Inflammatory central nervous system (CNS) diseases in childhood comprise a wide spectrum of heterogeneous conditions. We studied 4 children with primary CNS vasculitis in whom results of magnetic resonance imaging studies were abnormal but results of conventional angiography were normal. We determined that angiography-negative, biopsy-confirmed primary small-vessel CNS vasculitis is a previously unrecognized distinct disease entity in children. The diagnosis must be considered in a child with a progressive, acquired diffuse or focal neurologic deficit, even if the results of conventional angiography are normal. A lesional brain biopsy is required to confirm the diagnosis. Use of immunosuppressive therapy plus aspirin leads to an excellent neurologic outcome.
Inflammatory diseases of the central nervous system (CNS) in children are a challenging group of disorders with regard to diagnosis, classification, and therapy. CNS inflammation can be associated with infections, malignancies, metabolic diseases, and systemic collagen vascular disorders. The anatomic distribution of inflammation within the CNS can be primarily parenchymal, as is seen in multiple sclerosis. Less frequently, the inflammatory process predominantly attacks blood vessels, as seen in CNS vasculitis (1, 2). In children, primary or isolated CNS vasculitis is rare, because it is more commonly related to a generalized or systemic illness.
In adults, the diagnostic criteria for primary angiitis of the CNS (PACNS) include the following: an unexplained acquired neurologic deficit, angiographic or histologic features of CNS vasculitis, and no evidence of a systemic condition associated with these CNS findings (3). In the majority of patients with PACNS, abnormalities, albeit nonspecific, are present on cerebral angiograms (4). Brain biopsies in adult patients with PACNS frequently show granulomatous vasculitis of parenchymal and leptomeningeal arterial vessels in the brain (5); however, reports of nongranulomatous, lymphocytic CNS vasculitis have been published (6–8).
Childhood PACNS (cPACNS) has been described in the literature, in case reports and small case series (9–11). Thus far, no diagnostic criteria, disease classification, treatment regimens, and/or long-term outcome data have been reported. The diagnosis of cPACNS is based primarily on “typical angiographic findings” (10). Elective brain biopsies have rarely been performed in cases of suspected cPACNS, and biopsy specimens have been obtained predominantly from children who required the insertion of a ventriculoperitoneal shunt due to increased intracranial pressure (9) or for whom a biopsy was performed in order to exclude a malignant or infectious CNS process.
The aim of this study was to describe a new disease entity of angiography-negative primary CNS vasculitis of childhood.
Between January 1, 1990 and December 12, 2002, the diagnosis of primary CNS vasculitis was made in 66 patients attending The Hospital for Sick Children. After approval was obtained from the Research Ethics Board (file no. 0020020023), clinical and laboratory data for all patients were obtained and reviewed. Imaging studies were reanalyzed. None of the patients had an underlying systemic disease or a known cause of vasculopathy (e.g., collagen vascular disease, hemoglobinopathy, infection, dissection, thromboembolism, moyamoya disease, or metabolic disease).
In 62 patients the diagnosis of cPACNS was based on angiographic findings, while in 4 patients the results of conventional angiography were normal. In these 4 patients the diagnosis of cPACNS was confirmed by results of an elective brain biopsy. Additional patients with angiography-negative cPACNS were sought by reviewing the results of all brain biopsies (8) that had been performed to rule out CNS vasculitis during the study interval. The inception cohort therefore included all patients with angiography-negative, biopsy-confirmed primary CNS vasculitis of childhood who were seen at our institution during the study period.
Clinical data, including demographic information, the medical history of the patient and his or her family, the history of the patient's current illness, and results of detailed neurologic and rheumatologic examinations were obtained from prospectively collected, standardized assessments and entered into a designated Microsoft Access database (Microsoft, Seattle, WA). Treatment protocols, dosing, and side effects of medications were documented. Followup visits were assigned for each patient at 0, 3, 6, 12, 18, and 24 months and then yearly following diagnosis, as per the research protocol. In addition, the time of the last followup visit was determined. Treatment was given at the discretion of the treating rheumatologist. Response to treatment was noted when no further clinical and radiographic disease progression occurred and the patient showed improvement, including clinical improvement and regression of radiographic findings. Neurologic deficits were classified in standardized assessments using the previously validated Pediatric Stroke Outcome Measure (12).
Laboratory studies included the following: erythrocyte sedimentation rate (ESR); complete blood cell count (CBC), including the white blood cell (WBC) differential count; determination of the levels of C-reactive protein (CRP), serum immunoglobulin, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, lupus anticoagulant, and C3 and C4 complement; and urinalysis. The cerebrospinal fluid (CSF) was analyzed for cell count, protein level, and opening pressure. Autoantibody testing included antinuclear antibody, rheumatoid factor, anti–double-stranded DNA, anti-Ro, anti-La, anti-Sm, anti-RNP, antineutrophil cytoplasmic antibodies, and anticardiolipin antibodies. Viral and bacterial cultures, serology, and viral polymerase chain reaction were performed using both peripheral blood and CSF, according to the standardized institutional encephalitis workup.
All patients underwent computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and conventional angiography at the time of diagnosis. Conventional angiography was performed as follows: after cannulation and direct injection of contrast material into the anterior and posterior circulation, images were acquired and analyzed using digital subtraction software.
During followup, MRI and MRA were performed. MRI studies included standardized T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR)–weighted sequences, and diffusion-weighted images. Gadolinium-enhanced sequences were included when available. All imaging studies were blindly analyzed by 2 radiologists, and differences were resolved by consensus. Data from these analyses were entered into a designated radiology Microsoft Access database.
CNS lesions were identified by MRI. Lesional brain biopsies were performed through open craniotomy. Biopsy specimens included the leptomeninges, the cerebral cortex, and subjacent white matter. Brain biopsy specimens were fixed in paraffin and stained with hematoxylin and eosin and Movat's pentachrome. All biopsy specimens were assessed by electron microscopy. Immunohistochemistry staining was performed using monoclonal mouse anti-human antibodies and peroxidase. The specific antibody panel included anti-CD20 (B cell marker), anti-CD3 and anti-CD43 (T cell markers), and anti-CD45 (panlymphocytic marker).
All data, including those from the radiographic analysis, were collected and entered into 2 designated Access databases using the double data entry verification technique. Data were described as frequencies, medians with ranges, and means with standard deviations. Statistical analyses, including the chi-square test, Fisher's exact test, and Student's t-test, were performed in SAS (SAS Institute, Cary, NC).
The patient, a previously healthy 10-year-old girl, presented with a 2-week history of left-sided facial droop and a 2-day history of weakness in the left arm and leg, with difficulty walking. The results of her general physical examination were normal. Neurologic abnormalities included a left-sided hemiparesis with decreased ipsilateral muscle strength, sensory deficit, upgoing toe reflexes, and a facial droop. No constitutional symptoms, including fatigue and fever, were present. No intercurrent illness was reported. Laboratory measures of inflammation markers, including the CBC, the ESR, and the CRP level, were normal. MRI revealed T2-weighted bright abnormalities involving both basal ganglia and the right frontal lobe, in a nonarterial distribution. Results of both MRA and conventional angiography were normal. Clinically, the child improved spontaneously and was discharged without medications. A lumbar puncture was not performed.
Four weeks later, the patient presented with the recurrence of left-sided weakness. In addition, significant concentration difficulties, a severely compromised short-term memory, and urinary incontinence had developed (Table 1). The WBC count was elevated (25.0 × 109cells/liter), with 76% neutrophils, no bands, and 21% lymphocytes (Table 2). The lumbar puncture revealed an increased level of CSF protein (0.47 gm/liter), 9 × 106 WBCs/liter (mainly lymphocytes), and an increased opening pressure (87 cm H2O) (Table 2). A repeat MRI demonstrated new parenchymal lesions and progression of the previously documented abnormalities. Results of MRA were normal. A lesional brain biopsy of an area identified by MRI was performed.
Table 1. Clinical presentation of patients with angiography-negative childhood primary angiitis of the central nervous system
Preceding systemic symptoms
Fatigue, abdominal pain
Preceding diffuse neurologic deficit
Cognitive problems, worse school performance
Headache, behavior changes, poor school performance
The patient, a previously healthy 9-year-old girl, presented with uncontrolled left arm movements and a decreased level of consciousness, with a score of 6 on the Glasgow coma scale (possible range 0–15). She was intubated, ventilated, and treated with intravenous antibiotics for meningitis. The ESR was elevated, at 45 mm/hour. The WBC count was 10.6 × 109cells/liter, with 71% neutrophils, no bands, and 21% lymphocytes. The lumbar puncture showed normal levels of CSF protein and no pleocytosis. All cultures were negative. An electroencephalogram demonstrated a right frontotemporal focus, and MRI revealed a right parietal parenchymal lesion. Treatment with carbamazepine was started, and the patient was discharged but continued to have focal seizures.
One month later, severe toxic epidermolysis developed, and she was treated with intravenous immunoglobulin. The patient's anticonvulsive therapy was switched to clonazepam. After another month, she was readmitted because of the increased frequency and severity of seizures plus the new onset of rightsided weakness, headache, significant concentration difficulties with decreased school performance, and fever of 38.2°C. The ESR was now elevated at 95 mm/hour, and the WBC count was raised at 20.2 × 109cells/liter, with 81% neutrophils, 1% bands, and 13% lymphocytes (Tables 1 and 2). The repeat lumbar puncture again showed a normal CSF protein level, but this time pleocytosis was present, with a WBC count of 51 × 106 cells/liter (49% neutrophils, 43% lymphocytes, and 8% monocytes) (Table 2). Cultures remained negative. A repeat MRI demonstrated progression of the right parietal and temporal lesions, with evidence of a new right frontal lesion. The results of MRA and conventional angiography remained normal. A brain biopsy of the parietal lesion was performed.
The patient, a 16-year-old girl, presented with a 1-month history of headaches, flu-like symptoms without documented fever, significant behavior changes, and severe emotional instability. Depression had previously been diagnosed in this patient, and treatment with fluoxetine had been started. She reported poor, worsening school performance. At presentation, she showed an ataxic gait on the right side, a right gaze–evoked nystagmus, and a right-sided facial droop. Levels of inflammation markers were mildly elevated, with an ESR of 20 mm/hour, a CRP level of 45 mg/dl, and a raised WBC count of 16.3 × 109 cells/liter, with 87% neutrophils, no bands, and 11% lymphocytes (Table 2). The lumbar puncture revealed significant pleocytosis (WBC count 747 × 106 cells/liter, with 2% neutrophils, 74% lymphocytes, and 18% monocytes), increased CSF protein (0.75 gm/liter), and a high opening pressure (Table 2). MRI demonstrated right-sided cerebellar lesions and evidence of hydrocephalus. Results of conventional angiography and MRA were normal. A ventricular shunt was required, and a lesional brain biopsy was performed.
The patient, a previously healthy 5-year-old girl, presented with the inability to walk due to generalized weakness, abdominal pain, and a recent generalized tonic-clonic seizure. She was afebrile. The only abnormal marker of inflammation was an elevated ESR (108 mm/hour). The WBC count was 10.4 × 109cells/liter, with 74% neutrophils, no bands, and 26% lymphocytes (Table 2). Results of a CSF examination, including cultures, were completely normal. Over the next several days, the patient's condition deteriorated rapidly, and fever, focal seizures, choreaform movements, and a progressively decreasing level of consciousness developed (Table 1). A repeat examination of the CSF showed an increased protein level (0.6 gm/liter), no pleocytosis, but a high opening pressure (69 cm H2O) (Table 2). The MRI demonstrated multiple focal parenchymal lesions. Results of angiography were normal. A lesional biopsy of the parietal lobe was performed.
All 4 patients were female, with a mean age at the time of diagnosis of 10.2 years (range 5.1–16.4 years). Symptoms that occurred prior to the diagnosis, clinical features at presentation, and the duration of symptoms prior to biopsy, are shown in Table 1. Three children had nonspecific systemic symptoms (i.e., flu-like illness and low-grade fever). The fourth child was completely well until the time of her first visit. In all patients disease progressed within weeks, with worsening or acquisition of neurologic deficits. The most frequent neurologic signs and symptoms were neurocognitive dysfunction, headache, hemiparesis, and focal seizures (see Table 1).
All patients had laboratory evidence of systemic inflammation, as shown in Table 2. Repeated measurements showed that the levels of inflammation markers steadily increased during disease progression. An elevated ESR and mildly raised WBC count was seen in all of the patients. Elevated C3 levels were observed in 3 of the 4 children. Autoantibody testing was not helpful. One patient had positive anticardiolipin antibodies; no other autoantibodies were detected. Lupus anticoagulant was negative and the thrombophilia workup was normal in all patients tested. A CSF abnormality was present in all 4 patients, with an elevated level of CSF protein in 3 of 4 patients and CSF pleocytosis in 3 of 4 patients. However, results of the initial CSF examination were frequently normal. High opening pressure was seen in all 3 patients in whom it was measured.
CT. In all 4 patients, CT was performed at the time of diagnosis. In one patient (patient 3) a focal lesion plus evidence of raised intracranial pressure were noted. The other 3 CT scans obtained at the time of diagnosis did not show any abnormalities.
MRI. In all patients, MRI revealed evidence of multifocal lesions of both gray and white matter (Table 3). Unilateral and bilateral lesions were each seen in 50% of patients each. MRI lesions were best viewed on T2-weighted images and FLAIR sequences in all patients. Abnormalities were not detected on diffusion-weighted images. Gadolinium-enhanced studies were done in only 2 patients. In one of 2 children, lesions that were positive on T2-weighted and FLAIR MRI sequences showed gadolinium enhancement. In all patients, repeat MRI studies were performed prior to brain biopsy. MRI lesions rapidly progressed, reflecting progression of the clinical disease (Figures 1A and B). Followup MRI studies, which monitored immunosuppressive therapy, demonstrated regression of the size and/or complete resolution of CNS lesions closely correlating with resolution of clinical findings (Figure 1C). During followup, CNS lesions were consistently best viewed on T2-weighted images and FLAIR sequences. Gadolinium enhancement was no longer detectable.
Table 3. MRI characteristics in patients with angiography-negative childhood primary angiitis of the central nervous system*
Angiography. In all 4 patients, results of conventional angiography were normal. In one patient MRA had demonstrated possible CNS vessel stenosis, which was not confirmed on conventional angiography.
Findings on brain biopsy.
Lesional brain biopsy specimens from all patients demonstrated histologic features similar to those of lymphocytic CNS vasculitis. A transmural lymphocytic inflammation of small and medium-sized vessels of both white and gray matter was present (Figure 2). There was no evidence of viral inclusions in neurons or glial cells (on light or electron microscopy), endothelial tubuloreticular inclusions, or white matter demyelinization. Reactive changes of the brain parenchyma, including mild to moderate gliosis, and areas of vessel obliteration were seen. Immunohistochemical staining characterized the transmural infiltrate as consisting of mainly T cells with the memory phenotype. In addition, varying numbers of macrophages, B cells, and eosinophils were present. All patients had evidence of vasculitis in the leptomeninges in addition to the brain parenchyma. Vessel wall inflammation with various degrees of perivascular mononuclear infiltrates was observed. No granulomas were seen in any of the patients.
All patients received therapy with oral prednisone (2 mg/kg) and low-dose aspirin (3– 5 mg/kg). In 2 patients, a monthly intravenous pulse of cyclophosphamide (500–750 mg/m2) was added. Another patient was treated with oral azathioprine (2 mg/kg). The treatment regimens and responses are summarized in Table 4. The dose of prednisone was tapered slowly over a minimum of 6 months. Steroid side effects observed included significant weight gain (>10% of the baseline weight), hypertrichosis, and striae distensae. Transient lymphopenia was seen in children treated with intravenous cyclophosphamide pulses. No significant adverse events were noted.
Table 4. Treatment and outcome of patients with angiography-negative childhood primary angiitis of the central nervous system*
IV = intravenous.
IV pulse cyclophosphamide
IV pulse cyclophosphamide
Duration of immunosuppression
Time of last followup
Followup and outcome.
Patients were followed up for a mean period of 33 months (range 14–59 months). Although in the majority of patients disease progression occurred prior to diagnosis, all patients responded to therapy. No disease relapse was seen during the study interval. Complete neurologic recovery was seen in all 4 children. The average time until recovery was 14 months (range 10–18 months).
This study describes a newly recognized distinct disease entity in the spectrum of inflammatory CNS diseases of childhood: angiography-negative, small-vessel primary CNS vasculitis (cPACNS). A cohort of 4 patients was identified. Because cPACNS has previously been considered a disease of medium-to-large vessels, conventional angiography was the preferred diagnostic modality or gold standard for cPACNS (10). All 4 patients had clinical features suggestive of CNS vasculitis and consistent MRI findings but normal results of conventional angiography. A diagnostic lesional brain biopsy was performed, showing lymphocytic, small-vessel PACNS, a new distinct disease entity in children.
Clinical findings at the time of diagnosis of adult CNS vasculitis have been reported to include a wide spectrum of focal neurologic deficits (13). This clinical variability likely reflects the differing localization, size, and pathology of the affected CNS vessels (10). Our experience of rapidly progressing neurologic deficits including the addition of new and/or worsening of preexisting deficits is supported by the pediatric literature and is in contrast to a more indolent course reported in biopsy-proven granulomatous vasculitis as reported in the adult literature (4, 9). In the pediatric cases of CNS vasculitis reported in the literature, disease progression was most commonly rapid and led to a fatal outcome (9, 14). Our cohort was small and therefore may not capture the entire spectrum of clinical features at the time of diagnosis of small-vessel cPACNS. However, the data suggest that the development of newly acquired focal and, more importantly, diffuse neurologic deficits with rapid progression in a previously healthy child without evidence of any infection or malignancy should lead to the clinical suspicion of small-vessel cPACNS.
The clinical presentation of rapidly progressing acquired neurologic deficits suggests an inflammatory CNS lesion. All patients in our series had elevated levels of nonspecific inflammation markers at the time of brain biopsy. However, it is important to note that initially the results of these tests were frequently normal. CSF testing was an excellent diagnostic tool. At the time of diagnosis, 100% of the patients had abnormal results of CSF testing. However, as was seen with the inflammation markers in the peripheral blood, results of the CSF examination were frequently normal at the initial presentation. Opening pressure measurements during lumbar puncture were abnormal in all 3 patients tested. The diagnostic value, sensitivity, and specificity of the opening pressure measurement have to be determined in future studies.
Abnormal levels of systemic inflammation markers are infrequently reported in adult PACNS (3, 15) and in the limited literature of pediatric PACNS (10, 16). However, CSF abnormalities are common in adult PACNS (13, 17), whereas CSF data from previous pediatric case reports are controversial (14, 18, 19).
Investigations in patients with the new onset of significant cognitive dysfunction include CT, MRI, and angiography. CT failed to demonstrate any abnormality in 75% of the patients. CT has been shown to be less sensitive than MRI in adult PACNS (17). Calabrese demonstrated a sensitivity of MRI approaching 100% in biopsy-confirmed cases of PACNS (20, 21). All study patients showed multifocal parenchymal lesions involving both gray and white matter. Both unilateral and bilateral CNS involvement was seen. New lesions were primarily identified on T2 sequences but also demonstrated enhancement on FLAIR images, supporting their hyperemic, inflammatory character (22). In addition, in sequential studies of individual patients, FLAIR sequences closely correlated with clinical disease activity. Clinical disease progression was associated with the extension of preexisting lesions and/or development of new lesions on FLAIR sequences. In addition, lesions demonstrated on FLAIR sequences vanished rapidly with clinical improvement and response to treatment.
Two distinct histologic types of CNS vasculitis have been described in adults: lymphocytic and, more frequently, granulomatous vasculitis. The histologic characteristics of granulomatous CNS vasculitis include a transmural infiltrate with well-defined granulomas, evidence of giant cells, and areas of vessel wall necrosis (23, 24). Lymphocytic, nongranulomatous vasculitis is characterized by a transmural, predominantly T cell and B cell infiltrate, without evidence of granulomas (14, 19). However, most patients have positive results of angiography, and few case reports of angiography-negative CNS lymphocytic vasculitis have been published in the adult literature (6, 7).
All patients in our cohort demonstrated similar histologic features of lymphocytic vasculitis with intramural mononuclear lymphocytic infiltration of the small muscular arterial vessels. Both brain parenchymal vessels and leptomeningeal vessels were affected. The intramural infiltrate consisted of predominantly T cells and B cells, with various amounts of macrophages and some eosinophils. The degree of perivascular infiltration as well as reactive gliosis varied between patients. No granulomatous vasculitis was seen. It is possible that if it is left untreated, the lesion in patients with angiography-negative CNS vasculitis may progress to involve larger vessels that may be detected by angiography. However, there is no evidence in the literature to support this hypothesis, and we would suggest that a brain biopsy is indicated at the earliest time possible in order to confirm the suspected diagnosis of cPACNS.
The published literature on the treatment response in and outcome of cPACNS is limited. Earlier reports suggested a poor prognosis (14, 18, 24–26). More recent case reports have described a good response to steroids plus cyclophosphamide (9, 10). In a recent cohort study of 41 patients with adult PACNS, a relapse rate of 29% and an overall favorable outcome in 80% of patients were reported (27). In our study, all patients were treated with high-dose prednisone and low-dose aspirin. Three children received additional immunosuppressive agents (cyclophosphamide, azathioprine). Treatment led to rapid clinical improvement. Diffuse neurologic deficits improved within weeks to months, levels of inflammation markers normalized rapidly, and MRI FLAIR lesions vanished. None of the patients had persistently elevated levels of inflammation markers at the 3-month followup visit. The response of focal neurologic deficits to therapy was slower. This delayed recovery likely reflects ischemic CNS damage as opposed to persistent inflammatory lesions.
Angiography-negative PACNS is a new distinct disease entity in childhood. The diagnostic algorithm includes 1) clinical evidence of acquired focal and/or diffuse neurologic deficits in a previously healthy child, with rapid worsening over weeks; 2) elevated levels of inflammation markers in the blood and CSF, potentially requiring repetitive testing; 3) multifocal lesions on MRI with enhancement on T2 and FLAIR sequences; 4) normal results of conventional angiography; and 5) confirmation of the suspected diagnosis by results of brain and leptomeningeal biopsy demonstrating intramural CNS vessel infiltrates.
We suggest that angiography-negative small-vessel cPACNS should be included in the differential diagnosis of inflammatory diseases of the CNS. Early recognition of this new disease entity may be important, because in our study, treatment was associated with a favorable outcome.