of headache. Their mean ages of onset are 5 and 7 years, respectively. Diagnostic criteria and appropriate evaluation represent the key issues. Therapeutic recommendations include reassurance, lifestyle changes, and prophylactic as well as acute antimigraine therapy.

Treatment of primary headache in children: a multicenter hospital-based study in France.

The aim of this 6-month, prospective, multicenter study of 398 children and adolescents with primary headaches was to collect data on headache treatment in neuropediatric departments. Treatments were compared before and after consultation. Prior to consultation, the acute treatments that had been prescribed most frequently were paracetamol (82.2% of children) and non-steroidal anti-inflammatory drugs treatment (53.5%); 10.3% had received a prophylactic treatment. No differences in either acute or prophylactic treatment with respect to headache diagnosis were observed. After the neuropediatric consultation, paracetamol was replaced by a non-steroidal anti-inflammatory drug in about three-quarters of cases and by triptan in about one-quarter of cases. The number of children prescribed a prophylactic treatment nearly doubled, whereas there was a 5-fold and 23-fold increase in psychotherapy and relaxation training, respectively, between pre-referral and referral. We conclude that specific treatments were underused for primary headache.

Study on management of pediatric migraine by general practitioners in northern France.

The study explored the awareness of the Haute Autorité de Santé (High Health Authority, HAS) guidelines for migraine management in children among a random sample of 100 general practitioners (GPs) dichotomised in an urban and a rural group. A questionnaire conducted by phone included questions on knowledge of pediatric migraine acute treatment and preventive therapy, referral to a child neurologist as well as GPs awareness of HAS recommendations in general. Although 45% of GPs argued they were prescribing ibuprofen as first-line abortive drug, only 3% were aware of the recommended dose. Only 48% of GPs were agreeing to initiate preventive therapy. Fifty percent of GPs stated that they knew HAS guidelines but only 24% stated that they had read them. The only significant difference between urban and rural GPs concerned the initiation of preventive therapy. Continuing educational programmes on the implementation of pediatric migraine guidelines is strongly needed.

Comparison of seizure reduction and serum fatty acid levels after receiving the ketogenic and modified Atkins diet.

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p=0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p=0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet.

The classification of chronic daily headache in French children and adolescents: a comparison between the second edition of the International Classification of Headache Disorders and Silberstein-Lipton criteria.

Few data are available on the applicability of both the criteria proposed by Silberstein and Lipton (S-L) and the International Classification of Headache Disorders-II (ICHD-II) in the classification of children and adolescents with chronic daily headache (CDH). The International Headache Society recently added revised criteria (ICHD-IIR) for chronic migraine to its Appendix. We retrospectively reviewed all charts of 34 children and adolescents (<17 years) with primary CDH presenting to the outpatient clinic of the Universitary Department of Neuropediatrics of Lille between February 2004 and February 2006 and tried to classify their CDH according to both S-L criteria and the recently published ICHD-IIR. Thirty-two children (94%) and 33 children (97%) could respectively be successfully classified into one subtype of CDH according to the S-L classification and the ICHD-IIR. Transformed migraine was the most common diagnosis (61.8%), followed by new daily-persistent headache (20.6%) when the S-L criteria were used. Twenty-three children and adolescents (67.6%) could be classified under one of the migraine categories according to the ICHD-IIR classification. We think that both S-L and ICHD-II classifications, when used with detailed headache histories and diaries, are adequate to classify chronic daily headache in children and adolescents.