Karl B. Alstadhaug

Migraine and the hypothalamus

Migraine is a complex brain disorder where several neuronal pathways and neurotransmitters are involved in the pathophysiology. To search for a specific anatomical or physiological defect in migraine may be futile, but the hypothalamus, with its widespread connections with other parts of the central nervous system and its paramount control of the hypophysis and the autonomic nervous system, is a suspected locus in quo. Several lines of evidence support involvement of this small brain structure in migraine. However, whether it plays a major or minor role is unclear. The most convincing support for a pivotal role so far is the activation of the hypothalamus shown by positron emission tomography (PET) scanning during spontaneous migraine attacks. A well-known theory is that the joint effect of several triggers may cause temporary hypothalamic dysfunction, resulting in a migraine attack. If PET scanning had consistently confirmed hypothalamic activation prior to migraine headache, this hypothesis would have been supported. However, such evidence has not been provided, and the role of the hypothalamus in migraine remains puzzling. This review summarizes and discusses some of the clues.

Seasonal variation in migraine

Our group has previously shown that migraineurs, as opposed to individuals with other headaches, are more likely to have headache during the bright arctic summer than during the polar night season. We set out to investigate the impact of seasonal light exposure in migraine with and without aura. We performed a questionnaire-based study of 169 female volunteer migraineurs in an arctic area where light conditions during summer and winter seasons are extreme. We included 98 patients with migraine with aura (MA) and 71 with migraine without aura (MoA). One hundred and seven patients (63%) reported seasonal variation in migraine attack frequency. Close to half (47%) of patients with aura, but only 17% of patients without aura, reported more frequent attacks during the light season (P < 0.001). Patients with MA reported interictal light hypersensitivity and light exposure as an attack precipitating factor significantly more often than individuals with MoA. They also reported significantly more frequent use of sunglasses to prevent attacks. We found no significant differences between MA and MoA as regards sleep disturbances, use of oral contraceptives, impact of headache or circadian variations. Seasonal periodicity of migraine in an arctic population with more frequent attacks during the light season is a convincing phenomenon in MA but not in MoA. The amount of light exposure seems to be pivotal to this variation.

Prophylaxis of migraine with melatonin A randomized controlled trial

Background: A previous open-label study of melatonin, a key substance in the circadian system, has shown effects on migraine that warrant a placebo-controlled study. Method: A randomized, double-blind, placebo-controlled crossover study was carried out in 2 centers. Men and women, aged 18–65 years, with migraine but otherwise healthy, experiencing 2–7 attacks per month, were recruited from the general population. After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2 mg 1 hour before bedtime for 8 weeks. After a 6-week washout treatment was switched. The primary outcome was migraine attack frequency (AF). A secondary endpoint was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). Results: Forty-six subjects completed the study (96%). During the run-in phase, the average AF was 4.2 (±1.2) per month and during melatonin treatment the AF was 2.8 (±1.6). However, the reduction in AF during placebo was almost equal (p = 0.497). Absolute risk reduction was 3% (95% confidence interval −15 to 21, number needed to treat = 33). A highly significant time effect was found. The mean global PSQI score did not improve during treatment (p = 0.09). Conclusion: This study provides Class I evidence that prolonged-release melatonin (2 mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis. Classification of evidence: This study provides Class I evidence that 2 mg of prolonged release melatonin given 1 hour before bedtime for a duration of 8 weeks did not result in a reduction in migraine frequency compared with placebo (p = 0.497).

Treatment of Progressive Multifocal Leukoencephalopathy With Interleukin 7

IMPORTANCE No reliable treatment options are known for progressive multifocal leukoencephalopathy with underlying immunodeficiency. We describe successful compassionate use of recombinant human interleukin 7 in a patient with idiopathic CD4+ T-cell lymphocytopenia. OBSERVATIONS After the diagnoses of progressive multifocal leukoencephalopathy and idiopathic CD4+ T-cell lymphocytopenia were established, a 61-year-old man was treated with recombinant human interleukin 7 on November 1, 2012. Except for an episode of epilepsia partialis continua on January 16, 2013, a gradual clinical improvement was observed until March. Abnormalities shown on magnetic resonance imaging regressed; JC virus DNA in plasma, likely originating from the brain based on sequencing data, cleared; and increases in peripheral CD4+ T cells and JC virus intrathecal antibodies were observed. One year after treatment, the CD4+ T-cell count returned to baseline and the clinical improvement waned, possibly due to the patients complex epilepsy. On the latest evaluation on January 14, 2014, the patients condition was unchanged, with no signs of ongoing central nervous system infection. CONCLUSIONS AND RELEVANCE The present case argues strongly for proof of the treatment concept. However, deeper insight into the JC virus and its pathogenesis and the immune response during central nervous system infection as well as further clinical studies are needed before recombinant human interleukin 7 can be recommended for the treatment of other cases of immunodeficiency and progressive multifocal leukoencephalopathy.

Insomnia and Circadian Variation of Attacks in Episodic Migraine

Objectives.—To assess the influence of insomnia on the 24‐hour temporal pattern of migraine.

Circannual periodicity of migraine

Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty‐nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia‐related. By using Edwards’ model for recognition and estimation of cyclic trends, time‐series analysis was made. Fifty‐eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age ± SD was 36.9 ± 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08–1.55). When insomnia‐related attacks (n = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia‐related attacks in patients with MA.

Histamine in Migraine and Brain

Histamine has been studied in both health and disease since the initial description a century ago. With its vasodilative effect, it was suggested early on to be involved in the pathophysiology of migraine. Over the past 25 years, much has been learned about histamine as a neurotransmitter in the central nervous system. The role of this neurotransmitter system in migraine has not been previously reviewed.

Images From Headache: Recurrent Headache Due to MS Plaque

In 2004, a previously healthy 47-year-old female senior scientific officer experienced Lhermitte’s phenomenon and paresthesias involving neck, trunk, and all 4 extremities. Magnetic resonance imaging (MRI) disclosed 2 high-signal lesions; one periventricular in the right cerebral hemisphere, and one in the posterior part of the upper cervical medulla. Her sensory symptoms abated and additional evidence needed for a final diagnosis of multiple sclerosis (MS) was not provided. In October 2006, the patient arrived at the emergency room due to an infernal global thrusting head pain associated with vigorous vomiting.The headache had started 2 days earlier as stabbing pain around the jaws, behind the ears and in the neck/back of the head. Except for the face she also experienced global numbness and paresthesias. Neurological examination revealed general hyporeflexia, sensory deficit (all modalities) affecting the whole body except the face, and severe dysmetria in all extremities. Twenty milligrams morphine was given and the patient fell asleep. She woke without headache, but in the afternoon the second day in hospital she had a relapse and 1 g of methylprednisolone was given. Two and a half hours later, the patient was headache-free. Steroids were continued for 3 days. MRI on day 4 (Fig., A) was in all essentials identical to the one from 2004. Additional examinations were compatible with MS. Neuromyelitis optica immunoglobulin G was not found (examined at the Mayo Clinic in the USA). Due to progression of her sensory symptoms with gait difficulties, treatment with Immune Globulin Intravenous (Octagam, Octapharma, Stockholm, Sweden) was given. Five days after admission the patient again got increasing occipital headache, which rapidly spread frontally bilaterally. The pain got unbearable and large doses of opiates were given before she eventually fell asleep. She was headachefree until the evening the day after when she experienced right-sided hemicrania that also was excruciating. During the next fortnight, she experienced 6 more attacks analogous to those described. Several types of analgesics were given without effect, including nesacaine infusions and subcutaneous sumatriptan. A new MRI scan on day 17 (Fig., B) showed marked progression of the spinal lesion. Her sensory symptoms gradually improved, and she was headache-free from day 20. Six months later, the patient reported no headache after being discharged from hospital. She still experienced dysaesthesia from C2 and distally. MRI showed regression of the cervical plaque (Fig., C).

24-Hour Distribution of Migraine Attacks

Background.— It is a widespread opinion that migraine attacks arise more frequently in the morning and that circadian rhythms may be responsible for the temporal pattern in migraine. However, only one small prospective study has previously been published on this topic.

Acceptability, Feasibility, and Cost of Telemedicine for Nonacute Headaches: A Randomized Study Comparing Video and Traditional Consultations

Background The feasibility of telemedicine in diagnosing and treating nonacute headaches, such as primary headaches (migraine and tension-type) and medication-overuse headaches has not been previously investigated. By eliminating the need of travel to specialists, telemedicine may offer significant time and money savings. Objectives Our objective was to estimate the acceptance of telemedicine and investigate the feasibility and cost savings of telemedicine consultations in diagnosing and treating nonacute headaches. Methods From September 2012 to March 2015, nonacute headache patients from Northern Norway who were referred to neurologists through an electronic application system were consecutively screened and randomized to participate in either telemedicine or traditional specialist visits. All patients were consulted by two neurologists at the neurological department in Tromsø University Hospital. Feasibility outcomes were compared between telemedicine and traditional groups. Baseline characteristics and costs were then compared between rural and urban patients. Travel costs were calculated by using the probabilistic method of the Norwegian traveling agency: the cheapest means of public transport for each study participant. Loss of pay was calculated based on the Norwegian full-time employee’s average salary: < 3.5 hours=a half day’s salary, > 3.5 hours spent on travel and consultation=one day’s salary. Distance and time spent on travel were estimated by using Google Maps. Results Of 557 headache patients screened, 479 were found eligible and 402 accepted telemedicine participation (83.9%, 402/479) and were included in the final analyses. Of these, 202 received traditional specialist consultations and 200 received telemedicine. All patients in the telemedicine group were satisfied with the video quality, and 198 (99%, 198/200) were satisfied with the sound quality. The baseline characteristics as well as headache diagnostics and follow-up appointments, and the investigation, advice, and prescription practices were not statistically different between the two randomized groups. In addition, telemedicine consultations were shorter than traditional visits (38.8 vs 43.7 min, P<.001). The travel cost per rural individual (292/402, 73%) was €249, and estimated lost income was €234 per visit. The travel cost in the urban area (110/402, 27%) was €6, and estimated lost income was €117 per visit. The median traveling distance for rural patients was 526 km (range 1892 km), and the median traveling time was 7.8 hours (range 27.3 hours). Rural patients had a longer waiting time than urban patients (64 vs 47 days, P=.001), and fewer women were referred from rural areas (P=.04). Rural women reported higher pain scores than urban women (P=.005). Conclusion Our study shows that telemedicine is an accepted, feasible, time-saving, and cost-saving alternative to traditional specialist consultations for nonacute headaches. Trial Registration Clinicaltrials.gov NCT02270177; http://clinicaltrials.gov/ct2/show/NCT02270177 (Archived by WebCite at http://www.webcitation.org/6hmoHGo9Q)