Neurovascular Coupling in Type 2 Diabetes With Cognitive Decline. A Narrative Review of Neuroimaging Findings and Their Pathophysiological Implications.

Type 2 diabetes causes substantial long-term damage in several organs including the brain. Cognitive decline is receiving increased attention as diabetes has been established as an independent risk factor along with the identification of several other pathophysiological mechanisms. Early detection of detrimental changes in cerebral blood flow regulation may represent a useful clinical marker for development of cognitive decline for at-risk persons. Technically, reliable evaluation of neurovascular coupling is possible with several caveats but needs further development before it is clinically convenient. Different modalities including ultrasound, positron emission tomography and magnetic resonance are used preclinically to shed light on the many influences on vascular supply to the brain. In this narrative review, we focus on the complex link between type 2 diabetes, cognition, and neurovascular coupling and discuss how the disease-related pathology changes neurovascular coupling in the brain from the organ to the cellular level. Different modalities and their respective pitfalls are covered, and future directions suggested.

Intranasal ketamine for acute cluster headache attacks-Results from a proof-of-concept open-label trial.

OBJECTIVE: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. BACKGROUND: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack. METHODS: We conducted an open-label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in-hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment. RESULTS: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: -0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11-point NRS (mean difference: 4.3, 95% CI: 2.4-6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. CONCLUSION: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine.

Episodic and Chronic Cluster Headache: Differences in Family History, Traumatic Head Injury, and Chronorisk.

OBJECTIVE AND BACKGROUND: The diagnostic criteria of episodic and chronic cluster headache (cCH) were recently modified, yet pathophysiological differences between the two are still unclear. The aim of this cross-sectional study is to identify and characterize other differences between episodic and cCH. METHODS: Data from a retrospective, questionnaire- and interview-based study were analyzed with a focus on associated factors including traumatic head injury (THI), familial history, and change of phenotype. Attack patterns were analyzed using Gaussian and spectral modeling. RESULTS: 400 patients and 200 controls participated. A positive family history was more prevalent in chronic than episodic cluster headache (eCH) (34/146 (23%) vs 33/253 (13%), respectively, P = .008). A history of THI was more common in patients than controls (173/400 (43%) vs 51/200 (26%), respectively, P < .0001) and in chronic compared to eCH (77/146 (53%) vs 96/253 (37%), respectively, P = .004). Patients with a positive family history had a unique diurnal attack pattern with twice the risk of nocturnal attacks as patients who did not report family history. Patients reporting phenotype change had a chronobiological fingerprint similar to the phenotype they had experienced a transition into. A higher attack frequency in chronic patients was the only difference in symptom manifestation across all analyzed subgroups of patients. CONCLUSIONS: cCH is associated with a positive family history and THI. In familial CH, a peak in nocturnal chronorisk may implicate genes involved in diurnal-, sleep- and homeostatic regulation. The stereotypical nature of the CH attacks themselves is confirmed and differences between subgroups should be sought in other characteristics.

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives.

OBJECTIVE: A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. BACKGROUND: Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. METHODS: A Pubmed search was conducted: "Verapamil"[Mesh] and "Cluster Headache"[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled-trials or open labels studies), safety, and mechanism of effect. RESULTS: Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open-label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open-label studies support a dose-dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene-related peptide. CONCLUSION: Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood.

The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications.

The hallmark of primary headaches belonging to the group known as the trigeminal autonomic cephalalgias is unilateral headache accompanied by cranial autonomic symptoms. Being relatively rare and poorly understood, they represent a clinical challenge, leading to underdiagnosis and undertreatment. While the headache is the most obvious and disabling symptom, it is only part of a complex symptomatology which hints at the involved pathophysiological mechanisms. Activation of the trigeminal-autonomic reflex results in the aforementioned cranial autonomic symptoms, which are well understood; however, it is obvious that this brainstem reflex is regulated by higher centers that seemingly play a pivotal role in the attacks and the wide range of other symptoms indicating a homeostatic disturbance. These symptoms, as well as a number of well-validated findings, implicate the hypothalamus in the pathophysiology. over the course of the past 2-3 decades, novel therapies and technological advances have helped increase our knowledge of these clinical syndromes, and will likely continue to do so in the coming years as we witness the arrival of new drugs and neurostimulation options. In this review, the clinical presentation for cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and hemicrania continua is covered, along with our current understanding of the common pathophysiology and clinical manifestations.

Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months.

BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 ± 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point "after remission" was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 ± 86 (range 21-272) days after initiation of stimulation. On average, each patient's longest remission period lasted 149 ± 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % ± 25 % before, 49 % ± 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 ± 6.0 before, 55.2 ± 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability.

A Review of Cardiovascular Autonomic Control in Cluster Headache.

OBJECTIVE: This review aims to evaluate existing literature concerning cardiovascular autonomic function and CH. Suggestions about future research are offered and known difficulties in investigating the autonomic nervous system in cluster headache are discussed. BACKGROUND: Little is known of the pathophysiological mechanisms behind cluster headache. Cranial autonomic features are an inherent and diagnostic feature; however, a number of studies and clinical observations support the involvement of systemic autonomic control in its pathophysiology. Further, cluster headache attacks are apparently more easily triggered during periods of parasympathetic dominance. A better understanding of this interaction may provide insight into central autonomic regulation and its role in cluster headache. METHODS: A PubMed search was performed in April 2015 using the search terms "cluster headache," "cardiovascular," "autonomic nervous system," and "cardiac." References of identified articles were also searched for relevant articles. Studies were included if they contained data on cardiovascular or autonomic responses to autonomic tests, induced or spontaneous attacks. RESULTS: In total, 22 studies investigating cardiac autonomic control in cluster headache were identified. Three overall categories of investigations exist: (1) Those studying changes in heart rate, blood pressure, and electrocardiographic changes; (2) those employing various clinical autonomic tests; and finally (3) those using spectral and nonlinear analysis of heart rate variability. Although not completely congruent, overall, results suggest ictal hyperactivation of the parasympathetic branch and a sympathetic deficit. Subclinical autonomic dysregulation is also present in the pain-free state. CONCLUSION: Cardiac autonomic control is subclinically affected in cluster headache. The changes could be attributed to the suggested central dysregulation present in this disorder.

Reduced Baroreflex Sensitivity in Cluster Headache Patients.

OBJECTIVE AND BACKGROUND: Important elements of cluster headache (CH) pathophysiology may be seated in the posterior hypothalamus. Cranial autonomic features are inherent, but involvement of systemic autonomic control is still debated. We aimed to characterize autonomic function as investigated by baroreflex sensitivity (BRS) in CH patients. METHODS: Twenty-six active CH patients and an equal number of age-, sex-, and BMI-matched controls underwent head-up tilt table test and BRS was determined by the sequence method. RESULTS: Compared with controls, patients exhibited a blunted reactivity of RR intervals in response to falls and increases in systolic blood pressure (SBP) (15.3 vs. 20.0 ms/mmHg, P = .0041) in the supine position. Also, compared with controls, BRS was lower in patients having suffered an attack within the past 12 hours (n = 13, 12.5 vs. 22.3 ms/mmHg, P = .0091), opposed to those patients who had not (n = 13, 16.0 ms/mmHg, P = .1523). In the tilted position, the drop in SBP at the carotid sinuses was higher in patients who had recently suffered an attack. Despite this, they exhibited a less marked shortening of RR intervals when compared with patients who had been attack free for longer. CONCLUSIONS: CH patients exhibit a subclinical blunting of BRS that may be affected by the attacks themselves. The fast RR interval fluctuations used in this method reflects cardiovagal responses, thus the blunted responses are suggestive of dysfunction in the parasympathetic division of the autonomic nervous system or in the central relay of impulses from the baroreceptors.

Oxygen treatment of cluster headache: a review.

PURPOSE: Our aim was to review the existing literature to document oxygen's therapeutic effect on cluster headache. METHOD: A PubMed search resulted in 28 hits, and from these and their references we found in total 11 relevant studies. We included six studies that investigated the efficacy of oxygen treatment. One study is observational and the remaining five are RCTs. Another five studies were on hyperbaric oxygen treatment hereof two case studies. CONCLUSION: Oxygen therapy can be administered at different flow rates. Three studies investigate the effect of low-flow oxygen, 6-7 l/min, and found a positive response in 56%, 75% and 82%, respectively, of the patients. One study investigates high-flow oxygen, 12 l/min, and found efficacy in 78% of attacks. The effect of hyperbaric oxygen therapy has been investigated in a few small studies and there is evidence only for an acute, but not a prophylactic effect. Despite the fact that only a few high-quality RCT studies are available, oxygen treatment is close to an ideal treatment because it is effective and safe. However, sufferers of cluster headache do not always have access to oxygen because of logistic and financial concerns.