Indomethacin has no effect on trigeminally provoked parasympathetic output.

BACKGROUND: Unlike other non-steroidal anti-inflammatory drugs, indomethacin has been shown to be highly effective in two forms of trigeminal autonomic cephalalgias, hemicrania continua and paroxysmal hemicrania and in some forms of idiopathic stabbing headaches. This specificity is unique in the headache field. Previous findings suggest the involvement of the trigeminal autonomic reflex to play an important role in the pathophysiology of these diseases. METHODS: 22 healthy participants were enrolled in a double-blind, three-day within-subject design. The participants received indomethacin, ibuprofen or placebo in a randomized order. After an incubation period of 65 min the baseline lacrimation and the lacrimation during intranasal stimulation evoked by kinetic oscillation stimulation were assessed using Schirmer II lacrimation tests. The lacrimation difference in mm was calculated and compared in a repeated measures ANOVA. RESULTS: No significant differences were found between the three conditions. CONCLUSION: In our study, neither indomethacin nor ibuprofen had an inhibitory effect on the trigeminal autonomic reflex. We suggest that blocking this reflex may not be the treatment mechanism of indomethacin.

Hypothalamic activation discriminates painful and non-painful initiation of the trigeminal autonomic reflex - an fMRI study.

BACKGROUND: The role of the trigeminal autonomic reflex in headache syndromes, such as cluster headache, is undisputed but sparsely investigated. The aim of the present study was therefore, to identify neural correlates that play a role in the initiation of the trigeminal autonomic reflex. We further aimed to discriminate between components of the reflex that are involved in nociceptive compared to non-nociceptive processing. METHODS: Kinetic Oscillation Stimulation (KOS) in the left nostril was applied in order to provoke autonomic symptoms (e.g. lacrimation) via the trigeminal autonomic reflex in 26 healthy participants using functional magnetic resonance imaging. Unpleasantness and painfulness were assessed on a visual analog scale (VAS), in order to assess the quality of the stimulus (e.g. pain or no pain). RESULTS: During non-painful activation, specific regions involved in the trigeminal autonomic reflex became activated, including several brainstem nuclei but also cerebellar and bilateral insular regions. However, when the input leading to activation of the trigeminal autonomic reflex was perceived as painful, activation of the anterior hypothalamus, the locus coeruleus (LC), the ventral posteriomedial nucleus of the thalamus (VPM), as well as an activation of ipsilateral insular regions, was observed. CONCLUSION: Our results suggest the anterior hypothalamus, besides the thalamus and specific brain stem regions, play a significant role in networks that mediate autonomic output (e.g. lacrimation) following trigeminal input, but only if the trigeminal system is activated by a stimulus comprising a painful component.

The unique role of the trigeminal autonomic reflex and its modulation in primary headache disorders.

PURPOSE OF REVIEW: The trigeminal autonomic reflex is a physiological reflex with an important protective function which also plays a role in pathophysiological conditions, such as primary headache. It is not understood whether the autonomic symptoms in trigeminal autonomic cephalalgias and migraine are the consequence of severe trigeminal discharge or indeed directly driven by central generators as part of the pathophysiology, underlying these syndromes. RECENT FINDINGS: Modulating this reflex, and particularly the parasympathetic reflex arc, has been shown to be effective in treating headache. Among these modulators, left noninvasive vagal nerve stimulation has been shown to bilaterally inhibit the parasympathetic output of the reflex. Furthermore, the peripheral activation of the reflex, resulting in parasympathetic discharge, is not sufficient to provoke headache attacks in cluster headache patients, suggesting a central modulation. SUMMARY: Here, we review the anatomy and physiology of the trigeminal autonomic reflex and its involvement in primary headache. Possible candidates who have a modulating effect, including neurostimulation and pharmacological approaches, are described.

Vagus nerve stimulation modulates the cranial trigeminal autonomic reflex.

OBJECTIVE: The trigeminal autonomic reflex plays an important role in primary headache syndromes. Noninvasive vagal nerve stimulation (nVNS) may be an effective modulator of this reflex. METHODS: Twenty-two healthy volunteers underwent kinetic oscillation stimulation (KOS) of the left nostril as a reliable trigger of the trigeminal autonomic reflex. Previous to KOS, left cervical nVNS, sham simulation, or no stimulation was applied. Lacrimation was quantified using the standardized Schirmer ll test. RESULTS: Treatment with cervical nVNS significantly reduced lacrimation between no stimulation and nVNS on the ipsilateral side (minute 5: p = 0.026, ηp2 = 0.85, 95% confidence interval [CI] = 1.39-18.04; no stimulation: minute 5, 14.4 ± 9.3 mm; nVNS: minute 5, 4.7 ± 8.6 mm, mean ± standard deviation) as well as between sham stimulation and nVNS (minute 5: p = 0.030, ηp2 = 0.85, 95% CI = 1.04-17.24; sham: minute 5, 13.9 ± 6.4 mm). On the contralateral side, no significant increase between baseline and KOS was observed for nVNS (minute 5: p = 0.614, d = 0.12, 95% CI = -7.09 to 4.31; minute 5, 1.4 ± 11.5 mm) compared to both sham stimulation (minute 5: p = 0.023, d = 0.57, 95% CI = -11.46 to -0.96; minute 5, 6.2 ± 10.9 mm) and no stimulation (minute 5: p < 0.030, d = 0.62, 95% CI = -13.45 to -0.81; minute 5, 7.1 ± 11.4 mm). INTERPRETATION: Cervical nVNS resulted in a robust bilateral reduction of provoked lacrimation. This effect could be mediated either by direct bilateral activation of structures such as the nucleus of the solitary tract or by a top-down modulation via the hypothalamus. Ann Neurol 2018;84:886-892.

Peripheral provocation of cranial autonomic symptoms is not sufficient to trigger cluster headache attacks.

Background Recently it has been suggested that low frequency stimulation of the sphenopalatine ganglion (SPG) may provoke cluster-like attacks in cluster headache (CH) patients. The question arises whether a robust activation of cranial autonomic symptoms is sufficient to trigger CH attacks. Methods Kinetic oscillation stimulation (KOS) of the nasal mucosa generates ipsilateral marked autonomic symptoms, among which lacrimation is quantitatively measurable. KOS was applied to 29 CH-patients, including both episodic and chronic course. We measured lacrimation at rest and during stimulation, and assessed CH attacks within 24 hours after the experiment. Results Autonomic symptoms including lacrimation were robust and significantly generated, compared to rest. Six patients were lost to follow-up, but did not develop an attack during their stay in the clinic. Of the remaining 23 patients, none developed an attack in the next 4 hours after stimulation, despite marked cranial autonomic symptoms during stimulation. Discussion Peripheral stimulation close to the SPG generated a strong parasympathetic response. However, this stimulation was not sufficient to induce CH attacks, which suggests that a central component is crucial to attack generation.

Use of Web-Based Videos in a Community Pharmacy to Optimize Inhalation Technique.

Purpose: Numerous studies have demonstrated that incorrect use of inhalers prescribed to treat airway diseases is commonly observed and is associated with unfavorable clinical outcomes. The aim of the current study was to investigate whether inhalation technique can be improved by the demonstration of short training video sequences provided by the German Airway League. Patients and Methods: Patients filling a script for an inhalator in a community pharmacy were asked to demonstrate their inhalation technique which was rated using specific checklists. Patients not inhaling correctly demonstrated inhaler use again after having viewing the training video. Results: A total of 229 (n=229) patients were included in the study of whom 165 (n=165) (72.1%) made at least one critical mistake when inhaling. Training videos were only demonstrated to patients with incorrect inhaler technique. After having watched the video 80 (n=80) of 165 (n=165) (48.5%) patients with incorrect inhaler use at baseline demonstrated correct inhalation technique now and the number of critical mistakes decreased significantly (1 [0; 1] vs 2 [1.5; 3]; p<0.0001). Device use was demonstrated by a member of the study team to patients still not inhaling correctly (n=85) resulting in a correct technique in 64 (n=64) (75.3%) of these patients. Conclusion: Incorrect device use is still a major problem. Training videos could be an efficient part of a multi-modal approach to improve inhalation technique in clinical practice.

Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: An fMRI study.

OBJECTIVE: The trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex. METHODS: Twenty-one healthy participants were included in a 2-day, randomized, single-blind, within-subject design. The reflex was activated inside the MRI scanner using kinetic oscillation stimulation placed in the left nostril, resulting in an increase in lacrimation. After the first fMRI session, the participants received either sham vagus nerve stimulation or nVNS outside the scanner and underwent a subsequent fMRI session. RESULTS: nVNS prompted an increase in activation of the left pontine nucleus and a decreased activation of the right parahippocampal gyrus. Psychophysiologic interaction analyses revealed an increased functional connectivity between the left pontine nucleus and the right hypothalamus and a decreased functional connectivity between the right parahippocampal gyrus and the bilateral spinal trigeminal nuclei (sTN). CONCLUSIONS: These findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

nVNS sham significantly affects the trigeminal-autonomic reflex: A randomized controlled study.

OBJECTIVE: To determine whether high placebo effects observed in recently published clinical noninvasive vagal nerve stimulation (nVNS) trials can be attributed to an active modulation of the trigeminal-autonomic reflex by the sham device. METHODS: Twenty-eight healthy participants were investigated in a randomized, controlled, single-blind, within-participant design. The 4 different conditions of no stimulation, regular nVNS of the left cervical vagal nerve, stimulation of the posterior neck with the same device (sham I), and stimulation of the left cervical vagal nerve with a sham device (sham II) were applied in randomized order. Parasympathetic output (lacrimation) was provoked with kinetic oscillation stimulation (KOS) of the nasal mucosa. Lacrimation was quantified with the Schirmer II test, an objective measure of lacrimal secretion after local anesthesia, and the difference between baseline and KOS-induced lacrimation served as a measure of autonomic output. RESULTS: nVNS treatment resulted in a significant reduction of ipsilateral KOS-induced lacrimation compared to no stimulation (p = 0.003) and sham I (p = 0.02). A similar effect was observed for sham II (p = 0.003, p = 0.001). There was no significant difference between nVNS and sham II. CONCLUSION: These results suggest that both the regular nVNS and the sham device used in some of the clinical nVNS trials modulate the trigeminal-autonomic reflex. This could explain the high sham effect in these trials and suggests that stimulation of the posterior neck may be considered as a real sham condition.

Multiple erythema migrans--manifestation of systemic cutaneous borreliosis.

Erythema migrans is the clinical hallmark lesion of a stage I infection with Borrelia burgdorferi. Multifocal lesions are rarely observed in Europe and thus may be missed, in particular when the typical clinical appearance of the pronounced advancing margin is missing. We present three patients with such a clinical appearance which caused differential diagnostic problems. Multiple erythema migrans represent an early stage of systemic infection. Thus early diagnosis and rapid initiation of therapy are warranted.

Schnitzler syndrome: treatment failure to rituximab but response to anakinra.

Schnitzler syndrome is a rare disease characterized by a chronic urticarial rash and a monoclonal gammopathy. The exact pathogenesis is still uncertain and treatment remains a challenge. Here, we report a patient who was only recently given the diagnosis of Schnitzler syndrome although the typical symptoms had been present for about 6 years. Administration of the B-cell antibody rituximab did not exert any beneficial effect despite effective elimination of B cells and a reduction of the paraprotein. In contrast, injection of the interleukin-1-receptor antagonist anakinra caused a complete remission within a few days.