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OBJECTIVE: We sought to evaluate temporal response patterns to erenumab treatment in patients with episodic migraine. BACKGROUND: Although many patients treated with erenumab experience onset of efficacy as early as 1 week, clinical benefits of migraine preventive therapies may accrue with continued treatment. Furthermore, details about the maintenance of clinical responses have not been reported. METHODS: This was a post hoc analysis of a 6-month, randomized, double-blind, placebo-controlled, phase 3 study of erenumab for the prevention of episodic migraine. We analyzed temporal responses to erenumab using a threshold of ≥50% reduction from baseline in monthly migraine days (MMDs). RESULTS: During the 6-month treatment period, 73.7% (230/312) and 79.6% (253/318) of patients in the erenumab 70 mg (n = 312) and 140 mg (n = 318) groups, respectively, achieved a response in at least 1 month. In this group of responders, at least half reached first monthly response (first month with ≥50% reduction from baseline in MMDs) by month 2 and at least 75% of them by month 3. The remainder responded in months 4-6. Of patients in the erenumab 70 and 140 mg groups, 35.3% (110/312) and 41.8% (133/318), respectively, responded over months 1-3 (mean response over first 3 months). Of these patients, 81.8% (90/110) and 81.9% (109/133) maintained this response over months 4-6 (mean response over last 3 months) in the 70 and 140 mg groups, respectively. Many patients who did not achieve an initial response (≥50% reduction from baseline in MMDs during month 1) responded later with continued treatment, with approximately one-half or more of initial nonresponders responding by months 4-6. CONCLUSIONS: These results support guidelines recommending at least 3 months following the initiation of erenumab for migraine prevention before the assessment of response.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Adolescente , Adulto , Idoso , Cognição , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. METHODS: This is a post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). RESULTS: Among the erenumab 140 mg group (n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group (n = 188). CONCLUSION: A majority of erenumab-treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.
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Anticorpos Monoclonais Humanizados/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
BACKGROUND: Erenumab (erenumab-aooe in the US) effectively reduces monthly migraine days in episodic and chronic migraine. This traditional outcome does not capture the intensity of headache pain on days with migraine. METHODS: This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain. Cumulative monthly migraine pain intensity is the sum of the peak pain intensity scores (0 = no migraine to 3 = migraine day with severe pain) on migraine days. Change from baseline in cumulative monthly migraine pain and average monthly pain intensity was assessed over months 4 to 6 for episodic migraine and month 3 for chronic migraine; change in average monthly pain intensity was assessed among monthly migraine days responders/non-responders. RESULTS: Efficacy analysis included 946 patients for the episodic migraine study and 656 patients for the chronic migraine study. Cumulative monthly migraine pain decreased significantly with erenumab versus placebo (p < 0.001, for episodic migraine and chronic migraine). In addition, monthly average migraine pain intensity decreased significantly with erenumab versus placebo for episodic migraine (p < 0.01); decreases were non-significant for chronic migraine. In comparison with placebo-treated patients, a greater proportion of erenumab-treated patients were pain intensity responders regardless of threshold used. Episodic migraine and chronic migraine patients with a ≥50% reduction in monthly migraine days (responders) had a greater reduction in monthly average pain intensity than non-responders. CONCLUSIONS: Erenumab reduced cumulative monthly migraine pain in episodic migraine and chronic migraine patients and significantly reduced monthly average migraine pain in episodic migraine, demonstrating treatment benefit beyond reduction in migraine frequency.Clinical Trial Registration: ClinicalTrials.gov, NCT02456740; ClinicalTrials.gov, NCT02066415.
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Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Medição da Dor , Resultado do TratamentoRESUMO
BACKGROUND: In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline. RESULTS: In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM. CONCLUSIONS: In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM. TRIAL REGISTRATIONS: NCT02456740; NCT02066415; NCT02174861.
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Transtornos de Enxaqueca , Anticorpos Monoclonais Humanizados , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Ictal cutaneous allodynia, common in chronic migraine, is associated with reduced responses to acute treatment with triptans. Allodynia's impact on the efficacy of newer preventive treatments such as erenumab is unknown. METHODS: Post-hoc subgroup analysis of a double-blind, randomized, placebo-controlled 12-week study of erenumab in chronic migraine, contrasting those with no allodynia with those with moderate-severe allodynia assessed with the Allodynia Symptom Checklist-12, was undertaken. RESULTS: Of 648 randomized individuals with baseline Allodynia Symptom Checklist-12 scores, 386 (59.6%) had no allodynia and 153 (23.6%) had moderate-to-severe allodynia. Mean (standard deviation) baseline monthly migraine days were 17.6 (4.8) and 18.9 (4.3), respectively. Compared to placebo, the erenumab group had greater reductions in monthly migraine days and monthly acute migraine-specific medication days in both no allodynia and allodynia subgroups. Mean (95% confidence interval) treatment differences in change from baseline for monthly migraine days at week 12 were -2.5 (-3.7, -1.4) in the no allodynia subgroup and -3.3 (-5.3, -1.3) in the moderate-severe allodynia subgroup. Change in acute migraine-specific medication days were -3.3 (-4.3, -2.3) and -2.5 (-4.3, -0.8), respectively. CONCLUSIONS: Erenumab's efficacy in reducing monthly migraine days and acute migraine-specific medication days in chronic migraine was not impacted by the presence of moderate-severe ictal allodynia.Trial registration: ClinicalTrials.gov NCT02066415.
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Hiperalgesia , Transtornos de Enxaqueca , Anticorpos Monoclonais Humanizados , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Método Duplo-Cego , Humanos , Hiperalgesia/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Resultado do TratamentoRESUMO
INTRODUCTION: Erenumab, a first-in-class monoclonal antibody targeting the calcitonin gene-related peptide pathway, was approved by the US Food and Drug Administration in 2018 for the prevention of migraine in adults. There is limited data available on its impact in real-world settings. The study aim was to characterize the real-world treatment profiles, clinical outcomes, and healthcare resource utilization of patients prescribed erenumab from select major US headache centers. METHODS: A retrospective chart review of patients with migraine treated with erenumab for at least 3 months across five major headache centers was conducted. Data was collected from patient charts between April 2019 and April 2020 and included patient and clinical characteristics, migraine medication use, and outpatient visits. The date of the first prescription fill of erenumab was defined as the index date. The baseline period comprised the 3 months prior to the index date and the study period comprised the at least 3 months on erenumab treatment. RESULTS: Data from a total of 1034 patients with chronic migraine with a mean of 9.3 months of erenumab treatment were analyzed. Patients were on average 48 years old, 86% were female, and 79% were white. Patients had a mean of 5 preventive treatment failures prior to erenumab initiation. Patients used a mean of 2 preventive treatments (excluding erenumab) and 2 acute treatments during baseline and study periods. Among patients with effectiveness data, 45% of patients had improvement in physician-reported migraine severity and 35% experienced at least 50% reduction in mean headache/migraine days per month. The average number of monthly outpatient visits was 0.43 and 0.30 before and after erenumab initiation, respectively. CONCLUSION: In this predominantly refractory chronic migraine population treated in select headache centers, patients had fewer headache/migraine days per month and outpatient visits after initiating erenumab. However, patients largely continued to be managed via a polypharmacy approach after erenumab initiation.
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OBJECTIVE: To assess efficacy and tolerability of 1-year erenumab treatment in patients with episodic migraine. METHODS: Patients were randomized (n = 955; 1:1:1) during the 24-week double-blind treatment phase (DBTP) to monthly subcutaneous placebo or erenumab 70 or 140 mg. At week 24, 845 patients were rerandomized (1:1) to erenumab 70 or 140 mg during the 28-week dose-blinded active-treatment phase (ATP). Monthly migraine days (MMD), achieving ≥50%, ≥75%, and 100% reduction in MMD, and safety/tolerability were assessed. RESULTS: Mean MMD at DBTP baseline was 8.3. At week 52, mean changes (SE) from pre-DBTP baseline/week 24 (pre-ATP baseline) in MMD were -4.2 (0.2)/-1.1 (0.2) (70 mg) and -4.6 (0.2)/-1.8 (0.2) (140 mg) irrespective of treatment during the DBTP. For patients reducing dose from 140 (DBTP) to 70 mg (ATP), change in MMD from week 24 to 52 was -0.1 (0.3), and for those increasing from 70 (DBTP) to 140 mg (ATP), -1.8 (0.3). At week 52, 61.0%, 38.5%, and 19.8% of patients on erenumab 70 mg, and 64.9%, 40.8%, and 21.2% on erenumab 140 mg, achieved ≥50%, ≥75%, and 100% reduction in MMD from DBTP baseline, respectively. Among erenumab-treated patients in DBTP who showed ≥50% reduction in MMD during the last 3 months of DBTP and completed ATP, 86% showed sustained responses at ≥50% during the last 3 months of ATP. Safety of erenumab in ATP was similar to DBTP; exposure-adjusted incidence rates of adverse events were similar for either dose. CONCLUSION: Over 52 weeks, erenumab provided sustained efficacy in episodic migraine; the safety profiles were similar between erenumab dose groups in the presence of dose blinding. CLINICALTRIALSGOV IDENTIFIER: NCT02456740. CLASSIFICATION OF EVIDENCE: Class II evidence that 52 weeks of treatment with erenumab 70 and 140 mg subcutaneously monthly results in sustained reductions in monthly migraine days and similar dose tolerability for patients with episodic migraine.
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Analgésicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Patients with visual snow syndrome suffer from a continuous pan-field visual disturbance, additional visual symptoms, tinnitus, and non-perceptional symptoms. The pathophysiology of visual symptoms might involve dysfunctional visual cortex. So far, the extra-visual system has not been investigated. We aimed at identifying structural and functional correlates for visual and non-visual symptoms in visual snow syndrome. Patients were compared to age- and sex-matched controls using 18F-2-fluoro-2-deoxy-d-glucose PET (n = 20 per group) and voxel-based morphometry (n = 17 per group). Guided by the PET results, region of interest analysis was done in voxel-based morphometry to identify structural-functional correspondence. Grey matter volume was assessed globally. Patients had corresponding hypermetabolism and cortical volume increase in the extrastriate visual cortex at the junction of the right lingual and fusiform gyrus. There was hypometabolism in the right superior temporal gyrus and the left inferior parietal lobule. Patients had grey matter volume increases in the temporal and limbic lobes and decrease in the superior temporal gyrus. The corresponding structural and functional alterations emphasize the relevance of the visual association cortex for visual snow syndrome. The broad structural and functional footprint, however, confirms the clinical impression that the disorder extends beyond the visual system.
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Encéfalo/fisiopatologia , Transtornos da Visão/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Síndrome , Transtornos da Visão/diagnóstico por imagem , Transtornos da Visão/patologia , Adulto JovemRESUMO
OBJECTIVE: To assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial. METHODS: This was a double-blind, randomized, sham-controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline. RESULTS: A total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: -3.46 ± 2.32 versus -1.78 ± 1.89 ( p < 0.0001), or -59% versus -30% ( p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for 'migraine without aura' attacks: mean visual analogue scale reduction at 1 hour was -3.3 ± 2.4 for the verum group versus -1.7 ± 1.9 for the sham group ( p = 0.0006). For 'migraine with aura' attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was -4.3 ± 1.8 for the verum group versus -2.6 ± 1.9 for the sham group ( p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group. CONCLUSION: One-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks. STUDY PROTOCOL: ClinicalTrials.gov Identifier: NCT02590939.
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Terapia por Estimulação Elétrica/métodos , Transtornos de Enxaqueca/terapia , Manejo da Dor/métodos , Nervo Trigêmeo/fisiologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: After finding that the thienopyridines clopidogrel and prasugrel reduced migraine headache (MHA) symptoms in some patients with patent foramen ovale (PFO), this small pilot study was undertaken to determine whether ticagrelor, a nonthienopyridine P2Y12 inhibitor, would have similar MHA effects and might be better suited for a future randomized trial. METHODS: MHA patients were screened for PFO. Participants with documented right to left shunt (RLS) and ≥6 monthly MHA days received ticagrelor therapy for 28 days. Those with ≥50% reduction in monthly MHA days were deemed responders and completed 2 additional treatment months. RESULTS: The 40 participants had a mean age of 36.2 years and mean MHA frequency of 17.4 d/mo. A total of 39/40 were female. A total of 14/40 met criteria for episodic MHA, 26/40 for chronic MHA, 14/40 had migraine with aura, and 22/40 had a moderate-large RLS (Spencer grade ≥4). Seventeen of 40 participants (43%) were responders. MHA reduction continued through 3 treatment months in all responders. MHA responder rates were not statistically different in participants with episodic or chronic MHA, with or without aura, or with small/larger RLS shunt magnitude. Thirteen (32%) patients had medication side effects, without serious adverse events. CONCLUSION: P2Y12 inhibition with ticagrelor reduced MHA symptoms similarly to our previous thienopyridine experience, but participants seemed to have a less robust MHA benefit and more frequent side effects than with the thienopyridines, making it an inferior choice for a randomized trial. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ticagrelor reduced MHA symptoms in patients with PFO.
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Forame Oval Patente/complicações , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Ticagrelor/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
PURPOSE OF REVIEW: This article is intended to assist clinicians in distinguishing benign primary headache syndromes from serious headache presentations that arise from exogenous causes. RECENT FINDINGS: Although most cases of severe headache are benign, it is essential to recognize the signs and symptoms of potentially life-threatening conditions. Patients with primary headache disorders can also acquire secondary conditions that may present as a change in their baseline headache patterns and characteristics. Clinical clues in the history and examination can help guide the diagnosis and management of secondary headache disorders. Furthermore, advances in the understanding of basic mechanisms of headache may offer insight into the proposed pathophysiology of secondary headaches. SUMMARY: Several structural, vascular, infectious, inflammatory, and traumatic causes of headache are highlighted. Careful history taking and examination can enable prompt identification and treatment of underlying serious medical disorders causing secondary headache syndromes.
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Neoplasias Encefálicas/complicações , Transtornos Cerebrovasculares/complicações , Doenças Transmissíveis/complicações , Transtornos da Cefaleia Secundários/etiologia , Inflamação/complicações , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Transtornos da Cefaleia Secundários/diagnóstico , Transtornos da Cefaleia Secundários/terapia , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: The aim of the current study is to assess the safety and efficacy of external trigeminal nerve stimulation (e-TNS) via a transcutaneous supraorbital stimulator as an acute treatment for migraine attacks. MATERIALS AND METHODS: This was a prospective, open-labeled clinical trial conducted at the Columbia University Headache Center (NY, USA). Thirty patients who were experiencing an acute migraine attack with or without aura were treated with a one-hour session of e-TNS (CEFALY Technology) at the clinic. Pain intensity was scored using a visual analogue scale (VAS) before the treatment, after the one-hour treatment session, and at two hours after treatment initiation. Rescue migraine medication intake was recorded at 2 and 24 hours. RESULTS: Thirty patients were included in the intention-to-treat analysis. Mean pain intensity was significantly reduced by 57.1% after the one-hour e-TNS treatment (-3.22 ± 2.40; p < 0.001) and by 52.8% at two hours (-2.98 ± 2.31; p < 0.001). No patients took rescue medication within the two-hour observation phase. Within the 24-hour follow-up, 34.6% of patients used a rescue medication. No adverse events or subjective complaints were reported. CONCLUSIONS: The findings from this open-labeled study suggest that transcutaneous supraorbital neurostimulation may be a safe and effective acute treatment for migraine attacks, and merits further study with a double-blind, randomized, sham-controlled trial.
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Transtornos de Enxaqueca/terapia , Manejo da Dor/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Nervo Trigêmeo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the efficacy and tolerability of oral aprepitant, a substance P/neurokinin A receptor antagonist, in controlling nausea associated with IV dihydroergotamine (DHE) administered for medically refractory migrainous headache in patients not responding to standard antiemetics or with a history of uncontrolled nausea with DHE. METHODS: This was a retrospective chart review of prospectively collected hourly diary data and clinical notes of patients hospitalized between 2011 and 2015 for inpatient treatment with DHE. Patients were classified using the International Classification of Headache Disorders, 3rd edition (beta version). Peak and average daily nausea scores from hourly diaries, or daily entries of notes, and concurrent antiemetic use were collected and tabulated. RESULTS: Seventy-four patients, of whom 24 had daily diaries, with chronic migraine with or without aura, with or without medication overuse, or new daily persistent headache of a migrainous type, were identified. In 36 of 57 cases in which aprepitant was administered during hospitalization, there was a 50% reduction in the average daily number of as-needed antinausea medications. Of 57 patients, 52 reported that the addition of aprepitant improved nausea. Among 21 of 24 patients with hourly diary data, nausea scores were reduced and in all 12 with vomiting there was cessation of emesis after aprepitant was added. Aprepitant was well tolerated with no treatment emergent adverse events. CONCLUSIONS: Aprepitant can be effective in the treatment of refractory DHE-induced nausea and emesis. Given the broader issue of troublesome nausea and vomiting in acute presentations of migraine, general neurologists may consider what place aprepitant has in the management of such patients. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with medically refractory migraine receiving IV DHE, oral aprepitant reduces nausea.
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Analgésicos não Narcóticos/efeitos adversos , Antieméticos/uso terapêutico , Di-Hidroergotamina/efeitos adversos , Morfolinas/uso terapêutico , Náusea/tratamento farmacológico , Náusea/etiologia , Administração Intravenosa , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Aprepitanto , Di-Hidroergotamina/administração & dosagem , Humanos , Pacientes Internados , Transtornos de Enxaqueca/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks.
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Barreira Hematoencefálica , Di-Hidroergotamina/metabolismo , Transtornos de Enxaqueca , Nitroglicerina/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Vasoconstritores/metabolismo , Vasodilatadores/farmacologia , Adulto , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico por imagem , Transtornos de Enxaqueca/metabolismoRESUMO
OBJECTIVE: To assess the relationship between the phenotype of the "visual snow" syndrome, comorbid migraine, and typical migraine aura on a clinical basis and using functional brain imaging. BACKGROUND: Patients with "visual snow" suffer from continuous TV-static-like tiny flickering dots in the entire visual field. Most patients describe a syndrome with additional visual symptoms of the following categories: palinopsia ("afterimages" and "trailing"), entopic phenomena arising from the optic apparatus itself (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia, nyctalopia (impaired night vision), as well as the non-visual symptom tinnitus. The high prevalence of migraine and typical migraine aura in this population has led to the assumption that "visual snow" is caused by persistent migraine aura. Due to the lack of objective measures, alternative diagnoses are malingering or a psychogenic disorder. METHODS: (1) The prevalence of additional visual symptoms, tinnitus, and comorbid migraine as well as typical migraine aura was assessed in a prospective semi-structured telephone interview of patients with "visual snow." Correlations were calculated using standard statistics with P < .05 being considered statistically significant. (2) Areas with increased brain metabolism in a group of "visual snow" patients in comparison to healthy controls were identified using [(18) F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and statistical parametric mapping (SPM8 with whole brain analysis; statistical significance was defined by P < .001 uncorrected for multiple comparisons). RESULTS: (1) Of 120 patients with "visual snow," 70 patients also had migraine and 37 had typical migraine aura. Having comorbid migraine was associated with an increased likelihood of having palinopsia (odds ratio [OR] 2.8; P = .04 for "afterimages" and OR 2.6; P = .01 for "trailing"), spontaneous photopsia (OR 2.9; P = .004), photophobia (OR 3.2; P = .005), nyctalopia (OR 2.7; P = .01), and tinnitus (OR 2.9; P = .006). Typical migraine aura was associated with an increased likelihood of spontaneous photopsia (OR 2.4; P = .04). (2) After adjusting for typical migraine aura, comparison of 17 "visual snow" patients with 17 age and gender matched controls showed brain hypermetabolism in the right lingual gyrus (Montreal Neurological Institute coordinates 16-78-5; kE = 101; ZE = 3.41; P < .001) and the left cerebellar anterior lobe adjacent to the left lingual gyrus (Montreal Neurological Institute coordinates -12-62-9; kE = 152; ZE = 3.28; P = .001). CONCLUSIONS: -Comorbid migraine aggravates the clinical phenotype of the "visual snow" syndrome by worsening some of the additional visual symptoms and tinnitus. This might bias studies on "visual snow" by migraineurs offering study participation more likely than non-migraineurs due to a more severe clinical presentation. The independence of entoptic phenomena from comorbid migraine indicates "visual snow" is the main determinant. The hypermetabolic lingual gyrus confirms a brain dysfunction in patients with "visual snow." The metabolic pattern differs from interictal migraine with some similarities to migrainous photophobia. The findings support the view that "visual snow," migraine, and typical migraine aura are distinct syndromes with shared pathophysiological mechanisms that need to be addressed in order to develop rational treatment strategies for this disabling condition.
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Transtornos de Enxaqueca/complicações , Enxaqueca com Aura/complicações , Transtornos da Visão/complicações , Transtornos da Visão/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/epidemiologia , Enxaqueca com Aura/epidemiologia , Tomografia por Emissão de Pósitrons , PrevalênciaRESUMO
ATP7A is a copper-transporting ATPase critical for central and peripheral nervous system function. Mutations in ATP7A cause Menkes disease and occipital horn syndrome (OHS), allelic X-linked recessive conditions that feature vascular abnormalities ascribed to low activity of lysyl oxidase, a copper-dependent enzyme. From a recently created Menkes disease/OHS patient registry, we identified four of 95 patients with major congenital heart defects (4.2%), a proportion exceeding the general population prevalence (≈1%). In conjunction with mouse models of Menkes disease, OHS, and lysyl oxidase deficiency (which feature aortic aneurysms, irregular attachment between vascular endothelium and mesoderm, and other defects of embryological development) our observation suggests an important role of copper metabolism in cardiac development. Congenital heart disease may be an under-appreciated abnormality in Menkes disease, and should be considered in a broad differential diagnosis of cardiac defects found prenatally in male fetuses. Conversely, newborn infants with suspected or confirmed Menkes disease should be evaluated for heart disease by careful clinical examination and echocardiography, if indicated.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Síndrome dos Cabelos Torcidos/complicações , Mutação , ATPases Transportadoras de Cobre , Evolução Fatal , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome dos Cabelos Torcidos/diagnóstico , Síndrome dos Cabelos Torcidos/genética , PrognósticoRESUMO
Warfarin is commonly used to prevent stroke in patients with atrial fibrillation; however, patients on haemodialysis may not derive the same benefit from warfarin as the general population. There are no randomized controlled studies in dialysis patients which demonstrate the efficacy of warfarin in preventing stroke. In fact, warfarin places the dialysis patient at increased risk for haemorrhagic stroke and possibly ischaemic stroke. Additionally, warfarin increases the risk of major bleeding and has been associated with vascular calcification. Routine use of warfarin in dialysis for stroke prevention should be discouraged, and therapy should only be reserved for dialysis patients at high risk for thrombo-embolic stroke and carefully monitored if implemented.
Assuntos
Fibrilação Atrial/complicações , Diálise Renal , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Doença Crônica , Hemorragia/epidemiologia , Humanos , Nefropatias/terapia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Varfarina/efeitos adversosRESUMO
To probe mechanisms of cadmium (Cd) damage to the lung extracellular matrix (ECM), we developed Cd-resistant (CdR) rat lung fibroblasts (RFL6) by incubation with graded concentrations of Cd. CdR cells downregulated lysyl oxidase (LO), a copper (Cu)-dependent enzyme essential for crosslinking of collagen and elastin in the ECM, in conjunction with upregulation of other Cu-binding proteins including Cu,Zn-superoxide dismutase (SOD1), copper chaperone for SOD1 (CCS1), metallothionein (MT), and Menkes P-type ATPase (ATP7A), a Cu transporter in the membrane of the Golgi apparatus, as well as gamma-glutamylcysteine synthetase (gamma-GCS), an enzyme for glutathione biosynthesis. Reduction and loss of cytoplasmic distribution of LO in CdR cells were accompanied by its dislocation with the Menkes P-type ATPase and the endoplasmic reticulum marker. CdR cells displayed a defect in LO catalytic activity but an enhancement in Cu,Zn-SOD catalytic activity consistent with the protein expression levels of these enzymes. Although long-term Cd exposure of cells enhanced the Menkes P-type ATPase protein expression, actually, it reduced Cu-dependent catalytic activity of this enzyme in parallel with the deficiency of LO. The low level of 64Cu bound to the LO fraction and the high level of 64Cu bound to the MT fraction provide direct evidence for limitation of Cu bioavailability for LO existing in the CdR cells. These results suggest that downregulation of LO is linked with upregulation of other Cu-binding proteins and with alteration in Cu homeostasis in the CdR phenotype.
Assuntos
Cádmio/toxicidade , Cobre/metabolismo , Poluentes Ambientais/toxicidade , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Animais , Biomarcadores/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , ATPases Transportadoras de Cobre , Relação Dose-Resposta a Droga , Regulação para Baixo , Tolerância a Medicamentos , Matriz Extracelular , Fibroblastos/metabolismo , Fibroblastos/patologia , Glutamato-Cisteína Ligase/metabolismo , Homeostase/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Metalotioneína/metabolismo , Chaperonas Moleculares/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Regulação para CimaRESUMO
Receptor for advanced glycation end products (RAGE) has been proposed as a signal transduction receptor to promote neurite outgrowth and cell migration, by its interaction with a neurite outgrowth promoting protein, Amphoterin. Amphoterin has been shown to interact with sulfoglucuronyl carbohydrate (SGC). The developmental expression of RAGE, Amphoterin and SGC was studied in pre-natal and post-natal mouse cerebellum to establish their cellular and subcellular localization and function. The amount of RAGE in the cerebellum increased with age. RAGE was expressed pre-natally in the external germinal layer and post-natally in the plasma membranes of the granule neurons of the external and internal granule cell layers and in Purkinje cells. Immunocytochemical analysis by high magnification confocal microscopy showed that RAGE was co-expressed with Amphoterin and SGC in the cell surfaces of granule neurons. This co-localization of RAGE, Amphoterin, and SGC was confirmed in isolated and cultured granule neurons and in migrating granule neurons in explant cultures. Anti-RAGE antibodies inhibited neurite outgrowth and cell migration in explant and slice cultures, similar to anti-Amphoterin and anti-SGC antibodies shown previously. The results suggest that RAGE could act as a signaling molecule for neurite outgrowth and cell migration by its interaction with Amphoterin and that of Amphoterin with SGC.
Assuntos
Carboidratos/fisiologia , Movimento Celular/fisiologia , Cerebelo/metabolismo , Proteína HMGB1/metabolismo , Neuritos/fisiologia , Receptores Imunológicos/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Western Blotting/métodos , Cerebelo/citologia , Cerebelo/embriologia , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Produtos Finais de Glicação Avançada/metabolismo , Imuno-Histoquímica/métodos , Masculino , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Gravidez , Receptor para Produtos Finais de Glicação AvançadaRESUMO
HNK-1 antibody reactive sulfoglucuronyl carbohydrate (SGC) and SSEA-1 antibody reactive Lewis X (Lex) epitope are expressed on several glycolipids, glycoproteins, and proteoglycans of the nervous system and have been implicated in cell-cell recognition, neurite outgrowth, and/or neuronal migration during development. Interaction of SGC with its binding protein Amphoterin and interaction of Amphoterin with a cell-signaling molecule, receptor for advance glycation end product (RAGE) have been suggested to regulate neurite outgrowth and neuronal migration. The regulation of expression of SGC, Lex, Amphoterin, and RAGE was studied in embryonal carcinoma P19 cells after treatment with retinoic acid (RA). The untreated proliferating P19 cells strongly expressed the Lex epitope, which was mostly due to Lex-glycoproteins. P19 cells, when differentiated into neuron-like cells by RA, did not express the Lex epitope, but expressed increasing levels of SGC, with time in culture. Quantitative biochemical analyses showed that in the P19 cells after RA treatment, the amount of SGC-glycoproteins increased at a significantly higher level than sulfoglucuronyl glycolipid-1 (SGGL-1). The increase in the levels of SGGL-1 was due to 16-fold upregulation in the activity of lactosylceramide: N-acetylglucosaminyl-transferase (Lc3 synthase), which synthesizes the key intermediate lactotriosylceramide (Lc3Cer), for lacto- and neolacto-glycolipids. The large increase in the activity of Lc3 synthase appeared to regulate the levels of other neolacto glycolipids, such as Lc3Cer, nLc4Cer, nLc6Cer, disialosyl-nLc4Cer (LD1), and Lex-glycolipids. Strong upregulation of glucuronyl-transferase and modest twofold enhancement in the activity of the glucuronyl-sulfotransferase, which catalyze the final steps in the SGC synthesis, also would account for the large increase in the synthesis SGC-glycoproteins. RA also upregulated the synthesis of Amphoterin and RAGE in P19 cells. SGC, RAGE, and Amphoterin were co-localized in the RA-differentiated neurons. The initiation of neurite outgrowth along with co-ordinated upregulation of Amphoterin, RAGE, SGC-glycoproteins, and SGGLs in RA-treated P19 cells support the hypothesis that these molecules are involved in the neuronal process formation.