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Objective: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications., Background: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient., Methods: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance., Results: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin., Conclusion: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible., (© 2024 American Headache Society.)

Background: Cerebrospinal fluid-venous fistulas (CSFVF) are a common cause of spontaneous intracranial hypotension (SIH). Transvenous embolization has emerged as a reliable treatment option. We review the clinical presentation, imaging, and clinical outcomes of 100 consecutive CSFVF patients who underwent embolization over 2 years., Methods: Baseline clinical characteristics, imaging findings (including Bern SIH score), technical outcomes, and long-term imaging and clinical outcomes were collected. All patients had at least 3 months of clinical follow-up and had baseline MRI. 99/100 patients underwent follow-up imaging at ≥3 months post-treatment., Results: 100 patients were included. Mean imaging and clinical follow-up duration was 8.3±7.7 months and 15.0±6.8 months, respectively. The mean duration of symptoms before embolization was 40.9±52 months. Mean baseline Bern SIH score was 5.9±3.3. The most common baseline symptoms were headache (96 patients), tinnitus (55 patients), and cognitive dysfunction (44 patients). Technical success rate was 100%. Mean post-treatment Bern SIH score was 0.9±1.6 (P<0.0001). Following treatment, 95% of patients reported significant improvement or resolution in symptoms (58 patients reporting resolution and 37 reporting improvement). 5 patients reported no improvement. There were no major procedural or periprocedural complications. 10 patients had minor procedural complications that did not result in any change in management (Onyx emboli, venous perforation). 19 patients had rebound intracranial hypertension requiring acetazolamide therapy. 7 patients had recurrent fistula at the initially treated level., Conclusions: Transvenous embolization of CSFVF in SIH patients is safe and effective with a 95% treatment response, significant improvement in imaging outcomes, and a very low rate of complications., Competing Interests: Competing interests: WB holds equity in Nested Knowledge, Superior Medical Editors, Piraeus Medical, Sonoris Medical, and MIVI Neurovascular. He receives royalties from Medtronic and Balloon Guide Catheter Technology. He receives consulting fees from Medtronic, Stryker, Imperative Care, Microvention, MIVI Neurovascular, Cerenovus, Asahi, and Balt. He serves in a leadership or fiduciary role for MIVI Neurovascular, Marblehead Medical LLC, Interventional Neuroradiology (Editor in Chief), Piraeus Medical, and WFITN. The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT 1B and 5-HT 1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects., (Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: We report outcomes of spontaneous intracranial hypotension (SIH) patients who underwent transvenous embolization of cerebrospinal fluid-venous fistulas (CSFVFs) confirmed on digital subtraction myelography (DSM) performed at our institution., Methods: This is a retrospective evaluation of a prospectively collected database of SIH patients who underwent transvenous embolization of CSFVFs. Only patients who had fistulas confirmed on DSM performed at our institution were included. All patients had a baseline MRI and an MRI performed at least 90 days post-embolization, as well as clinical evaluation using the six item Headache Impact Test (HIT-6) and the Patient Global Impression of Change (PGIC) scales. Paired t-test was used to report changes in Bern MRI scores and HIT-6 scores at follow-up., Results: 40 patients were included (29 female, 11 male). Mean age was 57.4±10.3 years. Mean Bern score improved from 5.7±3.0 at baseline to 1.3±2.0 at follow-up (p<0.0001). Mean HIT-6 score at baseline was 67.2±11.1 and at follow-up was 41.5±10.1 (p<0.0001). Median PGIC was 1, with 36 patients (90.0%) reporting at least minimal improvement and 32 patients (82.5%) reporting much or very much improvement. Complications included persistent local site pain in 12 patients (30%), suspected rebound intracranial hypertension requiring medical intervention in 7 patients (17.5%), and asymptomatic tiny Onyx emboli to the lungs in 3 patients (7.5%)., Conclusions: Transvenous embolization of CSFVFs using Onyx is safe and effective, resulting in significant improvement in headache and overall clinical outcomes in nearly 90% of patients, and substantial improvements in brain MRI abnormalities., Competing Interests: Competing interests: WB consultant for Medtronic, Microvention, Stryker, Cerenovus, MIVI. No other financial relationships., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Migraine is a common and disabling disorder. Fibromyalgia has been shown to be commonly comorbid in patients with migraine and can intensify disability. The aim of this study was to determine if patients with co-morbid fibromyalgia and migraine report more depressive symptoms, have more headache related disability, or report higher intensity of headache as compared to patients with migraine only. Cases of comorbid fibromyalgia and migraine were identified using a prospectively maintained headache database at Mayo Clinic Rochester. One-hundred and fifty seven cases and 471 controls were identified using this database and the Mayo Clinic electronic medical record., Findings: Depressive symptoms as assessed by PHQ-9, intensity of headache, and migraine related disability as assessed by MIDAS were primary measures used to compare migraine patients with comorbid fibromyalgia versus those without. Patients with comorbid fibromyalgia reported significantly higher PHQ-9 scores (OR 1.08, p < .0001) and headache intensity scores (OR 1.149, p = .007). There was no significant difference in migraine related disability (OR 1.002, p = .075). Patients with fibromyalgia were more likely to score in a higher category of depression severity (OR 1.467, p < .0001) and more likely to score in a higher category of migraine related disability (OR 1.23, p = .004)., Conclusion: Patients with comorbid fibromyalgia and migraine report more depressive symptoms, higher headache intensity, and are more likely to have severe headache related disability as compared to controls without fibromyalgia. Clinicians who care for patients with migraine may consider screening for comorbid fibromyalgia particularly in patients with moderate to severe depressive symptoms, high headache intensity and/or high headache related disability. This is the first matched study to look at these characterisitcs, and it replicates previous findings from unmatched studies.

Background: We determined the prevalence of signs and symptoms of autonomic dysfunction in seizures of temporal lobe onset in children., Methods: We evaluated the prevalence and risk factors of peri-ictal autonomic changes in temporal lobe onset seizures in children from a single-center pediatric epilepsy monitoring unit between June 1, 2009 and October 31, 2013. Age, gender, epilepsy etiology, current antiepileptic drug therapy, ictal electroencephalographic lateralization, brain magnetic resonance imaging results, and the presence of generalized tonic-clonic seizures over the preceding year were recorded from medical record review., Results: Forty-nine children were identified (55% male, median age 10.1 years [interquartile range 5.5 to 13.9 years]). Overall, peri-ictal autonomic changes were observed in 32 of 49 patients (66%) and 91 of 172 evaluated seizures (53%). Tachycardia (51%), oxygen desaturation (33%), and salivation (27%) were the most frequent autonomic changes identified. Bradycardia occurred in one patient (2%)., Conclusions: Among pediatric patients with temporal lobe seizures, peri-ictal autonomic changes are frequent yet seldom require intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pseudorabies virus (PRV) is a neurotropic swine alpha herpesvirus that characteristically invades the nervous system and replicates within synaptically-linked populations of neurons. The invasive characteristics and ability of this family of viruses to replicate in neurons of the central nervous system (CNS) have been exploited to map functionally related populations of neurons in a variety of systems. In this report, we examined the effects of strain and concentration on the ability of PRV to infect retinal ganglion cells and pass transneuronally through central visual circuits. We find that the ability of virulent (PRV-Becker) and attenuated (PRV-Bartha) strains of PRV to produce a productive infection of visual circuitry is directly dependent upon the infectious of the injected virus. Injections of at least 10(5) total plaque forming units produce 100% infectivity, whereas lower infectious doses substantially reduce the percentage of animals exhibiting productive infection via this route of inoculation. Furthermore, the virulent strain of PRV consistently infects a higher percentage of animals across a broader range of titers than attenuated virus. These data demonstrate that viral titer and strain are important variables that should be considered in the design of studies and interpretation of data derived from investigations employing this pathogen for circuit analysis.

We have described three mutant strains of Pseudorabies virus that contain mutations in the signal sequence coding region of a nonessential envelope glycoprotein, gIII. The alterations disrupt, truncate, or eliminate the hydrophobic core domain of the signal sequence. Each mutant was assayed for its ability to promote the translocation of gIII across the endoplasmic reticulum membrane and the subsequent localization of the mature form of the glycoprotein to the infected cell surface or the virus envelope. Our results confirm and extend findings in other systems that the overall hydrophobicity of the signal sequence core region is a major determinant of translocation efficiency. We were unable to correlate simply the length of the core or the average hydrophobicity of core residues with export efficiency. Because our work involved the use of infectious virus mutants, we were able to identify a virus defect associated with a complete block in gIII export. This defect will facilitate a pseudo-reversion analysis of gIII signal sequence function.

Uptake and transneuronal passage of wild-type and attenuated strains of a swine alpha-herpesvirus (pseudorabies [PRV]) were examined in rat visual projections. Both strains of virus infected subpopulations of retinal ganglion cells and passed transneuronally to infect retino-recipient neurons in the forebrain. However, the location of infected forebrain neurons varied with the strain of virus. Intravitreal injection of wild-type virus produced two temporally separated waves of infection that eventually reached all known retino-recipient regions of the central neuraxis. By contrast, the attenuated strain of PRV selectively infected a functionally distinct subset of retinal ganglion cells with restricted central projections. The data indicate that projection-specific groups of ganglion cells are differentially susceptible to the two strains of virus and suggest that this sensitivity may be receptor mediated.

Uptake, replication, and transneuronal passage of a swine neurotropic herpesvirus (pseudorabies virus, PRV) was evaluated in the rat CNS. PRV was localized in neural circuits innervating the tongue, stomach, esophagus and eye with light microscopic immunohistochemistry. In each instance, the distribution of PRV-immunoreactive neurons was entirely consistent with that observed following injection of cholera toxin-horseradish peroxidase conjugate (CT-HRP). Injections of the tongue resulted in retrograde transport of PRV and CT-HRP to hypoglossal motor neurons, while preganglionic neurons in the dorsal motor vagal nucleus or somatic motor neurons in the nucleus ambiguus were labeled following injections of the stomach or esophagus, respectively. At longer times after infection, viral antigens were found in astrocytes adjacent to infected neurons and their efferent axons and second-order neuron labeling became apparent. The distribution of second-order neurons was also entirely dependent upon the site of PRV injection. Following tongue injection, second-order neurons were observed in the trigeminal complex, the brain-stem tegmentum and in monoaminergic cell groups. Injection of the stomach or esophagus led to second-order neuron labeling confined to distinct subdivisions of the neucleus of the solitary tract and monoaminergic cell groups. Comparative quantitative analysis of the number of PRV immunoreactive neurons present in the diencephalon and brain stem following injection of virus into both the eye and stomach musculature of the same animal demonstrated that retrograde transport of PRV from the viscera was more efficient and occurred at a much faster rate than anterograde transport of virus. These data demonstrate projection-specific transport of PRV in the nervous system and provide further insight into the means through which this neurotropic virus infects the nervous system.

An infectious herpesvirus mutant has been constructed in which a major structural envelope glycoprotein gene was replaced by a hybrid gene encoding a novel fusion protein consisting of the N-terminus of the viral glycoprotein joined to Escherichia coli beta-galactosidase (beta Gal). Specifically, we fused DNA encoding the first 157 amino acids of the structural glycoprotein gIII from pseudorabies virus strain Becker to the E. coli lacZ gene in a bacterial expression vector. The resulting hybrid gene was then used to replace the wild-type gIII gene in the virus by cotransfection of plasmid and viral DNA. The desired viral recombinants were identified by their inability to react with specific monoclonal antibodies that recognized only wild-type gIII protein. One such mutant virus, PRV-Z1, was chosen for further analysis. PRV-Z1 expressed a glycosylated gIII-beta Gal fusion protein after infection of PK15 cells. The fusion protein has no demonstrable beta Gal activity and, although glycosylated, remains sensitive to the enzyme endo-beta-N-acetylglucosaminidase H, unlike the mature gIII gene product, indicating that the fusion protein was incompletely processed.