of angiography in biopsy-proven PACNS cases was only 60 percent [50,51]. PACNS may be limited to the small vessels that are below the resolution of conventional angiography, which is particularly common when the pattern of infarction is predominantly subcortical, and thus a negative angiogram cannot be used to exclude the diagnosis of PACNS. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 12/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate In unusual cases of PACNS, the disease presents radiologically as a CNS mass lesion, manifested on angiography by the presence of an avascular mass effect. Proper interpretation of CNS angiograms requires insight into the clinical context of the specific patient, experience in reading abnormal angiograms, and thorough appreciation of the range of normal findings within the circulation of the internal carotid artery and its intracerebral branches ( image 1). Although it is not common to perform serial angiograms as a way of following response to treatment, repeat angiography is sometimes useful if the diagnosis remains unclear days to weeks after the performance of an initial study. A rapid change in angiographic appearance (eg, evolution from a flagrantly abnormal study to one that is essentially normal within days or weeks) argues compellingly for an RCVS rather than PACNS ( image 2) [29]. (See "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Brain and leptomeningeal biopsy Selecting patients for brain biopsy The gold standard for the diagnosis of PACNS is histopathology. A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. Sampling of the leptomeninges as well as the underlying cortex increases the diagnostic yield; however, the test characteristics of the brain biopsy are far from optimal. The sensitivity of brain biopsy for PACNS is approximately 75 percent, thus leaving the clinician with a false negative rate of 25 percent [50]. A meta-analysis revealed a diagnostic yield of 74.7 percent (95% CI 64.0-84.1 percent) for suspected PACNS [52]. Biopsies may also identify a cause other than PACNS in up to 39 to 50 percent of patients [53,54]. In other words, a brain biopsy not only establishes a diagnosis in the setting of suspected PACNS in roughly 70 percent of cases but also may provide an alternative diagnosis in a fair number of patients [55]. There are two settings of particular concern where obtaining tissue is paramount: The presence of a focal lesion on MR with characteristics that suggest an inflammatory or infectious process, but noninvasive approaches to diagnosis have failed. The presence of a mass lesion in the brain for which the principal concern is usually malignancy or abscess. PACNS is occasionally a surprise finding. In such cases, the finding of vasculitis on pathologic exam does not exclude the diagnosis of infection or malignancy, and appropriate stains and markers should be pursued for accurate diagnosis. Biopsy of a radiologically abnormal area heightens the sensitivity of brain/leptomeningeal biopsies. In the absence of a focal lesion within the brain parenchyma, the temporal tip of the https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 13/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate nondominant hemisphere is the preferred biopsy site [56]. Histopathology Histopathologic findings in the brain in patients with PACNS may include the presence of Langerhans or foreign body giant cells, necrotizing vasculitis, or lymphocytic vasculitis. PACNS is referred to as granulomatous angiitis of the CNS (GACNS) if the pathologic findings are those of granulomatous angiitis affecting the small and medium leptomeningeal and cortical arteries ( image 3) [23,57]. However, the classic finding of granulomatous segmental vasculitis with Langerhans or foreign body giant cells is present in less than 50 percent of the biopsies [58]. The biopsy is not granulomatous in most such cases, and only reveals lymphocytic vasculitis. Appropriate stains, viral studies, and cultures should be performed on the biopsies, since the finding of vasculitis does not preclude the diagnosis of an associated infection or a lymphoproliferative process that is causing the vasculitis. Because of the focal and segmental distribution of CNS vasculitis, a positive biopsy is diagnostic, but a single isolated negative biopsy does not exclude primary or secondary CNS vasculitis [58]. Establishing the diagnosis The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. (See 'Alternative diagnoses' above.) The diagnosis of PACNS can usually be made when all of the following are present: An acquired, otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings These clinical findings are consistent with the diagnostic criteria that were proposed in 1988 [34]. There are patients in whom the diagnosis of PACNS is made without meeting all the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. Lymphocytic PACNS This group of patients is distinguished by lymphocytic infiltration rather than granulomatous findings on the pathologic examination. When the pathologic https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 14/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate findings are predominantly lymphocytic, careful pathologic examination and immunophenotyping should be performed to rule out a lymphomatous CNS process. Angiographically defined PACNS This group is diagnosed by an abnormal cerebrovascular study and CSF examination, but with a normal CNS biopsy. The culprit vessel size involvement is usually medium-sized vessels rather than the small vessel typically seen in PACNS. In this subset, a diligent workup should be performed to rule out other vasculopathies, given the poor specificity of the cerebrovascular imaging study in the diagnosis of PACNS. Moreover, signs of inflammatory brain changes should be present, such as an abnormal CSF finding or enhancement of arterial vessel walls (in the absence of other causes of arterial enhancement). The RCVS, in particular, should be ruled out since this is a major mimic of this category. Mass lesion presentation These patients present with a solitary cerebral mass lesion. The diagnosis is usually a surprise after pathologic findings of a vasculitic process are observed as part of the pathologic evaluation. A complete analysis of the biopsy is mandatory to exclude alternative diagnoses, especially infection and malignancy even with the finding of vasculitis. TREATMENT Immunosuppressive therapy has been associated with success in central nervous system (CNS) vasculitis [1]. However, no prospective studies of any of the therapies described below have been conducted in patients with primary angiitis of the CNS (PACNS). Thus, our suggestions for treatment are influenced by anecdotal evidence related to PACNS and extrapolation of therapeutic strategies from other forms of vasculitis and retrospectively assessed experience with PACNS [1,21,22]. The suggested approach for the treatment of PACNS is similar to the therapy of severe polyarteritis nodosa. (See "Treatment and prognosis of polyarteritis nodosa", section on 'Moderate and severe PAN'.) Initial therapy of suspected PACNS If the initial clinical evaluation has excluded infection with a reasonable degree of confidence and PACNS remains a diagnostic possibility, empiric therapy with glucocorticoids may be appropriate while the full workup is completed. There have been no controlled trials in selecting the route of glucocorticoids in the management of the acute phase of PACNS. Some experts suggest avoiding intravenous pulse glucocorticoids, since this regimen is more likely to cloud the clinical picture by contributing to steroid-induced mental status changes, and suggest beginning the patient on the equivalent of prednisone 1 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 15/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate mg/kg per day (to a maximum of 80 mg/day, or its equivalent) until the diagnostic evaluation is complete. Treatment of PACNS Biopsy-confirmed cases with a picture of granulomatous inflammation on pathology, typical of granulomatous angiitis of the CNS (GACNS), should be treated with a combination of glucocorticoids and cyclophosphamide [19,21,22]. Failure to respond to these drugs after an appropriate treatment regimen should prompt the evaluation for an alternative diagnosis before additional treatment with an alternative immunosuppressive drug. Rituximab may be used in patients who are intolerant of cyclophosphamide (see 'Rituximab' below). The glucocorticoid and cyclophosphamide regimens used for PACNS are discussed below. (See 'Glucocorticoids' below and 'Cyclophosphamide' below.) The treatment of atypical/possible PACNS should be tailored according to the severity and the extent of the neurologic involvement. Atypical/possible PACNS patients should be treated initially with a high dose of glucocorticoids [22], and then tapered slowly. The decision of adding cyclophosphamide to the treatment regimen should be individualized according to the extent and the gravity of the neurologic deficits. Glucocorticoids High-dose glucocorticoids are required to achieve disease control in PACNS. We initiate therapy with prednisone at a dose of 1 mg/kg per day to a maximum of 80 mg/day, or its equivalent. Some experts begin with intravenous methylprednisolone, 15 mg/kg each day for three days [59]. Daily prednisone is begun on day 4. Glucocorticoids are associated with many potential treatment-related morbidities (see "Major side effects of systemic glucocorticoids"). Prophylactic approaches to prevent bone loss and opportunistic infections are discussed below. (See 'Prophylactic therapies' below.) Cyclophosphamide Either daily oral or intermittent (usually monthly) intravenous cyclophosphamide is reasonable as part of a remission induction strategy in PACNS [60]. Some clinicians prefer oral cyclophosphamide because of the ability to titrate the dose on a daily basis if necessary, thereby decreasing the likelihood of severe leukopenia. Other clinicians are more familiar with the intermittent administration of cyclophosphamide. Oral cyclophosphamide is begun at a dose of 1.5 to 2 mg/kg per day. In this setting, the white blood cell count (WBC) must be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia. The WBC count should remain above 3500/microL. The duration of the cyclophosphamide therapy is generally between three and six months, depending on when remission occurs and if there are any potential side effects that preclude the use of cyclophosphamide. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 16/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 2 The typical regimen for intravenous cyclophosphamide is 600 to 750 mg/m , infused once a month, generally for between three and six months [59]. A reduction in cyclophosphamide dose 2 is necessary if there is significant renal insufficiency with not more than 500 mg/m for patients with an estimated glomerular filtration rate less than 20 mL/min. Rituximab Limited data are available for the use of rituximab in PACNS [61,62]. Three cases were reported that described clinical and radiographic improvement in adults with PACNS after 2 treatment with rituximab (either as two 1 gram infusions separated by 14 days or as 375 mg/m weekly for four weeks) [61,62]. In one case, the diagnosis was made by angiographic findings and an abnormal cerebrospinal fluid (CSF), and rituximab was given as first-line therapy [61]. In another case, the diagnosis of PACNS was pathologically validated with evidence of a lymphocytic vasculitic process in the brain and spinal cord, and rituximab was used after the patient failed to improve with five monthly cyclophosphamide infusions [61]. In the third case, the diagnosis was confirmed by pathologic findings of granulomatous vasculitis, and rituximab was given as first-line therapy [62]. Prophylactic therapies The toxicities of PACNS treatments require the use of several prophylactic therapies to prevent bone loss and opportunistic infections. Osteoporosis prevention All patients treated with high-dose glucocorticoids are at risk for glucocorticoid-induced osteoporosis. The prevention and treatment of glucocorticoid-induced osteoporosis are discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".) Opportunistic infections Glucocorticoid and cyclophosphamide therapy are associated with an increased risk for opportunistic infection. Pneumocystis jirovecii, a common pathogen in immunosuppressed hosts, may cause a life-threatening pneumonia. In patients treated with the combination of high-dose prednisone and another immunosuppressive agent, we recommend prophylaxis against Pneumocystis pneumonia (PCP). Options for prophylactic regimens are discussed separately. The optimal duration of Pneumocystis prophylaxis after immunosuppressive therapy is tapered has not been defined. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.) Other Cyclophosphamide is associated with many potential treatment-related morbidities. Prophylactic approaches to these complications are discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 17/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Monitoring treatment The response to treatment is monitored by periodic reassessment of symptoms, neurologic findings, and neuroimaging abnormalities. It is very important to differentiate between disease damage and disease progression. Neurologic deficits due to cerebral or cerebellar infarction may resolve slowly or not at all. Thus, for some patients, a response to treatment may only be indicated by symptomatic improvement (eg, resolution of headache), but not the resolution of magnetic resonance (MR) lesions. A lack of new lesions on MRI is a more reliable way to assess for progression of the disease. With respect to neuroimaging, noninvasive studies are preferred to repeated angiography. A follow-up MR should be obtained four to six weeks after beginning treatment, then every three to six months throughout therapy, and subsequently according to the evolution of the disease. During the use of immunosuppressive treatment, patients require close clinical follow-up and laboratory monitoring in order to avoid preventable adverse effects of therapy. As an example, patients on daily cyclophosphamide should have complete blood counts checked every two weeks. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.) Duration of therapy and management of recurrent disease There are limited data available that address the optimal duration of therapy or the treatment of disease recurrence. The following approaches are based on the authors' experience and extrapolation from the treatment of other forms of vasculitis. Glucocorticoid taper After four to six weeks at the initial dose, prednisone tapering should begin. There is no standard tapering regimen for PACNS, but regimens similar to the one outlined below are appropriate. Assuming that a patient begins prednisone treatment at 60 mg/day and remains on this dose for six weeks, the following taper will require a total of 26 weeks to reach a daily dose of 5 mg: The prednisone dose should be tapered by 10 mg each week until a dose of 40 mg/day is reached. After one week on 40 mg per day, the prednisone dose should be tapered by 5 mg each week until the patient reaches 20 mg/day. After one week on 20 mg/day, the prednisone dose should be tapered by 2.5 mg each week until the patient reaches 10 mg/day. After one week on 10 mg/day, the prednisone dose should be tapered by 1 mg every two weeks until the patient reaches 5 mg/day. After two weeks on 5 mg/day, the daily prednisone dose should be tapered by 1 mg each month until the taper has been completed. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 18/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Deviations from this regimen may be necessary if patients develop a significant complication of glucocorticoid therapy or experience disease recurrence. If a flare in symptoms occurs while the glucocorticoid dose is being lowered, the dose should be increased to the lowest amount that previously suppressed the clinical manifestations. Once the patient improves to the level of their prior status or stabilizes, reductions in the dose can be tried again. Discontinuing cyclophosphamide Three to six months of cyclophosphamide is sufficient for many patients. At this time, cyclophosphamide should be discontinued after approximately six months and replaced with a less toxic medication for an additional six to twelve months of maintenance therapy, in a manner that is similar to that of the management of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Some clinicians switch from cyclophosphamide to azathioprine (2 mg/kg) or mycophenolate mofetil, which are favored over methotrexate, given its limited ability to cross the blood brain barrier. Data on the duration of the maintenance therapy is not available, and the decision on the duration of the therapy should be individualized, based upon the response to therapy. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.) In a single-center cohort of 44 patients with PACNS, relapses were reported in up to 59 percent of patients; relapse was defined as a reoccurrence or worsening of neurologic symptoms or worsening of existing and/or evidence of new abnormal neuroimaging findings on MRI consistent with PACNS activity [63]. Male patients were found to have a higher rate of relapse, but other predictors for relapses that had been identified from other case series were not confirmed in this study. Thus, more studies using a more uniform treatment regimen and relapse definition are needed to help identify factors affecting risk of relapse and response to therapy. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".) SUMMARY AND RECOMMENDATIONS Primary angiitis of the central nervous system (PACNS) most commonly involves small- and medium-sized cerebral blood vessels resulting in symptoms and signs of CNS dysfunction. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 19/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate It is defined by inflammation of the cerebral vasculature without angiitis in other organs. (See 'Introduction' above.) PACNS is a rare disease, and the cause is unknown. The median age at diagnosis is 50 years, although it can occur at almost every age. (See 'Epidemiology' above and 'Etiopathogenesis' above.) PACNS is characterized by a long prodromal period, with few patients presenting acutely. The vasculitis can affect any part of the CNS, causing the clinical manifestations to be highly variable and nonspecific. The most commonly reported symptom is a subacute and insidious headache. Other symptoms include cognitive impairment, stroke, and transient ischemic attack. Patients with PACNS who develop strokes usually present with more than a single stroke in different anatomic areas. (See 'Clinical manifestations' above.) The diagnosis of PACNS is challenging as the symptoms are generally nonspecific and there is no specific diagnostic test. The workup for patients who may have PACNS must proceed simultaneously with the systematic evaluation and exclusion of other disorders. While there is no characteristic presentation, there are some scenarios that are highly suspicious. PACNS should be suspected when strokes, more often recurrent, occur in young patients with no identifiable cardiovascular or hypercoagulable risk factors; or in the setting of chronic meningitis, recurrent focal neurologic symptoms, unexplained diffuse neurologic dysfunction, abnormal cerebrovascular imaging obtained in the setting of an unexplained neurological deficit, or unexplained spinal cord dysfunction not associated with systemic disease or any other process. (See 'Diagnostic approach' above and 'When to suspect the diagnosis' above.) In patients in whom a diagnosis of PACNS is suspected, an alternative diagnosis is more likely to be correct. As a result, careful exclusion of other disorders is essential. The most common clinical and radiologic mimickers are the reversible cerebral vasoconstriction syndromes (RCVS). Other alternative diagnoses include infection, systemic vasculitides and other systemic rheumatic diseases, atherosclerosis, cerebral emboli, intravascular lymphoma, and moyamoya. (See 'Alternative diagnoses' above.) Laboratory testing and serological assays are used primarily to exclude other etiologies of CNS dysfunction. Analysis of the cerebrospinal fluid (CSF) is a crucial part of the evaluation of patients with potential PACNS and should be performed in all patents unless there are contraindications. The CSF is abnormal in 80 to 90 percent of patients with pathologically documented disease. CSF findings are nonspecific but most commonly include an elevated https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 20/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate CSF protein and a modest lymphocytic pleocytosis. (See 'Evaluation' above and 'Laboratory testing to exclude alternative diagnoses' above and 'Lumbar puncture' above.) Various neuroimaging modalities can be used to assess for both parenchymal and vascular abnormalities in the evaluation of suspected PACNS. MRI should be performed in all patients. The selection of additional neuroimaging modalities depends on the initial MRI findings and individual patient characteristics. Conventional angiography remains an important part of the diagnostic testing for suspected PACNS, and our authors obtain angiography in patients who have MRI findings of multiple cortical and subcortical infarcts that are otherwise unexplained. Angiography can detect segmental narrowing in multiple vessels that are typical of, though not pathognomonic for, PACNS, and help further rule out alternative diagnoses such as atherosclerosis, moyamoya, and dissection. These tests may also be helpful in selecting a location for brain biopsy if needed. (See 'Neuroimaging' above.) A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. (See 'Brain and leptomeningeal biopsy' above.) The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. The diagnosis can usually be made when all of the following are present (see 'Establishing the diagnosis' above): An acquired otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings There are patients in whom the diagnosis of PACNS is made without all the meeting the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. (See 'Establishing the diagnosis' above.) We suggest treating PACNS with a combination of glucocorticoids and cyclophosphamide (Grade 2C). Treatment of atypical PACNS should be individualized according to the severity and the extent of the neurologic deficit. (See 'Treatment of PACNS' above.) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 21/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate We use measures to prevent osteoporosis and Pneumocystis infections during the treatment of PACNS. (See 'Prophylactic therapies' above.) The response to treatment is monitored by periodic reassessment of symptoms, neurologic findings, and neuroimaging abnormalities. It is important to differentiate between disease damage and disease progression. Neurologic deficits due to cerebral or cerebellar infarction may resolve slowly or not at all. Thus, for some patients, a response to treatment may only be indicated by symptomatic improvement (eg, resolution of headache), but not the resolution of magnetic resonance (MR) lesions. A lack of new lesions on MRI is a more reliable way to assess for progression of the disease. A follow-up MR should be obtained four to six weeks after beginning treatment, then every three to six months throughout therapy, and subsequently according to the evolution of the disease. (See 'Monitoring treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. 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Treatment of primary CNS vasculitis with rituximab: case report. Neurology 2014; 82:1287. 63. Schuster S, Ozga AK, Stellmann JP, et al. Relapse rates and long-term outcome in primary angiitis of the central nervous system. J Neurol 2019; 266:1481. Topic 8230 Version 31.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 26/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate GRAPHICS Carotid angiograms in primary angiitis of the central nervous system Left panel: An anteroposterior view of a right carotid angiogram in a patient with primary angiitis of the central nervous system (PACNS) reveals focal narrowing of multiple vessels in both the anterior and posterior systems. Right panel: A lateral view of a right carotid angiogram in PACNS demonstrates beading and multiple irregularities both proximally and distally. Courtesy of Leonard H Sigal, MD. Graphic 52006 Version 2.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 27/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Normal internal carotid artery angiogram An angiogram showing the normal radiographic appearance of the internal carotid artery and its branches. The internal carotid enters the skull at the carotid foramen, passes anteromedially, and then rises vertically (C6) to pass forward opposite the sella turcica (C4). The artery then passes upward within the dura (C3) and emerges below and medial to the anterior clinoid (C2), giving rise to the ophthalmic artery. The carotid then bifurcates (C1) to form the anterior and middle cerebral arteries. The anterior cerebral artery is directed anteromedially (A1) until it reaches the midline, where it turns upward (A2) to be joined by the anterior communicating artery. The middle cerebral artery extends laterally (M1). Courtesy of Leonard H Sigal, MD. Graphic 63788 Version 3.0