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Giorgio Lambru The Clinical, Therapeutic and Radiological Spectrum of SUNCT, SUNA and Trigeminal Neuralgia By Giorgio Lambru The Headache Group Institute of Neurology University College London London WC1N 3BG A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy (PhD) University of London 2018 I, Giorgio Lambru, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Dr Giorgio Lambru 1 Abstract 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= 2 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. 3 Acknowledgments I wish to acknowledge all the patients who participated in the work detailed in this thesis. My thanks and appreciation to Declan Chard, Indran Davagnanam, Paul Shanahan, Norazah Abu Bakara and Susie Lagrata for their aid in the completion of the thesis. My thanks to Khadija Rantell for the precious statistical support. My special thanks to Dr Manjit Matharu for imparting his knowledge and expertise, helping me to complete this thesis. Finally, I would like to dedicate this thesis to my family for their love and encouragement. 4 Publications The publications marked with an asterisk (*) are derived from work presented in the thesis. The remaining publications describe other collaborative work undertaken during the period of PhD study: Journals Abu Bakar N, Torkamani M, Tanprawate S, Lambru G, Matharu M, Jahanshahi M. The development and validation of the Cluster Headache Quality of life scale (CHQ). J Headache Pain 2016 Dec;17(1):79 Abu Bakar N, Tanprawate S, Lambru G, Torkamani M, Jahanshahi M, Matharu M. Quality of life in primary headache disorders: A review. Cephalalgia. 2016. 36(1):67- 91 Torkamani M, Ernst L, Cheung LS, Lambru G, Matharu M, Jahanshahi M. The neuropsychology of cluster headache: cognition, mood, disability and quality of life with chronic and episodic cluster headache. Headache. 2015;55(2):287-300 (*)Lambru G, Shanahan P, Matharu M. Exacerbation of SUNCT and SUNA syndromes during intravenous dihydroergotamine treatment: A case series. Cephalalgia. 2015. 35(12): 115-124 Lambru G, Matharu MS. Peripheral neurostimulation in primary headaches. Neurol Sci. 2014 May;35 Suppl 1:77-81. (*)Lambru G, Matharu MS. SUNCT, SUNA and trigeminal neuralgia: different disorders or variants of the same disorder? Curr Opin Neurol. 2014 Jun;27(3):325-31 5 (*)Lambru G, Shanahan P, Watkins L, Matharu MS. Occipital nerve stimulation in the treatment of medically intractable SUNCT and SUNA. Pain Physician. 2014 Jan- Feb;17(1):29-41. Lambru G, Abu Bakar N, Stahlhut L, McCulloch S, Miller S, Shanahan P, Matharu MS Greater occipital nerve blocks in chronic cluster headache: a prospective open-label study. Eur J Neurol. 2013 Dec 7. (*)Lambru G and Matharu M. SUNCT and SUNA: medical and surgical treatments. Neurol Sci. 2013 May;34 Suppl 1:75-81 Lambru G, Bakar NA, Matharu M. SUNA and red ear syndrome: a new association and pathophysiological considerations. J Headache Pain. 2013 Apr 8;14(1) Lambru G, Matharu MS. Management of trigeminal autonomic cephalalgias in children and adolescents. Curr Pain Headache Rep. 2013 Apr;17(4):323 Lambru G, Lagrata S, Matharu MS. Cutaneous Atrophy and Alopecia after Greater Occipital Nerve Injection Using Triamcinolone. Headache 2012. Nov- Dec;52(10):1596-9. Lambru G, Matharu MS. Trigeminal autonomic cephalalgias: A review of recent diagnostic, therapeutic and pathophysiological developments. Annals of Indian Academy of Neurology. 2012; 15(5): 51-61. Lambru G, Matharu MS. Occipital nerve stimulation in primary headache syndromes. Ther Adv Neurol Disord. 2012; 5(1):57-67. 6 Lambru G, Matharu M. Traumatic Head Injury in Cluster Headache: Cause or Effect? Curr Pain Headache Rep. 2012; 16(2):162-9. Lambru G, Nesbitt A, Shanahan P, Matharu MS Coexistence of hemiplegic migraine with SUNCT or SUNA: a case series. Cephalalgia. 2012; 32(3):258-62 Lambru G, Matharu M. Serotonergic Agents in the Management of Cluster Headache. Curr Pain Headache Rep. 2011 Apr;15(2):108-17. Book Chapters Lambru G and Matharu MS. Cluster headache and other trigeminal autonomic cephalalgias. In: Ishaq Abu-Arafeh editor. Childhood Headache. Cambridge University Press. 7 Table of Contents List of Tables ....................................................................................................... 11 List of Figures ...................................................................................................... 14 Chapter 1. SUNCT, SUNA & Trigeminal Neuralgia: focus on demographic, clinical characteristics, management strategies & pathophysiological hypotheses ........... 17 1.1. Introduction ................................................................................................... 17 1.2. Trigeminal Autonomic Cephalalgias ................................................................ 19 1.2.1. Cluster Headache .................................................................................................
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