The Clinical, Therapeutic and Radiological Spectrum of SUNCT, SUNA and Trigeminal Neuralgia

This thesis examines and compares the demographics, clinical phenotype, radiological findings and response to medical and surgical treatments of SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) and SUNA (short-lasting unilateral neuralgiform headache attacks with autonomic symptoms). Given the similarities between SUNCT, SUNA and trigeminal neuralgia (TN), the demographics and clinical phenotype of these disorders were also compared. In the first study (Chapter 2) a cohort of 133 patients (SUNA=63 and SUNCT=70) was phenotyped and the clinical characteristics of SUNA compared to those of SUNCT. Statistically significant predictors for SUNCT rather than SUNA were only found for ipsilateral ptosis [OR: 3.37 (95% CI: 1.50, 7.66), p<0.0001] and rhinorrhoea [OR: 2.42 (95% CI: 1.09, 5.41), p=0.034]. Furthermore, a significantly higher proportion of SUNCT patients (n=56, 80.0%) reported marked lacrimation compared to SUNA patients (n=20, 46.5%) (P<0.001). In the second study (Chapter 3) 45 SUNCT and 34 SUNA patients had high-resolution cisternal imaging MRI scans to asses the presence of trigeminal neurovascular conflict. The prevalence of neurovascular contact on the symptomatic trigeminal nerves was higher (57.3%) than on the asymptomatic trigeminal nerves (25%) (P≤0.001). Severe neurovascular contacts were considerably more prevalent on the symptomatic side (47.6%), compared to the asymptomatic side (11.8%) (P≤0.001). There was no statistically significant difference in the proportion of neurovascular contacts on the symptomatic nerves between SUNCT (61.7%) and SUNA (57.1%) (P=0.67). The presence of a vascular contact and its location at the root entry zone were strong predictors for the nerve to be symptomatic rather than asymptomatic. In the third study (Chapter 4) the response to treatments of 161 SUNCT and SUNA patients was analysed. Our findings suggest that lamotrigine was the most effective treatment (responders: SUNCT= 53.5%, SUNA= 57.9%) followed by oxcarbazepine (responders: SUNCT= 44.8%, SUNA= 47.0%); duloxetine and topiramate were more effective in SUNCT rather than SUNA (duloxetine responders: SUNCT= 45.0%, SUNA: 11.8%; p= 0.027; topiramate responders: SUNCT= 33.3%, SUNA= 10.7%; p=0.028). Amongst transitional treatments intravenous lidocaine led to a significant headache improvement in 83.3% SUNCT (n=25) and in 76.5% SUNA (n=13) patients (p=0.73). A greater occipital nerve block was beneficial in 27.3% (n=21) of patients for a median of 21 days (IQR: 53 days; range: 1 to 150 days), without any significant difference between SUNCT (24.4%; n=11) and SUNA (37.0%; n=10) patients (p=0.42). We found intravenous dihidroergotamine able to worsen or even to precipitate a de novo SUNCT/SUNA when administered to manage a different primary headache disorder. In the fourth study (Chapter 5) occipital nerve stimulation (ONS) was tried in nine and trigeminal microvascular decompression was tried in ten refractory, chronic SUNCT and SUNA patients. At a median follow-up of 38 months (range 24-55 months) ONS led to a marked headache improvement in eight of the nine patients (89%). One patient did not report any benefit from the stimulator at 24 months’ follow-up and opted to have the ONS explanted. At a mean follow-up fo 19.6 months (range: 12-36 months) after trigeminal microvascular decompression surgery, seven patients (70%) became headache-free after the operation. Five of the seven patients (71.4%) remained headache-free at the last follow-up. The remaining two patients were headache-free respectively for 9 and 12 months before the headache relapsed. There were no major surgical and post-surgical complications. A comparison of the clinical phenotype of SUNA (n=133) and TN (n=79) was undertaken in the last study (Chapter 6). Several similarities between SUNA and TN were found. Furthermore, some clinical features, namely pain location in V1 (OR: 11.29 95%CI: 3.92, 35.50, p<0.001), spontaneous only attacks (OR: 44.40, 95%CI: 4.50, 437.83, p=0.001) and a chronic pain pattern (OR: 13.19, 95%CI: 4.04, 43.08, p<0.001) predicted the diagnosis of SUNA rather than TN. Similarly duration of the attacks <1 minute (OR: 7.95, 95%CI: 2.30, 27.57, p=0.001) and the presence of a refractory period in between triggered attacks (OR: 0.06; 95%CI: 0.02, 0.28, p-value <0.001) were predictors for TN rather than SUNA. In summary our novel findings advance the clinical understanding of SUNCT and SUNA and suggest that their relationship with TN may represent` a clinical continuum between disorders. This view will hopefully open novel research directions towards a better understanding of these complex clinical entities

A six year retrospective review of occipital nerve stimulation practice--controversies and challenges of an emerging technique for treating refractory headache syndromes

BACKGROUND: A retrospective review of patients treated with Occipital Nerve Stimulation (ONS) at two large tertiary referral centres has been audited in order to optimise future treatment pathways. METHODS: Patient's medical records were retrospectively reviewed, and each patient was contacted by a trained headache expert to confirm clinical diagnosis and system efficacy. Results were compared to reported outcomes in current literature on ONS for primary headaches. RESULTS: Twenty-five patients underwent a trial of ONS between January 2007 and December 2012, and 23 patients went on to have permanent implantation of ONS. All 23 patients reached one-year follow/up, and 14 of them (61%) exceeded two years of follow-up. Seventeen of the 23 had refractory chronic migraine (rCM), and 3 refractory occipital neuralgia (ON). 11 of the 19 rCM patients had been referred with an incorrect headache diagnosis. Nine of the rCM patients (53%) reported 50% or more reduction in headache pain intensity and or frequency at long term follow-up (11-77 months). All 3 ON patients reported more than 50% reduction in pain intensity and/or frequency at 28-31 months. Ten (43%) subjects underwent surgical revision after an average of 11 ± 7 months from permanent implantation - in 90% of cases due to lead problems. Seven patients attended a specifically designed, multi-disciplinary, two-week pre-implant programme and showed improved scores across all measured psychological and functional parameters independent of response to subsequent ONS. CONCLUSIONS: Our retrospective review: 1) confirms the long-term ONS success rate in refractory chronic headaches, consistent with previously published studies; 2) suggests that some headaches types may respond better to ONS than others (ON vs CM); 3) calls into question the role of trial stimulation in ONS; 4) confirms the high rate of complications related to the equipment not originally designed for ONS; 5) emphasises the need for specialist multidisciplinary care in these patients

Trigeminal microvascular decompression for short-lasting unilateral neuralgiform headache attacks

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks (SUNHA) are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic SUNHA with magnetic resonance imaging evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an "excellent response", defined as 90-100% weekly reduction in attack frequency, or "good response", defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients of whom 31 had SUNCT and 16 had SUNA (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. Magnetic resonance imaging of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Post-operatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, SUNCT = 7 and SUNA = 3) reported no post-operative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between SUNCT and SUNA in the response to surgery (p = 0.463). Responders at the last follow-up were however more likely not to have interictal pain (77.42% vs 22.58%, p = 0.021) and to show morphological changes on the magnetic resonance imaging (78.38% vs 21.62%, p = 0.001). The latter outcome was confirmed in the Kaplan Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (p = 0.0001). All but one patient who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for short-lasting unilateral neuralgiform headache attacks patients with magnetic resonance evidence of neurovascular conflict with morphological changes

Excellent Response to OnabotulinumtoxinA : Different Definitions, Different Predictors

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle

Occipital nerve stimulation in primary headache syndromes

Chronic daily headache is a major worldwide health problem that affects 3–5% of the population and results in substantial disability. Advances in the management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments. However, a significant minority of these patients are intractable to conventional medical treatments. Occipital nerve stimulation (ONS) is emerging as a promising treatment for patients with medically intractable, highly disabling chronic headache disorders, including migraine, cluster headache and other less common headache syndromes. Open-label studies have suggested that this treatment modality is effective and recent controlled trial data are also encouraging. The procedure is performed using several technical variations that have been reviewed along with the complications, which are usually minor and tolerable. The mechanism of action is poorly understood, though recent data suggest that ONS could restore the balance within the impaired central pain system through slow neuromodulatory processes in the pain neuromatrix. While the available data are very encouraging, the ultimate confirmation of the utility of a new therapeutic modality should come from controlled trials before widespread use can be advocated; more controlled data are still needed to properly assess the role of ONS in the management of medically intractable headache disorders. Future studies also need to address the variables that are predictors of response, including clinical phenotypes, surgical techniques and stimulation parameters