A Dutch cost-effectiveness analysis of fremanezumab versus best supportive care in patients with chronic migraine and inadequate response to prior preventive therapy.

BACKGROUND: Chronic migraine (CM) is the most severe and burdensome subtype of migraine. Fremanezumab is a monoclonal antibody that targets the calcitonin gene-related peptide pathway as a migraine preventive therapy. This study aimed to conduct a cost-effectiveness analysis of fremanezumab from a societal perspective in the Netherlands, using a Markov cohort simulation model. METHODS: The base-case cost-effectiveness analysis adhered to the Netherlands Authority guidelines. Fremanezumab was compared with best supportive care (BSC; acute migraine treatment only) in patients with CM and an inadequate response to topiramate or valproate and onabotulinumtoxinA (Dutch patient group [DPG]). A supportive analysis was conducted in the broader group of CM patients with prior inadequate response to 2-4 different classes of migraine preventive treatments. One-way sensitivity, probabilistic sensitivity, and scenario analyses were conducted. RESULTS: Over a lifetime horizon, fremanezumab is cost saving compared with BSC in the DPG (saving of €2514 per patient) and led to an increase of 1.45 quality-adjusted life-years (QALYs). In the broader supportive analysis, fremanezumab was cost effective compared with BSC, with an incremental cost-effectiveness ratio of €2547/QALY gained. Fremanezumab remained cost effective in all sensitivity and scenario analyses. CONCLUSION: In comparison to BSC, fremanezumab is cost saving in the DPG and cost effective in the broader population.

Visual hypersensitivity in patients treated with anti-calcitonin gene-related peptide (receptor) monoclonal antibodies.

OBJECTIVE: To evaluate the effect of treatment with anti-calcitonin gene-related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine. BACKGROUND: Increased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light-aversive behavior. METHODS: In this prospective follow-up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L-VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e-diary, treatment effectiveness was assessed in weeks 9-12 compared to a 4-week pre-treatment baseline period. L-VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L-VISS scores and the reduction in monthly migraine days (MMD) was investigated. RESULTS: At 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L-VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L-VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L-VISS (ß = 0.2, p = 0.010) and the reduction in ictal L-VISS (ß = 0.3, p = 0.001). CONCLUSION: A decrease in visual hypersensitivity in patients with migraine after treatment with anti-CGRP (receptor) antibodies is positively associated with clinical response on migraine.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Could erectile dysfunction be a side effect of CGRP inhibition? A case report.

BACKGROUND: Recently, antimigraine drugs targeting the calcitonin gene-related peptide pathway have been approved for clinical use as preventive migraine medication. CASE REPORT: We present a case of a 54-year-old male migraine patient, who reported erectile dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide. His potency recovered after treatment discontinuation. DISCUSSION: As calcitonin gene-related peptide is involved in mammalian penile erection, erectile dysfunction is a conceivable side effect associated with calcitonin gene-related peptide inhibition. Postmarketing surveillance will elucidate the actual incidence of erectile dysfunction in patients using these new antimigraine drugs, and determine whether a causal relationship between calcitonin gene-related peptide inhibition and erectile dysfunction exists. This would be relevant not only because of the direct sexual consequences of erectile dysfunction, but also considering the potential cardiovascular consequences of calcitonin gene-related peptide (receptor) blockade and the association of both migraine and erectile dysfunction with cardiovascular disease. CONCLUSION: Erectile dysfunction might be an overlooked, but reversible side effect in male migraine patients using monoclonal antibodies that inhibit the calcitonin gene-related peptide pathway, including galcanezumab. This paper may raise clinical awareness and suggest that this potential side effect needs to be studied further.

Unilateral increased visual sensitivity in cluster headache: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache. METHODS: We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine. RESULTS: Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 ± 8.0 vs. 5.2 ± 5.5, chronic cluster headache: 13.7 ± 8.4 vs 5.6 ± 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 ± 5.2 vs 3.6 ± 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 ± 0.5 vs 3.8 ± 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 ± 5.5 vs. 3.7 ± 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants. CONCLUSION: Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.

Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations.

OBJECTIVE: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. METHODS: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. RESULTS: Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. SIGNIFICANCE: Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Enhanced pre-ictal cortical responsivity in migraine patients assessed by visual chirp stimulation.

BACKGROUND: Migraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain better insight into cortical responsivity changes in migraine we subjected patients to a short series of light inputs over a broad frequency range ("chirp" stimulation), designed to uncover dynamic features of visual cortex responsivity. METHODS: EEG responses to visual chirp stimulation (10-40 Hz) were measured in controls (n = 24) and patients with migraine with aura (n = 19) or migraine without aura (n = 20). Average EEG responses were assessed at (i) all EEG frequencies between 5 and 125 Hz, (ii) stimulation frequencies, and (iii) harmonic frequencies. We compared average responses in a low (10-18 Hz), medium (19-26 Hz) and high (27-40 Hz) frequency band. RESULTS: Responses to chirp stimulation were similar in controls and migraine subtypes. Eight measurements (n = 3 migraine with aura; n = 5 without aura) were assigned as "pre-ictal", based on reported headache within 48 hours after investigation. Pre-ictally, an increased harmonic response to 22-32 Hz stimulation (beta band) was observed (p = 0.001), compared to interictal state measurements. CONCLUSIONS: We found chirp responses to be enhanced in the 48 hours prior to migraine headache onset. Visual chirp stimulation proved a simple and reliable technique with potential to detect changes in cortical responsivity associated with the onset of migraine attacks.

Familial hemiplegic migraine treated by sodium valproate and lamotrigine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura that includes motor auras. Prophylactic treatment of FHM often has marginal effects and involves a trial-and-error strategy based on therapeutic guidelines for non-hemiplegic migraine and on case reports in FHM. METHODS: We assessed the response to prophylactic medication in an FHM family and sequenced the FHM2 ATP1A2 gene in all available relatives. RESULTS: A novel p.Met731Val ATP1A2 mutation was identified. Attack frequency was reduced significantly with sodium valproate monotherapy (n = 1) and attacks ceased completely with a combination of sodium valproate and lamotrigine (n = 2). CONCLUSIONS: We report dramatic prophylactic effects of sodium valproate and lamotrigine in an FHM2 family, making these drugs worth considering in the treatment of other FHM patients.

Parenting and restrictions in childhood epilepsy.

PURPOSE: From the overprotection literature, the predictive and interactional (moderation) effects of controlling and indulgent parenting on restrictions in children with epilepsy were examined. METHODS: Parents of 73 children with epilepsy completed questionnaires on parenting, restrictions, and functional status. Predictive and moderation effects were tested using multiple regression analysis. Moderation was tested with interactive computational methods. RESULTS: Restrictions were significantly (R(2)=.38, FΔ=6.59***, p<.001) predicted from seizure frequency (ß=.24*, p<.05), functional status (ß=-.42***, p<.001), and interaction between controlling and indulgent parenting (ß=.28**, p<.01). Moderation occurred predominantly for high values of control: controlling parents who were not indulgent imposed fewer restrictions. In contrast, controlling parents who were indulgent imposed more restrictions. CONCLUSION: Parents who were controlling and more indulgent imposed more restrictions. Clinicians should ask parents about parenting and restrictions. Future research should examine whether the current study's findings can be replicated.

Validity of health insurance data to identify people with epilepsy.

BACKGROUND: Large administrative databases may prove useful to assess epilepsy-related comorbidity and mortality. Despite their increased use, their validity as data source in epilepsy is yet under-ascertained. METHODS: Achmea is a large Dutch health insurance company covering about 25% of the population. We performed a retrospective cohort study using data from the Achmea Health Insurance Database (AHID) over the period 2006-2009. To assess the validity of epilepsy codes in the AHID, we randomly invited 1000 individuals (age 18-75 years insured by Achmea), attending an epilepsy centre or a district hospital during 2006-2009, to participate. Informed consent was provided and 293 were eligible for inclusion. We compared the diagnostic codes for epilepsy in AHID with the diagnosis in their case-notes (reference standard). As additional measure of validity, we compared prevalence of epilepsy codes in AHID (based on anonymized data of all 26.297 subjects with this code in AHID) with epilepsy prevalence rates in the general Dutch population to estimate an age-specific standardized prevalence ratio. RESULTS: We identified 293 participants with an epilepsy code in AHID. The majority (278) of them had a definite or possible diagnosis of epilepsy in the case-notes; i.e. a positive predictive value of 0.95 (95% CI 0.92-0.97). The overall prevalence of epilepsy codes in the AHID was slightly higher than the putative prevalence in the general Dutch population (7.4/1.000 vs. 6.8/1.000) with a Standardized Prevalence Ratio of 1.08 (95% CI: 1.08-1.09). CONCLUSIONS: Our findings demonstrate the validity of AHID data for a diagnosis of epilepsy and confirm previous work on using administrative data for epilepsy research.

Quantifying visual allodynia across migraine subtypes: the Leiden Visual Sensitivity Scale.

Enhanced sensitivity to light (photophobia) and patterns is common in migraine and can be regarded as visual allodynia. We aimed to develop and validate a questionnaire to easily quantify sensitivity to light and patterns in large populations, and to assess and compare visual allodynia across different migraine subtypes and states. We developed the Leiden Visual Sensitivity Scale (L-VISS), a 9-item scale (score range 0-36 points), based on literature and patient interviews, and examined its construct validity. Furthermore, we assessed ictal and interictal visual sensitivity in episodic migraine with (n = 67) and without (n = 66) aura and chronic migraine with (n = 20) and without (n = 19) aura, and in healthy controls (n = 86). Differences between migraine subtypes and states were tested using a linear mixed model with 3 fixed factors (episodic/chronic, with/without aura, and ictal/interictal). Test-retest reliability and construct validity of L-VISS were good. Leiden Visual Sensitivity Scale scores correlated in the expected direction with light discomfort (Kendall's τ = -0.25) and pattern glare tests (τ = 0.35). Known-group comparisons confirmed its construct validity. Within migraine subtypes, L-VISS scores were higher in migraine with aura versus without aura and in chronic versus episodic migraine. The linear mixed model showed all factors affected the outcome (P < 0.001). The L-VISS is an easy-to-use scale to quantify and monitor the burden of bothersome visual sensitivity to light and patterns in large populations. There are remarkable ictal and interictal differences in visual allodynia across migraine subtypes, possibly reflecting dynamic differences in cortical excitability.

Effects of a fast disintegrating/rapid release oral formulation of sumatriptan on functional ability in patients with migraine.

BACKGROUND: A new oral form of sumatriptan has been developed to facilitate tablet disintegration and drug dispersion and to mitigate the effects of gastric stasis that can accompany migraine. OBJECTIVE: To evaluate the effects on functional ability of the new fast disintegrating/rapid release formulation of sumatriptan. METHODS: Sumatriptan 50 mg (n = 137), 100 mg (n = 142), or placebo (n = 153) was administered early when pain was mild for the acute treatment of a single migraine attack in a randomized, double-blind, parallel-group, placebo-controlled clinical trial. For this report, main health-outcomes endpoints (which were secondary endpoints for this clinical trial that was primarily designed to assess pain-free efficacy) included functional ability measured through 2 h postdose on a 5-point scale and lost time equivalents, a composite measure of migraine-associated time missed from activities, and reduced effectiveness at activities through 24 h postdose. RESULTS: Normal functional ability was restored in a significantly (p < 0.05) greater percentage of patients treated with sumatriptan than placebo beginning 45 min postdose for sumatriptan 100 mg and 1 h postdose for sumatriptan 50 mg. During the 24 h after initial dosing, the median (range) lost time equivalents for the combination of paid work activities and activities outside of paid work were significantly lower in the groups treated with sumatriptan (1.1 [0-10] sumatriptan 100 mg; 0.8 [0-36] sumatriptan 50 mg) compared with placebo (2.9 [0-24]) (p < or = 0.01 each sumatriptan group versus placebo). The corresponding mean +/- SD values for lost time equivalents were 1.9 +/- 2.3 and 2.5 +/- 4.7 for sumatriptan 100 mg and 50 mg, respectively, compared with 3.5 +/- 4.3 for placebo. CONCLUSION: A new oral sumatriptan formulation confers rapid, sustained restoration of functional ability in the acute treatment of migraine so that patients can return rapidly to normal functioning at work and outside of work.

Parent-reported subjective complaints in children using antiepileptic drugs: what do they mean?

We used a parent-completed 20-item "side effect scale" quantifying complaints that parents perceive to be caused by antiepileptic drugs (AEDs) in 108 children with active epilepsy. We studied the associations between parent-reported complaints, severity of seizures, and restrictions due to epilepsy, and clinical data including number and AED load. In 85% of the children at least one complaint was reported, in less than 20% complaints were perceived as a substantial problem. In a multivariate analysis, there was no significant relationship between the "side effect scale" score and AED load, or the number of AEDs. However, complaints were associated with parent-reported frequency and severity of seizures. We conclude that the adverse effects of seizures or parental concern about the severity and intractability of seizures in their children may have influenced the reported complaints.

Seizure precipitants in a community-based epilepsy cohort.

Epileptic seizures can be provoked by several factors. Better understanding of these factors may improve a patient's sense of control and could reduce seizures. In daily practice, the recognition of seizure precipitants relies heavily on clinical or video-EEG evidence, which can be difficult to obtain. Studies of seizure provocation are largely based on selected hospital-based patient populations, which may lead to biased occurrence estimates. Self-reported seizure precipitants are rarely studied, yet are necessary to understand the experiences of patients and improve epilepsy management. We performed a cross-sectional community-based study of 248 epilepsy patients, selected by pharmacy records of anti-epileptic drug use. Self-reported seizure precipitants and potential associated characteristics were assessed using questionnaires. Almost half of all patients (47 %) reported one or more seizure precipitants, of which stress, sleep deprivation, and flickering lights were the most common. In this community-based setting, light-provoked seizures were especially frequent compared to the literature. Idiopathic generalized epilepsy (IGE), a lower age at seizure onset, and having auras or prodromes were found to be important independent prognostic factors associated with provoked seizures. IGE and a younger age at seizure onset have been linked to provoked seizures in earlier reports. The finding of auras or prodromes as a prognostic factor was unexpected, though case reports have described provoked seizures in patients having auras. Assessment of these factors may facilitate the early recognition of seizure precipitants in daily clinical practice. This is important for the optimization of epilepsy management for a large group of patients, as provoked seizures are expected to occur frequently.

[West Nile virus poliomyelitis after a holiday in Egypt]. / West-Nijl-viruspoliomyelitis na vakantie in Egypte.

BACKGROUND: Due to the worldwide near-extinction of poliovirus infections an acute presentation of poliomyelitis in the Netherlands has become extremely rare. However, in the differential diagnosis of such a disease presentation other pathogens need to be considered as well. CASE DESCRIPTION: A 44-year-old female presented with fever and a flaccid paresis of the left leg, following a holiday in Egypt. The laboratory investigation demonstrated an acute West Nile virus (WNV) infection, after which the diagnosis 'WNV poliomyelitis' was made. CONCLUSION: WNV poliomyelitis is a rare neurological complication of an infection with the WNV. The areas in Europe where WNV transmission to humans occurs are expanding. In the future, the number of neurological disorders caused by WNV is likely to increase, also in the Netherlands.

Nervous system adverse responses to topiramate in the treatment of neuropsychiatric disorders.

IMPORTANCE OF THE FIELD: Nervous system adverse drug reactions (NS-ADRs), such as cognitive complaints and paresthesia, are among the most frequent and clinically important ADRs of topiramate. Studying ADR profiles across disorders is clinically relevant because treatment decision-making in neuropsychiatry is highly guided by ADR profiles. AREAS COVERED IN THIS REVIEW: We used medline searches (until July 2009) to review the NS-ADRs of topiramate across the most investigated topiramate indications: alcohol dependence, essential tremor, binge-eating disorder, bulimia nervosa, migraine and epilepsy. We compared NS-ADRs between these disorders but did not carry out meta-analysis. WHAT THE READER WILL GAIN: ADR profiles greatly differed between disorders. Drop-outs due to ADRs highly varied between disorders: from 2% in the bulimia nervosa group to 29% in the migraine group. Paresthesia was the most common NS-ADR for all disorders but frequencies also differed between disorders. Cognitive complaints were frequent and were reported in comparable proportions. TAKE HOME MESSAGE: When prescribing topiramate in neuropsychiatry, physicians should be aware that NS-ADR profiles have been found to differ between disorders. Differences in drop-out rates due to ADRs and in frequencies of specific NS-ADRs across disorders must be taken into account when evaluating the potential harm of topiramate in clinical practice.