Cranial autonomic ganglia in headache disorders

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

Measurement and implications of the distance between the sphenopalatine ganglion and nasal mucosa: a neuroimaging study

Background Historical reports describe the sphenopalatine ganglion (SPG) as positioned directly under the nasal mucosa. This is the basis for the topical intranasal administration of local anaesthetic (LA) towards the sphenopalatine foramen (SPF) which is hypothesized to diffuse a distance as short as 1mm. Nonetheless, the SPG is located in the sphenopalatine fossa, encapsulated in connective tissue, surrounded by fat tissue and separated from the nasal cavity by a bony wall. The sphenopalatine fossa communicates with the nasal cavity through the SPF, which contains neurovascular structures packed with connective tissue and is covered by mucosa in the nasal cavity. Endoscopically the SPF does not appear open. It has hitherto not been demonstrated that LA reaches the SPG using this approach. Methods Our group has previously identified the SPG on 3T-MRI images merged with CT. This enabled us to measure the distance from the SPG to the nasal mucosa covering the SPF in 20 Caucasian subjects on both sides (n=40 ganglia). This distance was measured by two physicians. Interobserver variability was evaluated using the intraclass correlation coefficient (ICC). Results The mean distance from the SPG to the closest point of the nasal cavity directly over the mucosa covering the SPF was 6.77 mm (SD 1.75; range, 4.00-11.60). The interobserver variability was excellent (ICC 0.978; 95% CI: 0.939-0.990, p<0.001). Conclusions The distance between the SPG and nasal mucosa over the SPF is longer than previously assumed. These results challenge the assumption that the intranasal topical application of LA close to the SPF can passively diffuse to the SPG

Measurement and implications of the distance between the sphenopalatine ganglion and nasal mucosa: a neuroimaging study

Background Historical reports describe the sphenopalatine ganglion (SPG) as positioned directly under the nasal mucosa. This is the basis for the topical intranasal administration of local anaesthetic (LA) towards the sphenopalatine foramen (SPF) which is hypothesized to diffuse a distance as short as 1 mm. Nonetheless, the SPG is located in the sphenopalatine fossa, encapsulated in connective tissue, surrounded by fat tissue and separated from the nasal cavity by a bony wall. The sphenopalatine fossa communicates with the nasal cavity through the SPF, which contains neurovascular structures packed with connective tissue and is covered by mucosa in the nasal cavity. Endoscopically the SPF does not appear open. It has hitherto not been demonstrated that LA reaches the SPG using this approach. Methods Our group has previously identified the SPG on 3 T–MRI images merged with CT. This enabled us to measure the distance from the SPG to the nasal mucosa covering the SPF in 20 Caucasian subjects on both sides (n = 40 ganglia). This distance was measured by two physicians. Interobserver variability was evaluated using the intraclass correlation coefficient (ICC). Results The mean distance from the SPG to the closest point of the nasal cavity directly over the mucosa covering the SPF was 6.77 mm (SD 1.75; range, 4.00–11.60). The interobserver variability was excellent (ICC 0.978; 95% CI: 0.939–0.990, p < 0.001). Conclusions The distance between the SPG and nasal mucosa over the SPF is longer than previously assumed. These results challenge the assumption that the intranasal topical application of LA close to the SPF can passively diffuse to the SP

OnabotulinumtoxinA injection towards the SPG for treating symptoms of refractory chronic rhinosinusitis with nasal polyposis: a pilot study

Background and objective The main objective of this prospective, open, uncontrolled pilot study was to investigate the safety of administering onabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) in 10 patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP) using a novel injection tool, the MultiGuide®. Material and methods A one-month baseline period was followed by bilateral injections of 25 U BTA in the SPG and a follow-up of 12 weeks. The primary outcome was adverse events (AE), and the main efficacy outcome was a 50% reduction in visual analogue scale (VAS) symptoms for nasal obstruction and rhinorrhea in months 2 and 3 post-treatment compared to baseline. Results We registered 13 AEs, none of which were serious, however, one patient experienced diplopia which moderately affected his daily activities. The symptoms slowly improved and resolved 4 weeks after injection. Five patients were treatment responders with at least 50% median reduction in the nasal obstruction, and four were treatment responders concerning rhinorrhea. Conclusions Injection of BTA toward the SPG using the MultiGuide® in patients with CRSwNP appears to be safe but with a potential for moderately disabling side effects. The study indicates a beneficial effect on nasal obstruction

A prospective three-year follow-up study on the clinical significance of anti-neuronal antibodies in acute psychiatric disorders

The clinical significance of anti-neuronal antibodies for psychiatric disorders is controversial. We investigated if a positive anti-neuronal antibody status at admission to acute psychiatric inpatient care was associated with a more severe neuropsychiatric phenotype and more frequent abnormalities during clinical work-up three years later. Patients admitted to acute psychiatric inpatient care who tested positive for N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (CASPR2) and/or glutamic acid decarboxylase 65 (GAD65) antibodies (n = 24) were age – and sex matched with antibody-negative patients (1:2) from the same cohort (n = 48). All patients were invited to follow-up including psychometric testing (e.g. Symptom Checklist-90-Revised), serum and cerebrospinal fluid (CSF) sampling, EEG and 3 T brain MRI. Twelve antibody-positive (ab+) and 26 antibody-negative (ab−) patients consented to follow-up. Ab+ patients had more severe symptoms of depression (p = 0.03), psychoticism (p = 0.04) and agitation (p = 0.001) compared to ab− patients. There were no differences in CSF analysis (n = 6 ab+/12 ab−), EEG (n = 7 ab+/19 ab−) or brain MRI (n = 7 ab+/17 ab−) between the groups. In conclusion, anti-neuronal ab+ status during index admission was associated with more severe symptoms of depression, psychoticism and agitation at three-year follow-up. This supports the hypothesis that anti-neuronal antibodies may be of clinical significance in a subgroup of psychiatric patients