Migraines and Beyond: Advances in the Pathogenesis and Treatment of Chronic Headache Disorders, Second Edition

Background/Objectives: Pattern glare, associated with cortical hyperexcitability, induces visual distortions and discomfort, particularly in individuals susceptible to migraines or epilepsy. While previous research has primarily focused on transient EEG responses to patterned stimuli, this study aims to investigate how continuous presentation of pattern-glare stimuli affects neural adaptation over both fine (seconds) and coarse (entire experiment) temporal scales. Methods: EEG recordings were obtained from 40 healthy participants exposed to horizontal square-wave gratings at three spatial frequencies presented continuously for three seconds each across multiple trials. Participants’ susceptibility to visual stress, headaches, and discomfort was assessed using questionnaires before and during the experiment. The experiment employed a two-by-two design to evaluate habituation (exponentially decreasing response) and sensitisation (exponentially increasing response) effects at two different time granularities. Mass univariate analysis with cluster-based permutation tests was conducted to identify significant brain response changes during the period of constant stimulation, which we call the DC-shift period. Results: Significant effects were observed during the DC-shift period, indicating sustained hyper-excitation to the medium-pattern glare stimulus. In particular, the mean/intercept analysis revealed a consistent positive-going response to the medium stimulus throughout the DC-shift period, suggesting continued neural engagement. Participants reporting higher discomfort exhibited sensitisation at fine temporal granularity and habituation at coarser temporal granularity. These effects were predominantly localised to the right posterior scalp regions. Conclusions: The study demonstrates that individuals sensitive to pattern-glare stimuli exhibit dynamic neural adaptation characterised by short-term sensitisation and long-term habituation. These findings enhance the understanding of cortical hyperexcitability mechanisms and may inform future interventions for visual-stress-related conditions, such as migraines and epilepsy. Further research is needed to explore the underlying neural processes and validate these effects in clinical populations. Full article

Background: Headaches are a common symptom in healthcare workers (HCWs), mainly associated with high levels of stress. Different research has studied their incidence during the COVID-19 pandemic, most of them with correlational designs, and at the beginning of the pandemic and focused on the associated occupational variables. Aims: (1) To analyze the incidence of headaches in HCWs at the beginning of the COVID-19 pandemic and their maintenance six months later. (2) To explore the risk factors associated with their onset and maintenance, including sociodemographic, occupational, emotional symptomatology, and personality variables. (3) To propose a model to explain the chronification of stress in burnout, including the moderating role of chronic headaches. Methods: A prospective study (n = 259 HCWs) at three points in time during the COVID-19 pandemic, from the alarm state phase (T1: May–June 2020) to the post-pandemic stage (T3: April–July 2022), including an intermediate measure six months after T1 (T2). Descriptive analyses, Pearson’s chi-square, Student’s t, logistic regressions, and moderated mediation models were conducted using the Process package for SPSS. In addition to headaches, socio-demographic, occupational, emotional symptomatology, and personality variables were included. Results: At T1 the prevalence of headaches was 69.9%. At T2 the prevalence was 73.7%. Of these, 59.5% are T1–T2 sustained headaches. Headaches at T1 were associated with age (p = 0.010) (younger HCWs), professional category (p = 0.049) (nurses), service (p = 0.023) (ICU, COVID hospitalization), non-availability of PPE (p = 0.010), additional COVID-19 symptomatology (p < 0.001), and concern for contagion of family members (p < 0.001) (higher scores). In addition, HCWs with headaches had higher levels of stress (p = 0.001), anxiety (p = 0.001), depression (p = 0.041), and sleep disorders (p < 0.001). A subsequent logistic regression analysis showed that of the above variables, the presence of additional COVID-19 symptoms (p < 0.001) and depression (p = 0.010) were the predictor variables. With regard to the maintenance of headaches (T1–T2), anxiety (p = 0.035), stress (p = 0.001), and cognitive fusion (p = 0.013) were found to be the significant variables. The tested model proposes anxiety (T1) as antecedent, cognitive fusion (T2) as mediator, burnout (T3) as consequent, and chronic headaches (yes/no) as the moderating variable between anxiety and burnout (model 5). The model is significant (F = 19.84, p < 0.001) and contributes to the explanation of 36% of the variance of burnout. The relationships in the model are all statistically significant, and specifically chronic headaches contribute to a 6-fold increase in the likelihood of burnout. Conclusions: The present research differentiates between precipitating and maintenance factors of headaches in HCWs. The former, more studied in previous research, are usually related to sociodemographic and occupational variables and levels of anxiety and stress. Maintenance factors, scarcely explored, are related to the maintenance of emotional symptomatology and the inability to manage intrusive thoughts (i.e., cognitive fusion). Of particular interest is that the presence of chronic headaches itself is capable of producing burnout as a post-COVID syndrome. Full article

Objective: Evidence on prophylactic drugs for pediatric migraine is limited, especially when comorbid conditions contribute to treatment resistance. This study evaluated the efficacy of cyproheptadine in children with migraine and explored the impact of comorbid neurodevelopmental disorders and orthostatic intolerance (OI). Methods: We retrospectively analyzed pediatric migraine patients treated with cyproheptadine. Efficacy was assessed based on the reduction in headache frequency, with responders defined as patients experiencing at least a 50% reduction in headache episodes. Fisher’s exact test analyzed the relationship between efficacy and comorbid conditions or treatment sequence. Multiple logistic regression was performed to identify factors associated with adverse events. Results: In total, 155 children (71 males, 84 females) aged 3–15 years were included. Comorbid neurodevelopmental disorders and OI were present in 27 (17.4%) and 22 (14.2%) patients, respectively. Efficacy was evaluated in 148 patients, with 68.9% classified as responders. Patients with comorbid conditions showed lower efficacy. Responders required a lower dose of cyproheptadine (p = 0.039). Multiple logistic regression identified headache frequency, cyproheptadine dose, and comorbid OI and neurodevelopmental disorders as factors influencing treatment efficacy. Conclusions: Cyproheptadine is effective in treating pediatric migraine, though patients with neurodevelopmental disorders and OI demonstrated reduced efficacy. Full article

Cluster headache is a severe, poorly understood disorder for which there are as yet virtually no rationally derived treatments. Here, Lee Kudrow’s 1983 theory, that cluster headache is an overly zealous response to hypoxia, is updated according to current understandings of hypoxia detection, signaling, and sensitization. It is shown that the distinctive clinical characteristics of cluster headache (circadian timing of attacks and circannual patterning of bouts, autonomic symptoms, and agitation), risk factors (cigarette smoking; male gender), triggers (alcohol; nitroglycerin), genetic findings (GWAS studies), anatomical substrate (paraventricular nucleus of the hypothalamus, solitary tract nucleus/NTS, and trigeminal nucleus caudalis), neurochemical features (elevated levels of galectin-3, nitric oxide, tyramine, and tryptamine), and responsiveness to treatments (verapamil, lithium, melatonin, prednisone, oxygen, and histamine desensitization) can all be understood in terms of hypoxic signaling. Novel treatment directions are hypothesized, including repurposing pharmacological antagonists of hypoxic signaling molecules (HIF-2; P2X3) for cluster headache, breath training, physical exercise, high-dose thiamine, carnosine, and the flavonoid kaempferol. The limits of current knowledge are described, and a program of basic and translational research is proposed. Full article

Background: Ophthalmoplegic migraine (OM) is an uncommon variant of migraine characterised by headache and cranial nerve palsy, posing significant diagnostic and therapeutic challenges. Objective: This study aimed to describe an extremely rare OM variant with a partial therapeutic response. Clinical Case: A 34-year-old pregnant woman in gestational week 19.1 (G6P2A3) with a history of three consecutive spontaneous abortions presented at the emergency services with insidious onset and mild-to-moderate-intensity pulsatile bifrontal headache for 15 days, and the positional changes exacerbated this. At peak intensity, she experienced nausea, vomiting, tinnitus, and photophobia without phonophobia or osmophobia, prompting multiple visits to the emergency department. Despite a broad range of treatments, including intravenous fluids, analgesia, pericranial blocks, and preventive management, there was a non-significative improvement in the symptomatology described above. However, spontaneous resolution of this clinical picture was observed during the postpartum period. Results: This case highlights the complexity of ophthalmoplegic migraine, especially in the context of pregnancy, and raises questions about the underlying pathophysiological mechanisms. The absence of structural lesions on neuroimaging and postpartum resolution suggests a potential association with the hormonal and physiological changes associated with pregnancy. Conclusions: Despite limited scientific evidence, this report contributes to expanding the knowledge of this rare entity and emphasises the importance of a multidisciplinary approach to its management. Full article

Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are clinically effective in preventing the migraine attacks, photophobia, and migraine auras associated with headaches. However, no study has yet investigated the effectiveness of CGRP mAbs in preventing migraine aura without headache. Case report: A female patient of 49 years old presented with a long history (since age 10) of photosensitivity and typical migraine auras without a headache. The symptoms slightly responded to oral medication, lomerizine chloride, but did not completely resolve. Just one day after the administration of galcanezumab, her photo-hypersensitivity and migraine aura had completely resolved. Consequently, the administration of the oral migraine preventive medication was discontinued. Monthly galcanezumab at a dose of 120 mg was continuously given and she did not re-experience any auras or headaches. Conclusions: The use of CGRP mAbs can be considered as a potential treatment in preventing migraine aura without headache. Currently, CGRP mAb is indicated only for migraines with and without auras. Given our findings and the promising effects of this medication for this migraine subtype, a large clinical trial is required to better assess the effects and potential adverse events of CGRP mAb in patients with migraine aura without headache. Full article

The pathology of idiopathic intracranial hypertension (IIH), a disease characterized by papillary edema and increased intracranial pressure (IICP), is not yet understood; this disease significantly affects quality of life due to symptoms including vision loss, headache, and pulsatile tinnitus. By contrast, superficial siderosis (SS), a disorder in which hemosiderin is deposited on the surface of the cerebral cortex and cerebellum, potentially causes cerebellar ataxia or hearing loss. So far, no cases of IIH with infratentorial and supratentorial cortical SS have been reported. Herein, we report a case of a 31-year-old woman with obesity who developed this condition. The patient suddenly developed headache and dizziness, had difficulty walking, and subsequently became aware of diplopia. Fundus examination revealed bilateral optic nerve congestive papillae and right eye abducens disturbance. Head magnetic resonance imaging (MRI) showed prominent SS on the cerebellar surface and cerebral cortex. Lumbar puncture revealed IICP of 32 cmH₂O, consistent with the diagnostic criteria for IIH, and treatment with oral acetazolamide was started; subsequently, the intracranial pressure decreased to 20 cmH₂O. Her abduction disorder disappeared, and the swelling of the optic papilla improved. She was now able return to her life as a teacher without any sequelae. SS is caused by persistent slight hemorrhage into the subarachnoid space. In this case, both infratentorial and supratentorial cortical superficial SS was observed. Although cases of IIH complicated by SS are rare, it should be kept in mind that a causal relationship between IIH and SS was inferred from our case. Our findings also suggest that cerebrospinal fluid dynamic analysis using MRI is effective in diagnosing IIH and in determining the efficacy of treatment. Full article