Episodic Migraine With and Without Aura: Key Differences and Implications for Pathophysiology,Management, and Assessing Risks

Purpose of Review

To review the pathophysiologic, epidemiologic, and clinical evidence for similarities and differences between migraine with and without aura.

Recent Findings

The ICHD-3 has recently refined the diagnostic criteria for aura to include positive symptomatology, which better differentiates aura from TIA. Although substantial evidence supports cortical spreading depression as the cause of visual aura, the role (if any) of CSD in headache pain is not well understood. Recent imaging evidence suggests a possible hypothalamic origin for a headache attack, but further research is needed. Migraine with aura is associated with a modest increase in the risk of ischemic stroke. The etiology for this association remains unclear. There is a paucity of evidence regarding treatments specifically aimed at the migraine with aura subtype, or whether migraine with vs without aura responds to treatment differently. Migraine with typical aura is therefore often treated similarly to migraine without aura. Lamotrigine, daily aspirin, and flunarizine have evidence for efficacy in prevention of migraine with aura, and magnesium, ketamine, furosemide, and single-pulse transcranial magnetic stimulation have evidence for use as acute treatments. Although triptans have traditionally been contraindicated in hemiplegic migraine and migraine with brainstem aura, this prohibition is being reconsidered in the face of evidence suggesting that use may be safe.

Summary

The debate as to whether migraine with and without aura are different entities is ongoing. In an era of sophisticated imaging, genetic advancement, and ongoing clinical trials, efforts to answer this question are likely to yield important and clinically meaningful results.

     

Sleep Disorders and Migraine: Review of Literature and Potential Pathophysiology Mechanisms

Migraine shares a complex and poorly understood relationship with sleep. Patients consistently report poor sleep prior to migraine attacks and during them, identifying poor sleep as a migraine trigger. However, anecdotally, sleep is reported to serve a therapeutic role in terminating headache. Are the associations between migraine and sleep simply the result of various bidirectional relationships? A growing body of evidence suggests there may be a common underlying etiology as well. Our objective was to review studies of sleep and migraine from the last 2 decades utilizing validated subjective and objective measures of sleep and to explore potential mechanisms underlying this complex relationship by incorporating recent advances in neuroscience. We specifically focus on insomnia, obstructive sleep apnea, parasomnias, sleep related movement disorders, and REM sleep related disorders and their relationship to migraine. Parts of brainstem‐cortical networks involved in sleep physiology are unintentionally being identified as important factors in the common migraine pathway. Recent discoveries on anatomic localization (the hypothalamus as a key and early mediator in the pathophysiology of migraine), common mediating signaling molecules (such as serotonin and dopamine), and the discovery of a new CNS waste removal system, the glymphatic system, all point to a common pathophysiology manifesting in migraine and sleep problems.     

Non-linear renal function decline is frequent in patients with type 2 diabetes who progress fast to end-stage renal disease and is associated with African-Caribbean ethnicity and HbA1c variability

To our knowledge, there are no studies examining eGFR trajectories in an ethnically diverse cohort of T2DM patients with established DKD and long follow-up. We conducted a retrospective analysis of medical records of T2DM patients attending a specialist diabetes renal clinic in order to identify risk factors and specific eGFR trajectories associated with ESRD. There is limited information and long term follow-up on eGFR trajectories in ethnically diverse cohorts of T2DM patients with established diabetic kidney disease. We conducted a retrospective analysis of medical records of 398 T2DM patients (46.5% African-Carribean ethnicity) to identify risk factors and specific eGFR trajectories associated with end-stage renal disease (ESRD). A non-linear eGFR trajectory was observed in 59% of the 71 patients who reached ESRD. African-Caribbean ethnicity and glycaemic variability are independently associated with distinct non-linear eGFR trajectories that result in fast progression to ESRD. Clinicians should be aware that non-linear eGFR decline is frequent in patients with T2DM who have fast progression to ESRD. Predicting renal function decline based on patterns and early changes in eGFR trajectories and associated risk factors, may better enable individualized risk stratification and care for those at highest risk of rapid progression to ESRD.     

Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis.

AIMS: To evaluate clinical disease expression, non-invasive diagnosis, and prognosis in families with dominant vs. recessive arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations in related desmosomal proteins plakophilin-2 (PKP2) and plakoglobin (JUP), respectively. METHODS AND RESULTS: One hundred and eighty-seven individuals belonging to ARVC families, four with dominant PKP2 mutations and 12 with recessive JUP mutation underwent serial non-invasive cardiac assessment. Survival and arrhythmic events were evaluated prospectively up to 21 years (median 8.5 years). Sixteen of 22 PKP2 carriers and all 26 homozygous JUP carriers fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. Clinical disease expression did not differ significantly between PKP2 and JUP carriers. T-wave inversion in leads V1-V3, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles were the most sensitive/specific markers for identification of mutation carriers. QRS dispersion > or =40 ms was an independent predictor of syncope but not of sudden death. CONCLUSION: Mutations in PKP2 and JUP express similar cardiac phenotype. Non-invasive family screening may largely be based on T-wave inversion, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles to identify mutation carriers.     

The number of cysteine residues per mole in apolipoprotein E affects systematically synchronous neural interactions in women’s healthy brains

Apolipoprotein E (apoE) is involved in lipid metabolism in the brain, but its effects on brain function are not understood. Three apoE isoforms (E4, E3, and E2) are the result of cysteine–arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six apoE genotypes (E4/4, E4/3, E4/2, E3/3, E3/2, E2/2) yield five groups with respect to the number of cysteine residues per mole (CysR/mole), as follows. ApoE4/4 has zero cysteine residues per mole (0-CysR/mole), E4/3 has one (1-CysR/mole), E4/2 and E3/3 each has two (2-CysR/mole), E3/2 has three (3-CysR/mole), and E2/2 has four (4-CysR/mole). The use of the number of CysR/mole to characterize the apoE molecule converts the categorical apoE genotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale (0–4 CysR/mole). This allows the use of statistical analyses suitable for continuous variables (e.g. regression) to quantify the relations between various variables and apoE. Using such analyses, here, we show for the first time that apoE affects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and synchronous neural interactions (SNI) measured by magnetoencephalography (MEG) in 130 cognitively healthy women. At the one end of the CysR/mole range, the 4-CysR/mole (E2/2) SNI distribution had the highest mean, lowest variance, lowest range, and lowest coefficient of variation, whereas at the other end, 0-CysR/mole (E4/4) SNI distribution had the lowest mean, highest variance, highest range, and highest coefficient of variation. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis where the 4-CysR/mole (E2/2) SNI distribution occupied a separate branch by itself and the remaining CysR/mole SNI distributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These findings suggest that the 4-CysR/mole (E2/2) SNI distribution could serve as a reference distribution. When the SNI distributions of individual women were expressed as distances from this reference distribution, there was a substantial overlap among women of various CysR/mole. This refocuses the placement of individual brains along a continuous distance from the 4-CysR/mole SNI distribution, in contrast to the common categorical assignment to a specific apoE genotype. Finally, the orderly variation of SNI with the number of CysR/mole found here is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of apoE in the brain which emphasize the healthier stability conferred on the apoE molecule by the increasing number of cysteine–arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to the instability and increased chance of toxic fragmentation of the apoE molecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case (Mahley and Huang in Neuron 76:871–885, 2012a). However, our results also document the appreciable variation of SNI properties within the various CysR/mole groups and individuals which points to the existence and important role of other factors involved in shaping brain function at the network level.     

Interleukin-31: The “itchy” cytokine in inflammation and therapy

The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T_H2 cells play a central role in AD and release high levels of T_H2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.     

Metalloproteinase expression after desflurane preconditioning in hepatectomies: A randomized clinical trial

BACKGROUNDHepatectomy with inflow occlusion results in ischemia-reperfusion injury; however, pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients. The normal inflammatory response after a hepatectomy involves increased expression of metalloproteinases, which may signal pathologic hepatic tissue reformation. AIMTo investigate the effect of desflurane preconditioning on these inflammatory indices in patients with inflow occlusion undergoing hepatectomy.METHODSThis is a single-center, prospective, randomized controlled trial conducted at the 4^th Department of Surgery of the Medical School of Aristotle University of Thessaloniki, between August 2016 and December 2017. Forty-six patients were randomized to either the desflurane treatment group for pharmacological preconditioning (by replacement of propofol with desflurane, administered 30 min before induction of ischemia) or the control group for standard intravenous propofol. The primary endpoint of expression levels of matrix metalloproteinases and their inhibitors was determined preoperatively and at 30 min posthepatic reperfusion. The secondary endpoints of neutrophil infiltration, coagulation profile, activity of antithrombin III (AT III), protein C (PC), protein S and biochemical markers of liver function were determined for 5 d postoperatively and compared between the groups.RESULTSThe desflurane treatment group showed significantly increased levels of tissue inhibitor of metalloproteinases 1 and 2, significantly decreased levels of matrix metalloproteinases 2 and 9, decreased neutrophil infiltration, and less profound changes in the coagulation profile.  During the 5-d postoperative period, all patients showed significantly decreased activity of AT III, PC and protein S (vs baseline values, P < 0.05). The activity of AT III and PC differed significantly between the two groups from postoperative day 1 to postoperative day 5 (P < 0.05), showing a moderate drop in activity of AT III and PC in the desflurane treatment group and a dramatic drop in the control group. Compared to the control group, the desflurane treatment group also had significantly lower international normalized ratio values on all postoperative days (P < 0.005) and lower serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values on postoperative days 2 and 3 (P < 0.05).   Total length of stay was significantly less in the desflurane group (P = 0.009).CONCLUSIONDesflurane preconditioning can lessen the inflammatory response related to ischemia-reperfusion injury and may shorten length of hospitalization.     

Insight into the 24‐hour ambulatory central blood pressure in adolescents and young adults

This study attempted to investigate the behavior of 24‐hour central ambulatory blood pressure (ABP) in adolescents and young adults. Adolescents and young adults (age 10‐25 years) referred for elevated blood pressure (BP) and healthy volunteers had simultaneous 24‐hour peripheral (brachial) and central (aortic) ABP monitoring using the same automated upper‐arm cuff device (Mobil‐O‐Graph 24h PWA). Central BP was calculated by the device using two different calibration methods (C1SBP using peripheral systolic (pSBP)/diastolic BP and C2SBP using mean arterial/diastolic BP). A total of 136 participants (age 17.9 ± 4.7 years, 54% adolescents, 77% males, 25% volunteers, 34% with elevated peripheral ABP) were analyzed. Twenty‐four‐hour pSBP was higher than C1SBP, with this difference being more pronounced during daytime than nighttime (16.3 ± 4.5 and 10.5 ± 3.2 mm Hg, respectively, P < .001). Younger age, higher body height, and male gender were associated with greater systolic ABP amplification (pSBP‐C1SBP difference). C1SBP followed the variation pattern of pSBP, yet with smaller nighttime dip (8.4 ± 6.0% vs 11.9 ± 4.6%, P < .001), whereas C2SBP increased (2.4 ± 7.2%) during nighttime sleep (P < .001 for comparison with pSBP change). Older age remained independent determinant of larger nighttime BP fall for pSBP and C1SBP, whereas male gender predicted a larger nighttime C2SBP rise. These data suggest that the calibration method of the BP monitor considerably influences the diurnal variation in central BP, showing a lesser nocturnal dip than pSBP or even nocturnal BP rise, which are determined by the individual''s age and gender.