Abstract
Background and Purpose
For the management of central nervous system (CNS) vasculitis, it is crucial to differentiate between primary and secondary CNS vasculitis and to understand the respective etiologies. We assessed the etiology, characteristics, and outcomes of patients with CNS vasculitis.
Methods
A single-center retrospective chart review was conducted at the University of Utah, Department of Neurology, between February 2011 and October 2022.
Results
The median age of the 44 included patients at diagnosis was 54 years; 25.0% were men. Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits higher fever incidence (observed in infectious and connective tissue disorder [CTD]-associated vasculitis), low glucose levels (mostly in infectious vasculitis) and unique cerebrospinal fluid oligoclonal bands (observed in infectious and CTD-associated vasculitis). Patients with inflammatory cerebral amyloid angiopathy (CAA) were older and more commonly had microhemorrhage than primary angiitis of the CNS (PACNS). All patients with CTD-associated vasculitis had a known history of CTD at presentation. Brain biopsies were performed on 10 of 17 PACNS patients and 4 of 8 inflammatory CAA patients, confirming vasculitis in 7 and 4 patients, respectively. Intravenous methylprednisolone was the predominant induction therapy (63.6%), and cyclophosphamide was the most used adjunctive therapy. Cyclophosphamide, rituximab, azathioprine, and mycophenolate mofetil were utilized as maintenance therapy, often with concurrent prednisone. Patients with inflammatory CAA had a higher tendency for relapse rates than PACNS.
Conclusions
This study highlights the variations in patients’ characteristics, symptoms, and treatment for CNS vasculitis. Understanding these differences can lead to more efficient diagnostic and management strategies.
Keywords: central nervous system vasculitis, primary angiitis of the central nervous system, secondary vasculitis, vasculitis
Introduction
Central nervous system (CNS) vasculitis refers to a broad spectrum of conditions, which could present as stroke in young patients lacking traditional cerebrovascular risk factors and be life-threatening, especially when the underlying etiologies are untreated. 1 Primary CNS vasculitis, represented by primary angiitis of the CNS (PACNS), exclusively involves the CNS.2,3 Inflammatory cerebral amyloid angiopathy (CAA) is another primary CNS vasculitis categorized into amyloid-β-related angiitis (ABRA), with pronounced transmural inflammatory infiltration, and CAA-related inflammation, showing perivascular nondestructive inflammatory infiltration on biopsy. 4 A substantial clinical overlap between inflammatory CAA and PACNS complicates diagnosis. 5 Secondary CNS vasculitis, associated with a systemic process, encompasses a spectrum of causes, including connective tissue disorders (CTD), infection, systemic vasculitis, malignancy, and toxic substances/drugs. 1
PACNS is diagnosed in patients with (1) unexplained neurologic deficit, (2) evidence of classic angiographic or histopathologic features of PACNS, and (3) no evidence of systemic vasculitis or other conditions that could elicit the angiographic or pathological features. 6 Birnbaum and Hellman proposed that diagnosis is “definite” upon confirmation of the tissue biopsy specimen and “probable” in the absence of tissue confirmation if supportive findings exist on CNS imaging and in the cerebrospinal fluid (CSF) profile. 7 In clinical practice, definite PACNS diagnosis can be challenging owing to the inaccessibility of certain CNS tissues without risk of iatrogenic disability. 1 Understanding the differences between vasculitis types is crucial for optimal treatment, yet comparative data on their clinical features and outcomes are scarce, with no prospective treatment effectiveness studies to date. 8 We aimed to describe demographic, clinical characteristics, distinct laboratory and imaging findings, treatment, and outcomes of patients with CNS vasculitis at a tertiary referral center to develop a consistent data-driven approach for diagnosis and management of CNS vasculitis.
Methods
This single-center retrospective chart review included patients diagnosed with cerebral arteritis within the University of Utah Health system. We analyzed International Classification of Diseases 9 code 437.4 (cerebral arteritis) and 10 code I67.7 (cerebral arteritis, not classified elsewhere), coupled with at least one encounter with a neurologist, between February 2011 and October 2022. Patients with alternative diagnoses during follow-up or who had insufficient data were excluded. Demographic information, including age, sex, and race, symptoms, mortality status, and autoimmune disease history, was collected from patient charts. Time to diagnosis was determined by the difference between the symptom onset and diagnosis dates. Serum laboratory results, CSF analysis, and imaging, were recorded when available. Large cerebral vessel vasculitis was defined as affecting the internal carotid artery, M1 and A1 segments of the middle cerebral artery, intracranial vertebral artery, basilar artery, or P1 segment of the posterior cerebral artery. 9 Treatments, duration, and outcomes were collected by chart review. The degree of disability at presentation and the last visit was defined by medical records and categorized using the modified Rankin scale (mRS). The mRS is a 6-point disability scale that consists of six grades - 0: no neurologic signs or symptoms; 1: no disability in spite of symptoms; 2-5: increasing disability; and 6: death. 10 Follow-up period was defined by the date of initial evaluation to the date of last evaluation by a neurologist or death. Patients were initially classified into primary or secondary CNS vasculitis. Primary CNS vasculitis was further divided into PACNS and inflammatory CAA, while secondary CNS vasculitis was subdivided into four categories: (1) CTD-associated vasculitis, (2) infectious vasculitis, and (3) systemic vasculitis. The study procedures were approved by the local Institutional Review Board of the University of Utah (IRB_00108537).
Data Analysis
Continuous variables are expressed as mean ± standard deviation and median and interquartile ranges (IQR), and categorical variables are expressed as frequency (percentage). The unpaired two-tailed Mann–Whitney U-test was performed to compare continuous variables, Fisher’s exact test to compare categorical variables, and the chi-square test to compare mRS scores. The figure and tables were created and analyzed using Prism six software (GraphPad). P < .05 was considered significant.
Results
Of the 144 patients who met the search criteria, 44 met the inclusion criteria for this study (Table S1); 25.0% were male and 88.6% were White. The median age at diagnosis was 54 years (IQR, 41.0–62.2 years). Twenty-five (56.8%) and 19 (43.2%) were diagnosed with primary and secondary CNS vasculitis, respectively. Seventeen (38.6%) had PACNS, 8 (18.2%) had inflammatory CAA, 6 (13.6%) had CTD-associated vasculitis, 10 (22.7%) had infectious vasculitis, and 3 (6.8%) had systemic vasculitis (Table 1). Nine patients (20.5%) died during the study period (primary CNS vasculitis 4 (16.0%), secondary CNS vasculitis 5 (26.3%); Table S2).
Table 1.
Baseline Characteristics of Patients With Central Nervous System Vasculitis.
| Characteristic | n = 44 (%) |
|---|---|
| Median age, years [IQR] | 54 [41.0-62.2] |
| Sex | |
| Male | 11 (25.0) |
| Race | |
| Caucasian | 39 (88.6) |
| Hispanic | 3 (6.8) |
| Asian | 1 (2.3) |
| Pacific islander | 1 (2.3) |
| Vasculitis type | |
| Primary CNS vasculitis | 25 (56.8) |
| PACNS | 17 (38.6) |
| Inflammatory CAA | 8 (18.2) |
| Secondary CNS vasculitis | 19 (43.2) |
| Connective tissue disorder associated vasculitis | 6 (13.6) |
| Antiphospholipid syndrome | 2 (4.5) |
| Systemic lupus erythematosus | 2 (4.5) |
| Others a | 2 (4.5) |
| Vasculitis/vasculopathy secondary to infection | 10 (22.7) |
| Varicella zoster virus | 4 (9.1) |
| Herpes simplex virus-1 | 1 (2.3) |
| Bacterial meningitis | 2 (4.5) |
| Others b | 3 (6.8) |
| Systemic vasculitis c | 3 (6.8) |
| Mortality d | |
| Alive | 35 (79.5) |
| Dead | 9 (20.5) |
CAA, cerebral amyloid angiopathy; CNS, central nervous system; IQR, interquartile range; PACNS, primary angiitis of the central nervous system.
a1 case of Sjogren syndrome and 1 case of mixed connective tissue disorder.
b1 case of disseminated coccidioidomycosis, 1 case of West Nile virus, and 1 case of coronavirus disease 2019.
c1 case of giant cell arteritis, 1 case of Takayasu arteritis, and 1 case of granulomatous polyangiitis.
dMortality was assessed during the study period.
Clinical features, laboratory results, and main radiological features in the vasculitis cohort are summarized in Table 2. The median time to diagnosis was 30 (IQR, 18.0-202.0) days and 15 (IQR, 8.0-39.5) days in the primary and secondary CNS vasculitis groups, respectively. At diagnosis, the most frequent clinical presentations were headache (63.6%), altered cognition (43.2%), and focal weakness (38.6%). No significant presentation differences were observed between primary and secondary CNS vasculitis, except fever (0% vs 26.3%, P = .01) was more common in secondary CNS vasculitis (observed in infectious and CTD-associated vasculitis). Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits a higher incidence of low glucose levels (8.7% vs 41.2%, P = .02) (primarily observed in infectious vasculitis) and unique CSF oligoclonal bands (OCB) (0 vs 63.6%, P < .01) (observed in infectious and CTD-associated vasculitis). Brain magnetic resonance imaging (MRI) was conducted for all patients and was abnormal in every case. Acute or subacute stroke was more common in patients with secondary CNS vasculitis (94.7% vs 44.0%, P < .01), while microhemorrhage (48.0% vs 10.5%, P < .01) and hematoma (16.0% vs 0%, P = .03) were more common in primary CNS vasculitis (predominantly in inflammatory CAA). All patients underwent vessel imaging, and 33 (75%) showed signs of vasculitis, such as vessel enhancement and/or stenosis; 12 had large-middle vessel vasculitis and 21 had middle-small vessel vasculitis. Of the 18 primary CNS vasculitis patients with signs of vasculitis on vessel imaging, 15 (83.3%) had middle-small vessel involvement. Relapses were more frequent in primary CNS vasculitis (40% vs 10.5%, P = .04); however, there was no statistical difference in the proportion of mRS scores ranging from 0-3 and 4-6 at presentation and at the last follow-up between primary and secondary CNS vasculitis.
Table 2.
Baseline Epidemiological and Clinical Features of Patients With Central Nervous System (CNS) Vasculitis and Comparison of the Primary CNS Vasculitis and Secondary CNS Vasculitis Subgroups.
| All Patients (n = 44) | Primary CNS Vasculitis (n = 25) | Secondary CNS Vasculitis (n = 19) | P-value | |
|---|---|---|---|---|
| Epidemiological features | ||||
| Median age, years [IQR] | 54.0 [41.0-62.2] | 55.0 [45.0-63.0] | 50 [36.0-60.5] | .39 |
| Male, n (%) | 11 (25.0) | 3 (12.0) | 8 (42.1) | .04 |
| Autoimmune diseases history, n (%) | 8 (18.2) | 1 (4.0) | 7 (36.8) | .01 |
| Clinical presentation | ||||
| Median time between symptom onset to diagnosis, days [IQR] | 25 [11.0-63.0] | 30 [18.0-202.0] | 15 [8.0-39.5] | .05 |
| Fever, n (%) | 5 (11.4) | 0 (0) | 5 (26.3) | .01 |
| Headache, n (%) | 28 (63.6) | 16 (64.0) | 12 (63.2) | >.99 |
| Altered cognition, n (%) | 19 (43.2) | 11 (44.0) | 8 (42.1) | >.99 |
| Focal weakness, n (%) | 17 (38.6) | 8 (32.0) | 9 (47.4) | .36 |
| Aphasia/dysphasia, n (%) | 12 (27.3) | 6 (24.0) | 6 (31.6) | .73 |
| Sensory symptoms, n (%) | 10 (22.7) | 7 (28.0) | 3 (15.8) | .47 |
| Ataxia, n (%) | 7 (15.9) | 4 (16.0) | 3 (15.8) | >.99 |
| Dysarthria, n (%) | 9 (20.5) | 5 (20.0) | 4 (21.1) | >.99 |
| Diplopia, n (%) | 4 (9.1) | 2 (8.0) | 2 (10.5) | >.99 |
| Seizure, n (%) | 10 (22.7) | 8 (32.0) | 2 (10.5) | .15 |
| Laboratory results | ||||
| CRP > 3 mg/L, n/N (%) | 9/31 (29.0) | 3/19 (15.8) | 6/12 (50.0) | .06 |
| ESR > 20 mm/h, n/N (%) | 9/31 (29.0) | 3/19 (15.8) | 6/12 (50.0) | .06 |
| ANA ≥ 1:80, n/N (%) | 10/38 (26.3) | 6/23 (26.1) | 4/15 (26.7) | >.99 |
| dsDNA, n/N (%) | 3/20 (15.0) | 0/8 (0) | 3/12 (25) | .24 |
| ANCA, n/N (%) | 1/39 (2.6) | 0/24 (0) | 1/15 (6.7) | .38 |
| CSF analysis | ||||
| WBC > 5/μL, n/N (%) | 27/40 (67.5) | 15/23 (65.2) | 12/17 (70.6) | >.99 |
| Neu predominant, n | 11 | 7 | 4 | |
| Lym predominant, n | 16 | 8 | 8 | |
| Protein > 45 mg/dL, n/N (%) | 28/40 (70.0) | 15/23 (65.2) | 13/17 (76.5) | .50 |
| WBC >5/μL or protein > 45 mg/dL, n/N (%) | 33/40 (82.5) | 19/23 (82.6) | 14/17 (82.4) | >.99 |
| Glucose < 50 mg/dL and < 2/3 of the blood sugar level, n/N (%) | 9/40 (22.5) | 2/23 (8.7) | 7/17 (41.2) | .02 |
| Unique OCB > 1, n/N (%) | 7/31 (32.2) | 0/20 (0) | 7/11 (63.6) | <.01 |
| Imaging tests | ||||
| MRI abnormalities, n/N (%) | 44/44 (100) | 17/17 (100) | 27/27 (100) | 1 |
| Acute/subacute ischemic stroke a , n/N (%) | 29/44 (65.9) | 11/25 (44.0) | 18/19 (94.7) | <.01 |
| Single, n | 5 | 3 | 2 | |
| Multiple, n | 24 | 8 | 16 | |
| Microhemorrhage, n/N (%) | 14/44 (31.8) | 12/25 (48.0) | 2/19 (10.5) | <.01 |
| Hematoma, n/N (%) | 4/44 (9.1) | 4/25 (16.0) | 0/19 (0) | .03 |
| Subarachnoid hemorrhage, n/N (%) | 6/44 (13.6) | 3/25 (12.0) | 3/19 (15.8) | >.99 |
| Leptomeningeal lesion, n/N (%) | 9/44 (20.5) | 7/25 (28.0) | 2/19 (10.5) | .26 |
| Intraparenchymal contrast enhancement, n/N (%) | 21/44 (47.7) | 14/25 (56.0) | 7/19 (36.8) | .24 |
| Signs of vasculitis on vessel imaging, n/N (%) | 33/44 (75) | 18/25 (72.0) | 15/19 (78.9) | .73 |
| Large-middle vessels, n | 12 | 3 | 9 | |
| Middle-small vessels, n | 21 | 15 | 6 | |
| VW MRI enhancement, n/N (%) | 24/35 (68.6) | 13/23 (56.5) | 11/12 (91.7) | .06 |
| Median time from presentation to treatment, days [IQR] | 4.0 [1.0-7.5] | 6.0 [4.0-14.0] | 1.0 [0-2.0] | <.01 |
| Median follow up, months [IQR] | 25 [7.5-43.0] | 26.0 [11.0-44.0] | 16.0 [5.0-38.5] | .28 |
| Relapse (n) | ||||
| None | 32 | 15 | 17 | .04 |
| 1 | 6 | 4 | 2 | |
| ≥2 | 6 | 6 | 0 | |
| mRS at presentation (n) | ||||
| 0-3 | 21 | 13 | 8 | .56 |
| 4-6 | 23 | 12 | 11 | |
| mRS at last follow up (n) | ||||
| 0-3 | 27 | 15 | 12 | >.99 |
| 4-6 | 17 | 10 | 7 | |
ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; dsDNA, double stranded DNA; ESR, erythrocyte sedimentation rate; IQR, interquartile range; Lym, lymphocyte; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; Neu, neutrophil; OCB, oligoclonal band; VW, vessel wall; WBC, white blood cell.
aAcute stroke was defined as stroke occurring < 24 h from onset, and subacute stroke was defined as stroke occurring 24 h to 5 days from onset.
The main clinical presentations, laboratory results, and radiological features of inflammatory CAA and each secondary CNS vasculitis subclass compared to PACNS are summarized in Table 3. Notably, patients with inflammatory CAA were older and tended to have microhemorrhage (23.5% vs 100%, P < .01) compared to PACNS. All patients with CTD-associated vasculitis had a known history of CTD prior to vasculitis diagnosis, and they tended to demonstrate elevated erythrocyte sedimentation rate (ESR) (75% vs 7.1%, P = .02) and unique OCB (75% vs 0%, P < .01) in their CSF, compared to PACNS. Patients with infectious vasculitis, in comparison to those with PACNS, more frequently presented with fever (40% vs 0%, P = .01), had a higher incidence of low glucose levels in the CSF (66.7% vs 12.5%, P < .01), and exhibited unique OCB (80.0% vs 0%, P < .01). All patients with infectious vasculitis had acute/subacute stroke, and 7 (70%) had signs of large-middle vessel vasculitis on blood vessel imaging. Only three patients with systemic vasculitis (giant cell arteritis, Takayasu arteritis, and granulomatous polyangiitis) were included in our study. All patients had elevated C-reactive protein (CRP), and the patients with giant cell arteritis and Takayasu arteritis had very high ESRs of 63 and 92 mm/h (normal range: 0-20 mm/h), respectively. Two patients with systemic vasculitis underwent lumbar puncture; none had pleocytosis, elevated protein levels, or low glucose levels. Brain biopsy was performed in 10 patients with PACNS, seven of whom had a diagnostic result. The four patients who were diagnosed with PACNS but did not show evidence of vasculitis on vessel imaging had a brain biopsy, which demonstrated pathology consistent with vasculitis. On histologic examination, five patients had a lymphocytic pattern (two demonstrated a tumefactive lesion on imaging), one patient had a granulomatous pattern, and one patient had a necrotizing pattern. The two patients diagnosed with tumefactive PACNS had unremarkable vessel imaging findings, including vessel wall MRI, making brain biopsy crucial for the final diagnosis. Brain biopsy was also performed in four of eight patients with inflammatory CAA; all four demonstrated pathologic findings confirming the diagnosis, 2 of them were diagnosed with ABRA.
Table 3.
Clinical Features of Subgroups of Patients With Central Nervous System (CNS) Vasculitis.
| Characteristic | Primary CNS Vasculitis | Secondary CNS Vasculitis | |||
|---|---|---|---|---|---|
| PACNS (n = 17) | Inflammatory CAA (n = 8) | Connective Tissue Disorder (n = 6) | Infectious Vasculitis (n = 10) | Systemic Vasculitis (n = 3) | |
| Epidemiological Features | |||||
| Median age, years [IQR] | 51 [40.0-55.0] | 64.5 [61.0-68.0]* | 47 [38.0-55.0] | 48.5 [37.0-58.0] | 65 [51.0-75.0] |
| Male, n (%) | 3 (17.6) | 0 (0) | 2 (33.3) | 6 (60)* | 0 (0) |
| Autoimmune disease history | 1 | 0 | 6** | 1 | 0 |
| Clinical presentation | |||||
| Median time between symptom onset and diagnosis, day [IQR] | 30 [18.0-202.0] | 34 [19.0-108.0] | 15.5 [12.0-40.0] | 13 [7.0-27.0] | 36 [22.0-65.0] |
| Fever, n (%) | 0 (0) | 0 (0) | 1 (16.7) | 4 (40.0)* | 0 (0) |
| Headache, n (%) | 10 (58.8) | 6 (75.0) | 3 (50.0) | 7 (70.0) | 2 (66.7) |
| Altered cognition, n (%) | 6 (35.3) | 5 (62.5) | 3 (50.0) | 4 (40.0) | 1 (33.3) |
| Focal weakness, n (%) | 6 (35.3) | 2 (25.0) | 1 (16.7) | 6 (60.0) | 2 (66.7) |
| Aphasia/dysphasia, n (%) | 4 (23.5) | 2 (25.0) | 1 (16.7) | 4 (40.0) | 1 (33.3) |
| Sensory symptoms, n (%) | 5 (29.4) | 2 (25.0) | 1 (16.7) | 1 (10.0) | 1 (33.3) |
| Ataxia, n (%) | 3 (17.6) | 1 (12.5) | 1 (16.7) | 2 (20.0) | 0 (0) |
| Dysarthria, n (%) | 4 (23.5) | 1 (12.5) | 0 (0) | 4 (40.0) | 0 (0) |
| Diplopia, n (%) | 2 (11.8) | 0 (0) | 1 (16.7) | 1 (10.0) | 0 (0) |
| Seizure, n (%) | 6 (35.3) | 2 (25.0) | 1 (16.7) | 1 (10.0) | 0 (0) |
| Laboratory results | |||||
| CRP > 3 mg/L, n/N (%) | 1/14 (7.1) | 2/5 (40.0) | 2/4 (50.0) | 1/5 (20.0) | 3/3 (100)** |
| ESR > 20 mm/h, n/N (%) | 1/14 (7.1) | 2/5 (40.0) | 3/4 (75.0)* | 1/5 (20.0) | 2/3 (66.7) |
| ANA ≥ 1:80, n/N (%) | 5/17 (29.4) | 1/6 (16.7) | 3/5 (60.0) | 0/7 (0) | 1/3 (33.3) |
| dsDNA, n/N (%) | 0/8 (0) | NA | 3/6 (50.0) | 0/3 (0) | 0/3 (0) |
| ANCA, n/N (%) | 0/17 (0) | 0/7 (0) | 0/6 (0) | 0/6 (0) | 1/3 (33.3) |
| CSF analysis | |||||
| WBC > 5/μL, n/N (%) | 12/16 (75.0) | 3/7 (42.9) | 3/6 (50.0) | 9/9 (100) | 0/2 (0) |
| Neu predominant, n | 4 | 3 | 1 | 3 | – |
| Lym predominant, n | 8 | 0 | 2 | 6 | – |
| Protein > 45 mg/dL, n/N (%) | 9/16 (56.3) | 6/7 (85.7) | 5/6 (83.3) | 8/9 (88.9) | 0/2 (0) |
| WBC > 5/μL or protein > 45 mg/dL, n/N (%) | 13/16 (81.3) | 6/7 (85.7) | 5/6 (83.3) | 9/9 (100) | 0/2 (0) |
| Glucose < 50 mg/dL and < 2/3 of the blood sugar level, n/N (%) | 2/16 (12.5) | 0/7 (0) | 1/6 (16.7) | 6/9 (66.7)** | 0/2 (0) |
| Unique OCB > 1, n/N (%) | 0/15 (0) | 0/5 (0) | 3/4 (75.0) ** | 4/5 (80.0)** | 0/2 |
| Imaging tests | |||||
| MRI abnormalities, n/N (%) | 17/17 (100) | 8/8 (100) | 6/6 (100) | 10/10 (100) | 3/3 (100) |
| Acute/subacute ischemic stroke n/N (%) | 7/17 (41.2) | 4/8 (50.0) | 5/6 (83.3) | 10/10 (100)** | 3/3 (100) |
| Single, n | 0 | 3 | 0 | 1 | 1 |
| Multiple, n | 7 | 1 | 5 | 9 | 2 |
| Microhemorrhage, n/N (%) | 4/17 (23.5) | 8/8 (100)** | 0/6 (0) | 2/10 (20.0) | 0/3 (0) |
| Hematoma, n/N (%) | 1/17 (5.9) | 3/8 (37.5) | 0/6 (0) | 0/10 (0) | 0/3 (0) |
| Subarachnoid hemorrhage, n/N (%) | 1/17 (5.9) | 2/8 (25.0) | 1/6 (16.7) | 2/10 (20.0) | 0/3 (0) |
| Leptomeningeal lesion, n/N (%) | 5/17 (29.4) | 2/8 (25.0) | 0/6 (0) | 2/10 (20.0) | 0/3 (0) |
| Intraparenchymal contrast enhancement, n/N (%) | 9/17 (52.9) | 5/8 (62.5) | 2/6 (33.3) | 5/10 (50.0) | 0/3 (0) |
| Signs of vasculitis on vascular imaging, n/N (%) | 13/17 (76.5) | 5/8 (62.5) | 3/6 (50.0) | 10/10 (100) | 2/3 (66.7) |
| Large-middle vessels, n | 2 | 1 | 0 | 7 | 2 |
| Middle-Small vessels, n | 11 | 4 | 3 | 3 | 0 |
| VW MRI enhancement, n/N (%) | 8/15 (53.3) | 5/8 (62.5) | 2/2 (100) | 7/7 (100) | 2/3 (66.7) |
| Cerebral biopsy (%) | n = 10 | n = 4 | n = 0 | n = 0 | n = 0 |
| Not diagnostic, n (%) | 3 (30.0) | 0 | – | – | – |
| Signs of vasculitis, n (%) | 7 (70.0) b | 4 (100) c | – | – | – |
ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; CAA, cerebral amyloid angiopathy; CRP, C-reactive protein; CSF, cerebrospinal fluid, dsDNA, double-strand DNA; ESR, erythrocyte sedimentation rate; IQR, interquartile range; MRI, magnetic resonance imaging; Neu, Neutrophil; Lym, lymphocyte; OCB, oligoclonal band; PACNS, primary angiitis of the central nervous system; VW, vessel wall; WBC, white blood cell *P < .05 compared with the PACNS group **P < .01 compared with the PACNS group.
aOne patient did not receive treatment for vasculitis.
bFive patients had lymphocytic (two them had tumefactive lesions) lesions, one had lymphogranulomatous lesions, and one had granulomatous lesions.
cTwo patients had transmural inflammatory infiltrate, which is consistent with a diagnosis of amyloid-beta-related angiitis.
Treatments administered in each group are shown in Table 4. Intravenous methylprednisolone (IVMP) was used in 28 (63.6%) patients during induction therapy. The most common immunosuppressant used in addition to IVMP in PACNS, inflammatory CAA, and CTD-associated vasculitis as induction therapy was cyclophosphamide (47.1%, 25%, and 66.7%, respectively). Two patients with PACNS underwent plasma exchange (PLEX) in addition to IVMP and cyclophosphamide; both had a favorable outcome at their last follow-up (presented with an mRS of 4 and improved to mRS scores of 2 and 1). In the inflammatory CAA patient group, of the five who relapsed, induction therapy included IVMP in two, a combination of IVMP and cyclophosphamide in two, and high-dose prednisone in one. All three patients who did not experience relapse were treated with IVMP as their induction therapy. Most patients with infectious vasculitis (n = 8; 80%) were treated with antimicrobial drugs. Of those, 2 patients diagnosed with varicella zoster virus-associated vasculitis also received IVMP as induction therapy. Two patients, who received high-dose oral prednisone as induction therapy were ultimately diagnosed with post-viral infection CNS vasculitis. One patient with CTD-associated vasculitis did not receive any immunosuppressants. This patient had Sjogren syndrome-associated vasculitis involving the CNS and a history of poorly controlled type 2 diabetes complicated by diabetic foot ulcers and osteomyelitis. He had a right first metatarsal ray amputation, and immunosuppressants were held. He was continued on hydroxychloroquine, and vasculitis improved spontaneously.
Table 4.
Treatment and Outcome of Patients With Central Nervous System (CNS) Vasculitis Classified Into Groups.
| Characteristic | Primary CNS Vasculitis | Secondary CNS Vasculitis | |||
|---|---|---|---|---|---|
| PACNS (n = 17) | Inflammatory CAA (n = 8) | Connective Tissue Disorder (n = 6) | Infectious Vasculitis (n = 10) | Systemic Vasculitis (n = 3) | |
| Median time from presentation to treatment, days [IQR] | 6 [4.0-14.0] | 5.5 [3.0-19.0] | 2 [1.0-5.0] | 0 [0-2.0] | 0 [0-1.0] |
| Median time of follow-up, months [IQR] | 26 [9.0-43.0] | 29.5 [15.0-47.0] | 9.5 [7.0-45.0] | 27 [8.0-39.0] | 5 [5.0-17.5] |
| Induction therapy, n (%) | |||||
| IVMP pulse | 3 (17.6) | 5 (62.5) | 1 (16.7) | – | 1 (33.3) |
| IVMP pulse +CYC | 6 (35.3) | 2 (25.0) | 4 (66.7) | – | 1 (33.3) |
| IVMP pulse + CYC + PLEX | 2 (11.8) | – | – | – | – |
| IVMP pulse + MTX + Infliximab | – | – | – | – | 1 (33.3) |
| PO high dose prednisone a | 4 (23.5) | 1 (12.5) | – | 2 (20.0) | – |
| PO moderate dose prednisone b | 1 (5.9) | – | – | – | – |
| RTX | 1 (5.9) c | – | – | – | – |
| Antimicrobial drug | – | – | – | 4 (40.0) | – |
| Antimicrobial drug + steroid | – | – | – | 4 (40.0) d | – |
| None | – | – | 1 (16.7) | – | – |
| Maintenance therapy, n (%) | PACNS (n = 15) e | Inflammatory CAA (n = 8) | Connective tissue Disorder (n = 6) | Infectious vasculitis (n = 9) f | Systemic vasculitis (n = 3) |
| Prednisone only | 4 (26.7) | 4 (50.0) | 1 (16.7) | 1 (11.1) | 1 (33.3) |
| Prednisone + CYC | 4 (26.7) | 2 (25.0) | 1 (16.7) | – | – |
| Prednisone + RTX | 2 (13.3) | 1 (12.5) g | – | – | 1 (33.3) |
| Prednisone + AZA | 3 (20.0) | – | – | – | 1 (33.3) |
| Prednisone +MM | 1 (6.7) | – | 3 (50.0) | – | – |
| Antimicrobial drug | – | – | – | 4 (44.4) | – |
| Antimicrobial drug + prednisone | – | – | – | 2 (22.2) | – |
| None | 1 (6.7) | 1 (12.5) | 1 (16.7) | 2 (22.2) | – |
| Relapse, n (%) | |||||
| 0 | 12 (70.6) | 3 (37.5) | 5 (83.3) | 10 (100) | 2 (66.7) |
| 1 | 4 (23.5) | – | 1 (16.7) | – | 1 (13.3) |
| ≥2 | 1 (5.9) | 5 (62.5) | – | – | – |
| Chi-square test for trend (vs PACNS), P-value | – | .01 | .47 | .07 | .96 |
| mRS at presentation, n (%) | |||||
| 0-3 | 10 (58.8) | 3 (37.5) | 1 (16.7) | 6 (60.0) | 1 (33.3) |
| 4-5 | 7 (41.1) | 5 (62.5) | 5 (83.3) | 4 (40.0) | 2 (66.7) |
| 6 | – | – | – | – | – |
| mRS at last follow up, n (%) | |||||
| 0-3 | 12 (70.6) | 3 (37.5) | 3 (50) | 8 (80.0) | 1 (33.3) |
| 4-5 | 4 (23.5) | 2 (25) | 1 (16.7) | 0 (0) | 1 (33.3) |
| 6 | 1 (5.9) | 3 (37.5) | 2 (33.3) | 2 (20.0) | 1 (33.3) |
AZA, azathioprine; CAA, cerebral amyloid angiopathy; CYC, cyclophosphamide; IQR, interquartile range; IVMP, intravenous methylprednisolone; MM, mycophenolate mofetil; mRS, modified Rankin Scale; MTX, methotrexate; PACNS, primary angiitis of the central nervous system; PO, per oral; PLEX, plasma exchange; RTX, rituximab.
aEquivalent to prednisone ≥ 40 mg/day.
bEquivalent to prednisone < 40 mg/day.
cThe patient had poorly controlled type 1 diabetes mellitus.
dTwo patients with varicella zoster virus-associated vasculitis received IVMP, one patient with Streptococcus pneumoniae meningitis-associated vasculitis received dexamethasone, and one patient with disseminated Coccidioides immitis-associated vasculitis received methylprednisolone on the basis of a previous study regimen. 11
eOne patient moved, and another patient died before initiating maintenance therapy.
fOne patient died before initiating maintenance therapy.
gThe patient had a history of urothelial carcinoma with surveillance cystoscopy every 2 years.
Thirty-six of the 41 patients (87.8%) with follow-up information available required maintenance therapy. Prednisone was the most commonly prescribed maintenance therapy (n = 32, 88.9%). The most common immunosuppressant used in combination with prednisone in patients with PACNS and inflammatory CAA was cyclophosphamide (26.7% and 25%, respectively). Mycophenolate mofetil (MMF) was the most commonly used immunosuppressant combined with prednisone for the treatment of CTD-associated vasculitis (n = 3, 50%). Other immunomodulatory therapies used in our cohort were rituximab (n = 4, 11.1%) and azathioprine (n = 4, 11.1%).
Of the 44 included patients, 21 (47.7%) had an mRS score of 0-3 at presentation, indicating low or intermediate disability, and 23 (52.3%) had an mRS score of 4 or 5 at presentation, indicating severe disability. At last follow-up, twenty-seven patients (61.4%) had an mRS score of 0-3, and eight (18.2%) had an mRS score of 4-5, with a median follow-up duration of 25 months (IQR, 7.5-43.3 months). Nine patients (20.5%) died during the study follow-up period: three from infection, one from trauma, and five from undocumented or undetermined causes (Table S2). mRS score improvement of ≥1 and ≥2 points were seen in 24 (54.5%) and 9 (20.5%) patients, respectively. CNS vasculitis treatment was associated with improvement or stability in all groups upon comparing the mRS scores of 0-3 and 4-6 (Figure 1). Whereas 5 of 8 patients (62.5%) with inflammatory CAA relapsed two or more times; only 1 (5.9%) with PACNS relapsed up to two times. In the case of the patient diagnosed with PACNS with 2 relapses, the initial relapse occurred 7 months after the initial diagnosis, while off immunosuppressants. The second relapse occurred 16 months after the first, after prednisone taper and a series of 6 monthly cyclophosphamide infusions, while on maintenance MMF.
Figure 1.
Distribution of the modified Rankin Scale (mRS) at presentation and at last follow-up. The dotted lines indicate differences in the mRS categories (mRS scores of 0-3 vs 4-6). The P-value refers to the significance level of the chi-square test used to compare proportions. mRS, modified Rankin Scale; PACNS, primary angiitis of the central nervous system; CAA, cerebral amyloid angiopathy; CTD, connective tissue disorder; P, at presentation; F, at follow-up.
Discussion
CNS vasculitis diagnosis remains challenging owing to the lack of a specific diagnostic test. One study reviewed 31 patients with CNS vasculitis (PACNS = 18, secondary CNS vasculitis = 13) and found no difference upon comparing patient characteristics and neurological symptoms. 12 Our findings add to the growing body of literature concerning clinical characteristics, treatments, and outcomes of patients with CNS vasculitis. Systemic features, including weight loss, night sweats, and fever, are rare in patients with PACNS, and should prompt consideration of secondary CNS vasculitis. 1 No patient with PACNS in our cohort had a fever. Similarly, CRP and ESR could help distinguish PACNS from systemic conditions such as CTD-associated vasculitis and systemic vasculitis. A prior study of 101 patients with PACNS reported fever and elevated ESR in 9% and 22% of the patients, respectively. 2 CRP and ESR, as negative predictors for PACNS, may be useful. In our study, none of the patients diagnosed with primary CNS vasculitis had unique OCB in the CSF. In contrast, a substantial proportion of patients with CTD-associated vasculitis (75%) and infectious vasculitis (80%) exhibited unique OCBs. These findings could potentially aid in differentiating the etiologies of CNS vasculitis in clinical settings.
Inflammatory CAA is associated with vascular and perivascular inflammatory infiltrates, resulting in amyloid-beta deposition within the cortical or leptomeningeal vessel walls.13,14 It is known to cause recurrent microhemorrhage and cerebral lobar hemorrhage. The diagnostic criteria include age ≥40 years; patients typically present between 60-80 years of age.13,14 Our study results were consistent with these prior findings. Recurrence of inflammation despite treatment is a characteristic of inflammatory CAA, as seen in our cohort. These features help differentiate inflammatory CAA from PACNS and other CNS vasculitis types.
Vasculitis is a rare manifestation of systemic CTD; <10% of patients with systemic lupus erythematosus develop CNS vasculitis, which is rare as a primary manifestation of CTD.15,16 In our cohort, all patients with CTD-associated vasculitis had a history of autoimmune conditions prior to developing vasculitis. Additional larger cohorts are needed to better understand the temporal association between the systemic autoimmunity and CNS vasculitis.
Tumefactive PACNS, which manifests as mass-like brain lesions, has been reported in 5-29% patients with PACNS. 17 It preferentially involves small parenchymal and leptomeningeal vessels, which could be missed on commonly performed imaging studies, as in our cases. 17 Both patients in our study were initially suspected of having brain tumors and were diagnosed with PACNS after biopsy, illustrating the importance of brain biopsy. inflammatory CAA can also present as a tumefactive lesion and is challenging to differentiate from PACNS without histopathological evaluation. 18 Other secondary CNS vasculitis cases presenting with a tumefactive lesion are extremely rare. 19 While this could easily be misdiagnosed as a brain tumor, physicians should consider this underrecognized CNS vasculitis presentation and aim to differentiate the condition, as management and prognosis vary considerably.
Optimal CNS vasculitis management remains challenging, with no clear consensus on treatment approaches. Although high-dose steroids are commonly used as initial therapy, other immunosuppressive medications are also commonly reported. Some patients show complete symptom resolution, whereas others show residual deficits. The relapse and mortality rate of PACNS is reportedly 30-34% and 8-23%, respectively with median follow-up periods of 19-57 months.8,20,21 The most commonly used initial therapy for suspected PACNS is high-dose steroids, after excluding the possibility of infection. Maintenance therapy with glucocorticoids combined with an immunosuppressant, such as cyclophosphamide, has demonstrated encouraging results. 20
Our study contributes to the limited data on the use of steroids and other immunosuppressive agents for CNS vasculitis treatment. For PACNS, IVMP and cyclophosphamide were the most commonly used regimens for induction therapy, consistent with a previous systematic review. 21 Two patients in our PACNS cohort received PLEX in addition to IVMP and cyclophosphamide and had a favorable outcome. Data regarding PLEX for patients with PACNS is limited. One case report of a patient with rapidly progressive PACNS who presented with coma and was treated with IVMP, PLEX, and cyclophosphamide as induction therapy with rituximab recovered considerably (mRS score of 0 at 14 months). 22 PLEX could be considered in patients presenting with severe symptoms; however, a prospective study is required to confirm this finding.
inflammatory CAA treatment is poorly understood, with no large cohort prospective clinical trial data to guide practice. In a retrospective study of 48 patients, patients treated with immunosuppressive agents showed clinical and radiological improvement compared to those who did not receive treatment. 14 All patients with inflammatory CAA in our cohort received steroid as induction therapy; cyclophosphamide and rituximab were used for maintenance therapy with prednisone taper in 37.5%. Further studies are warranted to confirm these results and explore the differences in CNS vasculitis treatment options and outcomes.
Our study has several limitations. The patient population was predominantly Caucasian, likely due to the racial and ethnic composition of the regional referral area, which may limit the generalizability of our findings. Because the inclusion criteria in this study required at least one encounter with a neurologist, our population had a higher proportion of patients with neurological complaints and greater variety of neurological symptoms than previously reported studies. Although this strategy may have limited our ability to determine the frequency of neurological complications in the general population, it emphasized the diversity of neurological symptoms observed in CNS vasculitis and highlighted the challenge in distinguishing PACNS from other CNS vasculitis. Importantly, the lack of biopsy confirmation in many cases necessitates caution in interpreting our results, particularly regarding the diagnosis and categorization of CNS vasculitis. This factor, coupled with the retrospective, uncontrolled nature of our study and the practice patterns at our center, may introduce selection bias, particularly in drawing conclusions about treatment efficacy. Furthermore, the retrospective design and the possibility of incomplete medical records could have impacted the accuracy and completeness of the data. Finally, this study was conducted at a single center. Additional prospective studies evaluating CNS vasculitis in multicenter settings are warranted to validate our findings.
This study provides important insights into clinical characteristics, treatments, and outcomes of patients with CNS vasculitis. Patients with inflammatory CAA tend to be older, have microhemorrhages, and have a high recurrence rate. All patients with CTD-associated vasculitis had CTD diagnosed before they developed vasculitis, tend to have elevated ESR, and exhibit unique OCB. Infectious vasculitis tends to have a fever, low glucose in the CSF, and unique OCB, compared to PACNS. The most frequently used induction therapy in PACNS is a combination of glucocorticoids and cyclophosphamide, and the data raises the possibility that PLEX could be considered in patients presenting with severe deficits. These findings provide foundational retrospective data, along with other cohorts, to support the development of future prospective trials with the goal of developing improved diagnostic and effective treatment approaches for patients with CNS vasculitis.
Supplemental Material
Supplemental Material for Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort by Yoji Hoshina MD, Alen Delic, MSTAT, Ka-Ho Wong, MBA, Stephanie Lyden, MD, Robert Kadish, MD, Tammy L. Smith, MD, PhD, Melissa A. Wright, MD, Daisuke Shimura, PhD, and Stacey L. Clardy, MD, PhD in The Neurohospitalist
Acknowledgments
The authors thank Barbara Steinmetz Gural and the Siegal Rare Neuroimmune Association for their support.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Supplemental Material: Supplemental material for this article is available online.
ORCID iDs
Yoji Hoshina https://orcid.org/0000-0003-0228-664X
Daisuke Shimura https://orcid.org/0000-0002-9954-2162
Data Availability Statement
The datasets are available upon reasonable request, and the raw data supporting the conclusions of this article will be made available by the author. Requests to access the datasets should be directed to YH, yojihoshina0106@gmail.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Material for Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort by Yoji Hoshina MD, Alen Delic, MSTAT, Ka-Ho Wong, MBA, Stephanie Lyden, MD, Robert Kadish, MD, Tammy L. Smith, MD, PhD, Melissa A. Wright, MD, Daisuke Shimura, PhD, and Stacey L. Clardy, MD, PhD in The Neurohospitalist
Data Availability Statement
The datasets are available upon reasonable request, and the raw data supporting the conclusions of this article will be made available by the author. Requests to access the datasets should be directed to YH, yojihoshina0106@gmail.com.