The burden of migraine on acute and emergency services in a London teaching hospital.

OBJECTIVE: There is a lack of data on the burden of primary headache disorders such as migraine on emergency services. Existing data relies on a coding of "headache", which encompasses both primary and secondary headache of all causes; for example, subarachnoid haemorrhage. Guy's and St Thomas' NHS Trust in London is one of the UK's busiest emergency departments with 150,000 attendances per year. Our aim was to assess the healthcare resource utilisation of primary headaches, in particular migraine, in acute medical services. METHODS: We conducted an audit of all adult presentations to the emergency department of Guy's and St Thomas' Hospitals which were coded as "headache" over the first 6 months of 2018. We reviewed the initial diagnosis at presentation and also at discharge, investigations and outcome. RESULTS: Of 78,273 attendances to the emergency department, there were 976 presentations to the emergency department with "headache" as their primary complaint. "Migraine" was the most frequent of all diagnoses, accounting for 30% of all headache presentations and 25% of headache admissions. We calculated the cost of admitting and investigating migraine as £131,250 over the 6-month period. CONCLUSION: Emergency admissions for migraine represent an avoidable cost and burden for both the hospital and the migraineur. This data informs us about the need to develop better care pathways for migraine in the community and to improve headache education for physicians and patients.

Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Migraine: navigating the hormonal minefield.

Migraine affects 959 million people worldwide,1 with the highest prevalence being in women of childbearing age. The interplay between female hormones and migraine can be a challenging area to navigate since issues relating to pregnancy, contraception and the menopause are often out of the neurology comfort zone. This review aims to help the neurologist to manage women with migraine, from menarche to menopause.

Aneurysms in neurofibromatosis type 2: Evidence for vasculopathy?

There have been anecdotal reports of vasculopathy associated with Neurofibromatosis Type 2 (NF2). Given the increasing use of bevacizumab, a vascular endothelial growth factor inhibitor which results in an increased risk of bleeding, it is important to ascertain if there is a predisposition to vascular abnormalities in NF2. In our unit NF2 patients undergo annual MRI brain and internal auditory meatus imaging. We noted incidental intracranial aneurysms in some patients and sought to determine the prevalence of intracranial aneurysms in our cohort of NF2 patients. We conducted a retrospective audit of the MRI images of 104 NF2 patients from 2014 to 2016. Axial T2 brain MRI images were assessed for vascular abnormalities by two neuroradiologists blinded to patient's clinical details. Intracranial aneurysms were detected in four patients and an aneurysm clip related to previous surgery was noted in one additional patient. Using standard MRI imaging sequences alone we provide evidence of intracranial aneurysms in 4.4% of our cohort. This compares with an estimated overall prevalence of 3% in the general population. We discuss these findings as well as other evidence for a vasculopathy associated with NF2.

Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort.

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11-66 years), were followed for a median of 32.7 months (range 12.0-60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24 %) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5 %) had proteinuria. Of 36 patients followed for 36 months, 78 % were free from hypertension and 86 % were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire.

BACKGROUND: Neurofibromatosis 1 (NF1) is an inherited, multi-system, tumour suppressor disorder with variable complications that cause psychological distress and social isolation. The study aim was to develop and validate a disease-specific questionnaire to measure quality of life (QOL) in NF1 that is suitable both as an assessment tool in clinical practice and in clinical trials of novel therapy. METHODS: The Impact of NF1 on Quality of Life (INF1-QOL) questionnaire was developed by a literature search for common terms, focus group (n = 6), semi-structured interviews (n = 21), initial drafts (n =50) and final 14 item questionnaire (n = 50). Bivariate correlations between items, exploratory factor analysis, correlations with severity and EuroQol were employed. RESULTS: INF1-QOL showed good internal reliability (Cronbach's alpha 0.87), mean total INF1-QOL score was 8.64 (SD 6.3), median 7.00, range 0-30 (possible range 0-42); no significant correlations with age or gender. The mean total EuroQol score was 7.38 (SD 2.87), median 6.5, mean global EuroQol score was 76.34 (SD 16.56), median 80. Total INF1-QOL score correlated with total EuroQol r = 0.82, p < 0.0001. The highest impact on QOL was moderate or severe problems with anxiety and depression (32%) and negative effects of NF1 on role and outlook on life (42%). The mean inter-relater reliability for grading of clinical severity scores was 0.71 (range 0.65-0.79), and intra-class correlation was 0.92. The mean clinical severity score was 1.95 (SD 0.65) correlating r = 0.34 with total INF1-QOL score p < 0.05 and correlated 0.37 with total EuroQol score p < 0.01. The clinical severity score was mild in 17 (34%), moderate in 16 (32%) and 17 (34%) individuals had severe disease. CONCLUSIONS: INF1-QOL is a validated, reliable disease specific questionnaire that is easy and quick to complete. Role and outlook on life and anxiety and depression have the highest impact on QOL indicating the variability, severity and unpredictability of NF1. INFI-QOL correlates moderately with clinical severity. The moderate relationship between INF1-QOL and physician rated severity emphasizes the difference between clinical and patient perception. INFI-QOL will be useful in individual patient assessment and as an outcome measure for clinical trials.

Cilioretinal Artery Territory Infarction Associated With Papilledema in a Patient With Neurofibromatosis Type 2.

Cilioretinal artery territory infarction can occur in isolation or in association with other vascular compromise of the retinal circulation. Our patient, an 18-year-old woman with neurofibromatosis type 2, developed a cilioretinal artery territory infarction in the setting of papilledema. Our case, together with one previous report, suggests that cilioretinal artery territory infarction in the context of papilledema, although rare, is a real entity.

Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life.

In our clinical practice, we noticed a high frequency of headaches amongst NF1 patients. We sought to characterize the phenotype and prevalence of headache in our cohort of NF1 patients attending the London NF clinic and to determine the impact on quality of life. Participants over the age of 16 fulfilling diagnostic criteria for NF1 from the general NF1 outpatient clinics at Guy's and St. Thomas' NHS Foundation Trust and the nationally commissioned Complex NF1 service were asked to fill in a questionnaire during the clinic consultation. Data were recorded regarding the headache frequency, intensity, duration, and phenotype, and a validated quality of life questionnaire, HIT-6 was also completed by the participant. IHS (International Headache Society) criteria were used to diagnose migraine. One hundred fifteen patients (48 males, 67 females) completed the questionnaire. The age range of participants was 16-67 with a mean age of 36 years. Twenty-five reported no headaches. Seventy-five (65%) fulfilled IHS diagnostic criteria for migraine (15 with aura). The mean HIT-6 score was 56 (out of a maximum 78) implying a significant effect on quality of life. Migraine is common in our NF1 population and has a significant impact on quality of life. Patients may not volunteer information regarding headache and this should be actively sought during consultations and the headache phenotype should be carefully characterized.

Special considerations in migraine during pregnancy and lactation.

Migraine is estimated to affect 959 million people worldwide and has a female preponderance of 3:1. This is thought to be due to the influence of female hormones as before puberty both sexes are affected equally. The prevalence is highest in women of childbearing age at 24%. It is, therefore, important to have a good understanding of how pregnancy influences migraine and how to advise and manage women with migraine during pregnancy and lactation.

Current concepts in migraine and their relevance to pregnancy.

The prevalence of migraine in women of childbearing age is high, estimated at 24%. Migraine management during pregnancy and lactation can be challenging. Our understanding of the way in which medications affect the unborn fetus is still incomplete and the evidence is constantly changing with more recent emphasis on longitudinal studies and childhood development. The aim of this article is to describe the relationship between migraine and pregnancy and review the current evidence on treatment options in pregnancy and lactation.

A positron emission tomographic study in spontaneous migraine.

BACKGROUND: Functional brain imaging in acute migraine has proved challenging because of the logistic problems associated with an episodic condition. Since the seminal observation of brainstem activation in migraine, there has been only a single case substantiating this finding. OBJECTIVE: To test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomic localization with higher-resolution positron emission tomography than previously used. DESIGN: Using positron emission tomography with radioactive water (H(2)15O), we studied acute migraine attacks occurring spontaneously. Five patients underwent imaging in ictal and interictal states, and the differences were analyzed by means of statistical parametric mapping. SETTING: Tertiary referral center. PATIENTS: Six volunteers with episodic migraine were recruited from advertisements in migraine newsletters. One patient was excluded because of use of preventive medication. MAIN OUTCOME MEASURE: Brainstem activation during migraine state vs interictal state. RESULTS: Two patients had a typical migrainous aura before the onset of the headache. All of the attacks studied fulfilled standard diagnostic criteria for migraine. Comparing the migraine scans with interictal scans, there was significant activation in the dorsal pons, lateralized to the left (small volume correction, P = .003). Activation was also seen in the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes. There was an area of deactivation in the migraine phase also located in the pons, lateralized to the right. CONCLUSIONS: Our findings provide clear evidence of dorsal pontine activation in migraine and reinforce the view that migraine is a subcortical disorder modulating afferent neural traffic.

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.

OBJECTIVE: The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. METHODS: We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. RESULTS: Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. CONCLUSIONS: These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. CLASSIFICATION OF EVIDENCE: This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.

Neuroimaging of migraine.

Neuroimaging of migraine recently has provided us with further information regarding the pathophysiology of the disorder and posed important questions as to whether migraine is a progressive disorder. This article provides the background of imaging in migraine and discusses recent advances in the field.