Editorial Annals of Clinical Biochemistry 2014, Vol. 51(6) 629–630 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0004563214552286 acb.sagepub.com
Accurate diagnosis of subarachnoid haemorrhage Mark O McCarron1 and Maurice J O’Kane2
The annual incidence of subarachnoid haemorrhage (SAH) is nine cases per 100,000 population with 85% of SAH caused by rupture of a cerebral aneurysm.1,2 Case fatality in aneurysmal haemorrhage is around 40% with 30% of patients suffering a re-bleed within four weeks.2 Treatment is effective: with early diagnosis, appropriate medical management and aneurysmal obliteration, mortality and significant disability at one year can be reduced to 24%.3 It is estimated that 8% to 12% of patients with a thunderclap headache (abrupt headache of severe onset) will have had a SAH.4 Most cases of SAH are confirmed with a non-contrast computed tomography (CT) scan of brain; earlier imaging from headache onset improves the sensitivity for identifying SAH. In patients with a negative CT scan, a lumbar puncture is required to look for evidence of haemoglobin breakdown products in cerebrospinal fluid (CSF).5 In the late 1980s and early 1990s, it was estimated that about 2% of patients with SAH have a normal CT scan of brain if performed within 12 h of headache onset.6 There is, however, emerging evidence that a negative CT scan within 6 h of headache onset in patients who are neurologically intact and without neck pain, may be sufficiently sensitive to avoid the need for lumbar puncture to exclude SAH,7,8 but this has not yet been adopted by guidelines. Lumbar puncture for the detection of CSF xanthochromia, therefore, continues to be required for CT-negative patients. Delayed diagnosis of SAH remains common and frequently attracts medicolegal attention; 9% of the total neurological litigation has been attributed to misdiagnosis of SAH.9 In the 2011 UK national confidential enquiry into patient outcome and death (NCEPOD) from aneurysmal SAH, 49 of 383 patients (13%) did not have a timely diagnosis of aneurysmal SAH; this was mostly due to delayed CT scanning.10 Of the 12 patients in the cohort who did not have SAH
identified radiologically, 10 underwent lumbar puncture which confirmed the diagnosis. Spectrophotometric analysis of CSF for the presence of bilirubin is widely used in the UK and other European countries although visual inspection of the CSF for pigmentation remains common practice elsewhere.11 Other less commonly used approaches include the measurement of CSF ferritin and the direct measurement of CSF bilirubin.11 The UK National External Quality Assessment Scheme guidelines (revised in 2008)5 propose the measurement of net oxyhaemoglobin absorbance (NOA) and net bilirubin absorbance (NBA) in a CSF sample taken at least 12 h after headache onset. There are, however, limitations to this test. First, increased CSF bilirubin is not specific for SAH,12 and may occur in other conditions such as meningitis and spontaneous intracranial hypotension. Second, the diagnostic absorbance cut-offs proposed are somewhat arbitrary. The reference range for CSF bilirubin absorbance of 0.007 AU as a clear indication for angiography.5 This was based on review of a series of 740 CSF spectrophotometric scans from four centres on CT-negative patients (27 of whom had NBA >0.007 AU and proceeded to angiography). However, little clinical information was provided on the patient cohort, in particular the certainty with which a diagnosis of SAH had subsequently been confirmed 1
Department of Neurology, Altnagelvin Hospital, Londonderry, UK Department of Clinical Chemistry, Altnagelvin Hospital, Londonderry, UK 2
Corresponding author: Mark O McCarron, Department of Neurology, Altnagelvin Hospital, Londonderry BT47 6SB, UK. Email: [email protected]
630 or excluded. This raises the possibility of both spectrum and verification bias which may affect the diagnostic performance of the test. Although it is commonly suggested that bilirubin persists in the CSF for up to 2 weeks, this has only been demonstrated for patients with a CT brain scan showing SAH14 and there is anecdotal evidence that aneurysmal SAH with lumbar puncture at day 8 may not reach the NBA threshold of 0.007 AU.15 In this edition of the Annals, Birch et al.16 investigate whether CSF protein concentration can aid interpretation. In a series of 132 patients with NBA >0.007 AU and NOA >0.02 AU, those patients in whom a diagnosis of SAH was not confirmed had the highest CSF protein concentrations. Although Birch et al. could not identify a CSF protein concentration above which SAH could be reliably excluded, they remind us of the importance of clinical setting for the interpretation of CSF spectrophotometry. As highlighted by the NCEPOD survey,10 future improvements in the diagnosis of SAH will rest heavily on clinical skills in suspecting SAH at an earlier stage with timely CT scanning. CSF spectrophotometry will continue to play an important role, but further work is needed to define the diagnostic performance of spectrophotometry in CT-negative patients. Declaration of conflicting interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethical approval Not required.
Guarantor MOM.
Contributorship Both authors are responsible for the conception and preparation of the manuscript and approval of the final draft.
References 1. de Rooij NK, Linn FH, van der Plas JA, et al. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007; 78: 1365–1372.
Annals of Clinical Biochemistry 51(6) 2. van Gijn J and Rinkel GJE. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001; 124: 249–278. 3. Connolly ES, Rabenstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid haemorrhage. Stroke 2012; 43: 1711–1737. 4. Edlow JA, Malek AM and Ogilvy CS. Aneurysmal subarachnoid hemorrhage: an update for emergency physicians. J Emerg Med 2008; 34: 237–251. 5. Cruickshank A, Auld P, Beetham R, et al. Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2008; 45: 238–244. 6. Van der Wee N, Rinkel GJE, Hasan D, et al. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after anegative scan? J Neurol Neurosurg Psychiatry 1995; 58: 357–359. 7. 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 2011; 343: d4277. 8. Backes D, Rinkel GJ, Kemperman H, et al. Time dependent test characteristics of head CT in patients suspected of nontraumatic subarachnoid hemorrhage. Stroke 2012; 43: 2115–2119. 9. McNeill A. Neurological negligence claims in the NHS from 1995 to 2005. Eur J Neurol 2007; 14: 399–402. 10. National Confidential Enquiry into Patient Outcome and Death. Subarachnoid haemorrhage. Managing the flow, http://www.ncepod.org.uk/2013report2/downloads/ Managing%20the%20Flow_FullReport.pdf (2013, accessed 5 August 2014). 11. Nagy K, Skagervik I, Tumani H, et al. Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage? Clin Chem Lab Med 2013; 51: 2073–2086. 12. Horstman P, Linn FHH, Voorbij HAM, et al. Chance of aneurysm in patients suspected of SAH who have a ‘negative’ CT scan but a ‘positive’ lumbar puncture. J Neurol 2012; 259: 549–552. 13. Chalmers AH and Kiley M. Detection of xanthochromia in cerebrospinal fluid. Clin Chem 1998; 44: 1740–1742. 14. Vermeulen M, Hasan D, Blijenberg BG, et al. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 1989; 52: 826–828. 15. McCarron MO and Choudhari KA. Aneurysmal subarachnoid leak with normal CT and CSF spectrophotometry. Neurology 2005; 64: 923. 16. Birch K, Burrows G, Cruickshank A, et al. Cerebrospinal fluid total protein cannot reliably distinguish true subarachnoid haemorrhage from other causes of raised cerebrospinal fluid net bilirubin and net oxyhaemoglobin absorbances. Ann Clin Biochem 2014; 51: 657–661.
Copyright of Annals of Clinical Biochemistry is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Accurate diagnosis of subarachnoid haemorrhage Mark O McCarron1 and Maurice J O’Kane2
The annual incidence of subarachnoid haemorrhage (SAH) is nine cases per 100,000 population with 85% of SAH caused by rupture of a cerebral aneurysm.1,2 Case fatality in aneurysmal haemorrhage is around 40% with 30% of patients suffering a re-bleed within four weeks.2 Treatment is effective: with early diagnosis, appropriate medical management and aneurysmal obliteration, mortality and significant disability at one year can be reduced to 24%.3 It is estimated that 8% to 12% of patients with a thunderclap headache (abrupt headache of severe onset) will have had a SAH.4 Most cases of SAH are confirmed with a non-contrast computed tomography (CT) scan of brain; earlier imaging from headache onset improves the sensitivity for identifying SAH. In patients with a negative CT scan, a lumbar puncture is required to look for evidence of haemoglobin breakdown products in cerebrospinal fluid (CSF).5 In the late 1980s and early 1990s, it was estimated that about 2% of patients with SAH have a normal CT scan of brain if performed within 12 h of headache onset.6 There is, however, emerging evidence that a negative CT scan within 6 h of headache onset in patients who are neurologically intact and without neck pain, may be sufficiently sensitive to avoid the need for lumbar puncture to exclude SAH,7,8 but this has not yet been adopted by guidelines. Lumbar puncture for the detection of CSF xanthochromia, therefore, continues to be required for CT-negative patients. Delayed diagnosis of SAH remains common and frequently attracts medicolegal attention; 9% of the total neurological litigation has been attributed to misdiagnosis of SAH.9 In the 2011 UK national confidential enquiry into patient outcome and death (NCEPOD) from aneurysmal SAH, 49 of 383 patients (13%) did not have a timely diagnosis of aneurysmal SAH; this was mostly due to delayed CT scanning.10 Of the 12 patients in the cohort who did not have SAH
identified radiologically, 10 underwent lumbar puncture which confirmed the diagnosis. Spectrophotometric analysis of CSF for the presence of bilirubin is widely used in the UK and other European countries although visual inspection of the CSF for pigmentation remains common practice elsewhere.11 Other less commonly used approaches include the measurement of CSF ferritin and the direct measurement of CSF bilirubin.11 The UK National External Quality Assessment Scheme guidelines (revised in 2008)5 propose the measurement of net oxyhaemoglobin absorbance (NOA) and net bilirubin absorbance (NBA) in a CSF sample taken at least 12 h after headache onset. There are, however, limitations to this test. First, increased CSF bilirubin is not specific for SAH,12 and may occur in other conditions such as meningitis and spontaneous intracranial hypotension. Second, the diagnostic absorbance cut-offs proposed are somewhat arbitrary. The reference range for CSF bilirubin absorbance of 0.007 AU as a clear indication for angiography.5 This was based on review of a series of 740 CSF spectrophotometric scans from four centres on CT-negative patients (27 of whom had NBA >0.007 AU and proceeded to angiography). However, little clinical information was provided on the patient cohort, in particular the certainty with which a diagnosis of SAH had subsequently been confirmed 1
Department of Neurology, Altnagelvin Hospital, Londonderry, UK Department of Clinical Chemistry, Altnagelvin Hospital, Londonderry, UK 2
Corresponding author: Mark O McCarron, Department of Neurology, Altnagelvin Hospital, Londonderry BT47 6SB, UK. Email: [email protected]
630 or excluded. This raises the possibility of both spectrum and verification bias which may affect the diagnostic performance of the test. Although it is commonly suggested that bilirubin persists in the CSF for up to 2 weeks, this has only been demonstrated for patients with a CT brain scan showing SAH14 and there is anecdotal evidence that aneurysmal SAH with lumbar puncture at day 8 may not reach the NBA threshold of 0.007 AU.15 In this edition of the Annals, Birch et al.16 investigate whether CSF protein concentration can aid interpretation. In a series of 132 patients with NBA >0.007 AU and NOA >0.02 AU, those patients in whom a diagnosis of SAH was not confirmed had the highest CSF protein concentrations. Although Birch et al. could not identify a CSF protein concentration above which SAH could be reliably excluded, they remind us of the importance of clinical setting for the interpretation of CSF spectrophotometry. As highlighted by the NCEPOD survey,10 future improvements in the diagnosis of SAH will rest heavily on clinical skills in suspecting SAH at an earlier stage with timely CT scanning. CSF spectrophotometry will continue to play an important role, but further work is needed to define the diagnostic performance of spectrophotometry in CT-negative patients. Declaration of conflicting interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethical approval Not required.
Guarantor MOM.
Contributorship Both authors are responsible for the conception and preparation of the manuscript and approval of the final draft.
References 1. de Rooij NK, Linn FH, van der Plas JA, et al. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007; 78: 1365–1372.
Annals of Clinical Biochemistry 51(6) 2. van Gijn J and Rinkel GJE. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001; 124: 249–278. 3. Connolly ES, Rabenstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid haemorrhage. Stroke 2012; 43: 1711–1737. 4. Edlow JA, Malek AM and Ogilvy CS. Aneurysmal subarachnoid hemorrhage: an update for emergency physicians. J Emerg Med 2008; 34: 237–251. 5. Cruickshank A, Auld P, Beetham R, et al. Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann Clin Biochem 2008; 45: 238–244. 6. Van der Wee N, Rinkel GJE, Hasan D, et al. Detection of subarachnoid haemorrhage on early CT: is lumbar puncture still needed after anegative scan? J Neurol Neurosurg Psychiatry 1995; 58: 357–359. 7. 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 2011; 343: d4277. 8. Backes D, Rinkel GJ, Kemperman H, et al. Time dependent test characteristics of head CT in patients suspected of nontraumatic subarachnoid hemorrhage. Stroke 2012; 43: 2115–2119. 9. McNeill A. Neurological negligence claims in the NHS from 1995 to 2005. Eur J Neurol 2007; 14: 399–402. 10. National Confidential Enquiry into Patient Outcome and Death. Subarachnoid haemorrhage. Managing the flow, http://www.ncepod.org.uk/2013report2/downloads/ Managing%20the%20Flow_FullReport.pdf (2013, accessed 5 August 2014). 11. Nagy K, Skagervik I, Tumani H, et al. Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage? Clin Chem Lab Med 2013; 51: 2073–2086. 12. Horstman P, Linn FHH, Voorbij HAM, et al. Chance of aneurysm in patients suspected of SAH who have a ‘negative’ CT scan but a ‘positive’ lumbar puncture. J Neurol 2012; 259: 549–552. 13. Chalmers AH and Kiley M. Detection of xanthochromia in cerebrospinal fluid. Clin Chem 1998; 44: 1740–1742. 14. Vermeulen M, Hasan D, Blijenberg BG, et al. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry 1989; 52: 826–828. 15. McCarron MO and Choudhari KA. Aneurysmal subarachnoid leak with normal CT and CSF spectrophotometry. Neurology 2005; 64: 923. 16. Birch K, Burrows G, Cruickshank A, et al. Cerebrospinal fluid total protein cannot reliably distinguish true subarachnoid haemorrhage from other causes of raised cerebrospinal fluid net bilirubin and net oxyhaemoglobin absorbances. Ann Clin Biochem 2014; 51: 657–661.
Copyright of Annals of Clinical Biochemistry is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
