National Institute for Health Pituitary Disorders: Advances in - PowerPoint PPT Presentation

Disclosure Headache in Pituitary Tumor Patients Dr Goadsby reports grants & personal fees by proportion • National Institute for Health Pituitary Disorders: Advances in Diagnosis and Management Research, UK • Governments: European Union, Spain, Portugal, China, 24 th October 2015 Department of Defence, Australia, Kyrgystan NINDS Peter J Goadsby Industry : Amgen /Allergan • Consulting : ATI, AlderBio, Dr Reddys, BMS, B-I, Colucid, Eli-Lilly,, eNeura, Electrocore, Pfizer, • Zosano, Avanir, Heptares, Nupathe, Teva, Cipla, Ajinomoto, Akita, Wells Fargo, Ethicon, Promius, Journal Watch, Up-to-Date Reviews : Belgian Research Council, European Space Agency, Italian Telethon, Medical Research • Council UK, Medtronic, Migraine Research Foundation, Migraine Trust, Netherlands Research Council, NHMRC ACCME specific : I have no spousal/partner conflicts, nor relationships with companies that • market, distribute or resell health care goods or services consumed by, or used on, patients unless otherwise explicitly stated above. *Font scale for direct contributions in proportion to contribution Q4-14 to Q3-15 (Font ~ {Contribution/Total Group Income} * 100) Department of Neurology Pituitary Tumour Related Headache Pituitary Tumors & Headache Definition 7.4.4 Headache attributed to hypothalamic or pituitary hyper- or hyposecretion Description: Headache caused by a pituitary adenoma and hypothalamic or pituitary hyper- or hyposecretion, usually accompanied by disorder of temperature regulation, abnormal emotional state • Definition and/or altered thirst or appetite. It remits after successful treatment of the underlying disorder. Diagnostic criteria: • Pathophysiology & Questions A. Any headache fulfilling criterion C B. Hypothalamic or pituitary hyper- or hyposecretion (including prolactin, growth hormone (GH) and/or • Management adrenocorticotropic hormone (ACTH) hypersecretion), associated with pituitary adenoma, has been demonstrated C. Evidence of causation demonstrated by at least two of the following: 1. headache has developed in temporal relation to onset of hypothalamic or pituitary hyper- or hyposecretion 2. either or both of the following: a) headache has significantly worsened in parallel with worsening of the hypothalamic or pituitary hyper- or hyposecretion b) headache has significantly improved in parallel with improvement in the hypothalamic or pituitary hyper- or hyposecretion 3. Headache is associated with at least one of the following: a) disorder of temperature regulation b) abnormal emotional state c) altered thirst and/or appetite D. Not better accounted for by another ICHD-3 diagnosis. ICHD-3- β Cephalalgia 2013;33:629 1

Pituitary Tumors & Headache Pituitary Tumors & Headache How common are pituitary tumors? Some Questions • How common is a pituitary tumor? • Incidence rates in post-mortem studies vary from 1 to 40% 1 • Prevalence rates in imaging vary 1% to 40% 1 • Does size matter? • Population-based study in Iceland 2 – Microadenoma vs macroadenoma - Nationwide 1955-2012 - Identified 471 patients • Is there a typical headache? - In 2012 Prevalence: 115/100,000 • Does the endocrine disorder matter? - What is seen? * Non-Functioning 43%, PRL 40%, GH 11%, Cushings 6% – PRL, ACTH, GH or another mediator Ezzat et al ., Cancer 2004;101:613 1. Agustsson et al ., Eur J Endocrinol 2015;173:655 2. Pituitary Tumors & Headache Pituitary Tumors & Headache Some Questions Does size matter? Headache Score against Pituitary Volume • How common is a pituitary tumor? 3500 • Does size matter? 3000 c 2500 – Microadenoma vs macroadenoma Headache Score 2000 • Is there a typical headache? 1500 • Does the endocrine disorder matter? 1000 500 – PRL, ACTH, GH or another mediator 0 0 2 4 6 8 10 12 14 16 18 20 Pituitary Volume (mls) Levy et al ., Arch Neurol 2004;61:721 2

Pituitary Tumors and Headache Pituitary Tumors & Headache The Phenotype Some Questions Patients- % 1 n = 84 (% 2 ) • How common is a pituitary tumor? Clinical characteristics Male 71 • Does size matter? Female 29 Age 44 years – Microadenoma vs macroadenoma Tumour type • Does the endocrine disorder matter? Prolactinoma 37 (40) Acromegaly 33 (11) – PRL, ACTH, GH or another mediator Non-functioning adenoma 24 (43) Cushing’s disease 5 (6) • Is there a typical headache? Tumour characteristics macroadenoma 65 microadenoma 35 Cavernous sinus invasion 21 1. Levy et al ., Brain 2005;128:1921; 2. Agustsson et al ., Eur J Endocrinol 2015;173:655 Pituitary Tumors & Headache Trigeminal-autonomic reflex What is the mediator? Cranial Autonomic Symptoms 1. Conjunctival injection, lacrimation, or both 2. Nasal congestion, or rhinorrhoea, or both 3. Eyelid oedema thalamus 4. Forehead and facial sweating 5. Forehead/facial flushing 6. Sense of fullness in the ear 7. Miosis, or ptosis, or both CGRP PACAP dura mater superior salivatory n. V ganglion trigeminocervical complex sphenopalatine ganglion • Not Neuropeptide Y (Levy et al ., Eur J Neurol 2006;13:125-9) PACAP (pterygopalatine) • Not Vasoactive intestinal polypeptide (VIP) (Nathoo et al ., Acta Neurol VIP Nitric Oxide C 1 Scand 2005;111:317-322) • Not Calcitonin gene-related peptide/substance P (Levy et al ., Pituitary 2004;7:67-71) nitric oxide synthase C 2 CGRP- calcitonin gene-related peptide Goadsby & Lipton Brain 1997;120:193 PACAP- pituitary adenylate-cyclase activating peptide 3

Pituitary Adenylate-Cyclase Activating Peptide Secretin/Glucagon Superfamily Peptides PACAP PACAP and VIP • PACAP member of secretin/glucagon superfamily VIP 1 PACAP ↓ MCA Migraine VEL • Originally identified as hypothalamic activator of cAMP in pituitary cells VPAC 1 ++ ++ VIP 2 16% 0/12 • Two forms – PACAP-27 4/22 4 – PACAP-38 (mainly mammalian) VPAC 2 ++ ++ • Receptor PACAP383 16% 7/11 – Specific: PAC 1 16/22 4 – Shared: VPAC 1 and VPAC 2 (with VIP) PAC 1 + Jansen-Olesen et al ., Peptides 2004;25:2105 1. Rahmann et al ., Cephalalgia 2008;28:226 2. Henrik et al ., Brain 2009;132:16 3. VIP, vasoactive intestinal polypeptide; Amin et al . Brain 2014;137:779 PACAP, pituitary adenylate-cyclase activating peptide 4. PACAP and the trigeminovascular system CGRP, PACAP and Migraine • Anesthetised rats • Neurogenic dural vasodilation (NDV): Dural electrical stimulation (50-300 mA) eliciting dural blood vessel dilation • Stimulation of superior sagittal sinus in • PACAP is elevated in migraine without cat increases CGRP & PACAP in cat aura and normalised by sumatriptan * * * # pmol/L n = 15 9 9 VPAC1 VPAC2 PAC1  PG97-269  No effect  No effect VIP 6-28  No effect   PACAP 6-38 No effect CGRP- calcitonin gene-related peptide Zagami et al ., ACTN 2014;1:1036 Akerman & Goadsby, Science Trans Medicine 2015;7:1 PACAP- pituitary adenylate-cyclase activating peptide 4

PACAP and the Trigeminovascular System Pituitary Tumors & Headache Some Questions • How common is a pituitary tumor? • Does size matter? – Microadenoma vs macroadenoma • Does the endocrine disorder matter? – PRL, ACTH, GH or another mediator • Is there a typical headache? Akerman & Goadsby, Science Trans Medicine 2015;7:1 Pituitary Tumors & Headache Trigeminal Autonomic Cephalalgias The Phenotype (TACs)* Patients n = 84 (%) Migraine 3.1 Cluster Headache Episodic 30 a. Episodic Chronic 46 b. Chronic 3.2 Paroxysmal Hemicrania Trigeminal autonomic cephalalgia (TAC) a. Episodic Cluster headache 4 b. Chronic 3.3 SUNCT (Short-lasting Unilateral Neuralgiform headache SUNCT 5 attacks with Conjunctival injection and Tearing)/SUNA Other 3.4 Hemicrania continua Hemicrania continua 1 Primary Stabbing headache 27 3.4 Probable TAC “Pituitary Headache” 1 *Goadsby & Lipton Brain 1997;120:193 ICHD-3 β Cephalalgia 2013;33:629 Levy et al ., Brain 2005;128:1921 5