Flunarizine in migraine-related headache prevention: results from 200 patients treated in the UK.

BACKGROUND AND PURPOSE: For over 20 years, as a group we have been using flunarizine in primary headache disorders. Flunarizine is widely used in Europe, but not licensed in the UK. In September 2014, the National Institute for Clinical Excellence published supportive guidelines for flunarizine use in migraine, based on randomized controlled evidence that it is as effective as propranolol and topiramate in adults. METHODS: We reviewed a cohort of adult patients (n = 200) treated with flunarizine from our practice. The clinical information of these patients, i.e. diagnosis, dose, efficacy, side effects and duration of treatment, was collected. RESULTS: The most common indication for flunarizine use was chronic migraine, followed by migraine with aura, sporadic hemiplegic migraine, familial hemiplegic migraine and new daily persistent headache with migrainous features. Flunarizine was generally effective, with only 24% (n = 47) of patients reporting no clinical effect. The most common dose used was 10 mg per day. Duration of treatment information was available for 39% (n = 78) of patients. Of these patients, 64% (n = 50) continued treatment for more than 1 year. Doses up to 15 mg were generally well tolerated, with only 10.5% (n = 21) of patients stopping treatment due to adverse effects. The most common adverse events were tiredness, mood change and weight gain. CONCLUSION: The data provide supportive evidence from tertiary headache practice in the UK for the use of flunarizine in migraine. The data encourages development of future guidance regarding flunarizine use in headache centres in countries where its use is not routine.

Premonitory Symptoms of Migraine in Childhood and Adolescence.

PURPOSE OF REVIEW: Premonitory symptoms in migraine; symptoms occurring before the onset of migraine pain or aura, are an increasingly recognised area of interest within headache research. It has been recently documented in the literature that these symptoms also occur in children and adolescents, with a comparable phenotype to adults. This review discusses the wide presentation of premonitory symptoms in migraine in children and adolescents, and the importance of understanding how these early symptoms are mediated in order to ensure that targeted abortive therapies are developed in the future. Recognition of these symptoms by parents, guardians, teachers and carers is of importance in ensuring early and effective attack treatment. RECENT FINDINGS: A previous clinic-based questionnaire study in 103 children found a prevalence of premonitory symptoms in paediatric migraine of 67%, with a mean number of reported symptoms of two. A recent study found that in a clinic population of 100 children or adolescents with a migraine diagnosis who were preselected as having at least one premonitory symptom associated with their attacks, two or more premonitory symptoms were reported by 85% of patients. The most common symptoms were fatigue, mood change and neck stiffness. Although the population prevalence of premonitory symptoms in migraine within the paediatric population, or their ability to predict accurately the onset of an impending headache cannot be deduced from the retrospective studies performed to date, premonitory symptoms occur in children as young as 18 months old. Understanding the biological basis of these, and their heterogeneous phenotype may help future targeted therapeutic research, helping the development of drugs that act before the onset of pain, limiting the morbidity associated with the migraine attack.

Characterising the premonitory stage of migraine in children: a clinic-based study of 100 patients in a specialist headache service.

BACKGROUND: The premonitory stage of migraine attacks, when symptomatology outside of pain can manifest hours to days before the onset of the headache, is well recognised. Such symptoms have been reported in adults in a number of studies, and have value in predicting an impending headache. These symptoms have not been extensively studied in children. We aimed to characterise which, if any, of these symptoms are reported in children seen within a Specialist Headache Service. METHODS: We reviewed clinic letters from the initial consultation of children and adolescents seen within the Specialist Headache Service at Great Ormond Street Hospital between 1999 and 2015 with migraine in whom we had prospectively assessed clinical phenotype data. We randomly selected 100 cases with at least one premonitory symptom recorded in the letter. For these patients, the age at headache onset, presence of family history of headache, headache diagnosis, presence of episodic syndromes which may be associated with headache, developmental milestones, gestation at birth, mode of delivery and presence of premonitory symptoms occurring before or during headache were recorded. RESULTS: Of the 100 patients selected, 65 % were female. The age range of the patients was 18 months to 15 years at the time of headache onset. The most common diagnosis was chronic migraine in 58 %, followed by episodic migraine (29 %), New Daily Persistent Headache with migrainous features (8 %) and hemiplegic migraine (5 %). A history of infantile colic was noted in 31 % and was the most common childhood episodic syndrome associated with migraine. The most common premonitory symptoms recorded were fatigue, mood change and neck stiffness. The commonest number of reported premonitory symptoms was two. CONCLUSION: Premonitory symptoms associated with migraine are reported in children as young as 18 months, with an overall clinical phenotype comparable to adults. Better documentation of this stage will aid parents and clinicians to better understand the phenotype of attacks, better recognise migraine and thus initiate appropriate management. Larger studies with a broader base are warranted to understand the extent and implications of these symptoms for childhood and adolescent migraine.

Ataxia, ophthalmoplegia, and areflexia: what would you think?

We present here a case of carcinomatous meningitis presenting as Miller Fisher syndrome (MFS). There are four further cases described in the literature with evidence of tumour invasion within the central nervous system (CNS) shown either in cerebrospinal fluid examination or on histology. There are further five cases described in which an association between cancer and a Miller Fisher phenotype has been shown. Some of these have identified antiganglioside antibodies in the serum and, in one case, also showed antibodies deposited within the primary tumour itself. This raises a question as to whether there is a paraneoplastic form. It would be informative when further cases present in this way to histologically examine for malignant CNS invasion, and the presence of antiganglioside antibodies in both the malignant primary and areas of nervous system thought to be affected by MFS.

Acoustic reflectance of pharyngeal structures in children.

The aim of this study was to examine whether Eccovision Reflectance Pharyngometer could assess the anatomical structure of the upper airway in young children. Secondary aims were to assess changes in pharyngeal volume in children with tonsillar (Group A, n=13) and adenoidal hypertrophy (Group B, n=17) at pre- and post- surgical procedures, respectively and further compare them to children who underwent myringotomy (Control Group C, n=10). In all 40 children (aged 3-9 years, median 6 years) enrolled in this pilot prospective study, six recordings (equally dispersed at pre- and 3 month post- operation per subject) of the pharyngeal cavity along with demographic (age, gender), somatic (standing and sitting height, body weight, head and neck circumference) and anatomic (bimaxilliary and bregma) characteristics, were captured. No significant intra-subject variability was noted within the multiple measurements of the pharyngeal volume at pre- as well as post-incision (ANOVA, P>0.1) in all groups. However, in Group A there was a marked increase from pre- to post-pharyngeal volumes in males (P=0.007), which was not observed in females (P=0.13). In Group B pharyngeal volumes decreased from pre- to post- in both males (P=0.87) and females (P=0.34). On the contrary, in Group C there was no change in pharyngeal volumes. These findings contradicted the visual evaluation of the size of the removed tonsillar and/or adenoidal mass in the first two groups and thus suggested that Eccovision Pharyngometer does not reliably assess pharyngeal volumes in a pediatric population.

In vitro labeling of gonadal steroid hormone receptors in brain tissue sections.

Autoradiographic methods have been developed for measurement of gonadal steroid receptors in situ in brain tissue sections. Based on principles established previously for estrogen receptors in the rat brain using a 125I-labeled ligand, procedures have been developed for in vitro labeling of estrogen, androgen, and progestin receptors with commercially available tritiated ligands. Addition of protamine sulfate to the incubation buffer precipitates the receptors in situ in the tissue sections, allowing them to be detected autoradiographically after incubation with labeled steroid and subsequent washing to remove unbound and nonspecifically bound ligand. Occupied and unoccupied estrogen receptors can be measured selectively using appropriately modified incubation conditions. In the case of androgen and progestin receptors, unoccupied receptors are readily detected by in vitro labeling of tissue sections, but occupied receptors do not appear to label efficiently. Preliminary data suggest that these methods should be equally applicable to a variety of laboratory animals, including the rat, mouse, guinea pig, and monkey.

Immunocytochemical detection of androgen receptor in human temporal cortex characterization and application of polyclonal androgen receptor antibodies in frozen and paraffin-embedded tissues.

Immunocytochemical and biochemical studies have demonstrated the presence of androgen receptor protein in various regions of the rodent and non-human primate cortex. Localization of androgen receptor in the human brain has, however, not been studied as extensively, because of difficulties in obtaining suitable tissue samples. In the present study, we have localized androgen receptors in both frozen and paraffin-embedded temporal cortex from epileptic patients undergoing resection. Polyclonal antibodies were raised against fusion proteins containing fragments of the human androgen receptor protein. The antibodies were affinity-purified against the corresponding fusion protein. Immunoprecipitation and Western blotting using extracts from human cell lines demonstrated the specificity of the antibodies for the human androgen receptor and lack of cross-reactivity with other steroid hormone receptors. Immunocytochemistry was performed on frozen and paraffin sections of human temporal cortex and in paraffin-embedded benign hyperplastic prostates (BPH), as well as prostate and breast carcinomas, by the streptavidin-biotin-peroxidase method. Antigen-retrieval was performed in paraffin-embedded sections using microwave irradiation. Specific nuclear and cytoplasmic immunoreactivity for androgen receptor was detected in neurons, astrocytes, oligodendrocytes, and microglia cells of the temporal cortex. In contrast, only nuclear staining was observed in BPH, prostate and breast carcinomas. Immunoprecipitation of human temporal cortex lysate and subsequent Western blot analysis demonstrated the expression of a 98 kDa immunoreactive protein, slightly smaller than the reported molecular weight of the wild-type androgen receptor. These results provide further evidence for the expression of androgen receptor in the human temporal cortex. The use of these immunocytochemical techniques should enable the retrospective determination of possible changes in androgen receptor expression in a variety of archival paraffin-embedded tissues, including samples of the human central nervous system.