Calcitonin gene-related peptide (CGRP) monoclonal antibodies for migraine.

The introduction of calcitonin gene-related peptide monoclonal antibodies represents a step forward in preventive migraine treatment as the first agents to target the underlying pathogenesis of migraine. In trials they act more quickly, have better long-term adherence and appear to be better tolerated than other treatments. Major disadvantages are their high cost and unknown safety in pregnancy and in cardiovascular disease. To mitigate these concerns, they should be used according to guidance produced by professional bodies, with defined starting and stopping criteria. We do not yet know whether they are more effective than standard care; many patients may still be better treated by other means, in particular addressing lifestyle factors and medication-overuse headache.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).

A 44-year-old Caucasian man presented with seizures and cognitive impairment. He had marked retinal drusen, and MR brain scan showed features of cerebral small vessel disease; he was diagnosed with a leukoencephalopathy of uncertain cause. He died at the age of 46 years and postmortem brain examination showed widespread small vessel changes described as a vasculopathy of unknown cause. Seven years postmortem, whole-genome sequencing identified a homozygous nonsense HTRA1 mutation (p.Arg302Ter), giving a retrospective diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Severe acute disseminated encephalomyelitis complicating measles infection.

A 36-year-old man presented with an acute progressive encephalopathy, followed by tetraparesis and was diagnosed with acute disseminated encephalomyelitis (ADEM) complicating infection with measles virus. Despite demonstrating a typical rash and other early symptoms of measles infection, there was uncertainty around the initial diagnosis. Cerebrospinal fluid analysis and MRI of the brain and spinal cord were consistent with severe ADEM. He required treatment on intensive care but responded favourably to immunosuppressive therapy.This case highlights the importance of recognising acute measles infection, familiarity with the neurological complications and the potential for good outcome. Healthcare professionals must continue to play an active role in educating the public on the importance of maintaining herd immunity through universal immunisation.

Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience.

BACKGROUND: Evidence supports the use of non-invasive vagus nerve stimulation (nVNS; gammaCore®) as a promising therapeutic option for patients with cluster headache (CH). We conducted this audit of real-world data from patients with CH, the majority of whom were treatment refractory, to explore early UK clinical experience with nVNS used acutely, preventively, or both. METHODS: We retrospectively analysed data from 30 patients with CH (29 chronic, 1 episodic) who submitted individual funding requests for nVNS to the National Health Service. All patients had responded to adjunctive nVNS therapy during an evaluation period (typical duration, 3-6 months). Data collected from patient interviews, treatment diaries, and physician notes were summarised with descriptive statistics. Paired t tests were used to examine statistical significance. RESULTS: The mean (SD) CH attack frequency decreased from 26.6 (17.1) attacks/wk. before initiation of nVNS therapy to 9.5 (11.0) attacks/wk. (P < 0.01) afterward. Mean (SD) attack duration decreased from 51.9 (36.7) minutes to 29.4 (28.5) minutes (P < 0.01), and mean (SD) attack severity (rated on a 10-point scale) decreased from 7.8 (2.3) to 6.0 (2.6) (P < 0.01). Use of abortive treatments also decreased. Favourable changes in the use of preventive medication were also observed. No serious device-related adverse events were reported. CONCLUSIONS: Significant decreases in attack frequency, severity, and duration were observed in these patients with CH who did not respond to or were intolerant of multiple preventive and/or acute treatments. These real-world findings complement evidence from clinical trials demonstrating the efficacy and safety of nVNS in CH.

The migraine postdrome: An electronic diary study.

OBJECTIVE: To report migraine postdrome symptoms in patients who report nonheadache symptoms as part of their attacks. METHODS: A prospective daily electronic diary study was conducted over 3 months in 120 patients with migraine. Nonheadache symptoms before, during, and after headache were collected on a daily basis. Visual analogue scales were used to capture the overall level of functioning and the severity of the headache. The postdrome was defined as the time from resolution of troublesome headache to return to normal. RESULTS: Of 120 evaluable patients, 97 (81%) reported at least one nonheadache symptom in the postdrome. Postdrome symptoms, in order of frequency, included feeling tired/weary and having difficulty concentrating and stiff neck. Many patients also reported a mild residual head discomfort. In most attacks (93%), there was return to normal within 24 hours after spontaneous pain resolved. There was no relationship between medication taken for the headache and the duration of the postdrome. The severity of the migraine was not associated with the duration of the postdrome. Overall state of health scores remained low during the postdrome. CONCLUSION: Nonheadache symptoms in the postdrome were common and may contribute to the distress and disability in the patients studied. Postdrome symptoms merit larger observational studies and careful recording in clinical trials of acute and preventive migraine treatments.

Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program.

BACKGROUND: Single pulse transcranial magnetic stimulation (sTMS) is a novel treatment for acute migraine. Previous randomised controlled data demonstrated that sTMS is effective and well tolerated in the treatment of migraine with aura. The aim of the programme reported here was to evaluate patient responses in the setting of routine clinical practice. METHODS: Migraine patients with and without aura treating with sTMS had an initial review (n = 426) and training call, and then participated in telephone surveys at week six (n = 331) and week 12 during a 3-month treatment period (n = 190). RESULTS: Of patients surveyed with 3 month data (n = 190; episodic, n = 59; chronic, n = 131), 62 % reported pain relief, finding the device effective at reducing or alleviating migraine pain; in addition there was relief reported of associated features: nausea- 52 %; photophobia- 55 %; and phonophobia- 53 %. At 3 months there was a reduction in monthly headache days for episodic migraine, from 12 (median, 8-13 IQ range) to 9 (4-12) and for chronic migraine, a reduction from 24 (median, 16-30 IQ range) to 16 (10-30). There were no serious or unanticipated adverse events. CONCLUSION: sTMS may be a valuable addition to options for the treatment of both episodic and chronic migraine.

Reducing excess stiffness in Stiff Person Syndrome using CBT: A case study.

BACKGROUND: Stiff Person Syndrome (SPS) is a rare neurological condition, characterised by rigidity in the trunk and limbs. Comorbid anxiety is common and known to exacerbate stiffness. OBJECTIVE: This case study examines the extent to which psychological treatment of comorbid anxiety alleviated stiffness in a patient whose condition was exacerbated by social anxiety. METHODS: A patient was treated using cognitive behavioural therapy, focussing on reducing anxiety and therefore stiffness by addressing rumination, self-focussed attention, and distressing cognitions relating to walking in public. The patient's walking, stiffness, and anxiety were assessed during and post-therapy using questionnaires. RESULTS: Walking, stiffness, and anxiety improved during treatment. At five months' follow up, while the improvement in anxiety was maintained, walking and stiffness had deteriorated. The patient and his Neurologist felt that this deterioration was biological, rather than psychological in nature. CONCLUSIONS: This is the first published case where SPS has been ameliorated (albeit temporarily) using psychological therapy, and has important implications for future research and treatment.

A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations.

IMPORTANCE: α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES: To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS: We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES: We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS: We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE: These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

Mesothelioma and anti-Ma paraneoplastic syndrome; heterogeneity in immunogenic tumours increases.

We present a patient with opsoclonus and diffuse cerebellar signs who had an anti-Ma2 antibody-associated paraneoplastic syndrome secondary to a sarcomatoid mesothelioma. This case highlights the importance of early tumour detection, instigation of therapeutic measures, and the heterogeneity of underlying malignancies in neurological paraneoplastic syndromes.

A genetic study of Wilson's disease in the United Kingdom.

Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

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.

The dynamic regulation of cortical excitability is altered in episodic ataxia type 2.

Episodic ataxia type 2 and familial hemiplegic migraine are two rare hereditary disorders that are linked to dysfunctional ion channels and are characterized clinically by paroxysmal neurological symptoms. Impaired regulation of cerebral excitability is thought to play a role in the occurrence of these paroxysms, but the underlying mechanisms are poorly understood. Normal ion channels are crucial for coordinating neuronal firing in response to facilitatory input. Thus, we hypothesized that channel dysfunction in episodic ataxia type 2 and familial hemiplegic migraine may impair the ability to adjust cerebral excitability after facilitatory events. We tested this hypothesis in patients with episodic ataxia type 2 (n = 6), patients with familial hemiplegic migraine (n = 7) and healthy controls (n = 13). All subjects received a high-frequency burst (10 pulses at 20 Hz) of transcranial magnetic stimulation to transiently increase the excitability of the motor cortex. Acute burst-induced excitability changes were probed at 50, 250, 500 and 1000 ms after the end of the burst. This was done using single-pulse transcranial magnetic stimulation to assess corticospinal excitability, and paired-pulse transcranial magnetic stimulation at an interstimulus interval of 2 and 10 ms to assess intracortical inhibition and facilitation, respectively. The time course of burst-induced excitability changes differed between groups. Healthy controls showed a short-lived increase in excitability that was only present 50 ms after the burst. In contrast, patients with episodic ataxia type 2 showed an abnormally prolonged increase in corticospinal excitability that was still present 250 ms after the transcranial magnetic stimulation burst. Furthermore, while controls showed a decrease in intracortical facilitation during the 1 s period following the transcranial magnetic stimulation burst, patients with episodic ataxia type 2 had increased intracortical facilitation 1000 ms after the burst. Intracortical inhibition was unaltered between groups. Patients with familial hemiplegic migraine were not significantly different from either controls or patients with episodic ataxia type 2. Together, these findings indicate that patients with episodic ataxia type 2 have an excessive increase in motor cortex excitability following a strong facilitatory input. We argue that this deficient control of cortical excitability may set the stage for the emergence of paroxysmal neural dysfunction in this disorder.

Imaging patients with suspected brain tumour: guidance for primary care.

The number of referrals by primary care practitioners to secondary care neurology services, particularly for headache, may be difficult to justify. Access to imaging by primary care practitioners could avoid referral without compromising patient outcomes, but the decision to refer is based on a number of complex factors. Due to the paucity of rigorous evidence in this area, available data are combined with expert opinion to offer support for GPs. The study suggests management for three levels of risk of tumour: red flags>1%; orange flags 0.1-1%; and yellow flags<0.1% but above the background population rate of 0.01%. Clinical presentations are stratified into these three groups. Important secondary causes of headache where imaging is normal should not be overlooked, and normal investigation does not eliminate the need for follow-up or appropriate management of headache.

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.

The electrophysiology of migraine.

Migraine is currently regarded as a neurovascular disorder of trigeminal sensory processing, generated centrally, probably at the level of the brainstem. In the past, electrophysiological techniques have drawn no definite conclusions on either interictal or ictal changes in migraineurs compared with controls, largely because of methodological differences. Recently, two findings have been shown consistently: an interictal increasing lack of habituation of evoked potentials with a normalization at the start of the attack and strong intensity dependence of auditory evoked potentials. These findings substantiate migraine sufferers as having an abnormal trait interictally, with the attack characterized by a change in the state of central processing. Exploitation of these differences may be a useful tool to study the mechanism of action of drugs used for the treatment of migraine.