Disclosures. Sneddon Syndrome: Untangling the Web. Case Presentation. MRI head w/ and w/o contrast. Further Workup. Further Workup 10/26/2017

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1 Sneddon Syndrome: Untangling the Web Sadhana Murali, MD, PGY-4 University of Wisconsin-Madison WNS Conference October 27-28, 2017 Disclosures I have no relevant financial relationships with any commercial products and/or providers of commercial services discussed in this CME activity. Case Presentation 47 year-old male with PMH of HTN presented to a local ED with 4-6 months of worsening memory issues MRI head w/ and w/o contrast Initial neuro exam was non-focal Initial MRI was notable for multifocal, acute and subacute infarcts. Was admitted to the UW stroke service for further workup Further Workup TTE EF 65%, grade 1 diastolic dysfunction, moderately thickened mitral valves, cannot rule out vegetation, no PFO TEE Complex, shaggy, highly mobile relatively symmetric masses up to 13mm in length on both mitral leaflets. Further Workup CTA head and neck: Mild diffuse narrowing of the basilar artery Moderate to severe narrowing of bilateral PCAs High-grade stenosis of the left vertebral artery Subtle attenuation of multiple M3, M4 branches Anti-Cardiolipin IgG/IgM 51/14 (high) Beta-2 glycoprotein IgG/IgM 80/5 (high) 1

2 Further Management Concerned for antiphospholipid antibody syndrome Started on enoxaparin bridge to warfarin Discharged to acute rehab Stroke Clinic Follow Up: 1 month later Migraine-like headache Cognition continuing to worsen Requiring 24-hour supervision Family now helping with meds and finances Repeat MRI with expected evolution of infarcts Three months later No longer speaking in full sentences Developed a new road map -like rash over back, chest, upper extremities DIAGNOSIS IS Headache worsening Repeat MRI without any new changes Admitted for vasculopathy workup Repeat apl antibodies still high DIAGNOSIS IS SNEDDON SYNDROME DIAGNOSIS IS SNEDDON SYNDROME First described by Champion and Rook in Dr. Ian Sneddon then described six patients with livedo reticularis and stroke in

3 Sneddon Syndrome (SNS) Vasculopathy of small and medium sized arteries Rare condition, incidence of 1: 250,000 Sneddon Syndrome Subtypes 5 Antiphospholipid (apl) antibody-related 40-55% of cases Clinically indistinguishable from Affects women > men, mainly ages years Diagnostic hallmarks of livedo reticularis and stroke Can also present with headaches, seizures, cognitive decline, and other systemic involvement Systemic lupus erythematosus () With or without apl Pathophysiology unclear Without or APS May involve undiagnosed disorders OKAY, BUT WHAT IS SNEDDON SYNDROME REALLY??? OKAY, BUT WHAT IS SNEDDON SYNDROME REALLY??? List of Hypotheses Hypothesis #1: Primary vs Secondary Hypothesis #1: Primary vs secondary Primary Sneddon Secondary Sneddon Hypothesis #2: Spectrum of disorders Hypothesis #3: Sneddon s Dyad Hypothesis #4: NO EPONYMS!!! Hypothesis #5: Unique disorder Hypothesis #6: Unique disorder with similar pathophysiology Schellong, S., et al. Classification of Sneddon Syndrome,

4 Hypothesis #1: Primary vs Secondary Hypothesis #1: Primary vs Secondary Primary Sneddon Secondary Sneddon Primary Sneddon Secondary Sneddon?????? Schellong, S., et al. Classification of Sneddon Syndrome, 1997 Secondary Sneddon may be due to, APS, and other disorders yet to be identified Other Hypothesis # 2: Spectrum of disorders Hypothesis # 2: Spectrum of disorders Other Other Sneddon Syndrome Hypothesis #3: Sneddon s Dyad Hypothesis #3: Sneddon s Dyad LR + Stroke = Sneddon s Dyad 4

5 Hypothesis #3: Sneddon s Dyad Principles: Not its own disorder Dyad of symptoms Dyad part of different disorders Disorders yet to be discovered make up idiopathic subtype Hypothesis #4: Sneddon s Dyad Hypothesis #4: Sneddon s Dyad Hypothesis #4: Livedo Vasculopathy? NO EPONYMS! Hypothesis #4: Livedo Vasculopathy? Any other ideas?? Hypothesis #5: Unique Disorder 5

6 Hypothesis #5: Unique Disorder Hypothesis #5: Unique Disorder Hypothesis #5: Unique Disorder Sneddon Syndrome Hypothesis #5: Unique Disorder Sneddon Syndrome Pathophysiology different from APS or Hypothesis #6: Unique Disorder Hypothesis #6: Unique Disorder 6

7 Hypothesis #6: Unique Disorder Pathophysiology similar to APS and, but without apl Sneddon Syndrome Sneddon Syndrome or not Sneddon Syndrome What is the pathophysiology behind LR and stroke??? Sneddon Syndrome or not??? Sneddon Syndrome?????? What is the pathophysiology behind LR and stroke??? Possible Mechanisms 1 APS Antiphospholipid antibodies: Anticardiolipin IgG/IgM B2-glycoprotein IgG/IgM Lupus anticoagulants Antibodies may interact with 16 : Platelets activation/aggregation Clotting factors hypercoag. state Endothelial cells acts as growth factor Possible Mechanisms 1 APS Antiphospholipid antibodies: Anticardiolipin IgG/IgM B2-glycoprotein IgG/IgM Lupus anticoagulants Antibodies may interact with 16 : Platelets activation/aggregation Clotting factors hypercoag. state Endothelial cells acts as growth factor Two-hit hypothesis: Constant thrombotic state + trigger (infection) = thromboembolic event Possible Mechanisms Undiagnosed APS? Non-clinical apl Negative apl on initial workup Anti-endothelial cell antibodies 5 Factor V Leiden mutation 7 Antithrombin III 6 Anti-prothrombin antibodies 2 Protein S deficiency 4 Protein Z deficiency 3 7

8 Other apl: Antiphosphatidylserine (aps) Tuhrim et al (1999) found that aps is independently associated with ischemic stroke 13 Amory et al (2015) did not find an association between aps and ischemic stroke 14 Akhter et al (2013) found that aps is strongly associated with lupus anticoagulant (LA) 15 Proposed that it could be an alternative when LA cannot be obtained (therapeutic anticoagulation) Not routine, but aps can be obtained as a sendout test Anti-Endothelial Cell Antibodies (AECA) Antibody associated with occlusive lesions in arteries at the dermal-subdermal border 5 23/63 (35%) pts with SNS had positive serum antibodies compared to 5 : 28% of pts with polyarteritis nodosum 5% of pts with stroke without livedo 0% of healthy subjects 10/23 pts with AECA were also apl + AECA +/- groups clinically similar Protein Z Deficiency Possible Mechanisms Vitamin K-dependent glycoprotein that downregulates coagulation Protein Z found to be significantly lower in 38% of apl-negative SNS compared to 3.8% of healthy subjects 3 Protein Z deficiency also found to be independently associated with ischemic strokes 8 Vasculopathy with perivascular inflammatory infiltrates 16 Immune-mediated occlusive thrombosis 11 No evidence for true vasculitis Libman-Sacks endocarditis may provide an additional mech. Secondary Prevention Positive antiphospholipid antibodies Several studies 17 found high-intensity warfarin (INR > 3) to be more effective in reducing the risk of recurrent stroke compared to lowintensity warfarin (INR < 3) or aspirin 75mg More recent studies 18 found that moderate-intensity warfarin (INR 2.3) was equally efficacious to high-intensity warfarin (INR 3.3) NOACs not recommended currently due to lack of data Negative antiphospholipid antibodies No RCTs, case reports only with small sample sizes Unclear benefit of antiplatelets compared to anticoagulation for apl negative pts 5 Case reports of steroids/immunosuppressants being ineffective and potentially deleterious on stroke recurrence 5 General recommendations Recommend women to avoid OCPs/hormone replacement therapies Recommend smoking cessation and modifying other vascular risk factors. Conclusions SNS = livedo reticularis and stroke Pathophysiology and classification of SNS is not clear Consider repeating apl in idiopathic cases Consider a send-out test for non-clinical apl such as antiphosphatidylserine antibodies in apl - cases We should anticoagulate apl + pts Treatment not clear for apl pts We need more studies! 8

9 Thank you for listening! Thank you for listening! Thank you for listening! Any questions??? Any questions??? Any suggestions for a name??? 9

10 References 1. Schellong, S., et al. Classification of Sneddon Syndrome. VASA. Zeitschrift fur Gefasskrankheiten.1997, 26(3): Kalashnikova, L., et al. Antibodies to prothrombin in patients with Sneddon syndrome. Neurology 1999; 53: Ayoub, N., et al. Protein Z Deficiency in Antiphospholipid-Negative Sneddon s Syndrome. Stroke. 2004; 35: Sayin, R., et al., Sneddon syndrome associated with protein S deficiency with Protein S deficiency. Indian J Dermatol Venereol Leprol 2012; 78: Frances, C., et al., Prevalence of anti-endothelial cell antibodies in patients with Sneddon s syndrome. Journal of the American Academy of Dermatology Bolayir, E., et al. Sneddon s syndrome and antithrombin III. J Dermatol. 1999; 26: Besnier, R., et al. Factor V Leiden mutation in Sneddon syndrome. Lupus 2003; 12: Vasse, M., et al. Frequency of protein Z deficiency in patients with ischemic stroke. The Lancet. 2001; 357: Francès C, Papo T, Wechsler B, Laporte JL, Biousse V, Piette JC: Sneddonsyndrome with or without antiphospholipid antibodies. A comparative Study. Medicine 1999; 78: Otoyama, K., et al. A Case of Sneddon s Syndrome with Positive ANA and Anti-cardiolipin Antibodies: Primary Anti-phospholipid syndrome? The journal of dermatology 11. Kitagawa, Y., et al. Stroke in systemic lupus erythematosus. Stroke 1990: Wu, Shengjun, et al. Sneddon s syndrome: a comprehensive review of the literature. Orphanet J Rare Dis. 2014; 9: Tuhrim, S. et al. Antiphosphatidyl serine antibodies are independently associated with ischemic stroke. Neurology. 1999; 53: Amory, C. et al. Antiphospholipid Antibodies and Recurrent Thrombotic Events: Persistence and Portfolio. Cerebrovasc Dis. 2015; 40: Akhter, E. et al. Utility of antiphosphatidylserine/prothrombin and IgA antiphospholipid assays in. The Journal of Rheumatology. 2013; Caplan, Louis. Uncommon Causes of Stroke Khamashta, M.A., et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995; 332: Crowther, M.A, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003; 349: