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

The Emerging Clinical Relevance of Artificial Intelligence, Data Science, and Wearable Devices in Headache: A Narrative Review

This narrative review introduces key concepts in artificial intelligence (AI), data science, and wearable devices aimed at headache clinicians and researchers. PubMed and IEEEXplore were searched to identify relevant studies, and these were reviewed systematically. We identified six primary research topics. First, the most common application of AI and data science is in the diagnosis of headache disorders, with reported accuracies of up to 90%. Second, AI and data science are used for predicting headache disease trajectories and forecasting attacks. Third, prediction of treatment effects and data-driven individualization of treatment prescription demonstrate promising results, with accuracies ranging from 40% to 83%. Fourth, AI and data science can uncover hidden information within headache datasets, offering clinicians deeper insights. Fifth, wearables, combined with AI and data science, can improve remote monitoring and migraine management. Lastly, user experience studies indicate strong interest from both clinicians and patients in adopting these technologies. The potential applications of AI, data science, and wearable device technologies in headache research are vast. However, many studies are small pilot studies, and models often suffer from poor performance, limited reporting, and lack of external validation, which impede generalizability and clinical implementation.The Emerging Clinical Relevance of Artificial Intelligence, Data Science, and Wearable Devices in Headache: A Narrative ReviewpublishedVersio

Machine prescription for chronic migraine

Responsive to treatment individually, chronic migraine remains strikingly resistant collectively, incurring the second-highest population burden of disability worldwide. A heterogeneity of responsiveness, requiring prolonged—currently heuristic—individual evaluation of available treatments, may reflect a diversity of causal mechanisms, or the failure to identify the most important, single causal factor. Distinguishing between these possibilities, now possible through the application of complex modelling to large-scale data, is critical to determining the optimal approach to identifying new interventions in migraine and making the best use of existing ones. Examining a richly phenotyped cohort of 1446 consecutive unselected patients with chronic migraine, here we use causal multitask Gaussian process models to estimate individual treatment effects across ten classes of preventatives. Such modelling enables us to quantify the accessibility of heterogeneous responsiveness to high-dimensional modelling, to infer the likely scale of the underlying causal diversity. We calculate the treatment effects in the overall population, and the conditional treatment effects among those modelled to respond and compare the true response rates between these two groups. Identifying a difference in response rates between the groups supports a diversity of causal mechanisms. Moreover, we propose a data-driven machine prescription policy, estimating the time-to-response when sequentially trialling preventatives by individualized treatment effects and compare it to expert guideline sequences. All model performances are quantified out-of-sample. We identify significantly higher true response rates among individuals modelled to respond, compared to the overall population (mean difference of 0.034; 95% confidence interval 0.003 to 0.065; p = 0.033), supporting significant heterogeneity of responsiveness and diverse causal mechanisms. The machine prescription policy yields an estimated 35% reduction in time-to-response (3.750 months; 95% confidence interval 3.507 to 3.993; p < 0.0001) compared with expert guidelines, with no substantive increase in expense per patient. We conclude that the highly distributed mode of causation in chronic migraine necessitates high-dimensional modelling for optimal management. Machine prescription should be considered an essential clinical decision-support tool in the future management of chronic migraine

R1352Q CACNA1A variant in a patient with sporadic hemiplegic migrainem ataxia, seizures and cerebral oedema: A case report

Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.publishedVersio

The clinical characteristics of familial cluster headache

BACKGROUND: A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup. OBJECTIVES: To assess the rate and mode of inheritance of familial cluster headache in a tertiary referral centre for headache. To describe the clinical features of familial cluster headache. METHODS: A retrospective study conducted between 2007 and 2017. Cluster headache was confirmed in probands and affected relatives. Differences in demographics, clinical characteristics, and response-to-treatment in familial cluster headache were delineated through multivariate analysis using a control cohort of 597 patients with sporadic cluster headache. RESULTS: Familial cluster headache was confirmed in 48 (7.44%) patients and predominantly reflected an autosomal dominant mode of inheritance with reduced penetrance. Familial cases were more likely to report nasal blockage (OR 4.06, 95% CI; 2.600-6.494, p < 0.001) during an attack and a higher rate of concurrent short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (OR 3.76, 95% CI; 1.572-9.953, p = 0.004). CONCLUSION: These findings add to evidence suggesting a genetic component to cluster headache. Here, we demonstrated prominent nasal blockage, and a higher occurrence of concomitant short-lasting unilateral neuralgiform headache with conjunctival injection and tearing in this subgroup, further delineating the phenotype

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

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

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-1β (IL-1β) (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)-β (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-1β 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

Patient experience of diagnosis and management of spontaneous intracranial hypotension: a cross-sectional online survey

OBJECTIVES: To present the results of a survey of patients with spontaneous intracranial hypotension (SIH) secondary to spinal cerebrospinal fluid (CSF) leak, documenting the patient experience of its diagnosis and management as well as quantifying its impact on quality of life. DESIGN: A cross-sectional anonymous online survey was designed in conjunction with the CSF Leak Association patient charity. The survey included questions on diagnosis, investigations and treatments received, as well as validated disability and quality of life questionnaires. PARTICIPANTS: Sixty-four patients with a confirmed diagnosis of SIH who were receiving treatment within the UK were included in the analysis. The mean age was 42.8 years, 94% were female and 43 had ongoing symptoms of SIH. RESULTS: Patients who presented to their general practitioner with symptoms of SIH were seen an average three times before being referred to a specialist, and in just under half of patients, the diagnosis was not made by the first specialist they saw. There was variability in which investigations were performed and how urgently they were organised. The mean EuroQol (EQ-5D-5L) Visual Analogue Scale score was 36.4/100 and median Headache Impact Test-6 score was 68/78 (very severe impact). More than half of the respondents reported that they had to amend work duties due to SIH, more than a quarter reported that they had lost their job and two-thirds reported that their condition had affected their financial health. Only 23.4% of patients felt that they had received enough help and advice to manage their pain due to SIH. CONCLUSIONS: SIH is a highly disabling disorder, affecting multiple domains, including pain, mobility, activities of daily living, financial circumstances and employment. Diagnostic delay and misdiagnosis are common, and currently there is a lack of consistency in the investigation and management of SIH in the UK