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

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Headache in Pituitary Tumor Patients

Pituitary Disorders: Advances in Diagnosis and Management

24th October 2015

Peter J Goadsby

Department of Neurology

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

• therwise explicitly stated above.

*Font scale for direct contributions in proportion to contribution Q4-14 to Q3-15 (Font ~ {Contribution/Total Group Income} * 100)

Pituitary Tumors & Headache

• Definition
• Pathophysiology & Questions
• Management

Pituitary Tumour Related 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 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 Pituitary Tumors & Headache Some Questions

• 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 Pituitary Tumors & Headache How common are pituitary tumors?

• 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 Iceland2
• Nationwide 1955-2012
• 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;101:613 2. Agustsson et al., Eur J Endocrinol 2015;173:655

Pituitary Tumors & Headache Some Questions

• 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

Pituitary Tumors & Headache Does size matter?

Levy et al., Arch Neurol 2004;61:721 c

Headache Score against Pituitary Volume

Pituitary Volume (mls)

2 4 6 8 10 12 14 16 18 20

Headache Score

500 1000 1500 2000 2500 3000 3500

3 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?

Pituitary Tumors and Headache

The Phenotype

Patients- %1 n = 84 (%2) Clinical characteristics Male Female Age 71 29 44 years Tumour type Prolactinoma Acromegaly Non-functioning adenoma Cushing’s disease 37 (40) 33 (11) 24 (43) 5 (6) Tumour characteristics macroadenoma microadenoma 65 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

What is the mediator?

• 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;111:317-322)

• Not Calcitonin gene-related peptide/substance P (Levy et al., Pituitary

2004;7:67-71)

dura mater

V ganglion

sphenopalatine ganglion (pterygopalatine)

trigeminocervical complex C2 C1

Trigeminal-autonomic reflex

nitric oxide synthase superior salivatory n.

thalamus

CGRP PACAP Goadsby & Lipton Brain 1997;120:193 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

PACAP VIP Nitric Oxide

CGRP- calcitonin gene-related peptide PACAP- pituitary adenylate-cyclase activating peptide

4 Pituitary Adenylate-Cyclase Activating Peptide PACAP

• 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: PAC1 – Shared: VPAC1 and VPAC2 (with VIP)

Secretin/Glucagon Superfamily Peptides PACAP and VIP

↓MCA

VEL

Migraine VIP2 16% 0/12 4/224

PACAP383

16% 7/11 16/224 VIP1 PACAP VPAC1 ++ ++ VPAC2 ++ ++ PAC1 +

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. Brain 2014;137:779

VIP, vasoactive intestinal polypeptide; PACAP, pituitary adenylate-cyclase activating peptide

CGRP, PACAP and Migraine

pmol/L

Zagami et al., ACTN 2014;1:1036

*

*

n = 15 9 9

*

#

• Stimulation of superior sagittal sinus in

cat increases CGRP & PACAP in cat

CGRP- calcitonin gene-related peptide PACAP- pituitary adenylate-cyclase activating peptide

• PACAP is elevated in migraine without

aura and normalised by sumatriptan

PACAP and the trigeminovascular system

• Anesthetised rats
• Neurogenic dural vasodilation (NDV): Dural electrical

stimulation (50-300 mA) eliciting dural blood vessel dilation

Akerman & Goadsby, Science Trans Medicine 2015;7:1

VPAC1 VPAC2 PAC1 PG97-269  No effect No effect VIP6-28   No effect PACAP6-38 No effect   

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PACAP and the Trigeminovascular System

Akerman & Goadsby, Science Trans Medicine 2015;7:1

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?

Pituitary Tumors & Headache

The Phenotype

Patients n = 84 (%) Migraine Episodic Chronic 30 46 Trigeminal autonomic cephalalgia (TAC) Cluster headache SUNCT 4 5 Other Hemicrania continua Primary Stabbing headache “Pituitary Headache” 1 27 1

Levy et al., Brain 2005;128:1921

Trigeminal Autonomic Cephalalgias (TACs)*

3.1 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

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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. 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.

(Cephalalgia 2013;33:629)

3.1.1 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. 3.1.2 Chronic cluster headache * Occurring without a remission period, or with remissions lasting <1 month, for at least 1 year.

Comparison of cluster headache and capsaicin-induced pain Cluster Headache (n = 9) Capsaicin (n = 7)

(Pain 1998; 74:61) (Lancet 1998;351:275) PET-activity (functional change)

Cluster headache: structure and function

PET- functional activity Voxel-based morphometry

(Lancet 1998; 351:275-278) (Nature Med 1999; 5:836-838)

Migrene

• ensidig
• pulserende
• Moderat til

alvorlig

• Forverrelse ved

aktivitet

• kvalme/brekninge

r

• foto/fonofobia

Minst 2 av- Minst en av- Vanligvis episodisk hodepine (4-72 timer) med visse kjennetegn (& ingen annen årsak):

after Classification of Headache Disorders, 1988, 2004 & 2013

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Migraine

The Attacks & the Disorder

• Premonitory symptoms
• Pain

– unilateral – throbbing – movement worse

• Nausea
• Sensory sensitivity

– photophobia – phonophobia – osmophobia

• Aura
• 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

Attacks Disorder

“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

Pain Nausea, Photophobia, Phonophobia Aura

Tiredness, Yawning, Concentration, Mood, Polyuria, Washed-out

Hours to Days

Maniyar et al., Brain 2014;137:232

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 600-800mg
• Naproxen 500-1000mg
• tolfenamic acid 200mg

– Opioids

• ± Anti-emetics

– domperidone 10mg – ondansetron 4mg – prochlorperazine 5-10mg

• Specific

– ergotamine derivatives

• ergotamine
• dihydroergotamine

– Triptans- 5-HT1B/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 – 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

• In development

– CGRP monoclonal antibodies – CGRP receptor antagonists – Neuromodulation – NOS-based approaches – mGluR5: glurants – Orexin 1 & 2: rexants

Goadsby Ann Neurol 2013;74:423

Goadsby Ann Neurol 2013;74:423

Monoclonal Antibodies* for Migraine Prevention are Effective

• Amgen AMG 334

– Human IgG1 receptor CLR/RAMP1 – Phase II- episodic migraine1

• Alder Biopharmaceuticals- ALD 4032

– Humanized CGRP peptide antibody – Phase II: episodic migraine 32 & 6 months*

• Arteaus Therapeutics/Lilly- LY2951742

– Humanized CGRP peptide antibody – Phase II: episodic migraine3

• Labrys/Teva- LBR-101/TEV-481254

– Humanized CGRP peptide antibody – Phase II- chronic migraine4 – Phase II- episodic migraine5 1. Lenz et al., Cephalalgia 2015;35:[62]:5 2. Dodick et al., Lancet Neurol 2014;13:1100 3. Dodick et al., Lancet Neurol 2014;13:885 4. Bigal et al., Lancet Neurol 2015;14: in press 5. Bigal et al., Lancet Neurol 2015;14: in press * www.ama-assn.org: erenumab/vistinumab/alcanezumab N = 160 107 82 81 110 108 104 95 89 85 28* 53

Cluster headache Management- acute attacks

• Established

– Oxygen: 100% @ 10-12 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

Goadsby Continuum Lifelong Learning Neurology 2012;18:883

Cluster headache

management- preventive

• 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

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dura mater V ganglion Sphenopalatine ganglion trigeminal nucleus C2 C1 SSN

Trigeminal Autonomic Cephalalgias

trigeminal-autonomic activation facilitated by the brain

SUNCT Cluster headache

y = -12

Paroxysmal hemicrania Pain Hemicrania continua

Goadsby Continuum Lifelong Learning Neurology 2012;18:883