Evaluation of Brain Magnetic Resonance Indices in Migraine and Cluster Headache Patients

This study was undertaken to identify magnetic resonance imaging (MRI) biomarkers that differentiate migraine from cluster headache patients and imaging features that are shared. Clinical, functional, and structural MRI data were obtained from 20 migraineurs, 20 cluster headache patients, and 15 healthy controls. Support vector machine algorithms and a stepwise removal process were used to discriminate headache patients from controls, and subgroups of patients. Regional between-group differences and association between imaging features and patients' clinical characteristics were also investigated. The accuracy for classifying headache patients from controls was 80%. The classification accuracy for discrimination between migraine and controls was 89%, and for cluster headache and controls it was 98%. For distinguishing cluster headache from migraine patients, the MRI classifier yielded an accuracy of 78%, whereas MRI-clinical combined classification model achieved an accuracy of 99%. Bilateral hypothalamic and periaqueductal gray (PAG) functional networks were the most important MRI features in classifying migraine and cluster headache patients from controls. The left thalamic network was the most discriminative MRI feature in classifying migraine from cluster headache patients. Compared to migraine, cluster headache patients showed decreased functional interaction between the left thalamus and cortical areas mediating interoception and sensory integration. The presence of restlessness was the most important clinical feature in discriminating the two groups of patients. Functional biomarkers, including the hypothalamic and PAG networks, are shared by migraine and cluster headache patients. The thalamocortical pathway may be the neural substrate that differentiates migraine from cluster headache attacks with their distinct clinical features. ANN NEUROL 2023;93:729-742.

Since the pioneering reports of the so-called leonine face in cluster headache (CH) patients, cranial and facial features of these patients have been poorly investigated with conflicting results. We aimed to investigate whether abnormalities in craniometric measurements could characterize male CH patients and represent reliable and reproducible diagnostic biomarkers able to identify CH patients. Brain CT images were recorded between 2018 and 2020 in 24 male patients with CH and in 24 matched healthy controls (HC). Then, craniometric measurements were obtained, and logistic regression and receiver operating characteristic curves analyses were used to identify the craniometric abnormalities able to distinguish CH patients from HC. Logistic regression analyses showed that frontal bone height and facial width were able to discriminate, one independently from the other, CH patients from HC with an overall accuracy of 77%. The optimal cutoff score in detecting the probable presence of CH was 11.50 cm for frontal bone height and 13.30 cm for facial width. In the present study we found, for the first time by means of brain 3D computed tomography approach, abnormal craniometric measurements in CH patients when compared with HC. The absence of differences in smoke and alcohol intake suggests that the observed craniometric abnormalities may represent a specific feature of CH patients. The craniometric evaluation by means of brain 3D computed tomography could represent a widespread, noninvasive, and accurate tool to support CH diagnosis to avoid frequent misdiagnosis or delay in the diagnostic process.

The aim of this systematic review and meta-analysis (SR-MA) was to identify signaling molecule profiles and blood-derived biomarkers in migraine and cluster headache (CH) patients. Currently no migraine and CH valid biomarkers are available. Blood tests based on biomarker profiles have been used to gather information about the nervous system. Such tests have not yet been established within the primary headache field. Case-control and case-crossover studies investigating whole blood, plasma, and serum were identified worldwide. The qualitative synthesis focused on 9 signaling molecules (serotonin [5-HT], calcitonin gene-related peptide [CGRP], endothelin-1 [ET-1], neurokinin A, neurokinin B, neuropeptide Y, pituitary adenylate cyclase-activating peptide 38 [PACAP-38], substance P (SP), and vasoactive intestinal peptide) and the quantitative synthesis on 5-HT and CGRP (≥5 comparisons available). The meta-analysis was conducted using standard and 3-level random effect models. Fifty-four eligible studies were identified (87.0% migraine, 9.3% CH, 3.7% migraine, and CH), and 2768 headache patients and 1165 controls included. Comparable fluctuations of 5-HT, CGRP, ET-1, PACAP-38, and SP in blood were generally observed between migraine and CH. Significant findings were observed for some subgroups and strata, for example, higher interictal and ictal 5-HT venous blood levels (ratio of means = 1.32, 95% CI: 1.08; 1.61; ratio of means = 1.23, 95% CI: 1.01; 1.49) in episodic migraine with aura with a female-dominated case group, higher interictal CGRP blood levels in episodic migraine (ratio of means = 1.63, 95% CI: 1.18; 2.26), and chronic migraine (ratio of means = 1.89, 95% CI: 1.33; 2.68), and higher ictal CGRP blood levels (ratio of means = 1.35, 95% CI: 1.09; 1.68) in episodic migraine were observed. In most subgroups, the quantitative synthesis revealed a high degree of heterogeneity between studies in part explained by the blood sampling site, specimen source, blood specimen, and sex distribution. Other potential confounders were age, aura, study quality, menstrual cycle, and methodology (eg, storage temperature). Potential migraine and CH signaling molecule profiles and biomarkers were revealed. Nevertheless, the high degree of heterogeneity between studies impedes identification of valid biomarkers but allowed us to assess the presence of confounders. Consideration of the potential confounders identified in this SR-MA might be of importance in the experimental planning of future studies. This consideration could be incorporated through establishment of specific guidelines.

Background: Radiological markers that are useful in the diagnosis of normal pressure hydrocephalus include the Bicaudate index (BCI) and the Evans index (EI), which are practical indicators of ventricular volume. Worldwide, variation exists in normative studies for both these indices. The majority of research for EI and BCI is based on data from the Western population. The study has been performed on the South Karnataka population. Aims and Objectives: This study’s goal is to derive age and gender specific cutoff values on normative data of Evans and BCI. Materials and Methods: This was a prospective and observational study.Patients referred to “RL Jalappa Hospital” for computed tomography (CT) scan of the brain who meet the inclusion criteria will be included in this study. CT brain of all the patients will be performed in Siemens Somatom emotion 16 slice CT scanner. Ninety-seven were selected for this study, and EI and BCI were calculated for them. Results: The mean value of EI and BCI in our study was 0.26±0.02 and 0.1167±0.02, respectively. The difference in EI and BCI between males and females shown significant statistical difference between males and females but the values increased as increase in age. Conclusion: Our study for South Indian population concludes that EI and BCI have a significant statistical difference between males and females. Both EI and BCI values increase with age. Hence cutoff values of EI and BCI index according to age and gender are important for evaluation of hydrocephalus.

The value of the Evans and bicaudate indices for predicting poor cognitive performance and central atrophy. Results from the Atahualpa Project

Objective: Indexes obtained from two-dimensional and three-dimensional measurements are used to evaluate the brain's lateral ventricle (LV) structure. However, there were limited studies on how well the Evans index (EI) and the Bicaudate index (BI), which estimate LV volume, represent the LV volumetric index (LVVI) in the childhood and adolescence period. This study investigated the relationship between LVVI and linear indexes (EI and BI) in the pediatric period regarding age and sex factors. Method: This study was performed retrospectively in 588 individuals (267 [45.4%] females) aged 1-18 years with normal brain magnetic resonance images (MRI) between 2012 and 2021. LVVI was obtained by segmenting three-dimensional T1-weighted MRIs with volBrain1.0. LVVI was obtained by dividing the LV absolute volume by the total intracranial volume. We made linear measurements for EI and BI with the 3D Slicer. In this study, we compared the data obtained from individuals in 16 different age ranges between 1-18 years old with SPSS (ver.28). Results: In our study, we found the mean value of LVVI to be 0.656±0.372%. The mean values of EI and BI were 0.242±0.025 and 0.070±0.022, respectively. In the pediatric population, we found that mean values of EI and BI were significantly higher in males than in females (p

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes.Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer’s Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness.Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008).Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions.

The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs--Gs alpha, Gi alpha, and Gq alpha, were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Gi alpha mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gs alpha of Gq alpha mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gs alpha mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Gi alpha mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Gi alpha mRNA make individuals more susceptible to migraine.

Alcohol and Cluster Headaches

Background/Objectives: Personality traits in patients with cluster headache (CH) remain understudied compared to migraine patients. This could help improve diagnosis, identify comorbidities, and provide more personalized management of CH. This study aimed to characterize the personality profiles of patients with CH and compare them with those of patients with migraine. Methods: This cross-sectional, case–control observational study was conducted at a tertiary hospital’s headache unit (May–August 2024). Patients with CH were compared with migraine patients and healthy controls. Demographic and clinical data were collected, and the Minnesota Multiphasic Personality Inventory-3 (MMPI-3) was administered. Results: The study included 28 CH patients (17 with episodic and 11 with chronic CH), 55 migraine patients (34 with episodic migraine and 21 with chronic migraine), and 54 healthy controls. Both patient groups reported significantly more somatic and cognitive complaints than controls (p < 0.05). Compared to controls, the migraine group exhibited greater emotional dysfunction, social avoidance, demoralization, introversion, and social anxiety (p < 0.05), while the CH group showed greater impulsivity (p < 0.05). Directly comparing patient groups, migraine patients displayed greater social avoidance, emotional dysfunction, demoralization, and introversion than the CH group (p < 0.05). CH patients also showed a non-significant trend towards behavioral disinhibition, hypomania, a favorable self-image, juvenile conduct problems, substance abuse, and aggressiveness. Patients with CH did not present a higher risk of suicide compared to migraine patients. Conclusions: This study identified distinct personality profiles: Migraine patients exhibited greater emotional and interpersonal dysfunction (internal distress and withdrawal), while CH patients exhibited greater externalizing behavioral dysfunction, predominantly involving impulsivity.

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants Vmax and Km determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were found in cluster headache and migraine patients than in 50 healthy controls (19 males). The Vmax and Km values of the 5-HT uptake were significantly lower in cluster headache and migraine patients compared with 22 healthy controls (9 males). The 5-HT concentrations and the kinetics of the 5-HT uptake did not differ between cluster headache and migraine. In healthy controls a significant positive correlation was found between the 5-HT uptake rate at 0.25 microM and Km but not in cluster headache and migraine patients. The 5-HT concentrations in whole blood correlated positively with Vmax and Km, respectively, in cluster headache and with Km in healthy controls but not with Vmax nor with Km in migraine. There was no obvious relation between the kinetics of platelet monoamine oxidase (MAO) and the 5-HT uptake except for an increased incidence of low Vmax of MAO and low Km of the 5-HT uptake in cluster headache. The kinetics of the 5-HT uptake was apparently not related to the state of migraine. The results indicate a possible constitutional trait in cluster headache and migraine expressed as low 5-HT concentrations in whole blood and low Vmax and Km of the 5-HT uptake into platelets.

The intracranial fluid spaces (IFS), also known as "the extra-axial spaces," consist of the superficial cerebral sulci, the Sylvian fissures, the basal cisterns, the third ventricle, the fourth ventricle, and the two lateral ventricles. In diseases such as schizophrenia, Alzheimer's, Parkinson's, and especially hydrocephalus, IFS' enlargements are observed. Our study aimed to determine the mean values of IFS measurements in patients with schizophrenia and compare them with healthy controls. This work has been carried out on 188 cases, out of which 88 schizophrenia patients (56 men and 32 women) met the diagnostic criteria according to DSM-5 for schizophrenia and 100 healthy controls (50 men and 50 women). The 10 parameters have been used to evaluate IFS on magnetic resonance imaging (MRI) scans. The parameters showing statistically significant differences were higher in favor of the individual with schizophrenia. Except for the bifrontal index and Evan's index, most parameters (the bicaudate index, the fourth ventricle width, the fourth ventricle index, the maximum width of the anterior interhemispheric fissure, the maximum width of the right frontal subarachnoid space, the maximum width of the left frontal subarachnoid space, the maximum width of the right Sylvian fissure, and the maximum width of the left Sylvian fissure) were obtained statistically highly significant differences between the examined and control groups. In schizophrenia, it is more practical to evaluate brain atrophy using some parameters, especially the width of the Sylvian fissure and the bicaudate index.

Introduction:Evans index (EI) and Bicaudate index (BCI) are practical markers of ventricular volume and are helpful radiological markers in the diagnosis of normal pressure hydrocephalus. Worldwide, variation exists in normative studies for both these indices. Most of the studies conducted for EI and BCI are based on the Western population data. No study has been performed on the rural population of Central India. The purpose of this study is to develop normative data on EI and BCI that can be extrapolated for future reference.Materials and Methods:This was a retrospective study conducted from December 2018 to May 2019 in MGIMS Hospital, Sevagram, Maharashtra, India, which is a rural hospital in Central India. All patients with either a head injury or neurological complaints although with normal computed tomography (CT) brain were included in the study. Patients with diagnosed neurological disorder, clinical features suggesting hydrocephalus, or intracranial pathology on CT brain were excluded from the study. Five hundred and eleven patients were selected for this study, and EI and BCI was calculated for them.Results:The mean value of EI and BCI in our study was 0.2707 and 0.1121, respectively. Both indices showed a statistically significant difference between males and females. The value of both indices increased with age.Conclusion:Although our study is in agreement with the cutoff value of EI to diagnose dilated lateral ventricles as 0.3 for age <70 years, cutoff value of EI for the older population should be reconsidered to 0.34.

We evaluated the possibility that cluster headache may be a transmitted disorder, influenced by migraine genetics. In the first part of a two part study, 24 female cluster headache probands having at least one first degree relative with cluster headache were evaluated for familial histories of cluster and migraine headache. Headache histories of most parents, siblings and children were satisfactorily documented by either direct interview or by information provided by knowledgeable relatives. In approximately a third of relatives, the headache history could not be properly ascertained. The second part of the study evaluated occurrence rates of cluster and migraine headaches among first degree relatives of 200 female and 100 male cluster headache patients, and the proportion of affected relatives. These data were compared to those of 200 women and 100 men with migraine headache; family history data were, for the most part, provided by headache patients. Twenty-four of two hundred cluster headache women (12%) had at least one first degree relative with cluster headache. Three generations of cluster headache were found in 7/24 kindreds (29.17%). Parental cluster headache was found in 19 of the 24 probands (79.17%); in 14/19 (73.68%), transmission was from father to proband. fifty percent of cluster probands also had migraine headaches, and almost 50% had a family history of migraine. Similarly, of the larger population of 300 cluster patients, approximately 45% had a positive family history of migraine. f 1652 relatives of all cluster patients, 3.45% had cluster headache (thirteen times the expected frequency of cluster headache in the general population) and 17.55% had migraine headaches.(ABSTRACT TRUNCATED AT 250 WORDS)

In contrast to migraine and tension-type headache, the psychiatric comorbidities of cluster headache (CH) have not been well-studied. We assessed the presence of depression and anxiety in groups of episodic CH (ECH) and chronic CH (CCH) patients and compared CH patients with and without depression and anxiety. Sociodemographics, comorbidities, and selected headache features were ascertained from a clinic-based sample in a cross-sectional fashion from January 2007 to July 2010. Active depression and anxiety were assessed using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder 7-item (GAD-7) scales. Of 49 CH patients, ECH patients (n=32) had an earlier age of onset and consumed less caffeine than CCH patients (n=17). Rates of depression as defined by a PHQ-9 score ≥10 were low in both ECH (6.3%) and in CCH (11.8%) with similar mean PHQ-9 scores (3.1 vs 3.7, P=.69). Rates of anxiety as defined by a GAD-7 score ≥10 were also low in both ECH (15.6%) and CCH (11.8%) with similar mean GAD-7 scores (3.8 vs 3.4, P=.76). ECH patients in and out of active attack periods had similar levels of depression and anxiety. Depression and anxiety usually occurred together in ECH and CCH patients. CH patients who were depressed or anxious were more likely to present at a younger age and have attack-related nausea and prodromal symptoms. Depressed CH patients were also more likely to have another pain disorder and had undertaken twice as many prophylactic medication trials. In this clinic-based cross-sectional study, ECH and CCH patients had similarly low rates of depression and anxiety. Rates were lower than those reported for both episodic and chronic migraine.