Expert Opinion. Sentinel Headache CLINICAL HISTORY. Randolph W. Evans, MD; Esma Dilli, MD; David W. Dodick MD

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1 Headache 2009 the Authors Journal compilation 2009 American Headache Society ISSN doi: /j x Published by Wiley Periodicals, Inc. Expert Opinion (Headache 2009;49: ) Sentinel Headache Randolph W. Evans, MD; Esma Dilli, MD; David W. Dodick MD The evaluation of the first or worst headache can be challenging with a long list of possible causes including subarachnoid hemorrhage (SAH) that must be excluded. CLINICAL HISTORY A 35-year-old woman was seen with a chief complaint of the 2 worst headaches of her life. Six days previously, she awoke from sleep about 6 am with a non-stabbing pressure on the top of her head like her head was going to explode with an intensity of 10/10 with light and noise sensitivity but no nausea or other symptoms. She went to the emergency department that afternoon where a CT scan of the brain was negative. A lumbar puncture (LP) was not suggested. The headache resolved after about 18 hours. Three days previously, at about 10 am, she was having sex with her husband. At orgasm, she had an exactly similar headache with an intensity of 9/10 at the onset without associated symptoms. She took acetaminophen with codeine and the headache lasted about 8 hours. She had no further headaches. She told her sister, who is a physician, about the headaches, and who suggested a neurology consultation. There is a prior history of headaches for a few years about once a week described as a bifrontal Case history submitted by: Randolph W. Evans, MD, 1200 Binz #1370, Houston, TX 77004, USA. Expert opinion by: Esma Dilli, MD, and David W. Dodick, MD, Department of Neurology, Mayo Clinic, East Shea Blvd., Scottsdale, AZ 85259, USA. non-throbbing pain with an intensity of 3/10 without associated symptoms relieved by acetaminophen in about one hour. Past medical history was negative. Family history of her mother with a hemorrhagic stroke at age 60. Neurological examination was normal. An MRI of the brain the day of the initial consultation was normal. An MRA of the brain was reported as showing asymmetric flow-related enhancement of the distal right middle cerebral artery, which appeared to be due to overlapping arterial branches. No definite aneurysm was identified but a CTA was suggested. The CTA revealed a 4 mm aneurysm at the middle cerebral artery trifurcation. An cerebral angiogram the next day confirmed a 4 mm saccular aneurysm arising from the right middle cerebral artery trifurcation and a 2 mm saccular aneurysm arising at the junction of the M1 and minor M2 segments of the left middle cerebral artery. Both aneurysms had wide necks and were not amenable to endovascular treatment. An LP the same day produced clear cerebrospinal fluid (CSF) with the following results: glucose 54 mg/dl, protein 26 mg/dl, WBC 2/cmm, RBC 31/cmm. Spectrophotometry for xanthochromia is not available at this large medical center teaching hospital. The neurosurgeon was not entirely certain which, if either, aneurysm, had bled. The next day, the patient underwent clipping of the right middle cerebral artery aneurysm. Intraoperative inspection of the aneurysm revealed dense fibrous scarring with some hemosiderin staining around it. 599

2 600 April 2009 Questions. What was the cause of the headaches? Were these primary thunderclap? How common is the occurrence of 2 sentinel headaches? What would you have recommended as initial neuroimaging studies and with what urgency? What is the sensitivity of MRA and CTA for saccular aneurysms? What was this patient s risk of rebleeding from the aneurysm? Would use of spectrophotometry for the examination of the CSF preoperatively have been of utility? Should the patient have the left-sided aneurysm clipped? What is her risk of hemorrhage? EXPERT COMMENTARY The case is of a 35-year-old woman with a history of episodic tension-type headache presenting with 2 thunderclap headaches separated by 3 days. Her examination and imaging, including CT and MRI of the brain, were negative. Her LP was normal except for 31 RBC cm 2 CTA and then arteriography demonstrated 2 aneurysms: 4-mm right MCA and 2-mm left MCA aneurysms. Intraoperative clipping of the right MCA revealed fibrous scarring with hemosiderin around the aneurysm. The most important issue is to determine the cause of her thunderclap headache. Is it a sentinel hemorrhage or something else? The only way to be sure is to obtain the appropriate imaging and perform an LP after obtaining a detailed history and examination. She is otherwise healthy except for a history of episodic tension-type headache requiring acetaminophen. Given that her mother s hemorrhagic stroke may have been due to an aneurysmal SAH, it would be prudent to determine if other family members have a history of SAH or intracerebral hemorrhage. A positive family history would require 2 or more first or second degree family members with SAH secondary to aneursymal rupture. For individuals with 1 and 2 first-degree relatives with a history of SAH, the odds ratio is 2.15 and 51.0, respectively. 1 Overall lifetime risk of SAH for a person with 1 affected firstdegree relative is 1% at 50 years and 2% at 70 years. 2 The risk of SAH is 4 times greater in first-degree family members than the general population. 3 In addition, women are 1.6 times more likely than men to experience an SAH. 4 A single sentinel headache occurs in 10-43%. 5 The large range may be based on recall bias. The incidence of 2 sentinel headaches is unknown. Sentinel headaches occur within the 2 weeks preceding the hemorrhage with a peak within 24 hours prior to SAH. Not all sentinel headaches are warning leaks ; instead they maybe due to stretching or dissection in the aneurysmal wall. 6 All sentinel headaches from a minor leak should be taken seriously as approximately 74% have a major aneurysmal rupture within 24 hours to 4 weeks, half of which are fatal. 7 The presence of a sentinel headache has odds ratio of 10 for rebleeding compared with patients without a sentinel headache. 8 However, it is uncertain whether the number or size of aneurysms confounds the association between sentinel headache and rebleeding. Since 55% of patients with sentinel headache have a normal non-contrast CT head, LP and vascular imaging are necessary. 7 In this case, it is uncertain why an LP was not suggested in the emergency room. Some emergency department physicians may incorrectly and dangerously assume that a normal CT of the brain excludes SAH but, of course, CT will miss about 5% of SAH during the first 24 hours after the ictus increasing to 25% by day 3 and 50% by one week. Although reduced intracranial pressure from CSF drainage or increased systemic blood pressure from catecholamine release during the procedure can theoretically lead to increased pressure gradient and, therefore rebleeding, there should be no reason to delay an LP because the risk of missing an SAH is far greater than the risk of potentially worsening the bleed. In 2008, a prospective cohort study illustrated that a combination of negative CT head and LP (absence of xanthochromia on visual inspection and < RBC/L) was sufficient to rule out a SAH with a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 67%, 3.03, and 0, respectively. 9 In this case, the patient eventually had an atraumatic LP 6 days after her initial thunderclap headache. Her CSF was clear and normal except for an elevated red cell count of 31. The red cell count will decrease in the absence of continuous bleeding because it is degraded into heme products resulting in xanthochromic staining in the CSF.

3 Headache 601 Over 99% of US hospitals detect xanthochromia by visual inspection rather than spectrophotometry (the test is available in 0.3% of US hospitals). Spectrophotometry sensitivity of detecting xanthochromia is 100% from 12 hours to 2 weeks after a bleed, 70% at 3 weeks, and 40% at 4 weeks. 10,11 The sensitivity of head CT in SAH also decreases over time to 86% on day 2, 76% after 2 days, and 58% after 5 days. 12,13 Lumbar puncture has the highest sensitivity of ruling out an SAH but only 12 hours after the onset of the headache. Many patients, however, present to the ER with the worst headache of their life before the 12-hour mark, resulting in either another repeat LP at 12 hours if the initial LP was negative or pursuing other means of ruling out an SAH. In addition, although the sensitivity of spectrophotometry is 100% after 12 hours, the specificity is 75% with a positive predictive indicator of SAH of 3.3%. 14 Her LP was normal except for 31 RBC cm 2. This false positive rate may lead to unnecessary investigations and treatments with its own risks. 15 Conversely, visual inspection for xanthochromia has a low sensitivity of 47.3% (95% confidence interval %) 16 because CSF is either contaminated with oxyhemoglobin (red color) or the levels of bilirubin (yellow color) are too low for visual detection. 17 Despite the low sensitivity by visual inspection, overall the combination of CT and LP appears to be sufficient to rule out an SAH. 9 At this point, we know that the patient had 2 thunderclap headaches without any known risk factors and a normal neurological exam. Her initial non-contrast CT head is negative and her LP revealed clear CSF with 31 RBC. She therefore requires vascular imaging, CTA and/or MRA, to determine cause of the bleed. While all patients tend to have an urgent noncontrast CT scan, vascular imaging such as CTA or MR angiography is seldom performed in the acute setting. However, these vascular studies not only investigate etiologies of an SAH but they determine other possible causes of recurrent thunderclap headache such as venous sinus thrombosis, arterial dissections, reversible cerebral vasospasm syndrome, and vasculitis all of which are treatable conditions which, if undetected, could result in serious neurological morbidity and mortality. Her MRA was inconclusive; therefore, a CTA was performed revealing the right 4-mm wide neck aneurysms. The sensitivity of CTA or MRA depends on the size and location of the aneurysms. CTA sensitivity and specificity overall is 77-97% and %, respectively. 18 MRA sensitivity and specificity is 69-99% and 100%, respectively. 18 CTA sensitivity is 53% and 95% for aneurysms 2 mm and 7 mm, respectively, which explains why the conventional angiogram detected a 2 mm left MCA aneurysm that was missed on both the MRA and CTA. MCA aneurysm detection with CTA and conventional angiogram is 97% (specificity of 100%), which is higher than other arterial territories. Since there was no other etiology found to explain her findings, it was assumed that one or both of her aneurysms leaked. The issue is how to determine which aneurysm is the culprit. MRI may be useful to determine the origin of the bleed. The absence of subarachnoid blood on the head MRI is likely due to a minimum concentration of RBC/cc to detect hyperintense CSF on MRI fluid attenuated inversion recovery (FLAIR) sequences. 19 FLAIR MRI cannot replace LP to detect the presence of SAH since abnormalities occur in only 16.7% of SAH cases when CT findings are negative. 19 The combination of 3D CTA and 2D CT has been demonstrated to be useful in predicting the rupture point of MCA aneurysms, but the aneurysm size in those cases were larger (average > 8.5 mm) and were associated with significant hemorrhages. 20 This patient s thunderclap headache is likely due to the aneurysm based on the hemosiderin deposits around the aneurysm (you didn t describe that this was what was seen on CTA) and the lack of other risk factors for SAH such as hypertension, smoking, alcohol, vasoactive agents, trauma, endocarditis, or other vascular malformations. Treatment of the aneurysm within 24 hours of the bleed reduces the risk of rebleeding, which is approximately 4% within 24 hours, 1-2% per day for the first 2 weeks (30% within first 2 weeks) and 50% at 6 months At 6 days after her initial sentinel headache, her risk is about 7-14% within the next week.

4 602 April 2009 Table. Five-Year Accumulative Risk of Rupture Asymptomatic aneurysms <7 mm 7-12 mm mm >25 mm Cavernous ICA 0% 0% 3% 6% IC/MC/AC 1.5% 2.6% 14.5% 40% Posterior circulation % 14.5% 18.4% 50% ICA = internal carotid artery; IC = internal carotid; MC = middle cerebral; AC = anterior cerebral. The decision of whether to treat the left MCA aneurysm depends on the risk of an SAH and the risk of intervention. Multiple aneurysms are found in 20-30% 24 of cases; therefore, the presence of a second aneurysm in this patient is not rare. Although she had a sentinel headache with an aneurysm showing hemosiderin deposits around it, the left MCA aneurysm is small (2 mm) and unlikely (although uncertain) to be symptomatic. Her 5-year cumulative risk of asymptomatic aneurysmal rupture depends on location and size of the aneurysm (see Table). In this particular patient, the rupture rate of the asymptomatic left MCA aneurysm is greater than 0.07% per year 25 if one considers her sentinel headache was due to an SAH of the treated right MCA aneurysm. This is significantly different than symptomatic aneurysms (6.5% rupture rate per year) The differences in the rupture risk between the Rinkel and ISUIA 25 studies are based on the study design (population sample from which the data were collected) and therefore the ability to generalize the result depends on the target population. Also, the numbers are adjusted to yearly risks of rupture and do not consider the variable dynamics of aneursymal rupture. 27 Overall her risk of a left MCA aneurysm rupture is %, likely closer to 0.07% per year but we need to consider the fact that her initial event occurred at a younger age and that her risk may be higher up front. On the other hand, the morbidity, mortality, and rebleeding rate of intravascular coiling is %, %, and 2.6%, respectively, 28 while the risks associated with surgical clipping are %, %, and 0-0.9%. 28 Since the left MCA aneurysm has a wide neck and therefore not amenable to endovascular treatment, she would need to undergo another craniotomy for surgical clipping. Although being younger with no comorbidities would put her at a lower risk, the risk of surgery for a likely asymptomatic aneurysm is greater than the risk of an SAH. It would be prudent, instead, to treat any other risk factor associated with hemorrhage such as hypertension, hypercholesterolemia, excessive alcohol consumption, smoking, or OCP use that may develop in the future. In addition, follow-up vascular imaging is required to monitor the size, number, and character of the aneurysm(s). All patients presenting with a clear history of thunderclap headache should have an urgent noncontrast CT head, followed by an LP and vascular imaging (CTA or MRA) to rule out SAH and other mimics as delay may have lethal consequences. Follow-Up. After a discussion of the risk of SAH with the neurosurgeon as detailed above, the patient chose to have surgery on the left-sided aneurysm which was performed without complication 8 months after the first procedure. REFERENCES 1. Bor AS, Rinkel GJ, Adami J, et al. Risk of subarachnoid haemorrhage according to number of affected relatives: A population based case-control study. Brain. 2008;131: Teasdale GM, Wardlaw JM, White PM, et al. The familial risk of subarachnoid haemorrhage. Brain. 2005;128: Van der Jagt M, Hasan D, Bijvoet HW, et al. Validity of prediction of the site of ruptured intracranial aneurysms with CT. Neurology. 1999;52: Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneu-

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