Cranial autonomic ganglia in headache disorders
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Headache disorders are amongst the most prevalent causes of disability worldwide. Most of the effort to develop new therapeutics has focused on migraine. Patients suffering from less common headache disorders such as trigeminal neuralgia (TN) or cluster headache (CH) are also in need of new and better treatments. Our group has developed a new navigation based surgical tool that allows accurate targeting of small anatomical structures that might be involved in cranial and facial pain. Two previous pilot trials have used this technique to inject botulinum toxin type A (BTA) towards the sphenopalatine ganglion (SPG) in 10 patients with intractable chronic CH (1) and in 10 patients with intractable chronic migraine (2). In this Thesis, we further explore the possibilities of this new device. Most of the studies targeting the SPG do not localize the ganglion directly and use anatomical landmarks which have not been validated (3). Our group has depicted the SPG in living humans using MRI for the first time (4). Nonetheless, MRI might not always be available or some patients might have medical contraindications to undergo this examination. For this reason, we developed an algorithm to predict the location of the SPG using bony landmarks identified in CT-scans (paper 1). Classical TN is not classified under trigeminal autonomic cephalalgias but recent studies have shown that one third of the patients might present autonomic symptoms and the SPG has been involved in its pathophysiology. In paper 2, we conducted a pilot study with 10 patients with classical TN (ICHD-3 beta criteria). Patients were injected with 25 units (U) BTA towards the ipsilateral SPG. The primary outcome was the occurrence of adverse events (AEs). The main efficacy outcome was the number of TN attacks at weeks 5-8 after injection compared to baseline. CH is the most common trigeminal autonomic cephalalgia and it inflicts great suffering among patients. The SPG has been involved in its pathophysiology but no other cranial autonomic ganglia have been targeted in this condition. In paper 3 we describe the rational for the role of the otic ganglion (OG) in autonomic cephalalgias. The OG is a smaller and less studied cranial autonomic ganglion. It cannot be seen in CT-scans or in conventional MR imaging. Its relation to the mandibular nerve has been described to be constant in the literature, with the OG being in direct contact to the medial surface of the third division of the trigeminal nerve (5). The mandibular nerve can be easily localized in MRI. In order to target one structure, which cannot be directly depicted, at least one other anatomical landmark is necessary in addition to the mandibular nerve. The foramen ovale (FO) can be seen clearly in CT-images. One anatomicalcadaveric study describes that the OG “lies immediately below the FO”, however the distance between the FO and the OG was not reported in this study (5). In order to target the OG we measured the average distance between the FO and the OG in 21 high definition photographs of 21 infratemporal fossae from 18 cadavers (paper 3). In a pilot study with 10 patients with intractable chronic CH (paper 4), 5 patients were injected with 12.5 U of BTA and 5 patients with 25 U of BTA towards the ipsilateral OG. The primary endpoint was the occurrence of AEs. The main efficacy outcome was the number of attacks in month 2 after injection compared to baseline. Main findings of this Thesis: • The SPG localization can be predicted on CT-images using 2 bony landmarks. Localizing the SPG on CT-images will be important for patients with contraindications to undergo an MRI (e.g. claustrophobia, MR-incompatible metallic foreign bodies or stimulators, etc.), when access to MRI is limited, and in those patients where repeated injections are needed. • Injection of BTA towards the SPG in classical TN (ICHD-3 beta) appears to be safe. We did not find any indication for effect in reducing the number of TN attacks after injection of 25 U of BTA towards the SPG. A better understanding of the role of the SPG in TN is necessary. • The OG appears to have a constant location, being situated 4.5 mm inferior of the FO and medial to the mandibular nerve. The FO is easily localized on CT-scans and may be an interesting anatomical landmark when trying to develop navigation-based therapies towards the OG • Injection of BTA towards the OG in CH appears to be feasible and safe. We did not find a clear indication for effect in reducing the number of CH attacks after injection of 25 U of BTA towards the OG. A better description of the topography of the OG in living humans should precede further clinical studies targeting this structure.
Has partsPaper 1: Crespi, Joan Vidal; Bratbak, Daniel Fossum; Jamtøy, Kent Are; Tronvik, Erling Andreas. Prediction of the sphenopalatine ganglion localization in computerized tomography images. Cephalalgia 2019 https://doi.org/10.1177/2515816318824690 Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/)
Paper 2: Crespi, Joan Vidal; Bratbak, Daniel Fossum; Dodick, David W.; Matharu, Manjit; Jamtøy, Kent Are; Tronvik, Erling Andreas. Pilot study of injection of onabotulinumtoxinA toward the sphenopalatine ganglion for the treatment of classical trigeminal neuralgia. Headache 2019 ;Volum 59.(8) s. 1229-1239 https://doi.org/10.1111/head.13608 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0)
Paper 3: Crespi, Joan Vidal; Bratbak, Daniel Fossum; Tronvik, Erling Andreas. Anatomical landmarks for localizing the otic ganglion: A possible new treatment target for headache disorders. Cephalalgia 2019 https://doi.org/10.1177/2515816319850761 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/)
Paper 4: Crespi, Joan Vidal; Bratbak, Daniel Fossum; Dodick, David W.; Matharu, Manjit; Solheim, Ole; Gulati, Sasha; Berntsen, Erik Magnus; Tronvik, Erling Andreas. Open-label, multi-dose, pilot safety study of injection of onabotulinumtoxinA toward the otic ganglion for the treatment of intractable chronic cluster headache. Headache 2020 ;Volum 60.(8) s. 1632-1643 https://doi.org/10.1111/head.13889 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0)