Faculty Bibliography

BACKGROUND:Population-based studies have highlighted a close relationship between migraine and stroke. Migraine, especially with aura, is a risk factor for both ischemic and hemorrhagic stroke. Interestingly, stroke risk is highest for migraineurs who are young and otherwise healthy. MAIN BODY/UNASSIGNED:Preclinical models have provided us with possible mechanisms to explain the increased vulnerability of migraineurs' brains towards ischemia and suggest a key role for enhanced cerebral excitability and increased incidence of microembolic events. Spreading depolarization (SD), a slowly propagating wave of neuronal depolarization, is the electrophysiologic event underlying migraine aura and a known headache trigger. Increased SD susceptibility has been demonstrated in migraine animal models, including transgenic mice carrying human mutations for the migraine-associated syndrome CADASIL and familial hemiplegic migraine (type 1 and 2). Upon experimentally induced SD, these mice develop aura-like neurological symptoms, akin to patients with the respective mutations. Migraine mutant mice also exhibit an increased frequency of ischemia-triggered SDs upon experimental stroke, associated with accelerated infarct growth and worse outcomes. The severe stroke phenotype can be explained by SD-related downstream events that exacerbate the metabolic mismatch, including pericyte contraction and neuroglial inflammation. Pharmacological suppression of the genetically enhanced SD susceptibility normalizes the stroke phenotype in familial hemiplegic migraine mutant mice. Recent epidemiologic and imaging studies suggest that these preclinical findings can be extrapolated to migraine patients. Migraine patients are at risk for particularly cardioembolic stroke. At the same time, studies suggest an increased incidence of coagulopathy, atrial fibrillation and patent foramen ovale among migraineurs, providing a possible path for microembolic induction of SD and, in rare instances, stroke in hyperexcitable brains. Indeed, recent imaging studies document an accelerated infarct progression with only little potentially salvageable brain tissue in acute stroke patients with a migraine history, suggesting an increased vulnerability towards cerebral ischemia. CONCLUSION/CONCLUSIONS:Preclinical models suggest a key role for enhanced SD susceptibility and microembolization to explain both the occurrence of migraine attacks and the increased stroke risk in migraineurs. Therapeutic targeting of SD and microembolic events, or potential causes thereof, will be promising for treatment of aura and may also prevent ischemic infarction in vulnerable brains.

Several factors that modulate migraine, a common primary headache disorder, also affect susceptibility to cortical spreading depolarization (CSD). CSD is a wave of neuronal and glial depolarization and thought to underlie the migraine aura and possibly headache. Here, we tested whether caffeine, known to alleviate or trigger headache after acute exposure or chronic use/withdrawal, respectively, modulates CSD. We injected C57BL/6J mice with caffeine (30, 60, or 120 mg/kg; i.p.) once ( acute) or twice per day for one or two weeks ( chronic). Susceptibility to CSD was evaluated by measuring the electrical CSD threshold and by assessing KCl-induced CSD. Simultaneous laser Doppler flowmetry was used to assess CSD-induced cortical blood flow changes. Recordings were performed 15 min after caffeine/vehicle administration, or 24 h after the last dose of chronic caffeine in the withdrawal group. The latter paradigm was also tested in mice carrying the familial hemiplegic migraine type 1 R192Q missense mutation, considered a valid migraine model. Neither acute/chronic administration nor withdrawal of caffeine affected CSD susceptibility or related cortical blood flow changes, either in WT or R192Q mice. Hence, adverse or beneficial effects of caffeine on headache seem unrelated to CSD pathophysiology, consistent with the non-migrainous clinical presentation of caffeine-related headache.

BACKGROUND:Migraine has been identified as a risk factor of 30-day hospital readmission after surgery. We aimed to further characterize this association examining pain as a potentially migraine-associated, preventable reason for readmission. HYPOTHESIS:Compared to patients with no migraine, surgical patients with migraine are at increased risk of 30-day hospital readmission with an admitting diagnosis specifying pain. METHODS:This hospital registry study examined 150,710 patients aged 18 years and above, who underwent surgery with general anesthesia and mechanical ventilation between 2007 and 2015 at a tertiary care center and two affiliated community hospitals in Massachusetts, USA. RESULTS:Migraine was associated with an increased risk of 30-day pain-related readmission after surgery (adjusted odds ratio 1.42 [95% confidence interval 1.15-1.75]). The association was stronger for migraine with aura (compared to migraine without aura: Adjusted odds ratio 1.69 [95% confidence interval 1.06-2.70]; compared to no migraine: Adjusted odds ratio 2.20 [95% confidence interval 1.44-3.37]). The predicted adjusted risk of pain-related 30-day readmissions was 9.1 [95% confidence interval 5.3-13.0] in 1000 surgical patients with migraine with aura and 5.4 [95% confidence interval 4.2-6.6] in 1000 patients with migraine without aura, compared to 4.2 [95% confidence interval 3.8-4.5] in 1000 patients with no migraine. Furthermore, migraine was associated with an increased risk of postsurgical 30-day readmission due to a priori defined migraine-related pain (headache or abdominal pain) (adjusted odds ratio 1.55 [95% confidence interval 1.20-2.00]). CONCLUSION:Patients with migraine undergoing surgery are at increased risk of 30-day hospital readmission due to pain.

Migraine is a common chronic neurological disease that disproportionately affects women. Migraine has significant negative effects on physical, emotional, and social aspects of health, and can be costly for patients, employers, and society as a whole. Growing evidence supports the roles of sex and gender in migraine risk, pathophysiology, presentation, diagnosis, treatment, and management. However, sex and gender differences in migraine have received limited attention, which can impede advancements in migraine detection, treatment, care, and education. The Society for Women's Health Research convened an interdisciplinary expert panel of researchers, clinicians, and advocates for a roundtable meeting to review the current research on sex and gender differences in migraine. This review summarizes discussions from the roundtable and prioritizes areas of need that warrant further attention in migraine research, care, and education. Examining sex and gender differences in migraine and addressing knowledge gaps will decrease the health and economic burden of migraine for both women and men.

Hereditary multiple exostoses (HME) is a genetic condition characterized by the development of multiple osteochondromas during childhood and adolescence. On rare occasions, these bony tumors can be associated with vascular injury, most commonly involving the popliteal artery. Such patients typically present with vascular complications in adolescence and young adulthood. We report an autopsy study of an elderly man who presented with bilateral popliteal artery pseudoaneurysms in the setting of HME at age 81. This is the oldest patient presenting with a vascular complication due to HME reported to date, as well as the only known case of bilateral popliteal pseudoaneurysms caused by HME. This is also the only autopsy study of this vascular complication so far reported. Our case illustrates that vascular complications from HME can occur even in the elderly, and may show bilateral involvement.

Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7-PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine.

OBJECTIVE: To evaluate whether patients with migraine are at increased risk of perioperative ischemic stroke and whether this may lead to an increased hospital readmission rate. DESIGN/METHODS: Prospective hospital registry study. SETTING/METHODS: Massachusetts General Hospital and two satellite campuses between January 2007 and August 2014. PARTICIPANTS/METHODS: 124 558 surgical patients (mean age 52.6 years; 54.5% women). MAIN OUTCOME MEASURES/METHODS: The primary outcome was perioperative ischemic stroke occurring within 30 days after surgery in patients with and without migraine and migraine aura. The secondary outcome was hospital readmission within 30 days of surgery. Exploratory outcomes included post-discharge stroke and strata of neuroanatomical stroke location. RESULTS: 10 179 (8.2%) patients had any migraine diagnosis, of whom 1278 (12.6%) had migraine with aura and 8901 (87.4%) had migraine without aura. 771 (0.6%) perioperative ischemic strokes occurred within 30 days of surgery. Patients with migraine were at increased risk of perioperative ischemic stroke (adjusted odds ratio 1.75, 95% confidence interval 1.39 to 2.21) compared with patients without migraine. The risk was higher in patients with migraine with aura (adjusted odds ratio 2.61, 1.59 to 4.29) than in those with migraine without aura (1.62, 1.26 to 2.09). The predicted absolute risk is 2.4 (2.1 to 2.8) perioperative ischemic strokes for every 1000 surgical patients. This increases to 4.3 (3.2 to 5.3) for every 1000 patients with any migraine diagnosis, 3.9 (2.9 to 5.0) for migraine without aura, and 6.3 (3.2 to 9.5) for migraine with aura. : Patients with migraine had a higher rate of readmission to hospital within 30 days of discharge (adjusted odds ratio 1.31, 1.22 to 1.41). CONCLUSIONS: Surgical patients with a history of migraine are at increased risk of perioperative ischemic stroke and have an increased 30 day hospital readmission rate. Migraine should be considered in the risk assessment for perioperative ischemic stroke.

BACKGROUND:Calabadion 2 is a new drug-encapsulating agent. In this study, the authors aim to assess its utility as an agent to reverse general anesthesia with etomidate and ketamine and facilitate recovery. METHODS:To evaluate the effect of calabadion 2 on anesthesia recovery, the authors studied the response of rats to calabadion 2 after continuous and bolus intravenous etomidate or ketamine and bolus intramuscular ketamine administration. The authors measured electroencephalographic predictors of depth of anesthesia (burst suppression ratio and total electroencephalographic power), functional mobility impairment, blood pressure, and toxicity. RESULTS:Calabadion 2 dose-dependently reverses the effects of ketamine and etomidate on electroencephalographic predictors of depth of anesthesia, as well as drug-induced hypotension, and shortens the time to recovery of righting reflex and functional mobility. Calabadion 2 displayed low cytotoxicity in MTS-3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium-based cell viability and adenylate kinase release cell necrosis assays, did not inhibit the human ether-à-go-go-related channel, and was not mutagenic (Ames test). On the basis of maximum tolerable dose and acceleration of righting reflex recovery, the authors calculated the therapeutic index of calabadion 2 in recovery as 16:1 (95% CI, 10 to 26:1) for the reversal of ketamine and 3:1 (95% CI, 2 to 5:1) for the reversal of etomidate. CONCLUSIONS:Calabadion 2 reverses etomidate and ketamine anesthesia in rats by chemical encapsulation at nontoxic concentrations.

Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine.

Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.