National Institute for Health Research, UK

Size: px

Start display at page:

Download "National Institute for Health Research, UK"

Colin Gregory
5 years ago
Views:

1 Headache in Pituitary Tumor Patients Pituitary Disorders: Advances in Diagnosis and Management 24 th October 2015 Peter J Goadsby Disclosure Dr Goadsby reports grants & personal fees by proportion

1 1 Headache in Pituitary Tumor Patients Pituitary Disorders: Advances in Diagnosis and Management 24 th October 2015 Peter J Goadsby Disclosure Dr Goadsby reports grants & personal fees by proportion National Institute for Health Research, UK Governments: European Union, Spain, Portugal, China, Department of Defence, Australia, Kyrgystan NINDS 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. Department of Neurology *Font scale for direct contributions in proportion to contribution Q4-14 to Q3-15 (Font ~ {Contribution/Total Group Income} * 100) Definition Pathophysiology & Questions Management Pituitary Tumour Related Headache Definition 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 and/or altered thirst or appetite. It remits after successful treatment of the underlying disorder. Diagnostic criteria: A. Any headache fulfilling criterion C B. Hypothalamic or pituitary hyper- or hyposecretion (including prolactin, growth hormone (GH) and/or 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

2 Some Questions How common are pituitary tumors? How common is a pituitary tumor? Does size matter? Microadenoma vs macroadenoma Is there a typical headache?

PRL, ACTH, GH or another mediator Incidence rates in post-mortem studies vary from 1 to 40% 1 Prevalence rates in imaging vary 1% to 40% 1 Population-based study in

Ezzat et al., Cancer 2004;101:613 2. Agustsson et al., Eur J Endocrinol 2015;173:655 Some Questions Does size matter? How common is a pituitary tumor?

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

3 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?

microadenoma Patients- % 1 n = 84 (% 2 ) 71 29 44 years 37 (40) 33 (11) 24 (43) 5 (6) 65 35 Cavernous sinus invasion 21 1. Levy et al., Brain 2005;128:1921; 2. Agustsson et al.

3 3 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? Pituitary Tumors and Headache The Phenotype Clinical characteristics Male Female Age Tumour type Prolactinoma Acromegaly Non-functioning adenoma Cushing s disease Tumour characteristics macroadenoma microadenoma Patients- % 1 n = 84 (% 2 ) years 37 (40) 33 (11) 24 (43) 5 (6) Cavernous sinus invasion Levy et al., Brain 2005;128:1921; 2. Agustsson et al., Eur J Endocrinol 2015;173:655 What is the mediator? Cranial Autonomic Symptoms 1. Conjunctival injection, lacrimation, or both 2. Nasal congestion, or rhinorrhoea, or both 3. Eyelid oedema 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 Trigeminal-autonomic reflex superior salivatory n. thalamus V ganglion trigeminocervical complex Not Neuropeptide Y (Levy et al., Eur J Neurol 2006;13:125-9) Not Vasoactive intestinal polypeptide (VIP) (Nathoo et al., Acta Neurol Scand 2005;111: ) Not Calcitonin gene-related peptide/substance P (Levy et al., Pituitary 2004;7:67-71) sphenopalatine ganglion PACAP (pterygopalatine) VIP Nitric Oxide nitric oxide synthase CGRP- calcitonin gene-related peptide PACAP- pituitary adenylate-cyclase activating peptide C 1 C 2 Goadsby & Lipton Brain 1997;120:193

4 Pituitary Adenylate-Cyclase Activating Peptide PACAP Secretin/Glucagon Superfamily Peptides PACAP and VIP PACAP member of secretin/glucagon superfamily Originally identified as hypothalamic

Migraine VIP 2 16% 0/12 4/22 4 PACAP38 3 16% 7/11 16/22 4 1. Jansen-Olesen et al., Peptides 2004;25:2105 2. Rahmann et al., Cephalalgia 2008;28:226 3. Henrik et al., Brain 2009;132:16 4. Amin et al.

superior sagittal sinus in cat increases CGRP & PACAP in cat PACAP is elevated in migraine without aura and normalised by sumatriptan Anesthetised rats Neurogenic dural vasodilation (NDV): Dural

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

5 PACAP and the Trigeminovascular System Some Questions How common is a pituitary tumor? Does size matter?

PRL, ACTH, GH or another mediator Is there a typical headache?

Cephalalgias (TACs)* Migraine Episodic Chronic Trigeminal autonomic cephalalgia (TAC) Cluster headache SUNCT

5 5 PACAP and the Trigeminovascular System 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 The Phenotype Patients n = 84 (%) Trigeminal Autonomic Cephalalgias (TACs)* Migraine Episodic Chronic Trigeminal autonomic cephalalgia (TAC) Cluster headache SUNCT Other Hemicrania continua Primary Stabbing headache Pituitary Headache Cluster Headache a. Episodic b. Chronic 3.2 Paroxysmal Hemicrania a. Episodic b. Chronic 3.3 SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing)/SUNA 3.4 Hemicrania continua 3.4 Probable TAC *Goadsby & Lipton Brain 1997;120:193 ICHD-3β Cephalalgia 2013;33:629 Levy et al., Brain 2005;128:1921

6 Cluster Headache 3.1 Cluster headache A. At least five attacks fulfilling criteria B D B. Severe/very severe unilateral orbital, supraorbital and/or temporal pain 15 180 minutes (untreated) C.

at least one of the following symptoms or signs, ipsilateral to the headache: a) conjunctival injection and/or lacrimation b) nasal congestion and/or rhinorrhoea c) eyelid oedema d) forehead and

6 6 Cluster Headache 3.1 Cluster headache A. At least five attacks fulfilling criteria B D B. Severe/very severe unilateral orbital, supraorbital and/or temporal pain minutes (untreated) C. Either or both of the following: 1. at least one of the following symptoms or signs, ipsilateral to the headache: a) conjunctival injection and/or lacrimation b) nasal congestion and/or rhinorrhoea c) eyelid oedema d) forehead and facial sweating e) forehead and facial flushing f) sensation of fullness in the ear g) miosis and/or ptosis 2. a sense of restlessness or agitation D. Frequency: 0.5 to 8 per day E. Not better accounted for by another ICHD-3 diagnosis. Comparison of cluster headache and capsaicin-induced pain Episodic cluster headache * At least two cluster periods lasting from 7 days to 1 year (when untreated) and separated by pain-free remission periods of 1 month Chronic cluster headache * Occurring without a remission period, or with remissions lasting <1 month, for at least 1 year. (Cephalalgia 2013;33:629) Cluster Headache (n = 9) (Lancet 1998;351:275) Capsaicin (n = 7) (Pain 1998; 74:61) PET-activity (functional change) Cluster headache: structure and function Migrene Vanligvis episodisk hodepine (4-72 timer) med visse kjennetegn (& ingen annen årsak): PET- functional activity Voxel-based morphometry (Lancet 1998; 351: ) (Nature Med 1999; 5: ) Minst 2 av- ensidig pulserende Moderat til alvorlig Forverrelse ved aktivitet Minst en av- kvalme/brekninge r foto/fonofobia after Classification of Headache Disorders, 1988, 2004 & 2013

7 Attacks Migraine The Attacks & the Disorder Premonitory symptoms Pain unilateral throbbing movement worse Nausea Sensory sensitivity photophobia phonophobia osmophobia Aura Disorder Repeated

Hormonal Stress- relaxation The simple headaches have the same characters, and occur under the same causal conditions of heredity &c, as those in which there are additional other sensory symptoms

, Brain 2014;137:232 Hours to Days Pituitary Tumour Related Headache Definition Questions that we have addressed Management Choice of treatment in acute migraine Acute attack treatments Non-specific

7 7 Attacks Migraine The Attacks & the Disorder Premonitory symptoms Pain unilateral throbbing movement worse Nausea Sensory sensitivity photophobia phonophobia osmophobia Aura Disorder Repeated attacks < 15 days/month: Episodic 15 days/month: Chronic Family history Triggers (biology) Sleep: missing/excess Food: skipping meals Chemical: alcohol or nitroglycerin Weather Sensory: light, smells Hormonal Stress- relaxation The simple headaches have the same characters, and occur under the same causal conditions of heredity &c, as those in which there are additional other sensory symptoms Gowers 1893 Migraine and the Brain Tiredness, Yawning, Concentration, Mood, Polyuria, Washed-out Aura Pain Nausea, Photophobia, Phonophobia Maniyar et al., Brain 2014;137:232 Hours to Days Pituitary Tumour Related Headache Definition Questions that we have addressed Management Choice of treatment in acute migraine Acute attack treatments Non-specific aspirin 900mg Paracetamol (acetaminophen) 1g NSAIDS Ibuprofen mg Naproxen mg tolfenamic acid 200mg Opioids ± Anti-emetics domperidone 10mg ondansetron 4mg prochlorperazine 5-10mg Specific ergotamine derivatives ergotamine dihydroergotamine Triptans- 5-HT 1B/1D Sumatriptan - Oral (po): 25, 50 or 100mg - Nasal: 20mg - Rectal: 25mg - Transcutaneous patch: 6mg - Subcutaneous: 4 or 6 mg Almotriptan: 12.5mg po Eletriptan: 20, 40 or 80 mg po Frovatriptan: 2.5mg po Naratriptan: 2.5mg po Rizatriptan: 5 or 10mg po [MLT] Zolmitriptan: 2.5 or 5mg po [ODT] Goadsby Ann Neurol 2013;74:423

8 Preventive Treatments in Migraine Established use Amine Modulators β-blockers Serotonin antagonists: pizotifen Tricyclics: amitriptyline, nortriptyline Anti-convulsants Valproate Topiramate

8 8 Preventive Treatments in Migraine Established use Amine Modulators β-blockers Serotonin antagonists: pizotifen Tricyclics: amitriptyline, nortriptyline Anti-convulsants Valproate Topiramate Gabapentin Calcium channel blockers: flunarizine Onabotulinum toxin type A Angiotensin-based AII receptor antagonist: candesartan ACE inhibitor: lisinopril Melatonin Neutriceuticals (metabolic) Riboflavin Co-enzyme Q10 Butterbur Feverfew Goadsby Ann Neurol 2013;74:423 In development CGRP monoclonal antibodies CGRP receptor antagonists Neuromodulation NOS-based approaches mglur5: glurants Orexin 1 & 2: rexants Goadsby Ann Neurol 2013;74:423 Monoclonal Antibodies* for Migraine Prevention are Effective Amgen AMG 334 Human IgG1 receptor CLR/RAMP1 Phase II- episodic migraine 1 Alder Biopharmaceuticals- ALD Humanized CGRP peptide antibody Phase II: episodic migraine 3 2 & 6 months* Arteaus Therapeutics/Lilly- LY Humanized CGRP peptide antibody Phase II: episodic migraine 3 Labrys/Teva- LBR-101/TEV Humanized CGRP peptide antibody Phase II- chronic migraine 4 Phase II- episodic migraine 5 1. Lenz et al., Cephalalgia 2015;35:[62]:5 2. Dodick et al., Lancet Neurol 2014;13: Dodick et al., Lancet Neurol 2014;13: Bigal et al., Lancet Neurol 2015;14: in press 5. Bigal et al., Lancet Neurol 2015;14: in press * erenumab/vistinumab/alcanezumab 28* 53 N = Cluster headache Management- acute attacks Cluster headache management- preventive Established Oxygen: L/min Sumatriptan 6mg s/c 20mg IN Zolmitriptan 5mg NS Octreotide DHE nasal spray (2-4mg) Lignocaine intranasal (4-6%) Promising CGRP mechanism antagonists Short term Greater occipital nerve injection Prednisolone 1mg/kg po decreasing Frovatriptan 2.5mg po Dihydroergotamine 1mg iv Long term Verapamil to 920mg/day Topiramate Lithium Melatonin Other Gabapentin Neuromodulation nvns SPG ONS DBS Goadsby Continuum Lifelong Learning Neurology 2012;18:883 Goadsby Continuum Lifelong Learning Neurology 2012;18:883

9 9 Trigeminal Autonomic Cephalalgias trigeminal-autonomic activation facilitated by the brain Cluster headache y = -12 Paroxysmal hemicrania SUNCT Hemicrania continua dura mater Pain V ganglion SSN Sphenopalatine ganglion C1 trigeminal nucleus C2 Goadsby Continuum Lifelong Learning Neurology 2012;18:883

Migraine Migraine Age Specific Prevalence in the United States. Headache International Headache Society Classification

Migraine Migraine Age Specific Prevalence in the United States. Headache International Headache Society Classification 28 Primary Care Medicine Principles and Practice 29 October 28 Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu Department of Neurology Headache International Headache Society Classification