ORIGINAL ARTICLE Pituitary Volume and Headache Size Is Not Everything Miles J. Levy; H. Rolf Ja¨ger, MD; Michael Powell, FRCS; Manjit S. Matharu, MRCP; Karim Meeran, MD; Peter J. Goadsby, MD, PhD, DSc, FRACP, FRCP Background: Pituitary tumors are commonly associ- ache score and pituitary volume (r=−0.32, P=.01, Spear- ated with disabling headache. The accepted mecha- man rank correlation). There was also no association be- nisms for headache are dural stretch and cavernous si- tween cavernous sinus invasion and headache. There was nus invasion. a strong association between pituitary-associated head- ache and a family history of headache (␹2=8.36, P=.004). Objective: To determine if there is a relationship be- tween pituitary tumor size and the report of headache. Conclusions: These data suggest that a pituitary tumor– associated headache may not simply be a structural prob- Design: We prospectively studied 63 patients who were lem. Other factors such as family history of headache, and initially seen with pituitary tumors. Clinical headache the endocrine activity of the tumor may be equally im- scores, pituitary tumor volume, and the extent of cav- portant determinants of headache. Elucidating these mecha- ernous sinus invasion were obtained for each patient. nisms will aid in the treatment of these patients and fur- ther our understanding of other headache syndromes. Results: The prevalence of headache was 70%. There was no positive correlation the between clinical head- Arch Neurol. 2004;61:721-725 EADACHE, A WELL-RECOG- mas,6 with approximately 12.5% report- nized feature of pitu- ing the symptom.3 Recurrence of head- itary disease, may be dis- ache after treatment may be a clinical sign abling.1,2 The reported of further disease activity.7 Somatostatin incidence of headache in analogues, such as octreotide, can have an pituitary disease ranges with tumor type immediate analgesic effect in acromegaly- H 8-10 from 33% to 72% and has been reported associated headache, in the absence of to be particularly high in prolactinomas.3 reduction in tumor size.11 This may be a bio- It has long been considered that head- chemical effect or a direct effect of activa- ache is related to tumor size and dural tion of somatostatin receptors with antino- stretch.2,4 The explanation for dural stretch ciceptive effects in the brain.12 as a cause of headache is that the expan- A variety of headache phenotypes have sion of a pituitary tumor within the sella been associated with pituitary tumors. turcica stimulates afferent fibers innervat- These include severe and intractable mi- ing the dura mater, which are certainly graine,13 trigeminal autonomic cephal- known to be pain producing.5 Involve- gias,14 such as cluster headache,15,16 short- ment of the cavernous sinus has also been lasting, unilateral neuralgiform headache From the Headache Group invoked to explain headache3 since the si- attacks with conjunctival injection and tear- (Mr Levy and Drs Matharu and nus contains the ophthalmic branch of the ing,17,18 and trigeminal neuralgia.19 In such Goadsby) and the Department trigeminal nerve and the internal carotid cases, conventional preventive and abor- of Radiology (Dr Ja¨ger), artery, both of which could generate head tive headache treatment can often prove to Institute of Neurology, pain. However, the mechanical explana- be ineffective, yet medical treatment of the Department of Neurosurgery, tion for pituitary tumor–related head- pituitary disease can completely resolve the National Hospital for ache has never been systematically ex- symptoms. For example, there are re- Neurology and Neurosurgery (Dr Powell), and the plored, although its implications for ported cases of microprolactinomas mani- Department of Endocrinology, management and understanding of the festing with severe headache that have re- Hammersmith and Charing clinical problem are profound. solved immediately with the administration Cross Hospitals Trust Headache can be a prominent feature of dopamine agonists20,21 as well as the im- (Dr Meeran), London, England. of acromegaly, even with microadeno- pressive analgesic effects of somatostatin (REPRINTED) ARCH NEUROL / VOL 61, MAY 2004 WWW.ARCHNEUROL.COM 721 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 analogues in acromegaly.9,10 However, there are also ex- toms. A retrospective clinical headache score covering the pe- amples of significant exacerbations of headache with the riod closely related to the magnetic resonance images (MRIs) administration of dopamine-agonists in patients with pro- was calculated using the following formula: 17,22 lactinomas. (1) Headache Frequency (Days per Week) The fact that headache can be dramatically improved ϫHeadache Duration (Hours per Day) or worsened by endocrine treatments, in the absence of any ϫHeadache Severity for Peak Attack measurable change in pituitary size, suggests that pitu- (Range, 0 [no pain] to 10 [worst pain imaginable]) itary tumor–associated headache may be a biochemical- neuroendocrine problem rather than a structural one. The To validate this measurement, 22 of the 63 recruited patients aim of this study was to examine systematically the rela- (one third of the cohort) were randomly asked to complete pro- tive importance of size and cavernous sinus invasion in pi- spective headache diaries, in which an hourly headache score tuitary tumor–associated headache to test directly the hy- was documented for a 2-week period. These diaries were sent pothesis that local mechanical effects are preeminent in the to a separate headache specialist, masked to the initial evalu- causation of headache in these patients. ation and the MRI findings, who calculated a mean clinical head- ache score for each patient. The diary score and the retrospec- METHODS tive score were then compared. The presence of a family history of headache was documented in the course of the complete medi- Sixty-three patients who were initially seen with pituitary dis- cal history. ease were prospectively studied (Table 1). All patients were seen in the same unit for treatment of newly diagnosed pitu- PITUITARY VOLUME itary disease, which included both surgical and medical man- agement options. Headache, pituitary volume, and cavernous The pretreatment MRIs were performed on several different MRI sinus invasion were assessed prospectively with clinical evalu- scanners, all at 1.5 T. All examinations included coronal and ation of headache and structural data being collected by dif- sagittal T1-weighted spin-echo sequences with a maximum sec- ferent investigators in a masked fashion. tion thickness of 3 mm, before and after intravenous adminis- tration of a gadolinium-based contrast medium. All MRIs were HEADACHE assessed by the same neuroradiologist (H.R.J.). For the assess- ment of the tumor volume, it was assumed that pituitary tu- 23 Before commencement of treatment, all patients were inter- mors are ellipsoid. Using Cavalieri’s principle, pituitary tu- viewed by a trained headache fellow or specialist (M.J.L., M.S.M., mor volume was calculated after performing measurements of and P.J.G.). The clinical data collected included the presence tumor diameter in 3 orthogonal planes (Figure 1A-B), using or absence of headache and the frequency and severity of symp- the following equation: 4 ␲ (2) Volume=[ /3 (a/2·b/2·c/2)] Table 1. Clinical Headache Scores* and Tumor Activity If the tumor was large and multilobed, the tumor volume was Mean assumed to consist of separated ellipses and the sum of each No. of Headache lobe volume was calculated (Figure 1C). Tumor Subtype Patients Female, % Score Growth hormone 12 66 758 CAVERNOUS SINUS INVASION Prolactin 17 83 659 Thyrotropin 3 66 600 We assessed 3 different parameters for the assessment of pres- Craniopharyngioma 5 20 362 ence and degree of cavernous sinus involvement: Nonfunctioning adenoma 20 80 194 Corticotropin 6 100 200 1. Encasement of the internal carotid artery, distinguish- ing 4 grades: no encasement, less than 25% to 50%, more than Abbreviation: ACTH, adenocorticotrophin-stimulating hormone. 50% to 75%, and more than 75% to 100%. *Clinical headache score = headache frequency (days per 2. Crossing of the 3 lines connecting the cross sections week) ϫ headache duration (hours per day) ϫ headache severity (range, through the distal internal carotid arteries (intercarotid lines): 0 [none] to 10 [severe]). medial, median, and lateral. A B C Figure 1. Calculation of pituitary volume for a single-lobed tumor (A and B) and a multilobed tumor (C) assuming the tumor to be ellipsoid. Using 3 orthogonal 4 lines (a, b, and c), Volume=[ /3 ␲(a/2·b/2·c/2)]. (REPRINTED) ARCH NEUROL / VOL 61, MAY 2004 WWW.ARCHNEUROL.COM 722 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 A B MdnL C MdIL LL 2 Hypophys ICA 3 1 5 4 Figure 2. Cavernous sinus invasion. A, The venous compartments are 1, medial; 2, superior; 3, lateral; and 4, carotid sulcus. Hypophys indicates the pituitary gland; ICA, internal carotid artery. B, The intercarotid lines are medial line (MdL), median line (MdnL), and lateral line (LL). The shaded area is the pituitary gland. C, The carotid artery encasement indicates grade 1, less than 25%; grade 2, more than 25% to 50%; grade 3, more than 50% to 75%; and grade 4, more than 75% to 100%. The shaded area is the pituitary gland. Adapted from Cottier et al.24 3. Extension of the tumor into the venous compart- ments of the cavernous sinus. 1400 Based on a modification of the classification system de- 1200 scribed by Cottier et al,24 we distinguished among tumor ex- tension into the superior, lateral, and inferior venous compart- 1000 ments (Figure 2). Invasion of the medial compartment had 800 not proved significant in previous studies24 and the inferolat- eral venous and carotid sulcus compartments were grouped to- 600 gether as the inferior compartment in this study.