Efficacy and Tolerability of Calcitonin Gene-Related Peptide-Targeted Monoclonal Antibody Medications as Add-on Therapy to OnabotulinumtoxinA in Patients with Chronic Migraine.

BACKGROUND: We examined the efficacy and tolerability of calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP-targeted mAbs) as add-on therapy for patients with chronic migraine (CM) undergoing treatment with onabotulinumtoxinA (onabot) who require additional preventive therapy. METHODS: We reviewed medical records of patients with CM receiving treatment with onabot who were subsequently prescribed a CGRP-targeted mAb medication. The primary outcome was the change in number of monthly headache days (MHDs) reported. Secondary outcomes were change in headache pain severity, discontinuation due to lack of tolerability, and severe adverse events. RESULTS: Of 153 patients, 111 (72.5%) reported a decrease in either MHDs or headache pain severity, with documentation of MHDs in 66 patients. Among these 66 patients, the average number of MHDs before initiation of onabot treatment was 25.7. After onabot treatment, an average decrease of 10.9 MHDs was reported (P < 0.001). After the addition of a CGRP-targeted mAb medication, patients experienced a further decrease of 5.7 MHDs (P < 0.001). With combined therapy, patients reported a total decrease of 16.6 MHDs (P < 0.001). Adverse effects occurred in 13 patients (8.5%) after addition of the CGRP-targeted mAb and included constipation, injection site reaction, and fatigue. No serious adverse events were reported. CONCLUSION: Adding a CGRP-targeted mAb to onabot in patients with CM was associated with further reductions in MHDs without major tolerability issues across a range of mAbs. This retrospective review supports the conduct of a well-designed double-blind study adding a CGRP-targeted mAb or placebo to onabot.

Neurology of Preeclampsia and Related Disorders: an Update in Neuro-obstetrics.

PURPOSE OF REVIEW: Preeclampsia and related hypertensive disorders of pregnancy affect up to 10% of pregnancies. Neurological complications are common and neurologists often become involved in the care of obstetric patients with preeclampsia. Here, we review the definition(s), epidemiology, clinical features, and pathophysiology of preeclampsia, focusing on maternal neurological complications and headache as a common presenting symptom of preeclampsia. RECENT FINDINGS: Neurological symptoms are early and disease-defining features of preeclampsia. Neurological complications of preeclampsia may include headaches, visual symptoms, cerebral edema, seizures, or acute cerebrovascular disorders such as intracerebral hemorrhage or reversible cerebral vasoconstriction syndrome. A history of migraine is an independent risk factor for vascular diseases during pregnancy, including preeclampsia and maternal stroke. The pathophysiology of both preeclampsia and migraine is complex, and the mechanisms linking the two are not fully understood. Overlapping clinical and pathophysiological features of migraine and preeclampsia include inflammation, vascular endothelial dysfunction, and changes in vasoreactivity. Neurological complications are recognized as a major contributor to maternal morbidity and mortality. Pregnant and postpartum women commonly present with headache, and red flags in the clinical history and examination should prompt urgent neuroimaging and laboratory evaluation. A focused headache history should be elicited from patients as part of routine obstetrical care to identify patients at an increased risk of preeclampsia and related hypertensive disorders of pregnancy. Collaborative models of care and scientific investigation in the emerging field of neuro-obstetrics have the common goal of reducing the risk of maternal neurological morbidity and mortality from preeclampsia.

Psychological Factors Associated With Chronic Migraine and Severe Migraine-Related Disability: An Observational Study in a Tertiary Headache Center.

OBJECTIVE: To evaluate the relationships among modifiable psychological factors and chronic migraine and severe migraine-related disability in a clinic-based sample of persons with migraine. BACKGROUND: Evidence evaluating relationships between modifiable psychological factors and chronic migraine and severe migraine-related disability is lacking in people with migraine presenting for routine clinical care. METHODS: Adults with migraine completed surveys during routinely scheduled visits to a tertiary headache center. Participants completed surveys assessing chronic migraine (meeting criteria for migraine with ≥15 headache days in the past month), severe migraine disability (Migraine Disability Assessment Scale score ≥ 21), and modifiable psychological factors (depressive symptoms [Patient Health Questionnaire-9], anxious symptoms [Generalized Anxiety Disorder-7], Pain Catastrophizing Scale and Headache Specific Locus of Control). Logistic regression evaluated relationships between modifiable psychological factors and chronic migraine and severe migraine disability. RESULTS: Among 90 eligible participants the mean age was 45.0 (SD = 12.4); 84.8% were women. One-third (36.0%) met study criteria for chronic migraine; half of participants (51.5%) reported severe migraine-related disability. Higher depressive symptoms (OR = 1.99, 95% CI = 1.11, 3.55) and chance HSLC (OR = 1.85, 95% CI = 1.13, 1.43) were associated with chronic migraine. Higher depressive symptoms (OR = 3.54, 95%CI = 1.49, 8.41), anxiety symptoms (OR = 3.65, 95% CI = 1.65, 8.06), and pain catastrophizing (OR = 1.95, 95% CI = 1.14, 3.35), were associated with severe migraine-related disability. CONCLUSIONS: Psychiatric symptoms and pain catastrophizing were strongly associated with severe migraine-related disability. Depression and chance locus of control were associated with chronic migraine. This study supports the need for longitudinal observational studies to evaluate the relationships among naturalistic variation in psychological factors, migraine-related disability, and migraine chronification.

Emerging treatments for the primary headache disorders.

Migraine and cluster headache are common, episodic, often chronic and disabling disorders of the brain. Although there are many standard treatment techniques, none are ideal. This article reviews various novel pharmacologic and device-related treatments for migraine and cluster headache. Emphasis is given to recent advances in the development of monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) and its receptor, including promising results from phase 2 trials studying the safety and efficacy of LY2951742, ALD403 and TEV-48125, three anti-CGRP mAbs. Other new pharmacologic treatments discussed include the 5-HT1F receptor agonist lasmiditan and glial cell modulator ibudilast. Also reviewed is neuromodulation for migraine and cluster headache, including promising recent results of randomized controlled trials studying sphenopalatine ganglion stimulation, trigeminal nerve stimulation, transcutaneous vagus nerve stimulation, and transcranial magnetic stimulation. Finally, we discuss patch, inhaled, and intranasal methods of triptan and dihydroergotamine delivery.

New treatments for headache.

Migraine and cluster headache are primary headache disorders commonly encountered in clinical practice. Despite the profound disability caused by these primary headache disorders, available acute and preventive treatment options are limited. Recent understanding of headache pathophysiology has led to the development of new drug formulations and novel drug targets that are extremely promising. This article will highlight several of the new treatments that are currently under investigation including novel delivery mechanisms of already existing medications, calcitonin gene-related peptide (CGRP) receptor antagonists, antibodies to CGRP and its receptor, serotonin receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neuromodulation. If data is supportive, these therapies will be welcome additions to the headache specialist's armamentarium.

Depression and anxiety in episodic and chronic cluster headache: a pilot study.

BACKGROUND: In contrast to migraine and tension-type headache, the psychiatric comorbidities of cluster headache (CH) have not been well-studied. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cluster headache associated with a sixth nerve palsy: a case report.

BACKGROUND: Cluster headache is a rare primary headache disorder characterized by recurrent, stereotyped short-lasting attacks of severe, unilateral head pain accompanied by autonomic symptoms. METHODS/RESULTS: Ophthalmic features such as conjunctival injection, lacrimation, ptosis and miosis occur in the vast majority of patients with cluster headache, whereas co-existent ocular movement disorders are rare. CONCLUSIONS: To the best of our knowledge, only two documented cases of cluster headache with external ocular movement disorders have been reported. We describe herein an additional case with this unusual finding and discuss the putative pathophysiology of cluster headache associated with ophthalmoparesis.

Elective Hospitalizations for Intractable Headache: Outcomes and Response Predictors.

OBJECTIVE: To review our inpatient experience treating a variety of headache disorders with heterogeneous therapies and to determine outcomes and predictors of response. METHODS: We conducted an institutional review board-approved retrospective chart review of elective inpatient headache admissions from the Montefiore Headache Center from 2014 to 2018. We examined factors associated with response and outcomes at discharge and posthospitalization follow-up in an intractable population. Patients received different classes of IV medications including antiemetics, neuroleptics, dihydroergotamine, lidocaine, steroids, valproic acid, and nerve blocks, and home preventive medications were either continued or changed before discharge. Improvements were defined at discharge by headache intensity compared with before hospitalization. RESULTS: Among the 83 admissions, pain improvement at discharge occurred in 90.4% (n = 75) of the overall sample, 89.5% (n = 60) of those with chronic migraine, 75.0% (n = 9) of patients with new daily persistent headache, and 89.5% (n = 34) of all those with acute medication overuse. Fifty-six patients (67.5%) reported improvement of a 3-or-more-point reduction in headache intensity at discharge, with a mean reduction of 4.84 ± SD 2.51 (range 1-10). Of the 66 patients who received IV dihydroergotamine, 59 (89.4%) of them improved at discharge. Of the 11 (13.2%) patients who received IV lidocaine, 7 (63.6%) improved. Of the 14 (16.9%) patients who received nerve blocks, all 14 (100%) improved at discharge. Of the 75 patients who had improved at discharge, 63 (84%) followed up and 50 (79.4%) of those patients remained improved. At the second follow-up, 68 (81.9%) patients returned for follow-up on average of 71 days (range 10-283) after discharge. CONCLUSIONS: Our inpatient headache experience featured numerous treatments with high rates of improvement in the short and intermediate term for all headache disorders. These results may suggest that stratified hospitalized care including polytherapy may be useful for many patients.

Peripheral nerve blocks in the treatment of migraine in pregnancy.

OBJECTIVE: To describe the use of peripheral nerve blocks in a case series of pregnant women with migraine. METHODS: A retrospective chart review of all pregnant patients treated with peripheral nerve blocks for migraine over a 5-year period was performed. Injections targeted greater occipital, auriculotemporal, supraorbital, and supratrochlear nerves using local anesthetics. RESULTS: Peripheral nerve blocks were performed 27 times in 13 pregnant women either in a single (n=6) or multiple (n=7) injection series. Mean patient age was 28 years and gestational age was 23.5 weeks, and all women had migraine, including 38.5% who had chronic migraine. Peripheral nerve blocks were performed for status migrainosus (51.8%) or short-term prophylaxis of frequent headache attacks (48.1%). Before peripheral nerve blocks were performed, oral medications failed for all patients and intravenous medications failed for most. In patients with status migrainosus, average pain reduction was 4.0 (±2.6 standard deviation) (P<.001) immediately postprocedure and 4.0 (±4.4 standard deviation) (P=.007) 24 hours postprocedure in comparison to preprocedure pain. For patients receiving peripheral nerve blocks for short-term prophylaxis, immediate mean pain score reduction was 3.0 (±2.1 standard deviation). No patients had any serious immediate, procedurally related adverse events, and the two patients who had no acute pain reduction ultimately developed preeclampsia and had postpartum headache resolution. CONCLUSION: Peripheral nerve blocks for treatment-refractory migraine may be an effective therapeutic option in pregnancy.

The pipeline in headache therapy.

Migraine is a common, disabling, neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms. The advent of the triptan class of medication in the 1990s revolutionized the acute treatment of migraine, but many migraineurs do not respond optimally or at all to triptans, have intolerable adverse effects, or have contraindications to their use. Preventive pharmacotherapy has advanced mostly through serendipity, with new drugs being found effective while being used for other indications. There remains a significant need for new medications and devices that can provide effective, rapid, and sustained pain relief without adverse effects or recurrence. Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation. This article covers innovative delivery mechanisms, calcitonin gene-related peptide receptor antagonists, antibodies to calcitonin gene-related peptide and its receptor, 5-HT1F receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neurostimulation.