Treatment of hemiplegic migraine with anti-calcitonin gene-related peptide monoclonal antibodies: A case series in a tertiary-care headache center.

Hemiplegic migraine (HM) is a subtype of migraine with aura that includes motor weakness; such headaches can be excruciating. The presence of not only headache but also aura symptoms of HM increase the burden on patients, and the treatment of HM is sometimes challenging. Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway are novel migraine preventive treatments that have shown promising efficacy in patients with migraine; however, there have been no reports regarding their efficacy in HM to date. Six patients with HM were treated with galcanezumab in a tertiary-care headache center. After 3 months of treatment, the number of monthly days with headache of at least moderate severity was reduced in three patients. The number of days each month with weakness was also reduced in four patients. Furthermore, the Patient's Global Impression of Change and change in Migraine Disability Assessment total score, were improved in five of the six patients after the treatment; however, the change from baseline in days with bothersome symptoms did not show any specific trends in our patients. Notably, no adverse events were reported during the treatments. The mechanism underlying the improvement in aura symptoms in our patients is not clear; however, we speculate that a small amount of CGRP mAbs have a direct mode of action in the central nervous system; alternatively, blocking the CGRP pathway in the periphery may secondarily inhibit cortical spreading depression. While prudence must be practiced, galcanezumab was still generally effective in HM and well tolerated. Further prospective clinical studies will more clearly elucidate the effects of CGRP mAbs in patients with HM.

Cranial autonomic symptoms in migraine are related to central sensitization: a prospective study of 164 migraine patients at a tertiary headache center.

BACKGROUND: Cranial autonomic symptoms (CASs) during migraine attacks are reported to be quite common regardless of ethnicity. In our previous study investigating 373 migraineurs, we found that 42.4% of them had CASs. The patients with CASs more frequently had cutaneous allodynia than did those without CASs, and we speculated that CASs were associated with central sensitization. The present study searched for substantial evidence on the relationship between CASs and central sensitization in migraine patients. METHODS: This was a prospective cross-sectional study. We studied a new independent cohort of 164 migraineurs who presented to the Tominaga Hospital Headache Center from July 2018 until December 2019. The clinical features of CASs according to the criteria in ICHD-3 (beta) were investigated. We also evaluated central sensitization based on the 25 health-related symptoms utilizing the validated central sensitization inventory (CSI), and each symptom was rated from 0 to 4 resulting a total score of 0-100. RESULTS: The mean age was 41.8 (range: 20 to 77) years old. One hundred and thirty-one patients (78.9%) were women. Eighty-six of the 164 (52.4%) patients had at least 1 cranial autonomic symptom. The CSI score of the patients with ≥3 CASs reflected a moderate severity and was significantly higher than in those without CASs (41.9 vs. 30.7, p = 0.0005). The score of the patients with ≥1 conspicuous CAS also reflected a moderate severity and was significantly higher than in those without CASs (40.7 vs. 33.2, p = 0.013). The patients in the CSI ≥40 group had lacrimation, aural fullness, nasal blockage, and rhinorrhea, which are cranial autonomic parasympathetic symptoms, significantly more frequently than those in the CSI < 40 group. CONCLUSIONS: Migraine patients with CASs showed significantly greater central sensitization than those without such symptoms. In particular, cranial parasympathetic symptoms were more frequent in centrally sensitized patients than in nonsensitized patients, suggesting that cranial parasympathetic activation may contribute to the maintenance of central sensitization. TRIAL REGISTRATION: This study was retrospectively registered with UMIN-CTR on 29 Aug 2020 ( UMIN000041603 ).

Cranial Autonomic Symptoms of Migraine in Japan: Prospective Study of 373 Migraine Patients at a Tertiary Headache Center.

OBJECTIVE: To clarify the detailed clinical characteristics of cranial autonomic symptoms (CAS) of Japanese patients with migraine and to get insight into the pathophysiological implications. BACKGROUND: Recent studies reported that CAS in migraine is causing diagnostic confusion with cluster headache or sinus headache; however, most reports have concerned Caucasians, and Asian data are scarce. The regional differences in the clinical characteristics of primary headaches between Caucasians and Asians have also been revealed recently. METHOD: This was a cross-sectional study. We investigated 373 patients with migraine in a tertiary headache center with face-to-face interviews. RESULTS: According to our findings, 158/373 (42.4%) patients with migraine had CAS and were characterized by more frequent cutaneous allodynia than those without CAS, suggesting the contribution of central sensitization; however, there were no statistically significant differences in pulsating pain or motion sensitivity as signs of peripheral sensitization. In contrast to the previous study, osmophobia was found to be significantly related to CAS. CONCLUSION: CAS in patients with migraine is common not only in Caucasians but also in Asians. Central sensitization seems to contribute more than peripheral sensitization to CAS manifestation, and osmophobia might be noteworthy among Asian patients with migraine. To avoid a misdiagnosis, we emphasize the need for comments on CAS in the international classification of headache disorders migraine criteria.

[Unable to Work Due to Migraine for Which Tryptan is Taken 14 Times a Month or Less: How to Choose Preventive Medication].

Migraineurs often experience severe headache attacks and their quality of life is inhibited. Most migraineurs treat their headaches with acute treatment, but preventive treatment is often not chosen appropriately. Because migraine attack frequency and medication overuse are risk factors for headache progression (chronification) and medication-overuse headache, it is possible that preventive medication may also reduce risk progression. Therefore, it is necessary to select preventive medication if required.

[Three Japanese cases of hypnic headache].

We described three cases of hypnic headache with successful treatment by lithium carbonate or caffeine. This is the first detail report of Japanese cases. An endocrinological test and rhythm analyses of ambulatory blood pressure (ABP) and heart rate variability in a case suggested possible association between hypnic headache and hypothalamic-pituitary dysfunction. Case 1: A 48-year-old female migraineur complained of new-onset nocturnal headaches. Her headache awakened her from sleep between 1 AM and 2 AM. The headache occurred 3-4 times per week and lasted from 1 hour to 2 hours. The headache were moderate intensity and bilateral dull throbbing pain that located in the forehead to temples. There was no accompanying symptoms such as nausea, phonophobia, photophobia, nor the other autonomic features including conjunctival injection or tearing during the headache attacks. Physical and neurological examinations showed normal results except slight weakness and mild dysesthesia of the left arm due to a vertebral disk herniation at C5/6 level. In the pituitary endocrinological test, the prolactin level remarkably increased in response to the TRH loading. The single cosinor analysis demonstrated significant circadian rhythm of ABP parameters. However, the analysis did not demonstrate any significant circadian rhythm of Holter ECG parameters of time domain analysis and frequency analysis. Receiving 200 mg lithium bicarbonate before sleep, her nocturnal headache completely disappeared. Case 2: A 68-year-old woman had been followed up by her chronic tension-type headache since her forties. At her 66-years, she suffered from a new nocturnal headache. She awoke from sleep by the headache about 3 AM and the headache lasted 30 min. Moderate, dull headache located on her left temple to parietal head, 3-4 times/week. She was able to go back asleep without any medication after spontaneous headache cessation. She first complained the nocturnal headache at the 10 months later of the new headache appearance. She received 200 mg caffeine just before sleep and her headache has been disappeared. Case 3: 70-year-old women had been regularly visited our clinics for her migraine and chronic tension-type headache. She received amitriptyline and her headaches was well controlled. At her 69 years, she complained nocturnal headache. It occured every other day. The headache was moderate pulsative dull pain on the occipital region and lasted 90 minutes without any autonomic symptoms. Headache began between midnight and 1 AM. She told us her new nocturnal headache one year later of the onset. Oral caffeine (200 mg) just before sleep did not improve her headache and caused insomnia. Receiving 100 mg lithium before sleep, her hypnic headache disappeared completely. These three cases are compatible with the diagnostic criteria proposed in ICHD-II. There were some patients with hypnic headache in Japan and neurologists should pay attentions to this form of benign headache, because some beneficial treatments are currently available.

Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura.

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin-angiotensin-aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls (p<0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p<0.01; odds ratio=5.26, 95% confidence interval: 1.69-16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.

Somatosensory evoked high-frequency oscillations in migraine patients.

OBJECTIVE: To explore additional evidence concerning generators of somatosensory evoked high-frequency oscillations (HFOs). METHODS: We recorded HFOs in migraine patients. Subjects were 19 healthy normal subjects and 19 migraineurs. Electrical stimuli were delivered alternately to the right and left median nerves at their wrists. EEGs were recorded from C3'-Fz, C4'-Fz, Erb1-Erb2, Erb2-Erb1 and Cv6-Fz using a 0.3 Hz low-frequency filter and a 3000 Hz high-frequency filter. Responses to 5000 stimuli were averaged. For separation of HFOs from underlying N20, the digitized wide-band signals were digitally bandpass filtered (400-800 Hz) and averaged. RESULTS: There were no significant differences in peak latencies and amplitudes for N9, N13, N20 and P25 components between normal controls and migraineurs. Root-mean-square amplitudes for HFOs in migraineurs were significantly diminished compared with normal controls. CONCLUSIONS: A diminished inhibitory mechanism in the somatosensory system may exist in migraineurs. It remains to determine what cell populations contribute to generating HFOs. SIGNIFICANCE: This indicates that there is a dysfunction in cortical information processing in the somatosensory cortex of migraineurs.

[Hemicrania continua: the first Japanese case report].

A 47-year-old woman suffered from strictly unilateral headache, characterized by "jabs and jolts" and a pressing quality in temporal-parietal regions on her left side. Her headache was continuous. The pain from her headache was severe enough to prohibit her daily activities and fluctuated from moderate to severe during the daytime. After treatment with a 75 mg daily dose of indomethacin, her headache was completely resolved. Where patients with chronic daily headaches are unresponsive to standard therapies, a trial of indomethacin is warranted.

Increased plasma transforming growth factor-beta1 in migraine.

BACKGROUND AND OBJECTIVES: Migraine is characterized by the peripheral and central sensitization of pain perceptive neural systems, and neurogenic inflammation is a key step in the development of migraine headache. We focused on transforming growth factor-beta1 (TGF-beta1), which is a multifunctional proinflammatory cytokine. To address the possibility of TGF-beta1 involvement in migraine, we investigated the plasma level of TGF-beta1 in patients with migraine headache during headache-free periods. SUBJECTS AND METHODS: Sixty-eight subjects with migraine participated: 23 with migraine with aura (MWA) and 45 without aura (MWoA). We recruited 58 healthy subjects without headache as controls. In addition, we examined 12 subjects with episodic tension-type headache. Platelet poor plasma (PPP) was obtained from subjects during headache free-periods. TGF-beta1 levels in PPP were determined by enzyme-linked immunosorbent assay. RESULTS: The TGF-beta1 level in PPP was 2.62*+/- 0.23 (mean +/- SE) ng/mL in migraine, 2.08 +/- 0.20 ng/mL in tension-type headache, and 1.80 +/- 0.09 ng/mL in controls (P= .007, ANOVA; *P < .01, post hoc tests vs. the controls). CONCLUSION: TGF-beta1 in PPP was significantly increased in patients with migraine during headache-free periods. TGF-beta1 may play some role in the development of migraine headache.

Static stabilometry in patients with migraine and tension-type headache during a headache-free period.

The vestibulospinal system was evaluated using a stabilometric method in patients with migraine and episodic tension-type headache during headache-free periods. Migraine patients often complain of dizziness or vertigo during headache attacks and some exhibit these symptoms between attacks. Computerized static stabilometry is a reliable and non-invasive technique to evaluate the equilibrium function in various diseases. The subjects consisted of 21 patients with migraine, 12 patients with episodic tension-type headache and, age- and sex-matched controls. We performed two sets of static stabilometric measurements with eyes open (EO) and eyes closed (EC) for 30 s. The averages of two sessions of the following six stabilometric parameters were used for the analysis: locus length (LNG), environmental area (ENV-AREA), rectangle area (REC-AREA), locus length per second, locus length per environ area (L/E), and root mean square area. Romberg quotients (EC/EO) of these six parameters were also analyzed. The mean values of LNG, ENV-AREA and REC-AREA in the EC session in the migraine group were significantly greater than those in the controls (P < 0.05, Mann-Whitney rank sum test). Romberg quotients of all stabilometric parameters except the L/E in the migraine group were significantly greater than in the controls. Patients with episodic tension-type headache did not show any differences in the stabilometric study from the controls. The present findings suggest that patients with migraine show a significant increase of the body sway during the EC session, which indicates an underlying dysfunction in the vestibulospinal system.

Population-based door-to-door survey of migraine in Japan: the Daisen study.

OBJECTIVES: To determine prevalence and characteristics of migraine in Japan, and to investigate use of medical care and whether food preference is associated with risk of migraine. METHODS: Structured questionnaires were given to all adult residents (N = 5758; 2681 men and 3077 women) in Daisen, a rural community in western Japan. Second questionnaires, specific to headache, were given to 1628 residents with headache. A telephone survey was also carried out. Statistical Packages for the Social Sciences analyzed the data. RESULTS: The 1-year prevalence of migraine was 2.3% (migraine with aura, 0.4% and without aura, 1.9%) in men and 9.1% (migraine with aura, 1.0% and migraine without aura, 8.1%) in women. Overall prevalence of migraine in Daisen was 6.0% (95% confidence interval [CI], 5.4% to 6.6%). Women observed a 5.9-fold higher risk of migraine than men (odds ratio, 5.9; 95% CI, 4.5 to 8.0; P <.0001, after age adjustment, by logistic analysis). Fatigue and loss of vigor were predominant premonitory symptoms of migraine. Fatigue, mental stress, and lack of sleep were the main headache triggers. Over a 3-month period, 20.3% of migraineurs experienced time or days off work due to headache. Only 7.3% of those with migraine with aura and 5.3% of those with migraine without aura had consulted a physician, and of those with migraine, 61.0% with aura and 71.8% without aura had never visited a medical doctor for their headache. Consumption of alcohol and cigarette smoking did not influence the risk for migraine or tension-type headache, after age and gender adjustment (logistic analysis). Migraineurs consume significantly more fatty/oily foods, coffee, and tea than nonheadache subjects of the same community. Migraineurs consume significantly fewer fish than nonheadache residents. CONCLUSIONS: Only a few Japanese migraineurs receive benefits of medical services and recent advances of headache medicine. Public education concerning headaches is one of the most urgent issues in Japan.