Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Refractory occipital neuralgia treatment with nerve decompression surgery: a case series.

Background: The management of refractory occipital neuralgia (ON) can be challenging. Selection criteria for occipital nerve decompression surgery are not well defined in terms of clinical features and best preoperative medical management. Methods: In total, 15 patients diagnosed with ON by a board-certified, fellowship-trained headache specialist and referred to a plastic surgeon for nerve decompression surgery were prospectively enrolled. All subjects received trials of occipital nerve blocks (NB), at least three preventive medications, and onabotulinum toxin (BTX) prior to surgery before referral to a plastic surgeon. Treatment outcomes included headache frequency (headache days/month), intensity (0-10), duration (h), and response to medication/injectable therapies at 12 months postoperatively. Results: Preoperatively, median headache days/month was 30 (20-30), intensity 8 (8-10), and duration 24 h (12-24). Patients trialed 10 (±5.8) NB and 11.7 (±9) BTX cycles. Postoperatively, headache frequency was 5 (0-16) days/month (p < 0.01), intensity was 4 (0-6) (p < 0.01), and duration was 10 (0-24) h (p < 0.01). Median patient-reported percent resolution of ON headaches was 80% (70-85%). All patients reported improvement of comorbid headache disorders, most commonly migraine, and a reduction, discontinuation, or increased effectiveness of medications, NB and BTX. Conclusion: All patients who underwent treatment for refractory ON by a headache specialist and plastic surgeon benefited from nerve decompression surgery in various degrees. The collaborative selection criteria employed in this study may be replicable in clinical practice.

Treatment Delay From Onset of Occipital Neuralgia Symptoms to Treatment with Nerve Decompression Surgery: A Prospective Cohort Study.

BACKGROUND: The aim of this study was to a) evaluate the time between onset of occipital neuralgia symptoms and nerve decompression surgery, b) perform a cost comparison analysis between surgical and non-surgical treatment of occipital neuralgia and c) report postoperative results of nerve decompression for occipital neuralgia. METHODS: 1,112 subjects who underwent screening for nerve decompression surgery were evaluated for occipital neuralgia. 367 (33%) patients met the inclusion criteria. Timing of occipital neuralgia symptom onset and pain characteristics were prospectively collected. Cost associated with the non-surgical treatment of occipital neuralgia was calculated for the period between onset of symptoms and surgery. RESULTS: 226 (73%) patients underwent occipital nerve decompression. The average time between onset of occipital neuralgia and surgery was 19 years (7.1-32). Postoperatively, the median number of pain days per month decreased by 17 (0-26, 57%) (p < 0.001), the median pain intensity decreased by 4 (2-8, 44%) (p < 0.001), and median pain duration in hours was reduced by 12 (2-23, 50%) (p < 0.001). The annual mean cost of non-surgical occipital neuralgia treatment was $28,728.82 ($16,419.42-$41,198.41) per patient. The mean cost during the 19-year timeframe prior to surgery was $545,847.75($311,968.90-$782,769.82). CONCLUSION: This study demonstrates that patients suffer from occipital neuralgia for an average of 19 years prior to undergoing surgery. Nerve decompression reduces symptom severity significantly and should be considered earlier in the treatment course of occipital neuralgia that is refractory to conservative treatment to prevent patient morbidity and decrease direct and indirect healthcare costs. IRB REGISTRATION NUMBER & NAME: Weill Cornell Medicine: 23-04025985, Prospective Cohort Study Investigating Long- Term Outcomes After Headache Surgery.The Massachusetts General Hospital: 2012P001527, Correlation of pre-operative pain self-efficacy and post-operative migraine-specific symptoms and disability.

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine-Clinical Considerations: A Narrative Review.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

The Diagnosis and Management of Posttraumatic Headache with Associated Painful Cranial Neuralgias: a Review and Case Series.

BACKGROUND: Cranial neuralgias are common in the setting of posttraumatic headache. They may exacerbate underlying primary headache disorders and therefore may be overlooked in clinical practice. Frequently, cranial neuralgias generate neuropathic symptoms such as lancinating pain and sensory dysesthesias. Cranial neuralgias are identified based on a clinical history of focal neuropathic pain and physical exam findings including tenderness with palpation and percussion, at times eliciting radiating pain or paresthesias in the corresponding sensory nerve distribution. PURPOSE OF REVIEW: This article is a brief review of the literature and a retrospective report of 2 cases of posttraumatic headache with associated painful cranial neuralgias. RECENT FINDINGS: Two patients presented with headaches that met criteria for posttraumatic headache, but their history and physical examination suggested the presence of a focal painful cranial neuralgia. One patient was diagnosed with auriculotemporal neuralgia, which was exquisitely responsive to an auriculotemporal nerve block. The second patient was diagnosed with supratrochlear neuralgia, which was effectively treated with a supratrochlear nerve block. In both cases, adequate treatment of the painful cranial neuralgia resulted in significant improvement of the baseline PTH. Painful cranial neuralgias frequently occur within the clinical spectrum of posttraumatic headache, but are often undiagnosed. Treatment options for painful cranial neuralgias are often different than those traditionally employed for posttraumatic headache without cranial neuralgias, which can include peripheral nerve blockade, neuropathic medications, and in refractory cases, peripheral nerve decompression surgery.

Transient Horner syndrome associated with COVID-19: A case report.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has spread as a global pandemic with significant morbidity and mortality. As the prevalence of COVID-19 has risen, so has the diversity of its clinical presentation. SARS-CoV-2 is considered to have neuroinvasive and neurotropic qualities that can lead to central and peripheral nervous system manifestations. We describe a 65-year-old woman who developed new-onset unilateral ptosis and mitosis following a diagnosis of COVID-19. To our knowledge, this is the first reported case describing transient Horner syndrome in association with COVID-19.

Prevalence of Occipital Neuralgia at a Community Hospital-based Headache Clinic.

BACKGROUND: Occipital neuralgia (ON) is a paroxysmal disorder involving lancinating pain that originates in the neck or skull base with superior radiation toward the apex. ON more commonly occurs in patients with other coexisting headache disorders. There are limited data regarding the prevalence of ON. This study aims to demonstrate the prevalence of ON in a community hospital-based headache clinic. METHODS: This IRB-approved retrospective study was conducted at the Cambridge Health Alliance Headache Clinic. Medical records of patients presenting with headache as a chief complaint were reviewed from January 2010 to September 2015. RESULTS: Of 800 study patients, 81% were females (n = 648). A total of 195 patients were diagnosed with ON, and 146 patients had a positive occipital Tinel sign on examination. Isolated ON was present in 15.38% (n = 30) of patients. Multiple regression analysis demonstrated that the odds of ON were higher in patients with chronic migraine vs episodic migraine (adjusted odds ratio = 2.190 [95% confidence interval: 1.364-3.515]), even when adjusted for significant covariates. CONCLUSION: ON occurred in nearly 25% of patients presenting with a chief complaint of headache to a community hospital-based headache clinic. Among patients with ON, 15% presented with ON as the chief complaint without another coexisting headache disorder. As such, up to 85% of ON cases occurred in patients having an additional headache type. Approximately 75% of patients with ON had a positive occipital Tinel sign on examination. Elevated body mass index, higher age at presentation, and chronic migraine increased the odds of having ON. Undiagnosed or inadequate treatment of ON can increase the frequency and intensity of other comorbid headache disorders.

Erenumab-Induced Severe Nausea Leading to Smoking Cessation: A Retrospective Case Series.

OBJECTIVE: Erenumab is a novel treatment modality with a relatively benign and safe side effect profile, currently approved for the prevention of migraine headache. We present 3 cases with chronic migraine who are cigarette smokers were prescribed erenumab, and developed an intense smoking-induced nausea which eventually led to smoking cessation. METHODS: A multicenter retrospective review of 3 cases with cigarette smoking, one of whom was also smoking marijuana, suffering from chronic migraine resistant to multiple preventive therapies was studied. All were prescribed monthly injections of erenumab 70 mg. Response in terms of headache frequency and intensity and smoking habits was obtained through medical record review. RESULTS: Out of 3 patients, 2 reported reduced headache frequency and intensity. All patients developed severe nausea while smoking cigarettes after their first dose of erenumab, leading to smoking cessation. One patient co-smoked marijuana, which did not result in nausea after being treated. CONCLUSION: To the best of our knowledge, this is the first report of severe nausea secondary to erenumab administration and smoking cigarettes, which finally resulted in complete cigarette smoking cessation. As such, further study is indicated on the benefit of erenumab and other calcitonin gene-related peptide antagonists in migraineurs who smoke to promote smoking cessation.

Non-invasive vagus nerve stimulation for primary headache: A clinical update.

BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified. METHODS: We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS. RESULTS: Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed. CONCLUSION: Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.

Novel non-pharmacological insomnia treatment - a pilot study.

OBJECTIVE: The objective of this prospective pilot study was to examine the effects of a novel non-pharmacological device (BioBoosti) on insomnia symptoms in adults. METHODS: Subjects with chronic insomnia were instructed to hold the device in each hand for 8 mins for 6 cycles on a nightly basis for 2 weeks. Outcomes tested included standardized subjective sleep measures assessing sleep quality, insomnia symptoms, and daytime sleepiness. Sleep was objectively quantified using electroencephalogram (EEG) before and after 2 weeks of treatment with BioBoosti, and wrist actigraphy throughout the study. RESULTS: Twenty adults (mean age: 45.6±17.1 y/o; range 18-74 y/o) were enrolled in the study. No significant side effects were noted by any of the subjects. After 2 weeks of BioBoosti use, subjects reported improved sleep quality (Pittsburgh Sleep Quality Index: 12.6±3.3 versus 8.5±3.7, p=0.001) and reduced insomnia symptoms (Insomnia Severity Index: 18.2±5.2 versus 12.8±7.0, p<0.001). Sleepiness, as assessed by a visual analog scale, was significantly reduced after treatment (5.7±2.8 versus 4.0±3.3, p=0.03). CONCLUSION: BioBoosti use yielded an improvement in insomnia symptoms. Larger placebo-controlled studies are needed to fully assess efficacy.

Headache Attributed to Autonomic Dysreflexia: Clinical Presentation, Pathophysiology, and Treatment.

A patient presenting with marked elevation in blood pressure and concurrent headache often presents a diagnostic challenge for even the most seasoned clinician. When marked hypertension and headache occur in a patient with a history of upper spinal cord injury, the patient should be presumed to have autonomic dysreflexia until proven otherwise. Autonomic dysreflexia can at times trigger headaches, hypertension, and variations in pulse, as well other autonomic signs and symptoms. Autonomic dysreflexia is a medical emergency for which appropriate treatment may be life-saving. In this review, we address the historical origins, risk factors, pathophysiology, diagnostic criteria, clinical presentation, differential diagnosis, and treatment of headache attributed to autonomic dysreflexia. Included are two case presentations from the authors' clinic, which illustrate the diagnosis and treatment of headache attributed to autonomic dysreflexia.

Getting to the Heart of the Matter: Migraine, Triptans, DHE, Ditans, CGRP Antibodies, First/Second-Generation Gepants, and Cardiovascular Risk.

PREMISE: The science of migraine pathophysiology has advanced significantly since the 1930's. Imaging techniques, neurochemical analysis, clinical trials, and the clinical experience of providers treating migraine patients have not only sharpened our understanding of the disease, but have also led to the development of novel neural-based targets. Targeted therapies such as calcitonin gene-related peptide (CGRP) antibodies and "Second Generation" CGRP receptor antagonists (Gepants) have not only demonstrated efficacy, but have not resulted in any significant cardiovascular nor other serious adverse events. "First Generation" Gepants were associated with liver toxicity. PROBLEM: Triptans and dihydroergotamine (DHE) are contraindicated in patients with hemiplegic and basilar migraine based on theories of migraine pathophysiology from the 1930s. While our understanding of migraine has evolved substantially, perceived concerns of safety from almost a century ago continue to preclude their use in certain patient populations. POTENTIAL SOLUTION: While migraine aura was once thought to be primarily due to vasoconstriction, current evidence debunks this concept. For instance, hemiplegic migraine is the consequence of genetic mutations resulting in channelopathies without evidence of cerebral ischemia or infarction. Evidence of basilar artery constriction as postulated in basilar migraine is also lacking. This recognition has led the International Headache Society to rename basilar-type migraine to migraine with brainstem aura. The following discussion reviews current literature with respect to migraine as a neuronal disorder, as well as the published data on the safety of triptans, DHE, Ditans (a novel class of 5-HT1f receptor agonists), CGRP antibodies, and Gepants.

A retrospective analysis of triptan and dhe use for basilar and hemiplegic migraine.

BACKGROUND: Patients with basilar migraine (BM) and hemiplegic migraine (HM) have been excluded from triptan and DHE clinical trials due to a potential risk of ischemic vascular events, and the FDA mandates that package labeling state that they are contraindicated in BM and HM. The objective of this study was to demonstrate that triptans and DHE can be used for the abortive treatment of BM and HM without significant adverse ischemic vascular events. METHODS: A retrospective chart review of patients with BM features or HM who received acute abortive treatment with either triptans or DHE was conducted at 4 headache centers to assess the frequency of ischemic vascular events after administration. The diagnoses of BM or HM were made by headache specialists based on The International Classification of Headache Disorders, 2nd edition (ICHD-II). Searchable terms included BM, vertigo, dysarthria, diplopia, hemiplegia/hemiparesis, facial droop, weakness, confusion, altered consciousness, confusion, ataxia, and aphasia, as well as all triptans or DHE. RESULTS: The study included 67 patients with BM features and 13 patients with HM. Among those receiving triptans, 40 were in the BM group and 5 were in the HM group. Among those receiving DHE, 27 were included in the BM group and 8 were in the HM group. No side effects of stroke or myocardial infarction were reported. In the triptan group, 5 patients reported adverse effects that included GI upset, rash, neck dystonia, nightmares, and flushing. In the DHE group, 5 patients had adverse events that included chest tightness, dystonic reaction, transient asymptomatic anterior T wave inversion, and agitation. CONCLUSION: In this retrospective study, triptans and DHE were used with no reported, subsequent acute/subacute ischemic vascular events for the abortive treatment of migraines with basilar and hemiplegic-type features. Although the small sample sizes generated theoretical statistical event rates of 4.5% for BM and 23% for HM, there has been no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.

No Laughing Matter: Gelastic Migraine and Other Unusual Headache Syndromes.

Primary and secondary headache disorders have established diagnostic criteria in the International Classification of Headache Disorders IIIb, as well as classic findings, which although not part of the formal criteria are often suggestive of a particular diagnosis. At times, headache disorders can involve unusual symptoms that lack an identifiable secondary cause. This review will discuss some of these unusual symptoms, including headache associated auditory and olfactory symptoms, as well as two case reports involving gelastic migraine and migrainous thoracalgia.

A touchy subject: an assessment of cutaneous allodynia in a chronic migraine population.

BACKGROUND: Cutaneous allodynia (CA) is a common feature of migraine, which has a complex underlying pathophysiology that is not well understood. In addition to pain, photophobia, phonophobia, osmophobia, nausea, and vomiting, CA can contribute to the overall disability caused by migraine. The presence of CA can be established via a validated questionnaire. Validated questionnaires and other tests are rarely performed in clinical practice. As such, current prevalence estimates for CA may be an underestimation. METHODS: Utilizing a validated questionnaire, we assessed the presence of CA in consecutive patients (n=44) presenting with chronic migraine at a tertiary headache center. RESULTS: CA appears to be quite prevalent, at ~90%, among female patients with chronic migraine. CONCLUSION: CA prevalence in chronic migraine may be underestimated in the literature, and larger studies may better demonstrate a more accurate estimate of its prevalence.

An Analysis of UCNS Certified Headache Center Patient Intake Forms.

OBJECTIVE: Compare the similarities and differences among headache intake forms from headache centers with United Council of Neurologic Subspecialties (UCNS) accredited headache medicine fellowships in the United States. Patient intake forms establish a first communication with patients. There have been no studies evaluating them at headache centers. Analysis of these forms can provide insight into their content and potential for improvement. METHODS: This observational study involved collection and analysis of intake forms from 25 UCNS fellowship accredited headache centers from July 2014 to October 2014. Forms were compared and contrasted in terms of data fields included, response format, and use of validated assessment tools. RESULTS: Forms shared many common elements, yet were highly variable in content, style, scales, and methods of analysis. Twenty percent (5/20) of centers did not have a formal intake form. Forms ranged from 1 to 28 pages. Seventy percent (12/17) utilized a check box format, 23% (4/17) utilized an open ended/fill in the blank format, and 6% (1/17) utilized a circle the response(s) format. Family history was inquired about in 82% (14/17) of forms and past medical history (PMH) in 58% (10/17) of forms. Gender questions were asked 82% (14/17) of the time for women, 29% (5/17) for men. Eighty-eight percent (15/17) of forms had questions concerning any type of previous medication tried. DISCUSSION: Patient intake forms are useful for clinical purposes, but vary markedly between UCNS headache centers. Ultimately, a universal intake form could be generated, providing a research-based alternative to the form currently used at each center. Use of a standardized intake form by UCNS centers would streamline data collection, a good first step in the eventual generation of a headache registry.

A tale of two systems: cardiac cephalalgia vs migrainous thoracalgia.

The practice of headache medicine is challenging, and excluding secondary causes of headaches is essential for proper diagnosis and treatment. The evaluation of secondary headaches often leads to investigations involving organ systems other than the nervous system. As such, headache, which is typically thought to be neurologic in origin, can be a manifestation of cardiac pathology in the form of cardiac cephalalgia. Conversely, chest pain, which is typically thought to be cardiac in origin, could be a manifestation of a neurologic disease process in the form of atypical migraine aura. In the presented cases, we demonstrate headaches that involve cardiac and neurologic pathology with atypical presentations.