Primary Small-vessel Central Nervous System Vasculitis in Children

Abstract & Commentary

By Dara Jamieson, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Jamieson reports she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil, and is on the speaker's bureau for Boehringer Ingelheim and Merck.

Synopsis: Brain biopsy is necessary to make the diagnosis of small-vessel primary angiitis of the central nervous system in children, prior to treatment with steroids and immunosuppressant medications.

Source: Elbers J, et al. Brain biopsy in children with primary small-vessel central nervous system vasculitis. Ann Neurol 2010;68:602-10.

Hunder G, et al. Primary central nervous system vasculitis: Is it a single disease? Ann Neurol 2010;68:573-574.

Hutchinson C, et al. Treatment of small vessel primary CNS vasculitis in children: An open-label cohort study Lancet Neurol 2010;9; 1078-1084.

Friedman N. Small vessel childhood primary angiitis of the CNS: First steps toward a standardised treatment regimen. Lancet Neurol 2010;9;1042-1044.

Primary angiitis of the central nervous system (PACNS) is an immune-mediated inflammatory process directed toward blood vessels of the CNS. The disease is recognized in adults, but also has been associated with variable clinical and radiological presentations, and devastating neurological consequences in children.

Elbers et al. characterized the clinical and histopathological features of brain biopsies, obtained through extended burr holes, in a total of 13 children (aged 5 to 17 years) with small-vessel PACNS of childhood (SVcPACNS) from 1998 to 2008 at a single center. Presenting features included seizures (85%), headache (62%), and cognitive decline (54%). Inflammatory markers were elevated in 12 of 13 children. All patients had some abnormality (e.g., increased opening pressure, pleocytosis, or increased protein) on CSF analysis. MRIs showed T2 hyperintensities in multiple or diffuse locations in most, but not all, scans; no scans showed restricted diffusion. All children with diagnostic biopsies had negative cerebral angiography, ruling out large vessel PACNS. Brain biopsy confirmed SVcPACNS in 11 patients with intramural lymphocytic infiltrate; two had only nonspecific perivascular inflammation. All 6 non-lesional biopsies from the non- dominant frontal lobe yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to biopsy, prior steroid treatment, and inadequate specimen sampling.

The authors concluded that in children presenting with new onset severe headaches, seizures, or cognitive decline, the diagnosis of SVcPACNS confirmed by a brain biopsy should be considered. Although non-lesional biopsies may succeed in yielding the diagnosis, lesional biopsies increase diagnostic accuracy. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the diagnosis.

Hutchinson et al. evaluated a treatment protocol and described the long-term neurological outcomes in a single-center open-label cohort study of children with biopsy-proven SVcPACNS. Median age at diagnosis was 9.8 years (range 5.5–17.8 years) and median follow-up was 33 months (range 1–86 years). Induction therapy with steroids and pulses of intravenous cyclophosphamide was followed by maintenance therapy with either azathioprine or mycophenolate mofetil. Clinical and neurological assessments, quality-of-life measures, and laboratory markers were performed at baseline, 3, 6, 9, 12, 18, and 24 months, then yearly. Brain imaging was performed at baseline, 6, 12, 18, and 24 months. The pediatric stroke outcome measure (PSOM) score at 24 months measured neurological outcome. Of 19 children who met the inclusion criteria, 14 completed induction and received maintenance therapy with azathioprine (n = 9) or mycophenolate mofetil (n = 5). Of 13 patients who completed 24 months' follow-up, nine had a good neurological outcome by PSOM. Eight of 19 patients experienced disease flares. Four patients achieved remission of disease off medication.

The authors concluded that this treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with SVcPACNS. Because of adverse events and neurological flares associated with azathioprine treatment, mycophenolate mofetil is the preferred maintenance medication. Appropriate diagnosis of children with this disorder is crucial because good neurological outcome may be achieved with standardized treatment.


These papers, and their accompanying editorials, emphasize that PACNS is a disease of any age, including children. Vasculitis involving small vessels of the CNS is difficult to diagnose with neuroimaging techniques or other non-invasive testing. Diffuse or multifocal MRI abnormalities, without clear foci of ischemia or infarction, overlap with other neurological disorders. Small vessel disease is usually angiographically negative. Spinal fluid is non-specific. Only brain biopsy can diagnose SVcPACNS, which appears to be a low-risk, but high-yield, procedure. Unfortunately, none of these pediatric cases was analyzed for vascular amyloid deposition which may be found on biopsy of PACNS in adults. While treatment with immunosuppressant medication in children (i.e., steroids and pulses of intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil) may have long-term consequences, the neurological damage of SVcPACNS warrants aggressive treatment and close follow-up.