Strategies for treatment of childhood primary angiitis of the central nervous system

Results

The search strategy identified a total of 2,596 articles, with 1 additional study identified by author MT (figure 1). Of 2,597 articles screened for title and abstract, 110 articles had full-text retrieval for assessment of inclusion criteria and 9 original articles were included for detailed analysis^{2,4,9,14,–,19} (figure 1). Reasons for article exclusion included: treatment description missing (n = 24), exclusion of pediatric population (n = 8), not PACNS (n = 5), case reports <5 children (n = 20), book chapters/reviews/editorials (n = 39), and abstract only (n = 5). Seven studies were deemed high quality after quality assessment was conducted. Study characteristics are summarized in table. Of 9 studies reviewed, 4 described the same study population from Lahore, Pakistan^16,–,19; 4 studies described the same population from Toronto, Canada^2,4,9,14; and 1 reported a case series from Los Angeles, US.¹⁵

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Figure 1 Prisma 2009 flow diagram

The Pakistani group^16,–,19 identified children <16 years of age subsequently diagnosed with cPACNS at their center between January 2009 and December 2010. Diagnostic categorization was two-fold: based on stroke characteristics and cPACNS subtype. A total of 68 patients were identified: 50 presented with ischemic stroke, 10 with hemorrhagic stroke, and 8 with both ischemic and hemorrhagic lesions. Alternatively, 51 patients were classified as APNP-cPACNS and 17 as APP-cPACNS. Diagnoses were based on conventional angiography (CA) and/or MRA in all patients.

Induction therapy, 3 days of IV methylprednisolone (IVMP), and/or IV immunoglobulin for 5 days with subsequent oral prednisone taper over 30 days, was completed by 56 patients. Patients with ischemic stroke also received IV heparin and subsequent oral anticoagulation therapy. Supplementary calcium and vitamin D were prescribed with anticonvulsants, antipsychotics, antibiotics, antivirals, and antacids as needed. A total of 12 patients died before completing induction therapy from complications involving cerebral artery and/or parenchymal bleeding. The remaining 41 patients were allocated to 24 months of maintenance therapy consisting of either aspirin (ASA) daily for ischemic stroke or together with daily azathioprine for progressive arteriopathies. Despite a clearly delineated therapeutic regimen, the Pakistani group reported conflicting data in regard to the number of patients assigned to each therapy across the 4 studies. Both the initial study by Malik et al.¹⁹ and Alhaboob et al.¹⁶ identified 41 patients assigned to ASA alone and 15 patients to ASA together with azathioprine for 24 months. However, Malik et al.¹⁷ indicated that 40 patients were assigned to the 24 months ASA only group, and 16 patients to ASA and azathioprine, with ASA duration increased to 60 months in this study. Malik et al.¹⁸ did not provide details of induction therapy, only that ischemic infarcts were initially treated with IV heparin. From this group, 40 patients were discharged on ASA for 24 months and 14 received adjunctive azathioprine therapy.

The Pakistani group reported mortality and morbidity across different intervals. Remission was described as a complete absence of disease activity in clinical symptoms, exam findings, lab markers, and imaging for at least 3 months, and relapse was defined as an emergence of signs/symptoms of stroke confirmed by neuroimaging (CA and/or MRA) after remission. All 4 studies documented mortality at discharge in 12 patients (17·6%). Malik et al.^17,–,19 reported clinical state at time of discharge for all survivors, defined as neurologic assessment for motor, visual, and/or speech difficulties. Normal examination was reported in 11 (20%), minor disability in 14 (25%), moderate disability in 11 (20%), and severe disability in 20 (35%) patients. Malik et al.¹⁵ described relapse in a total of 30 patients (54%) during maintenance therapy. From the ASA only group, 18 patients (45%) relapsed within the first 24 months, which resulted in 10 deaths, and of the remaining 22 patients (55%) who completed ASA therapy, 5 relapsed and 5 died. Overall mortality in the ASA group was 15/40 (38·5%). Of the 16 patients on maintenance with ASA and azathioprine, 2 patients (13%) relapsed within 24 months and both survived. The number of deaths reported was 5 (31%): 3 patients died from massive cerebral hemorrhage, and 2 of 3 patients died after relapse within 6 months of successfully completing therapy. Therefore, the overall mortality during maintenance reported by Malik et al.¹⁷ at a medium follow-up of 34 months was 20 (35·7%) of the initial 56 survivors, either as a direct result or as a complication of first or second relapse, with 5 deaths reportedly due to non-cPACNS causes. Malik et al.¹⁷ also reported the outcome at last follow-up using the PSOM.¹³ From the 32 patients assessed: 8 (25%) a normal outcome, 10 (31%) minor disabilities, 10 (31%) moderate disabilities, 4 (13%) severe disabilities, and 4 patients were lost to follow-up.

The Canadian studies^2,4,9,14 similarly identified patients from the same center, though each study varied in sample size and diagnostic subtype. Benseler et al.² identified 62 children <18 years of age between January 1990 to December 2002 diagnosed with AP-cPACNS: 42 APNP-cPACNS and 20 APP-cPACNS. Diagnoses were based on MRA and/or CA abnormalities.

All patients received antithrombotic therapy with ASA, heparin, or warfarin. A total of 41 patients (65%) continued with this treatment approach long-term: 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS. In contrast, 22 patients (35%) received immunosuppressive intervention with steroids alone or a combination of steroids and IV cyclophosphamide: 9 (41%) APNP-cPACNS and 13 (59%) APP-cPACNS. Benseler et al.² measured outcome at last evaluation (mean 20 months) as complete neurologic recovery, defined as neurologic deficit severity score of 0 on PSOM; any other deficit severity score was defined as incomplete recovery. A total of 22 patients (35%) made a complete neurologic recovery: 13 (31%) of APNP-cPACNS and 9 (45%) of APP-cPACNS. No deaths were reported.

Hutchinson et al.⁹ identified 19 patients <18 years of age with AN-cPACNS diagnosis between January 2002 and December 2009. MRA, venography, and CA were used. Diagnosis in all patients was based on a confirmatory biopsy. Patients received induction and maintenance therapy for 24 months. Induction therapy was defined as 6 months of IV cyclophosphamide monthly, together with Pneumocystis jiroveci pneumonia prophylaxis, oral prednisone daily, supplementary calcium, vitamin D, and anticonvulsants/antipsychotics as needed. Thirteen patients (68%) completed induction and went on to maintenance therapy. Maintenance consisted of an additional 18 months of therapy, with 5 patients (35%) assigned to mycophenolate mofetil (MMF) and 9 (65%) assigned to azathioprine with anticonvulsants/antipsychotics as needed. Seven (78%) of 9 patients on azathioprine switched to MMF because of treatment failure or intolerance. Only 5 patients (36%) completed maintenance therapy and were taken off medication. Primary outcome was assessed on PSOM at 24 months, with good outcome defined as a score of ≤0·5 across each of the 4 domains. Secondary outcomes included treatment efficacy and safety, determined by PSOM at 12 months and final follow-up, disease flare, and discontinuation of immunosuppressants. Good neurologic outcome on PSOM at 12 months was reported in 8 (50%) of 16 patients and 9 (70%) of 13 at final follow-up. Disease flare during treatment was described in 8 patients (42%): 2/19 (11%) during induction, 5/14 (36%) during maintenance, and 1/5 (20%) off medication. No patients relapsed on MMF. Of 5 patients who completed maintenance therapy, 4 achieved remission, defined as complete absence of disease activity in clinical symptoms, examination findings, lab markers, and imaging for at least 3 months. Safety was determined by mortality, serious infection, and each of cataracts, avascular necrosis, vertebral fractures, or type II diabetes mellitus. No patients in this study died; however, 2 were reported to have had a serious infection requiring hospital admission; 1 developed cataracts, 1 avascular necrosis, and 3 with vertebral fractures. No diabetes mellitus was reported. Pediatric Quality of Life (PedsQL)²⁰ was reported for both child and parent at final follow-up, together with cognitive outcome testing by the Weschler Intelligence Scale for Children IV and Weschler Adult Intelligence Scale III at 14 months postdiagnosis. Abnormal scores were defined as any index scores that were ≥1 SDs below the mean of the normative sample. The PedsQL questionnaire was completed by 17 patients and 15 parents: median physical score was 78 (range = 0–100) for children and 66 (range = 9–100) for parents, and median psychosocial score 73 (range = 27–100) for children and 63 (range = 37–100) for parents. Cognitive outcome was assessed in 10 children: Full Scale Intelligence Quotient was reported as abnormal in 8 (80%), working memory in all 10 (100%), verbal comprehension in 7 (70%), perceptual reasoning in 6 (60%), and processing speed in 5 (50%).

Cellucci et al.⁴ identified 39 patients <18 years of age between June 2001 and October 2010 diagnosed with cPACNS: 14 AP-cPACNS, not further subdivided, and 25 AN-cPACNS. AP-cPACNS diagnosis was based on CA and/or MRA (n = 14). AN-cPACNS diagnosis was based on confirmatory biopsy in 22 patients. Patients without biopsy had features, blood work, and lumbar puncture consistent with AN-cPACNS. Some patients with AP-cPACNS were also represented in the Benseler et al.² study and in the Hutchinson et al.⁹ study.

All 14 patients with AP-cPACNS received ASA, and 9 (64%) received additional anticoagulation with unfractionated/low-molecular weight heparin for 2 months. High-dose prednisone was prescribed in all but 1 patient with AP-cPACNS, with a varied tapering schedule: 2–6 months in 6 patients (46%) and 12 months in 7 (54%). IV cyclophosphamide over 6 months followed by MMF or azathioprine was given to a further 7 patients (54%) with AP-cPACNS; 1 patient with AP-cPACNS received anticoagulation therapy only. High-dose prednisone with 12-months taper was prescribed in all patients with AN-cPACNS. IV cyclophosphamide for 6 months in combination with azathioprine or MMF was reported in 20 patients (80%) with AN-cPACNS, while azathioprine or MMF alone as induction/maintenance therapy was described in 3 patients (12%) with AN-cPACNS. Two patients (8%) with AN-cPACNS did not receive therapy. Outcomes were reported serially across 24 months and included disease activity as measured by the Physicians Global Assessment (PGA), a visual analog scale with a score of zero indicating no disease activity and 10 indicating severe activity; von Willebrand factor (vWF) antigen levels where high numbers indicate high disease activity with >1·40 IU/mL being considered abnormal; and neurologic outcome on PSOM with good outcome defined as a score of ≤0·5 across each domain. Disease activity was elevated at time of diagnosis, but significantly decreased over time in all patients (p < 0·001). vWF antigen levels decreased over time (p < 0·001). PSOM summary scores decreased significantly over time (p < 0·001), with 52% of patients having a good neurologic outcome at 12 months, and 65% at 24 months. A total of 6 (15%) developed disease flare during follow-up defined as an increase in PGA by at least 1 cm in presence of recurrent symptoms, laboratory changes, and/or MRI findings. No patients died.

Elbers et al.¹⁴ described 27 patients <18 years of age with AP-cPACNS diagnosed between January 1998 and December 2013. Diagnosis was based on MRA and DSA abnormalities. Patients might overlap with the Benseler et al.² and Cellucci et al.⁴ studies. Acute treatment with unfractionated heparin was described in 23 patients (85%): 5 subsequently transitioned to warfarin, 17 to ASA, and none in 1. ASA alone, or with immunosuppression, was described in the remaining 4 patients. Two patients received chronic immunosuppression with MMF and 1 received plasmapheresis. IVMP together with a 3-month oral steroid taper was described in 12 patients, with no long-term immunosuppression. An additional 7 patients were treated with acyclovir. Outcomes included vascular imaging at 12 months, assessed using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria and described as improved (normal angiography, improved flow, or fewer abnormal vessels), stable (no change in flow abnormality or number of involved vessels), or worsened (involvement of new vessels or worsening of an existing flow abnormality by at least 1 point on follow-up imaging), and possibly discordant (worsened patients where a new or worsening arterial abnormality coexisted with an improved or normalized vessel), as well as stroke recurrence. The NASCET criteria scores vessel narrowing from 1 to 4 progressing from normal (0%–9%), to mild (10%–29%), moderate (30%–69%), and severe stenosis (70%–99%) or complete occlusion (no flow detected). A total of 10 (37%) patients were described as improved, 4 of which received steroids as treatment; 6 (22%) as stable, 2 of which received steroids; and 11 (41%) worsened with 7 described as discordant, 6 of which received steroids. Stroke recurrence was reported in 4 patients (15%). No patients died.

Gallagher et al.¹⁵ described 5 cases of AP-cPACNS at their center with no fixed treatment regimen. Diagnosis was based on MRA and/or CA abnormalities. Two patients were treated with IVMP, either at their first or subsequent disease presentation. All patients received IV cyclophosphamide; however, 1 discontinued after the first infusion due to intolerance. All patients received oral prednisone of varying doses; 2 received short-term (<6 months) steroid therapy, 2 remained on oral steroids long-term (>6 months), and 1 was lost to follow-up after 6 months. One patient received long-term treatment with azathioprine and 2 with methotrexate. Four (80%) of the 5 patients received anticoagulation therapy with either ASA or warfarin during their illness. No validated outcome measures were used to assess outcomes for these patients; however, at last follow-up, 3 patients were reported as neurologically asymptomatic, 1 had mild residual deficits, and 1 was lost to follow-up but continued on treatment at their last documented visit.