Tim P Jürgens

Neuromodulation of chronic headaches: position statement from the European Headache Federation

The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases.Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches.In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile.

Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache

ABSTRACT Deep‐brain stimulation (DBS) of the posterior hypothalamus has been shown to be clinically effective for drug‐resistant chronic cluster headache, but the underlying mechanism is still not understood. The hypothalamus as an important centre of homeostasis is connected among others to the trigeminal system via the trigeminohypothalamic tract. We aimed to elucidate whether hypothalamic stimulation affects thermal sensation and pain perception only in the clinically affected region (the first trigeminal branch) or in other regions as well. Thus, we examined three groups: chronic cluster headache patients with unilateral DBS of the posterior hypothalamus (n = 11), chronic cluster headache patients without DBS (n = 15) and healthy controls (n = 29). Perception and pain thresholds for hot and cold stimuli were determined bilaterally in all subjects supraorbitally, at the forearm, and in the lower leg. In DBS patients, thresholds were determined with the stimulator activated and inactivated. Cold pain thresholds at the first trigeminal branch were increased on the stimulated side in the DBS group compared to healthy subjects (p = .015). The DBS group also had higher cold detection thresholds compared to non‐implanted cluster headache patients (p < .05). Short‐term interruption of stimulation did not induce any changes in DBS patients. Clinically relevant differences were found neither between non‐stimulated cluster headache patients and healthy controls nor between the affected and the non‐affected sides in the chronic cluster headache patients without DBS. These results support the notion that neurostimulation of the posterior hypothalamus is specific for cluster headache and only affects certain aspects of pain sensation.

Pearls and pitfalls: Neurostimulation in headache

Context A variety of neuromodulatory approaches available today has broadened our therapeutic options significantly especially in drug refractory patients with chronic cluster headache and chronic migraine. Overview It is a dynamic field with a current trend to non-invasive transcutaneous stimulation approaches. However, sound studies providing evidence for the widespread use of these novel approaches are sparse. For invasive approaches, occipital nerve stimulation is now widely considered the treatment of first choice in chronic trigeminal autonomic cephalgias and – with limitations – chronic migraine. Although equally effective, deep brain stimulation is considered second-line treatment in cluster headache because of its potentially life-threatening side effects. Most recently, stimulation of the sphenopalatine ganglion has also been shown to effectively abort acute cluster headache attacks. Interesting other upcoming approaches include transcutaneous supraorbital nerve stimulation and transcutaneous vagal nerve stimulation. Conclusion Pearls and pitfalls of common invasive and non-invasive neuromodulatory approaches and open questions are summarised in this review along with recommendations for future studies.

Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks

Background Glutamate is implicated in migraine pathophysiology; amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonists represent a potential therapeutic approach because of their anti-excitatory actions. Methods This randomized, double-blind, proof-of-concept study assessed the efficacy of the AMPA receptor antagonist, BGG492 (250 mg), vs placebo and sumatriptan (100 mg), in 75 subjects with acute migraine attacks. Efficacy was measured using the Patient Migraine Diary. Pharmacokinetic and safety data were collected. Results Improvement from severe/moderate to mild/no headache pain (primary response) was reported in 58%, 58%, and 54% of BGG492-treated subjects at 2, 3, and 4 hours post-dose (p = 0.2, 0.5, and 0.5 vs placebo), respectively, compared with 68%, 84%, and 92% sumatriptan-treated subjects, and 40%, 48%, and 44% in the placebo group. Percentages of subjects with ≥ 2-point improvement in pain score from baseline at 2 hours were 29%, 40%, and 16% for BGG492, sumatriptan, and placebo, respectively. Pain-free response at 2 hours was reported for 25%, 24%, and 16% of BGG492, sumatriptan, and placebo subjects, respectively. Adverse events were reported by 80%, 56%, and 60% of BGG492, sumatriptan, and placebo subjects, respectively. Conclusions Proof-of-concept criterion was not met (≥ 25% BGG492 subjects with a primary response vs placebo at two timepoints). BGG492 was comparable to sumatriptan in terms of pain-free response.

Treatment of Cluster Headache in Pregnancy and Lactation

Cluster headache is a rare disorder in women, but has a serious impact on the affected womans life, especially on family planning. Women with cluster headache who are pregnant need special support, including the expertise of an experienced headache centre, an experienced gynaecologist and possibly a teratology information centre. The patient should be seen through all stages of the pregnancy. A detailed briefing about the risks and safety of various treatment options is mandatory. In general, both the number of medications and the dosage should be kept as low as possible. Preferred treatments include oxygen, subcutaneous or intranasal sumatriptan for acute pain and verapamil and prednisone/ prednisolone as preventatives. If there is a compelling reason to treat the patient with another preventative, gabapentin is the drug of choice. While breastfeeding, oxygen, sumatriptan and lidocaine for acute pain and prednisone/prednisolone, verapamil, and lithium as preventatives are the drugs of choice. As the individual pharmacokinetics differ substantially, adverse drug effects should be considered if unexplained symptoms occur in the newborn.

Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2–1581 per patient) were evaluated. At 24 months, 45% (n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% (n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers?

BackgroundCertain environmental stimuli are frequently reported as typical triggers of migraine pain. Whether these so-called triggers are independent precipitators of migraine pain or mere symptoms of the premonitory phase of migraine remains to be elucidated.MethodsIn this retrospective cohort study of 1010 migraine patients of a tertiary headache center we assessed the frequency of common trigger factors, premonitory symptoms and accompanying symptoms as well as basic headache characteristics and demographic data.ResultsPremonitory symptoms with an onset of 2 or more hours prior to the headache were present in 38.9% of migraine patients, the most frequent being a tense neck, phonophobia and difficulty concentrating. There was a clear overlap of certain trigger factors and the presence of corresponding premonitory symptoms: flickering or bright light as a trigger was associated with higher frequency of photophobia in the premonitory phase. The same applied to the presence of food craving and osmophobia in the premonitory phase and certain foods or odours as trigger factors.ConclusionsOur data thus support the view that commonly reported trigger factors of migraine are not so much independent precipitators of migraine pain, but that they are most likely just misinterpreted results of enhanced attention to certain stimuli mediated by typical premonitory symptoms of migraine pain.

Migraine trait symptoms in migraine with and without aura

Objectives: The aim of the study was to determine whether various transient sensory and neuropsychological symptoms (SNS) were associated with migraine using a custom questionnaire. Methods: In this hypothesis-generating case-control study, the frequencies of transient SNS in 219 patients with migraine (149 without aura and 70 with aura) were compared with 161 age- and sex-matched healthy controls using a custom questionnaire. Patients from a tertiary academic headache center in Hamburg were contacted by regular mail. Healthy controls without a history of migraine were recruited by means of a screening questionnaire and consecutively approached by e-mail. Results: The presence of both migraine and aura was associated with significantly higher frequencies of autokinesis, metamorphopsia, dyschromatopsia, cinematographic vision, illusionary visual spread, and synesthesia (for all comparisons: corrected p < 0.05). Double vision, inverted 2- and 3-dimensional vision, and altered perception of body weight and size were found more often in patients with migraine without aura than in those with aura. In contrast, aura was associated with the occurrence of visual splitting and corona phenomenon (for all comparisons: corrected p < 0.05). No relevant association with migraine was found for micropsia and macropsia, teleopsia and pelopsia, inverted vision, out-of-body experience, Doppelgänger phenomenon, complex visual hallucinations, and altered perception of body position in space. Conclusions: The observed SNS seem to belong to a physiologic spectrum of multisensory phenomena. Some of these phenomena were significantly accentuated in patients with migraine and may therefore be termed migraine trait symptoms. However, these results will have to be confirmed in a prospective study with face-to-face interviews.

Indomethacin-induced de novo headache in hemicrania continua—fighting fire with fire?:

Introduction The response to indomethacin is an important feature for the diagnosis of hemicrania continua. Case description We report the case of a 34-year-old female patient with a one-year history of strictly unilateral continuous headache with accompanying ipsilateral autonomic symptoms. As diagnostic testing was unremarkable, hemicrania continua was suspected. A dose of 150 mg of indomethacin/day reduced the headache by 80%. Although an increase to 225 mg/day led to a further reduction of headaches, a new onset of moderate to severe pulsating migrainous bilateral headache developed. Discussion As shown in older studies, indomethacin can induce de novo headaches in a presumably dose-related fashion although the exact mechanism in uncertain. A treatable secondary origin of the indomethacin-induced headaches in patients with hemicrania continua or paroxysmal hemicrania (such as reversible cerebral vasoconstriction syndrome or aseptic meningitis) should be considered and excluded by further diagnostic testing if headaches persist after discontinuation of indomethacin.

Outpatient Combined Group and Individual Cognitive–Behavioral Treatment for Patients With Migraine and Tension-Type Headache in a Routine Clinical Setting

To test the long‐term clinical effectiveness (follow‐up at 3, 6 and 12 months) of an outpatient combined group and individual cognitive‐behavioral treatment (CBT) for headache patients following standard medical care. A decrease in headache intensity, frequency, headache‐specific impairment, depression, and change of pain‐related cognitions was expected.