Spontaneous intracranial hypotension.

Spontaneous intracranial hypotension (SIH) is a highly disabling but treatable secondary cause of headache. Recent progress in neuroradiological techniques has catalysed understanding of its pathophysiological basis and clinical diagnosis, and facilitated the development of more effective investigation and treatment methods. A UK-based specialist interest group recently produced the first multidisciplinary consensus guideline for the diagnosis and treatment of SIH. Here, we summarise a practical approach to its clinical and radiological diagnosis, symptomatic and non-targeted interventional treatment, radiological identification of leak site and targeted treatment of the leak once it has been localised.

Multidisciplinary consensus guideline for the diagnosis and management of spontaneous intracranial hypotension.

BACKGROUND: We aimed to create a multidisciplinary consensus clinical guideline for best practice in the diagnosis, investigation and management of spontaneous intracranial hypotension (SIH) due to cerebrospinal fluid leak based on current evidence and consensus from a multidisciplinary specialist interest group (SIG). METHODS: A 29-member SIG was established, with members from neurology, neuroradiology, anaesthetics, neurosurgery and patient representatives. The scope and purpose of the guideline were agreed by the SIG by consensus. The SIG then developed guideline statements for a series of question topics using a modified Delphi process. This process was supported by a systematic literature review, surveys of patients and healthcare professionals and review by several international experts on SIH. RESULTS: SIH and its differential diagnoses should be considered in any patient presenting with orthostatic headache. First-line imaging should be MRI of the brain with contrast and the whole spine. First-line treatment is non-targeted epidural blood patch (EBP), which should be performed as early as possible. We provide criteria for performing myelography depending on the spine MRI result and response to EBP, and we outline principles of treatments. Recommendations for conservative management, symptomatic treatment of headache and management of complications of SIH are also provided. CONCLUSIONS: This multidisciplinary consensus clinical guideline has the potential to increase awareness of SIH among healthcare professionals, produce greater consistency in care, improve diagnostic accuracy, promote effective investigations and treatments and reduce disability attributable to SIH.

New daily persistent headache: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of the epidemiology, precipitants, phenotype, comorbidities, pathophysiology, treatment, and prognosis of primary new daily persistent headache. METHODS: We searched PubMed/Medline, EMBASE, Cochrane, and clinicaltrials.gov until 31 December 2022. We included original research studies with any design with at least five participants with new daily persistent headache. We assessed risk of bias using National Institutes of Health Quality Assessment Tools. We used random-effects meta-analysis where suitable to calculate pooled estimates of proportions. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis compliant study is registered with PROSPERO (registration number CRD42022383561). RESULTS: Forty-six studies met inclusion criteria, predominantly case series, including 2155 patients. In 67% (95% CI 57-77) of cases new daily persistent headache has a chronic migraine phenotype, however new daily persistent headache has been found to be less likely than chronic migraine to be associated with a family history of headache, have fewer associated migrainous symptoms, be less vulnerable to medication overuse, and respond less well to injectable and neuromodulatory treatments. CONCLUSIONS: New daily persistent headache is a well described, recognisable disorder, which requires further research into its pathophysiology and treatment. There is a lack of high-quality evidence and, until this exists, we recommend continuing to consider new daily persistent headache a distinct disorder.

Trigeminal microvascular decompression for short-lasting unilateral neuralgiform headache attacks.

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single-centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic short-lasting unilateral neuralgiform headache attacks with MRI evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an 'excellent response', defined as 90-100% weekly reduction in attack frequency, or 'good response', defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients, of whom 31 had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and 16 had short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. MRI of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Postoperatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing = 7 and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms = 3) reported no postoperative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks in the response to surgery (P = 0.463). Responders at the last follow-up were, however, more likely to not have interictal pain (77.42% versus 22.58%, P = 0.021) and to show morphological changes on the MRI (78.38% versus 21.62%, P = 0.001). The latter outcome was confirmed in the Kaplan-Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (P = 0.0001). All but one patient, who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for patients suffering short-lasting unilateral neuralgiform headache attacks with MRI evidence of neurovascular conflict with morphological changes.

Phenotype of new daily persistent headache: subtypes and comparison to transformed chronic daily headache.

BACKGROUND: It is unknown whether new daily persistent headache (NDPH) is a single disorder or heterogenous group of disorders, and whether it is a unique disorder from chronic migraine and chronic tension-type headache. We describe a large group of patients with primary NDPH, compare its phenotype to transformed chronic daily headache (T-CDH), and use cluster analysis to reveal potential sub-phenotypes in the NDPH group. METHODS: We performed a case-control study using prospectively collected clinical data in patients with primary NDPH and T-CDH (encompassing chronic migraine and chronic tension-type headache). We used logistic regression with propensity score matching to compare demographics, phenotype, comorbidities, and treatment responses between NDPH and T-CDH. We used K-means cluster analysis with Gower distance to identify sub-clusters in the NDPH group based on a combination of demographics, phenotype, and comorbidities. RESULTS: We identified 366 patients with NDPH and 696 with T-CDH who met inclusion criteria. Patients with NDPH were less likely to be female (62.6% vs. 73.3%, p < 0.001). Nausea, vomiting, photophobia, phonophobia, motion sensitivity, vertigo, and cranial autonomic symptoms were all significantly less frequent in NDPH than T-CDH (p value for all < 0.001). Acute treatments appeared less effective in NDPH than T-CDH, and medication overuse was less common (16% vs. 42%, p < 0.001). Response to most classes of oral preventive treatments was poor in both groups. The most effective treatment in NDPH was doselupin in 45.7% patients (95% CI 34.8-56.5%). Cluster analysis identified three subgroups of NDPH. Cluster 1 was older, had a high proportion of male patients, and less severe headaches. Cluster 2 was predominantly female, had severe headaches, and few associated symptoms. Cluster 3 was predominantly female with a high prevalence of migrainous symptoms and headache triggers. CONCLUSIONS: Whilst there is overlap in the phenotype of NDPH and T-CDH, the differences in migrainous, cranial autonomic symptoms, and vulnerability to medication overuse suggest that they are not the same disorder. NDPH may be fractionated into three sub-phenotypes, which require further investigation.

Cytokines in primary headache disorders: a systematic review and meta-analysis.

BACKGROUND: The role of inflammation and cytokines in the pathophysiology of primary headache disorders is uncertain. We performed a systematic review and meta-analysis to synthesise the results of studies comparing peripheral blood cytokine levels between patients with migraine, tension-type headache, cluster headache, or new daily persistent headache (NDPH), and healthy controls; and in migraine between the ictal and interictal stages. METHODS: We searched PubMed/Medline and Embase from inception until July 2022. We included original research studies which measured unstimulated levels of any cytokines in peripheral blood using enzyme-linked immunosorbent assay or similar assay. We assessed risk of bias using the Newcastle-Ottawa Quality Assessment Scale. We used random effects meta-analysis with inverse variance weighted average to calculate standardised mean difference (SMD), 95% confidence intervals, and heterogeneity for each comparison. This study is registered with PROSPERO (registration number CRD42023393363). No funding was received for this study. RESULTS: Thirty-eight studies, including 1335 patients with migraine (32 studies), 302 with tension-type headache (nine studies), 42 with cluster headache (two studies), and 1225 healthy controls met inclusion criteria. Meta-analysis showed significantly higher interleukin (IL)-6 (SMD 1.07, 95% CI 0.40-1.73, p = 0.002), tumour necrosis factor (TNF)-α (SMD 0.61, 95% CI 0.14-1.09, p = 0.01), and IL-8 (SMD 1.56, 95% CI 0.03-3.09, p = 0.04), in patients with migraine compared to healthy controls, and significantly higher interleukin-1ß (IL-1ß) (SMD 0.34, 95% CI 0.06-0.62, p = 0.02) during the ictal phase of migraine compared to the interictal phase. Transforming growth factor (TGF)-ß (SMD 0.52, 95% CI 0.18-0.86, p = 0.003) and TNF-α (SMD 0.64, 95% CI 0.33-0.96, p = 0.0001) were both higher in patients with tension-type headache than controls. CONCLUSIONS: The higher levels of the proinflammatory cytokines IL-6, IL-8 and TNF-α in migraine compared to controls, and IL-1ß during the ictal stage, suggest a role for inflammation in the pathophysiology of migraine, however prospective studies are required to confirm causality and investigate the mechanisms for the increase in cytokine levels identified. Cytokines may also have a role in tension-type headache. Due a lack of data, no conclusions can be made regarding cluster headache or NDPH.

The prevalence of headache disorders in Postural Tachycardia Syndrome: A systematic review and meta-analysis of the literature.

BACKGROUND: Headache is a common presentation of postural tachycardia syndrome, yet robust prevalence data is lacking. OBJECTIVES: To undertake a systematic review and meta-analysis to estimate the prevalence of headache disorders in postural tachycardia syndrome, and to explore the potential shared pathophysiological mechanisms that underpin these conditions as well as treatment options. METHODS: Three databases were searched for publications evaluating prevalence of migraine (primary outcome) and general and orthostatic headache (secondary outcomes) in patients with postural tachycardia syndrome. Two independent reviewers selected studies and extracted data. A random-effects meta-analysis calculated the pooled prevalence of migraine in postural tachycardia syndrome. A narrative literature review explored the pathophysiology and treatment options for concurrent headache disorders and postural tachycardia syndrome. RESULTS: Twenty-three articles met inclusion criteria. Estimated pooled prevalence of migraine in postural tachycardia syndrome was 36.8% (95% CI 2.9-70.7%). Various shared pathophysiological pathways for these conditions, as well as proposed treatment strategies, were identified.Limitations: Heterogeneity of study design, populations, and methodology for identifying headache disorders and postural tachycardia syndrome limited the generalisability of results. CONCLUSIONS: Migraine is a commonly reported comorbidity in POTS, however the true prevalence cannot be determined from the current literature. Further studies are required to assess this comorbidity and investigate the underlying mechanisms, as well as identify effective treatment strategies.

Machine phenotyping of cluster headache and its response to verapamil.

Cluster headache is characterized by recurrent, unilateral attacks of excruciating pain associated with ipsilateral cranial autonomic symptoms. Although a wide array of clinical, anatomical, physiological, and genetic data have informed multiple theories about the underlying pathophysiology, the lack of a comprehensive mechanistic understanding has inhibited, on the one hand, the development of new treatments and, on the other, the identification of features predictive of response to established ones. The first-line drug, verapamil, is found to be effective in only half of all patients, and after several weeks of dose escalation, rendering therapeutic selection both uncertain and slow. Here we use high-dimensional modelling of routinely acquired phenotypic and MRI data to quantify the predictability of verapamil responsiveness and to illuminate its neural dependants, across a cohort of 708 patients evaluated for cluster headache at the National Hospital for Neurology and Neurosurgery between 2007 and 2017. We derive a succinct latent representation of cluster headache from non-linear dimensionality reduction of structured clinical features, revealing novel phenotypic clusters. In a subset of patients, we show that individually predictive models based on gradient boosting machines can predict verapamil responsiveness from clinical (410 patients) and imaging (194 patients) features. Models combining clinical and imaging data establish the first benchmark for predicting verapamil responsiveness, with an area under the receiver operating characteristic curve of 0.689 on cross-validation (95% confidence interval: 0.651 to 0.710) and 0.621 on held-out data. In the imaged patients, voxel-based morphometry revealed a grey matter cluster in lobule VI of the cerebellum (-4, -66, -20) exhibiting enhanced grey matter concentrations in verapamil non-responders compared with responders (familywise error-corrected P = 0.008, 29 voxels). We propose a mechanism for the therapeutic effect of verapamil that draws on the neuroanatomy and neurochemistry of the identified region. Our results reveal previously unrecognized high-dimensional structure within the phenotypic landscape of cluster headache that enables prediction of treatment response with modest fidelity. An analogous approach applied to larger, globally representative datasets could facilitate data-driven redefinition of diagnostic criteria and stronger, more generalizable predictive models of treatment responsiveness.

Is pituitary MRI screening necessary in cluster headache?

OBJECTIVE: To determine the prevalence and clinical predictors of pituitary adenomas in cluster headache patients, in order to determine the necessity of performing dedicated pituitary magnetic resonance imaging in patients with cluster headache. METHODS: A retrospective study was conducted of all consecutive patients diagnosed with cluster headache and with available brain magnetic resonance imaging between 2007 and 2017 in a tertiary headache center. Data including demographics, attack characteristics, response to treatments, results of neuroimaging, and routine pituitary function tests were recorded. RESULTS: Seven hundred and eighteen cluster headache patients attended the headache clinic; 643 underwent a standard magnetic resonance imaging scan, of whom 376 also underwent dedicated pituitary magnetic resonance imaging. Pituitary adenomas occurred in 17 of 376 patients (4.52%). Non-functioning microadenomas (n = 14) were the most common abnormality reported. Two patients, one of whom lacked the symptoms of pituitary disease, required treatment for their pituitary lesion. No clinical predictors of those adenomas were identified after multivariate analysis using random forests. Systematic pituitary magnetic resonance imaging scanning did not benefit even a single patient in the entire cohort. CONCLUSION: The prevalence of pituitary adenomas in cluster headache is similar to that reported in the general population, thereby precluding an over-representation of pituitary lesions in cluster headache. We conclude that the diagnostic assessment of cluster headache patients should not include specific pituitary screening. Only patients with standard brain magnetic resonance imaging findings or symptoms suggestive of a pituitary disorder require brain magnetic resonance imaging with dedicated pituitary views.

Long-Term Outcomes of Occipital Nerve Stimulation for New Daily Persistent Headache With Migrainous Features.

OBJECTIVES: New daily persistent headache (NDPH) is a subset of chronic headache where the pain is continuous from onset. Phenotypically it has chronic migraine or chronic tension type features. NDPH is considered to be highly refractory. Occipital nerve stimulation (ONS) has been used for treatment of refractory chronic migraine but there are no specific reports of its use for NDPH with migrainous features. MATERIALS AND METHODS: Nine patients with NDPH with migrainous features were identified as having had ONS implants between 2007 and 2014 in a specialist unit with experience of using ONS in chronic migraine. Moderate to severe headache days were compared at baseline and follow-up. A positive response was defined as at least 30% reduction in monthly moderate to severe headache days. RESULTS: Patients had suffered NDPH for a median of 8 years (range 3-16 years) and had failed a median of 11 previous treatments (range 8-15). After a median follow-up of 53 months (range 27-108 months), only a single patient showed a positive response to ONS. At no point did the cohort as a whole show any change in monthly moderate to severe headache days or disability scores. CONCLUSION: Our experience suggests that ONS is not effective in the treatment of NDPH with migrainous features even in centers with experience in treating chronic migraine with ONS. The difference in response rates of chronic migraine and NDPH with migrainous features supports the concept of a different pathophysiology to the two conditions.

The sensitivity to change of the cluster headache quality of life scale assessed before and after deep brain stimulation of the ventral tegmental area.

BACKGROUND: Cluster headache (CH) is a trigeminal autonomic cephalalgia (TAC) characterized by a highly disabling headache that negatively impacts quality of life and causes limitations in daily functioning as well as social functioning and family life. Since specific measures to assess the quality of life (QoL) in TACs are lacking, we recently developed and validated the cluster headache quality of life scale (CH-QoL). The sensitivity of CH-QoL to change after a medical intervention has not been evaluated yet. METHODS: This study aimed to test the sensitivity to change of the CH-QoL in CH. Specifically we aimed to (i) assess the sensitivity of CH-QoL to change before and following deep brain stimulation of the ventral tegmental area (VTA-DBS), (ii) evaluate the relationship of changes on CH-QoL with changes in other generic measures of quality of life, as well as indices of mood and pain. Ten consecutive CH patients completed the CH-QoL and underwent neuropsychological assessment before and after VTA-DBS. The patients were evaluated on headache frequency, severity, and load (HAL) as well as on tests of generic quality of life (Short Form-36 (SF-36)), mood (Beck Depression Inventory, Hospital Anxiety and Depression Rating Scale), and pain (McGill Pain Questionnaire, Headache Impact Test, Pain Behaviour Checklist). RESULTS: The CH-QoL total score was significantly reduced after compared to before VTA-DBS. Changes in the CH-QoL total score correlated significantly and negatively with changes in HAL, the SF-36, and positively and significantly with depression and the evaluative domain on the McGill Pain Questionnaire. CONCLUSIONS: Our findings demonstrate that changes after VTA-DBS in CH-QoL total scores are associated with the reduction of frequency, duration, and severity of headache attacks after surgery. Moreover, post VTA-DBS improvement in CH-QoL scores is associated with an amelioration in quality of life assessed with generic measures, a reduction of depressive symptoms, and evaluative pain experience after VTA-DBS. These results support the sensitivity to change of the CH-QoL and further demonstrate the validity and applicability of CH-QoL as a disease specific measure of quality of life for CH.

Nutcracker syndrome mimicking new daily persistent headache: A case report.

INTRODUCTION: Compression of the duodenum and left renal vein between the aorta and superior mesenteric artery usually leads to symptoms of proximal bowel obstruction or hematuria and, more rarely, nonspecific mild headaches. CASE: A young woman presented with new daily persistent headache refractory to numerous pharmacological treatments, onabotulinumtoxinA, nerve blocks, and occipital nerve stimulation. Following several years of daily severe headache, worsening abdominal pain and intolerance for food intake led to the discovery of aortomesenteric compression. Surgical treatment gave prompt improvement in gastric symptoms but also essentially resolved the headache. CONCLUSION: This is the first description of new daily persistent headache in association with aortomesenteric compression as well as marked improvement of headache following aortomesenteric decompression. In patients with new daily persistent headache and orthostatic symptoms one may consider a differential diagnosis of Nutcracker syndrome, especially in patients with comorbid hypermobility syndromes, hematuria or gastric symptoms.

Balancing immunosuppression and infection: recurrent enterovirus encephalitis in SLE.

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare of SLE, with enterovirus still present in the cerebrospinal fluid (CSF). There are no evidence-based specific treatments for enterovirus encephalitis, but she responded well to intravenous immunoglobulin alongside pulsed methylprednisolone and rituximab. This case highlights the difficulties in managing people with co-existing infective and autoimmune conditions, especially if each affects the CNS. A viral infection and SLE flare can resemble one another clinically, although here the radiological differentiation of CNS lupus versus enterovirus encephalitis helped to guide the diagnosis.

Abdominal migraine and cyclical vomiting syndrome.

Abdominal migraine and cyclical vomiting syndrome (CVS) are characteristic syndromes which have overlapping characteristics with migraine but lack the cardinal symptom of headache. Both abdominal migraine and CVS are characterized by recurrent attacks of nausea, vomiting, and/or abdominal pain lasting hours to a few days, with symptom freedom between attacks. Both abdominal migraine and CVS typically occur in children and adolescents, who often go on to develop more typical migraine headaches when older, but may also present for the first time in adults. Due to their shared characteristics and association with migraine headaches, abdominal migraine and CVS are sometimes called "migraine equivalents," and their pathophysiology is assumed to overlap with migraine headache. This chapter describes what is known about the clinical characteristics, epidemiology, pathophysiology, and prognosis of abdominal migraine and CVS, and explores their relationship to migraine. We also review the existing evidence for the nonpharmacological management, acute treatment of attacks, and preventive treatments for both abdominal migraine and CVS.

Epidemiology of migraine.

Migraine affects over a billion people worldwide and brings with it a huge burden of disability. It is a disease which disproportionally affects the working age population which heightens its economic impact, both at the individual family level and the societal level. Women are significantly more affected by migraine at every age and in all social and geographical groups. At the most severe end of the spectrum, chronic migraine is associated with poorer overall physical and mental health as well as increased risk of unemployment and lower household income. Estimates of the incidence and prevalence of migraine vary with sex, race, ethnicity, geography, socioeconomic, and educational status, suggesting there are many factors at play. In many cases, it is not clear whether these factors are causative of migraine, the effects of migraine, or (as is most likely) a combination of both. Future studies should aim to clarify these links, so that modifiable factors can be addressed where possible and those at risk of developing chronic migraine might receive targeted treatment at an early stage.

Diagnosis and treatment evaluation in patients with spontaneous intracranial hypotension.

Spontaneous intracranial hypotension is characterized by an orthostatic headache and audiovestibular symptoms alongside a myriad of other non-specific symptoms. It is caused by an unregulated loss of cerebrospinal fluid at the spinal level. Indirect features of CSF leaks are seen on brain imaging as signs of intracranial hypotension and/or CSF hypovolaemia as well as a low opening pressure on lumbar puncture. Direct evidence of CSF leaks can frequently, but not invariably, be observed on spinal imaging. The condition is frequently misdiagnosed due to its vague symptoms and a lack of awareness of the condition amongst the non-neurological specialities. There is also a distinct lack of consensus on which of the many investigative and treatment options available to use when managing suspected CSF leaks. The aim of this article is to review the current literature on spontaneous intracranial hypotension and its clinical presentation, preferred investigation modalities, and most efficacious treatment options. By doing so, we hope to provide a framework on how to approach a patient with suspected spontaneous intracranial hypotension and help minimize diagnostic and treatment delays in order to improve clinical outcomes.

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache.

Background: Many patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective. Objective: To assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients. Method: We prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3 months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies. Results: 17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3 months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month. Conclusion: This study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies.

Association of Clinical and Neuroanatomic Factors With Response to Ventral Tegmental Area DBS in Chronic Cluster Headache.

BACKGROUND AND OBJECTIVES: Deep brain stimulation (DBS) of the ventral tegmental area (VTA) is a surgical treatment option for selected patients with refractory chronic cluster headache (CCH). We aimed to identify clinical and structural neuroimaging factors associated with response to VTA DBS in CCH. METHODS: This prospective observational cohort study examines consecutive patients with refractory CCH treated with VTA DBS by a multidisciplinary team in a single tertiary neuroscience center as part of usual care. Headache diaries and validated questionnaires were completed at baseline and regular follow-up intervals. All patients underwent T1-weighted structural MRI before surgery. We compared clinical features using multivariable logistic regression and neuroanatomic differences using voxel-based morphometry (VBM) between responders and nonresponders. RESULTS: Over a 10-year period, 43 patients (mean age 53 years, SD 11.9), including 29 male patients, with a mean duration of CCH 12 years (SD 7.4), were treated and followed up for at least 1 year (mean follow-up duration 5.6 years). Overall, there was a statistically significant improvement in median attack frequency from 140 to 56 per month (Z = -4.95, p < 0.001), attack severity from 10/10 to 8/10 (Z = -4.83, p < 0.001), and duration from 110 to 60 minutes (Z = -3.48, p < 0.001). Twenty-nine (67.4%) patients experienced ≥50% improvement in attack frequency and were therefore classed as responders. There were no serious adverse events. The most common side effects were discomfort or pain around the battery site (7 patients) and transient diplopia and/or oscillopsia (6 patients). There were no differences in demographics, headache characteristics, or comorbidities between responders and nonresponders. VBM identified increased neural density in nonresponders in several brain regions, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and amygdala, which were statistically significant (p < 0.001). DISCUSSION: VTA DBS showed no serious adverse events, and, although there was no placebo control, was effective in approximately two-thirds of patients at long-term follow-up. This study did not reveal any reliable clinical predictors of response. However, nonresponders had increased neural density in brain regions linked to processing of pain and autonomic function, both of which are prominent in the pathophysiology of CCH.