1. eEdE-57 Thunderclap Headache Beyond Aneurysms- A Clinically Integrated Approach Daniel Strauchler, MD 1 Daniel Berlin, MD MSc 2 Joseph Platnick 3 X Wu 4 Ajay Malhotra, MD 1 1 Yale New Haven Hospital, New Haven, CT, 2 Neurology Group Bergen, Ridgewood, NJ, 3 Radiology Associates of Ridgewood, Waldwick, NJ, 4 Yale University School of Medicine, New Haven, CT

2. Purpose/ Outline Define thunderclap headache (TH) Review the differential diagnosis of TH Is it possible to clinically distinguish between benign and malignant causes of TH? Review the workup of TH- role of LP and CTA – Present case series of 119 patients undergoing CTA for headaches Case presentations

3. Definition of Thunderclap headache (1986) Very severe headache which reaches maximum intensity within 1 minute

4. Differential diagnosis Subarachnoid hemorrhage Reversible vasoconstrictive syndrome/ Posterior reversible leukoencephalopathy syndrome Cerebral venous sinus thrombosis/ Cortical vein thrombosis Arterial dissection Orgasmic/exertional headache Spontaneous intracranial hypotension Pituitary apoplexy Primary thunderclap headache Parenchymal hemorrhage Cerebral infarct Infection (including bacterial, viral, and aseptic meningitis and sinusitis) – For comprehensive differential list see Devenney et al. The journal of headache and pain. 2014;15:49.

5. Thunderclap headache (TH) Landtblom et al. Cephalalgia 2002 Prospective study of 137 patients presenting within 10 days of TH to emergency dept in Sweden over 1.5 year period Each patient was examined by a neurologist, had CT head acutely, and if necessary lumbar puncture was performed Each patient was followed up by telephone on a regular basis for 1 year

6. Patients with TH Women Men All All patients 57% 43% 137 SAH 13 10 23 (17%) Median age 58 (32-79) Non-SAH 65 49 114 (83%) Median age 39 (18-86)

7. CT and CSF findings FindingPatients (n) SAH23 Cerebral infarction5 Intracerebral hemorrhage3 Aseptic meningitis4 Cerebral edema1 Sinus thrombosis1

8. Results Incidence of TH was 43/100,000 adult population/yr 17% of patients had SAH (23/137) 5/23 patients with SAH required LP for diagnosis 8% of patients had coital headache (1/5 had SAH) 86% of patients had headache onset over 2 seconds Majority of patients were resting at time of TH (60%) There is an increased prevalence of primary headaches in patients with non-SAH TH

9. Can clinical characteristics distinguish SAH from non-SAH TH? ”Headache characteristics in SAH and benign TH” Prospective study of 102 patients who presented with TH Only 2 characteristics occurred exclusively in pts with SAH: seizures and diplopia Landtblom A et al. Cephalalgia 2002;22:354-360 Linn et al. J. Neuro, Neurosurg, Psychiatry 1998; 65; 791-793

10. Study Conclusions TH is mostly a benign condition In most cases, it was not possible to determine the cause of TH TH due to SAH versus non-SAH cannot be distinguished based on clinical grounds- ancillary testing is necessary Study Limitation Vascular imaging was not performed

11. Case Series We retrospectively reviewed 119 Cases of patients presenting with headache who underwent CTA of head and neck in addition to noncontrast CT of head. 9/119 (8%) were positive including: 3 - subarachnoid hemorrhage related to aneurysm. 2 - intraventricular hemorrhage of unknown etiology 1 – arteriovenous malformation 1- arteriovenous fistula in scalp 1 – parenchymal (hypertensive) hemorrhage 1- parenchymal (metastasis) hemorrhage 110/119 (92%) were essentially negative or unchanged. Of which: 3- venous thrombosis diagnosed subsequently of MRV 3- cerebrovascular accident diagnosed subsequently on MRI 13 – had aneurysms (2 newly diagnosed, 8 previously treated, 3 known)

12. Small percentage of cases 3/119 (3%) with subarachnoid hemorrhage compared with previous studies likely reflects scanning of patients without true TH (worst at onset). 2/106 (2%) with new aneurysm (after excluding those with known or treated aneurysms, which likely was factor in repeat imaging) is within range of previously reported prevalence on unruptured aneurysms suggesting that these are incidental. Case Series

13. Workup of TH: Importance of LP CT head within 12 hours of TH has 98% sensitivity for SAH detection CT head at 1 day post SAH is 95% sensitive Van der Wee et al. J. of Neuro, Neurosurg, Psychiatry 1995; 58: 357-359 CT head at 5 days post SAH is about 60% sensitive A LP can reliably distinguish true SAH from traumatic tap only after 12 hours have elapsed from symptom onset (the time it takes for xanthochromia to develop) Xanthrochromia is best detected by spectrophotometry over visual inspection Evidence from a prospective study using multidetector scanners with at least four detectors suggests that negative scans can reliably exclude subarachnoid hemorrhage if obtained within the first six hours after onset of the headache Perry et al. BMJ 2011;343:d4277 Suggests LP may not be needed if patient is scanned within 6 hours.

14. Some have argued that combining noncontrast CT and CTA can replace LP in excluding aneurysmal subarachnoid hemorrhage, arguing that combining CT sensitivity for subarachnoid hemorrhage and CTA sensitivity for aneurysm yields greater than 99% posttest probability to exclude aneurysmal subarachnoid hemorrhage. 1 However, others have countered based on utility analysis that frequent use of CTA in patients with thunderclap headache with limited utility and arguing that a negative CTA does not exclude the presence of subarachnoid blood, and the detection of aneurysm does not confirm it as being the cause of SAH. 2 – CT with no follow-up was shown to be the best strategy when the pre-test probability of SAH is low ( 99.6%). Otherwise, LP should be the preferred strategy for follow- up. 1 McCormack et al Acad Emerg Med 2010;17:444–51 2 Wu et al EMJ. Jun 4 2015. Controversy: Can CTA replace LP?

15. Controversy: TH with normal CT and LP: Is further investigation necessary? Conditions such as arterial dissection, cerebral sinus thrombosis, and vasoconstrictive syndromes require further diagnostic imaging Angiography can detect a symptomatic unruptured intracranial aneurysm Out of more than 200 patients with TH who had normal CT and LP, none developed SAH in followup Aneurysm detected on angiography does not necessarily mean it is symptomatic YES NO

16. Case 1 25-year-old man with chronic history of migraine presents with thunderclap headache- different from his usual headaches- while having a bowel movement. Social history: 1 pack/day smoker, habitual marijuana use CT head at that time was normal He returned to ED 1 week later for multiple recurrent thunderclap headache. Repeat head CT shows new right occipital subcortical hypodensity. MRI shows corresponding FLAIR signal hyperintensity.

17. Differential diagnosis includes: Migrainous infarction, Subarachnoid hemorrhage with subsequent vasospasm, Posterior reversible leukoencephalopathy syndrome/Reversible vasoconstrictive syndrome, Stroke While consent for LP was being obtained the patient developed severe visual field abnormalities bilaterally. CTA followed by catheter angiogrpahy demontrates focal areas of vasoconstriction in various artery distributions Case 1 continued

18. Definition A group of disorders characterized by prolonged but reversible vasoconstriction of cerebral arteries associated with recurrent thunderclap which can be associated with other neurologic symptoms. Diagnostic Criteria (2007) Acute and severe headache (usually thunderclap) with or without focal deficits or seizures, Uniphasic course (without new symptoms more than 1 month after onset), Segmental vasoconstriction of cerebral arteries, No evidence of aneurysmal SAH, Normal or near-normal CSF profile, Complete or substantial normalization of arteries on follow-up angiography (3 months from onset) Treatment (No randomized trials exist, only observational data and expert opinion) Verapamil IA was injected into bilateral ACA, MCA, and PCA with moderate improvement in vessel caliber Nimodipine 60mg q4 hours x 3 weeks, Induced hypertension 160-180 SBP, Daily transcranial doppler evaluation, Abstain from marijuana Clinical Course Transcranial doppler showed fluctuating vasospasm for about 10 days before normalizing CTA 2 weeks after admission showed some overall improvement but persistent irregularities Precipitating factors: 60% due to vasoactive drug: Cannabis most common, SSRI, Nasal decongestants 38% spontaneous 12% peripartum state Case 1 - Reversible Cerebral Vasoconstriction Syndrome

19. RCVSVasculitis PresentationAcuteSubacute progressive headache CSFNormalPleocytosis MRIUsually normal, can see infarcts, SAH Abnormal-multifocal infarctions AngiographyMedium-large vesselSmall Vessel TreatmentCa channel blockerImmunosuppressants

20. Reversible Cerebral Vasoconstriction Syndrome Clinical course: Mean of 4 thunderclap headaches over 1-4 weeks Triggers: Valsalva maneuver (sex, exertion, sneezing, bending) Moderate headache persists between exacerbations 1/3 of patients deteriorate after initial diagnosis Intracranial hemorrhage, SAH, seizures occurred in first 3 days Ischemic events occurred around day 12 90-95% of patients have a benign syndrome despite severe vasoconstriction Case 1

21. Case 2 21-year-old woman presents to ED (for 3 rd time) with 1 month of severe right side-locked head pain. She has had 1 day of left hemiparesis. Daily and continuous headache characterized as severe pressure (as if “head will explode”) with episodes of sudden severe worsening No fever, no meningismus 2 weeks of worsening pulsatile tinnitus PMH: “Similar headache” 5 years ago with normal MRI Medications: OCP Prior imaging: normal CT head and MRA head Exam: Right eye ptosis, left papilledema, left arm and left drift Clinical Differential Diagnosis Hemicrania continua Intracranial mass Idiopathic intracranial hypertension Cerebral sinus thrombosis Dense Clot in Superior Sagital Sinus Normal CT 3 weeks prior TI hyperintensity in right transverse sinus MRV 9 months post treatmentMRV at time of diagnosis

22. MRI DWIADC Case 2 Mild diffusion restriction in right frontoparietal region on Diffusion Weighted Imaging (right image) and ADC map (left image)

23. Case 2- Dural Veinous Thrombosis Hypercoagulable workup positive for lupus anticoagualant Pathogenesis: Cerebral vein thrombosis causes local edema/venous infarction - Cytotoxic edema - Vasogenic edema Cerebral sinus thrombosis causes intracranial hypertension A prothrombotic risk factor found in 85% of patients with CST Epidemiology: Incidence: 5 people/ 1 million Diagnosis D-dimer: Very good negative predictive value in patients with abnormal neurological exams but not helpful in patients with isolated headache Imaging gold standard: MRI and MRV with and without contrast Acute treatment: For children or adults, with or without hemorrhagic venous infarction, anticoagulation therapy with either LMWH or unfractionated heparin is recommended (level 1B). NEJM 2005 Jugular veins 12% Transverse sinuses 86% Vein of Galen and internal cerebral veins 11% Superior sagittal sinus 62% Cortical veins 17% Straight Sinus 18% Incidence of involved Sinuses and Veins

24. Evaluation and Treatment OCP stopped Hypercoagulable panel sent Lovenox 1mg/kg BID->Coumadin Hydration 150cc/hr NS Monitored in ICU Headaches controlled Hypercoagulable workup – + lupus anticoagulant – Heterozygous prothrombin gene mutation Case 2

25. Dural Veinous Thrombosis Most data regarding demographics, clinical features, natural history, and treatment is derived from the International Study on Cerebral Vein and Dural Sinus Thrombosis (624 pts) Ferro et al. Stroke 2004; 35: 664-670 -Epidemiology: Incidence: 5 people/ 1 million

26. Dural Veinous Thrombosis

27. Dural Veinous Thrombosis: Risk factors A prothrombotic risk factor found in 85% of patients with CST

28. Case 3-Primary thunderclap headache 42-year-old woman with lifelong history of migraine presents to ED (3 rd time in 1 week) with thunderclap headache which began during a bowel movement 4 years prior: Admitted for status migranosis and CT head, LP, and CTA were normal. Differential Diagnosis Status Migranosis, Cluster headache, Primary cough headache /Valsalva-maneuver headache, Primary thunderclap headache, Idiopathic intracranial hypertension Primary thunderclap headache Diagnostic criteria: Severe head pain, Abrupt onset, reaching maximum intensity within 1 minute, Lasting for >5 minutes, Not better accounted for by another diagnosis 46% of patients with primary thunderclap headache have baseline primary headache disorders Primary cough headache Diagnostic criteria: At least 2 headaches episodes, Occur in association with cough, strain, or other valsalva maneuver, Sudden onset, Lasting 1 sec- 2 hours Scatter white matter FLAIR signal abnormalities are unchanged from 5 years prior Normal MRV Normal MRA

29. Case 3 Treatment -Indomethacin 50mg TID -Inderal 40mg BID -Tapered off these medications over 2 months without headache recurrence

30. Primary Thunderclap Headache 46% of patients with primary thunderclap headache have baseline primary headache disorders Linn et al. J. Neuro 1999; 246: 946-948 Number of patients with recurrent TH 103 patients followed for 1 year 25% had recurrent events No SAH in followup “Long term follow-up of 71 patients with TH mimicking SAH” 3.3 year average followup 17% had recurrent event No SAH in followup Wijdicks et al. The Lancet 1988; 68-69 Landtblom A et al. Cephalalgia 2002;22:354-360

31. Summary/Conclusion Majority of TH will have a benign etiology Comprehensive testing should be considered to exclude secondary causes- CT head without contrast is recommended first test. If continued clinical suspicion for subarachnoid hemorrhage despite negative CT (and CT performed after 6 hours of headache onset), LP should be performed. There is no reliable way to clinically distinguish primary from secondary TH. In patients with recurrent thunderclap headache, consider angiographic imaging to evaluate for RVCS. In women with progressively worsening headache who are on oral contraceptive pills, consider cerebral sinus thrombosis Primary thunderclap headache is a diagnosis of exclusion.

32. References 1. Wu X, Kalra VB, Durand D, Malhotra A. Utility analysis of management strategies for suspected subarachnoid haemorrhage in patients with thunderclap headache with negative CT result. Emergency medicine journal : EMJ 2016;33:30-6. 2. van der Wee N, Rinkel GJ, Hasan D, van Gijn J. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after a negative scan? Journal of neurology, neurosurgery, and psychiatry 1995;58:357-9. 3. Schwedt TJ. Thunderclap headaches: a focus on etiology and diagnostic evaluation. Headache 2013;53:563-9. 4. Schwedt TJ. Clinical spectrum of thunderclap headache. Expert review of neurotherapeutics 2007;7:1135-44. 5. Savitz SI, Edlow J. Thunderclap headache with normal CT and lumbar puncture: further investigations are unnecessary: for. Stroke; a journal of cerebral circulation 2008;39:1392-3. 6. Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ (Clinical research ed) 2011;343:d4277. 7. Linn FH, Rinkel GJ, Algra A, van Gijn J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. Journal of neurology, neurosurgery, and psychiatry 1998;65:791-3. 8. Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson G, Johansson I. Sudden onset headache: a prospective study of features, incidence and causes. Cephalalgia : an international journal of headache 2002;22:354-60. 9. Fine B, Singh N, Aviv R, Macdonald RL. Decisions: does a patient with a thunderclap headache need a lumbar puncture? CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2012;184:555-6. 10. Ducros A, Bousser MG. Thunderclap headache. BMJ (Clinical research ed) 2013;346:e8557. 11. Devenney E, Neale H, Forbes RB. A systematic review of causes of sudden and severe headache (Thunderclap Headache): should lists be evidence based? The journal of headache and pain 2014;15:49.