A 4-year-old girl presents with headaches and symptoms suggestive of a cerebrovascular stroke (vomiting with some language and speech delays). She has a past medical history of a clinically diagnosed Varicella Zoster Virus (VZV) infection 6 months ago. There's no history of strokes or clotting disorders in her personal or family history.
Similarly to case 1 (Q24, N = 70 responses), the majority of respondents suggested that initial investigations should include blood test (94.3%), emergency MRI of the brain including an MRI angiography (92.9%), lumbar puncture and CSF analysis (88.6%), and brain CT scan including CT angiography (31.4%). Of the participants who considered blood tests essential (Q25, N = 70 responses), 98.6% would request full blood count including complete white cell count; 97.1% clotting tests including PTT, INR, fibrinogen and D dimers, and 90.0% would order immunology tests including ANA, ENA, complement factors, cardiolipin antibodies and ANCA; 42.9% suggested blood tests for adenosine deaminase 2 activity (ADA2) and 41.4% for interferon gamma release assay (IGRA) to exclude tuberculosis (Table 5).
When asked about blood immunology (Q26, N = 70 responses), 94.3% considered anti-phospholipid antibodies as required, followed by antinuclear antibodies, ANCA, anti-dsDNA antibodies, complement factors and activation of the complement cascade, and anti-NMDA and aquaporin antibodies. Of the 70 participants requesting a lumbar puncture (Q27, N = 70 responses), 98.6% considered cell counts and differentiation, followed by protein (95.7%), glucose (92.9%), microbial cultures (90.0%), opening pressure (84.3%), oligoclonal bands (81.4%), lactate (78.5%), and anti-NMDA and aquaporin antibodies (54.3%). Of 68 participants who considered emergency MRI (Q28, N = 68 responses), 88.2% requested MRI angiography, followed by FLAIR (73.5%), diffusion-weighted sequences (73.5%), T1FS with contrast medium (54.4%), T2FS (50.0%), T1 with FS (41.2%), and TIRM/STIR (39.7%) (Table 5).
Next, the participants were informed that autoantibodies in CSF and blood come back negative, there's no evidence for clotting disorders or infection (including negative for TB and VZV PCR in CSF, serum VZV IgG positive, IgM borderline positive). Blood and CSF inflammatory markers remain within normal limits. DWI sequences unveiled altered diffusion capacity in the left hemisphere; Time of flight MR Angiography (TOF-MRA-)sequences demonstrate narrow caliber of left distal internal carotid artery and proximal anterior and medial cerebral artery. Post-gadolinium MRI sequences reveal contrast enhancement of the thickened vascular wall in the affected segments. Conventional angiography showed incomplete occlusion of the left A. cerebri media (Supplementary Material 1).
Respondents were then asked to choose the 5 most important differential diagnoses to consider (Q29, N = 70 responses). Most respondents (81.4%) considered p-cPACNS, likely transient related to VZV, followed by ischaemic stroke (70.0%), transient p-cPACNS not related to VZV (62.9%), CNS tuberculosis (61.4%) and infections e.g., meningitis (32.9%) (Table 6).
When asked which medication to administer for induction treatment (Q30, N = 69 responses), 53/69 (76.8%) respondents suggested IVMP over 5 days, followed by 18/69 who considered intravenous Cyclophosphamide every month for 4-6 months (26.1%), 12/69 MMF (17.4%), 9/69 (13.0%) oral Prednisolone, and 2/69 Azathioprine (2.9%). None of the participants chose oral Cyclophosphamide for induction treatment. Respondents were asked how long to continue oral corticosteroid treatment including slow taper for (Q34, N = 66 responses), they answered: 3 months (25/66, 37.9%), 6 months (23/66, 34.9%), 12 months (7/66, 10.6%), 18 months (0/66, 0.0%), 24 months (2/66, 3.0%) and 36 months (1/66, 1.5%). Five of 66 respondents answered no to prescribing oral corticosteroid treatment (7.6%).
Considering prophylaxis of thromboembolic events (Q31, N = 67 responses), most responders agreed on administering IV Heparin initially as anticoagulation treatment (52.2%) in the acute phase, followed by ASA (29.9%), a combination of ASA and clopidogrel (6.0%) and warfarin (4.5%). Considering post-acute phase prophylaxis (Q32, N = 66 responses), a majority of responders would prescribe Aspirin (53.0%), followed by subcutaneous Heparin (18.2%), a combination of Aspirin and Clopidogrel (9.1%), warfarin (7.6%), clopidogrel or DOACs (4.6% each). Regarding discontinuation of anticoagulation treatments (Q35, N = 63 responses), respondents answered after 3 months (11.1%), 6 months (17.5%), 12 months (20.6%), 18 months (3.2%), 24 months (12.7%) and 35 months (6.4%). Five of 63 respondents answered they would not administer anticoagulation treatment (7.9%) (Table 7).
Monitoring of disease activity and damage using MRI (Q36, N = 69 responses) was suggested after 3 months by 60/69 (87.0%) respondents, after 6 months by 32/69 (46.4%) and after 12 months by 25/69 (36.2%). Eight of 69 respondents would repeat MRI after 18 months (11.6%), 17/69 after 24 months (24.6%) and 6/69 after 36 months (8.7%). Clinical follow up (Q37, N = 70 responses) was considered reasonable at 3 months by 58/70 respondents (82.9%), at 6 months by 24/70 (34.3%), 12 months by 24/70 (34.3%), 18 months by 16/70 (22.9%), 24 months by 18/70 (25.7%), and after 36 months by 14/70 (20.0%).
To assess how participants would alter their approach based on evidence of VZV infections temporally associated with p-cPACNS, they were provided with alternative test results: After the first line investigations, suppose the autoantibodies in CSF and blood come back negative, there's no evidence for clotting disorders, but the VZV PCR in the CSF comes back as positive.
As a result of positive testing for VZV (Q38, N = 68 responses), the majority of the respondents indicated they would treat the patients with IV Acyclovir treatment over 14 days (58/68, 85.3%), 32/68 (47.1%) of responders indicated initially treating with IVMP over 5 days followed by oral Prednisolone. Less common answers indicated by participants were induction with oral Prednisolone, followed by oral Prednisolone taper (10/68, 14.7%), IV Cyclophosphamide (2/68, 2.9%), MMF induction treatment (2/68, 2.9%), Azathioprine (1/68, 1.5%). None of the participants indicated they would treat the patient with oral Cyclophosphamide (Fauci scheme).