Postcarotid endarterectomy Posterior reversible encephalopathy syndrome (PRES) Neurosurgical manipulation of intracerebral arteries Spinal subdural hematoma Unruptured saccular cerebral aneurysm Adapted from: Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 3:91. Graphic 101277 Version 4.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 25/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 26/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 27/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Typical neuroimaging features of reversible cerebral vasoconstriction syndrome (A) Head CT angiogram: sagittal, maximum-intensity projection image showing the classic "sausage on a string" appearance of both anterior cerebral arteries. (B) Head CT: axial image showing subarachnoid hemorrhage overlying the right frontal lobe (arrow). (C) Brain MRI: axial FLAIR image in the same patient showing the right frontal subarachnoid hemorrhage (arrow) as well as multiple dot-shaped hyperintensities (arrowhead) within the sulci of both hemispheres, suggesting the presence of dilated cortical surface arteries. (D) Brain MRI: axial FLAIR image showing the posterior-predominant crescentic hyperintense signal in the cortical-subcortical regions (dashed arrow). Corresponding DWI and SWI (not shown) were normal. These findings suggest the presence of brain edema as described in the posterior reversible leukoencephalopathy syndrome. (E) Brain MRI: axial DWI showing ischemic lesions (short arrows) in the bilateral "watershed" regions of the middle and posterior cerebral arteries. (F) Head CT scan: axial image showing a left frontal parenchymal hemorrhage. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 28/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS: reversible cerebral vasoconstriction syndrome; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted image; SWI: susceptibility-weighted image. Reproduced with permission from: Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: Analysis of 139 cases. Arch Neurol 2011; 68:1005. Copyright 2011 American Medical Association. All rights reserved. Graphic 101799 Version 9.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 29/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Brain lesions in reversible cerebral vasoconstriction syndrome Representative brain images from patients with RCVS are shown to highlight different lesion patterns. The numbers in parenthesis show the percentages of the lesion patterns; totals exceed 100% due to lesion combinations. (A) No acute parenchymal lesion (24%). Normal axial DWI, GRE, and FLAIR images are shown. The hyperintense dot sign is present on FLAIR (far right, arrow). (B) Border zone/watershed infarcts (25%). On the far left, DWI shows typical symmetric, posterior infarcts that spare the cortical ribbon. In https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 30/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate the middle and on the far right, DWI shows widespread watershed infarcts. (C) Vasogenic edema (28%). Subcortical crescent-shaped T2- hyperintense lesions consistent with the posterior reversible encephalopathy syndrome are seen on FLAIR. (D) Hemorrhagic lesions (42%). The two images on the left (axial GRE) show simultaneous lobar and deep intraparenchymal hemorrhages. The two images on the right show convexal subarachnoid hemorrhages on CT and axial GRE. (E) Lesion combinations (28%). The two images on the left show bilateral watershed infarcts on DWI and the two images on the right show lobar as well as convexal subarachnoid hemorrhages on axial FLAIR and CT, all in the same patient. RCVS: reversible cerebral vasoconstriction syndrome; DWI: diffusion- weighted images; GRE: gradient-echo; FLAIR: fluid-attenuated inversion recovery; CT: computed tomography. From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109962 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 31/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Convexal subarachnoid hemorrhage in a patient with reversible cerebral vasoconstriction syndrome (A) CT scan of a 56-year-old man with severe headaches showing presence of superficial convexal SAH along bilateral posterior frontal lobes (arrows). (B) Conventional angiogram performed a day later shows multiple vessel narrowings (arrows) involving the branches of the posterior and anterior cerebral arteries. A repeat angiogram performed four weeks later showed restitution of normal arterial caliber (not shown). SAH: subarachnoid hemorrhage. From: Kumar S, Goddeau RP Jr, Selim MH, et al. Atraumatic convexal subarachnoid hemorrhage: Clinical presentation, imaging patterns, and etiologies. Neurology 2010; 74:893. Copyright 2010 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 101281 Version 5.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 32/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Resolution of vasoconstriction in a patient with reversible cerebral vasoconstriction syndrome MR angiogram shows multiple focal stenoses involving peripheral branches of both middle (arrows) and posterior (arrowheads) cerebral arteries (A). Repeat imaging six weeks later shows spontaneous resolution of several areas of stenosis (B). https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 33/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate MR: magnetic resonance. Courtesy of Glenn A Tung, MD, FACR. Graphic 135022 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 34/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome Note the multiple areas of stenosis (arrows) and dilatation in multiple vessels (arrowheads) of the M2 branch of the middle cerebral artery (A) and their resolution after one month (B). Reproduced with permission from: Hajj-Ali RA, Furlan A, Abou-Chebel A, Calabrese LH. Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup. Arthritis Rheum 2002; 47:662. Copyright 2002 John Wiley & Sons, Inc. Graphic 66139 Version 4.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 35/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Summary of critical elements for the diagnosis of reversible cerebral vasoconstriction syndromes (RCVS) 1. Single or (most often) recurrent thunderclap headaches. 2. Multifocal segmental cerebral artery vasoconstriction demonstrated on cerebral angiography (with CTA, MRA, or DSA) that usually develops within a week of symptom onset. 3. No evidence for aneurysmal SAH. 4. Brain imaging findings are often normal, or may show vasogenic edema (PRES) and/or FLAIR sulcal hyperintensities (dot sign). Infarcts, if present, are usually symmetric and distributed along border zones of arterial territories. Intraparenchymal hemorrhage and/or nonaneurysmal convexity SAH may be present in some cases of RCVS. RCVS: reversible cerebral vasoconstriction syndromes; CTA: computed tomography angiography; MRA: magnetic resonance angiography; DSA: digital subtraction angiography; FLAIR: fluid-attenuated inversion recovery; PRES: posterior reversible encephalopathy syndrome; SAH: subarachnoid hemorrhage. Modi ed from Annals of Internal Medicine, Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: Reversible cerebral vasoconstriction syndromes, Volume 146, Issue 1, Pages 34-44. Copyright 2007 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc. Graphic 101236 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 36/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS score 2 Criteria Value Recurrent or single TCH Present 5 Absent 0 Carotid artery (intracranial) narrowing Affected 2 Not affected 0 Vasoconstrictive trigger Present 3 Absent 0 Sex Female 1 Male 0 Subarachnoid hemorrhage Present 1 Absent 0 In a retrospective study of consecutive patients with RCVS (n = 30) or non-RCVS arteriopathy (n = 80), recurrent or single thunderclap headache, vasoconstrictive trigger, female sex, and convexity subarachnoid hemorrhage were predictors of RCVS; intracranial carotid artery involvement (ie, segmental narrowing) was a negative predictor. In the derivation cohort, RCVS scores 5 had a high specificity and sensitivity (99 and 90%, respectively) for diagnosing RCVS, while scores 2 had a high specificity and sensitivity (100 and 85%) for excluding RCVS; intermediate scores of 3 to 4 had a lower 2 specificity and sensitivity (86 and 10%) for diagnosing RCVS. Performance was similar in the validation cohort. RCVS: reversible cerebral vasoconstriction syndrome; TCH: thunderclap headache. From: Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. RCVS score and diagnostic approach for reversible cerebral 2 vasoconstriction syndrome. Neurology 2019; 92:e639. DOI: 10.1212/WNL.0000000000006917. Copyright 2019 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121439 Version 3.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 37/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS score performance 2 RCVS2 score Specificity Sensitivity PPV NPV Derivation cohort Score 5 or 99 (93, 100) 90 (73, 98) 96 (82, 100) 96 (90, 99) higher* Score 3 or 4* 86 (77, 93) 10 (2, 27) 21 (5, 51) 72 (62, 80) Score 2 or 100 (88, 100) 85 (75, 92) 100 (95, 100) 71 (55, 84) lower Validation cohort Score 5 or 94 (82, 99) 86 (80, 91) 98 (94, 100) 67 (54, 78) higher* Score 3 or 4* 83 (69, 92) 11 (6, 17) 68 (46, 85) 22 (16, 28) Score 2 or lower 96 (92, 99) 77 (62, 88) 86 (71, 95) 93 (88, 97) NPV: negative predictive value; PPV: positive predictive value; RCVS: reversible cerebral vasoconstriction syndrome. Values for a RCVS diagnosis. Values for a non-RCVS diagnosis. From: Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. RCVS score and diagnostic approach for reversible cerebral vasoconstriction syndrome. Neurology 2019; 92:e639. DOI: 10.1212/WNL.0000000000006917. Copyright 2019 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material 2 is prohibited. Graphic 121448 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 38/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Distinguishing reversible cerebral vasoconstriction syndrome (RCVS) from primary angiitis of the central nervous system (PACNS) Sensitivity Specificity PPV NPV Variable (95% CI) (95% CI) (95% CI) (95% CI) Recurrent TCH* 74 (67-81) 98 (89-100) 99 (95-100) 53 (43-64) Single TCH* 15 (10-22) 96 (85-99) 92 (75-99) 25 (19-32) Plus normal brain MRI 2 (0-5) 100 (92-100) 100 (30-100) 23 (18-30) Plus FLAIR dot sign 10 (6-16) 100 (92-100) 100 (79-100) 25 (19-32) Plus border zone-only 3 (1-6) 100 (92-100) 100 (40-100) 23 (18-30) infarcts Plus vasogenic edema (PRES) 4 (1-8) 100 (92-100) 100 (54-100) 24 (18-30) Plus ICH or cSAH 9 (5-15) 96 (85-99) 88 (64-98) 24 (18-31) No TCH; positive angiogram* 11 (6-17) 49 (34-64) 42 (23-58) 14 (9-20) Plus normal brain MRI 1 (0-3) 100 (92-100) 100 (17-100) 23 (17-29) Plus border zone-only infarcts 5 (2-9) 98 (89-100) 88 (47-98) 23 (18-30) Plus ICH or cSAH 3 (1-6) 98 (89-100) 80 (29-97) 23 (17-29) Plus vasogenic edema (PRES) 3 (1-7) 100 (92-100) 100 (48-100) 23 (18-30) Plus FLAIR dot sign 6 (3-11) 94 (83-99) 75 (43-94) 23 (18-30) No TCH; positive angiogram; for the diagnosis of PACNS: Plus deep/brainstem 38 (35-54) 100 (98-100) 100 (81-100) 85 (79-89) infarcts Plus CSF abnormal 28 (16-43) 99 (95-100) 87 (60-98) 82 (76-88) Plus both of the above 28 (16-43) 100 (98-100) 100 (75-100) 83 (77-87) CI: confidence intervals; PPV: positive predictive value; NPV: negative predictive value; TCH: thunderclap headache; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; ICH: intracerebral hemorrhage; cSAH: convexal subarachnoid hemorrhage; CSF: cerebrospinal fluid. Values shown are for the diagnosis of RCVS. Abnormal is >5 cells and >80 mg/dL. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 39/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109960 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 40/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Distinguishing reversible posterior leukoencephalopathy syndrome (RPLS) and reversible cerebral vasoconstriction syndrome (RCVS) Reversible posterior Reversible cerebral Feature leukoencephalopathy vasoconstriction syndrome syndrome Clinical Encephalopathy 50-80% 10-15% Seizures 60-75% 0-20% Status epilepticus 5-15% Rare Headache 50% 90-95% Visual deficits 33% 30-40% Focal neurologic deficit 10-15% 9-63% Imaging Vasogenic cerebral edema 100% 15-40% Ischemic stroke 15-30% 33% Lobar hemorrhage 10-25% 15% Sulcal subarachnoid blood 3-8% 40% Segmental vasoconstriction 30-70% 100% Coexisting vascular lesion (eg, dissection, aneurysm) Uncommon 20% Contrast enhancement 20% Uncommon From: Singal AB. Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome as syndromes of cerebrovascular dysregulation. Continuum 2021; 27:1301. DOI: 10.1212/CON.0000000000001037. Copyright 2021 American Academy of Neurology. Adapted with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 135024 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 41/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Diagnostic findings for the more common causes of thunderclap headache Clinical Lumbar Cause Brain CT Angiography Brain MRI features puncture Aneurysmal Altered Subarachnoid Elevated red Ruptured Subarachnoid subarachnoid hemorrhage consciousness, seizures, blood in basilar blood cells, xanthochromia aneurysm, vasospasm blood in basilar cisterns and meningismus cisterns and sylvian sylvian fissures fissures Reversible cerebral Recurrent thunderclap Normal, or subarachnoid Normal, mild white blood Multifocal multivessel Normal, or subarachnoid vasoconstriction headaches blood along cell elevation, vasoconstriction blood along syndrome cortical surface/sulci mild protein elevation cortical surface/sulci, ischemic stroke, cerebral edema, intracerebral hemorrhage Carotid and Neck pain, Normal, or Normal Dissected Normal, or vertebral artery dissection symptoms related to cerebral ischemia, Horner syndrome (carotid ischemic stroke artery, multifocal, segmental vasoconstriction if associated with reversible cerebral ischemic stroke dissection) vasoconstriction syndrome Cerebral venous sinus Focal neurologic Dense triangle sign Elevated opening Venous sinus thrombosis Normal, or venous thrombosis deficits, (clot inside pressure, high infarctions with altered mental status, visual the sinus), cord sign protein hemorrhage; MRI evidence of changes (thrombosed cortical or intraluminal thrombus on T1, deep vein), venous T2, and susceptibility- hemorrhages weighted imaging sequences Spontaneous Orthostatic Normal, or Low opening Normal Pachymeningeal intracranial headache, subdural pressure enhancement, https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 42/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate hypotension auditory collections sagging brain, muffling subdural collections CT: computed tomography; MRI: magnetic resonance imaging. From: Schwedt TJ. Thunderclap Headache. Continuum (Minneap Minn) 2015; 21:1058. DOI: 10.1212/CON.0000000000000201. Copyright 2015 American Academy of Neurology. Reproduced with permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited. Graphic 113418 Version 5.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 43/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Basilar artery vasoconstriction in RCVS DSA (left vertebral artery injection) shows well-opacified extradural left vertebral artery (arrows) and multiple of narrowing of the intracranial vertebral, basilar, and posterior cerebral arteries (arrowheads) (A). High-reso contrast-enhanced vessel wall MR image shows wall of the basilar artery uniformly thickened and without enhancement, consistent with vasoconstriction (B and inset). RCVS: reversible cerebral vasoconstriction syndrome; DSA: digital subtraction angiography; MR: magnetic resonance. Courtesy of Glenn A Tung, MD, FACR. Graphic 135025 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 44/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 45/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Contributor Disclosures Aneesh Singhal, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 46/46