Primary Central Nervous System Vasculitis With Prominent Leptomeningeal Enhancement

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1 ARTHRITIS & RHEUMATISM Vol. 58, No. 2, February 2008, pp DOI /art , American College of Rheumatology Primary Central Nervous System Vasculitis With Prominent Leptomeningeal Enhancement A Subset With a Benign Outcome Carlo Salvarani, 1 Robert D. Brown, Jr., 1 Kenneth T. Calamia, 2 Teresa J. H. Christianson, 1 John Huston, III, 1 James F. Meschia, 2 Caterina Giannini, 1 Dylan V. Miller, 1 and Gene G. Hunder 1 Objective. Primary central nervous system vasculitis (PCNSV) is an uncommon condition that affects the brain and spinal cord. This study was undertaken to evaluate the clinical features and outcomes among patients with PCNSV who presented with prominent gadolinium meningeal enhancement on magnetic resonance imaging (MRI). Methods. Through retrospective review using the Mayo Clinic medical records linkage system, we identified 101 consecutive patients with PCNSV based on brain biopsy or conventional angiography (or both) between January 1, 1983, and December 31, We evaluated data on demographics, clinical findings, laboratory studies, imaging, biopsy of brain or spinal cord (or both), treatment, and neurologic outcome. Results. MRIs showed prominent leptomeningeal enhancement in 8 of 101 patients with PCNSV. In 6 of those 8, cerebral angiography or magnetic resonance angiography results were normal, but biopsy of the brain or spinal cord showed vasculitis in all 8. Granulomatous vascular inflammation was found in 6 specimens and was associated in 4 cases with vascular Supported by a grant from the Mayo Foundation, Rochester, Minnesota. 1 Carlo Salvarani, MD (current address: Arcispedale S. Maria Nuova, Reggio Emilia, Italy), Robert D. Brown, Jr., MD, MPH, Teresa J. H. Christianson, BS, John Huston, III, MD, Caterina Giannini, MD, Dylan V. Miller, MD, Gene G. Hunder, MD: Mayo Clinic, Rochester, Minnesota; 2 Kenneth T. Calamia, MD, James F. Meschia, MD: Mayo Clinic, Jacksonville, Florida. Address correspondence and reprint requests to Robert D. Brown, Jr., MD, MPH, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN brown.robert@ mayo.edu. Submitted for publication February 22, 2207; accepted in revised form October 12, deposits of -amyloid peptide. All 8 patients had a prompt response to therapy, with resolution of the MRI meningeal enhancement. Although 3 of the 8 patients had relapses during followup, the overall outcome was favorable. Patients with meningeal enhancement, compared with patients without enhancement, more commonly had substantial abnormalities of cerebrospinal fluid (100% versus 58%; P 0.02) and amyloid angiopathy (50% versus 12%; P 0.03). Conclusion. Prominent gadolinium leptomeningeal enhancement on MRI may point to a distinct subtype of PCNSV with small leptomeningeal artery vasculitis and rapid response to therapy. Primary central nervous system vasculitis (PCNSV) is an uncommon condition in which vascular inflammatory lesions are limited to the brain and spinal cord. PCNSV has been generally considered a progressive CNS disorder that has a fatal course unless treated vigorously with glucocorticoids and immunosuppressive drugs (1 3). However, Calabrese et al (4) described a subset of patients who had a diagnosis based on angiography alone and who appeared to have a more benign course. These patients were characterized by a rapid onset of neurologic deficit, mild cerebrospinal fluid (CSF) abnormalities, a good response to therapy, and a favorable outcome. For these cases, the term benign angiopathy of the CNS was subsequently proposed (5). In a more recent retrospective study, however, Woolfenden et al (6) observed 10 similar patients whose diagnosis was established with angiography and who did not have a similar benign monophasic course or a favorable neurologic outcome. The different results in these studies indicate that further investigation is 595

2 596 SALVARANI ET AL Table 1. Clinical features of the 101 patients with PCNSV, according to the presence or absence of meningeal enhancement on MRI* Presence of meningeal enhancement (n 8) Absence of meningeal enhancement (n 93) Sex Male 6 (75) 37 (40) Female 2 (25) 56 (60) Age at diagnosis, median (range) years 58 (30 78) 46 (17 84) Days from symptom onset to diagnosis, 37 (16 426) 43 (0 1,913) median (range) Headache 6 (75) 58 (62) Cognitive disorder 6 (75) 45 (48) Focal manifestations 8 (100) 90 (97) Intracerebral hemorrhage 1 (12) 7 (8) Systemic manifestations 2 (25) 14 (15) CSF abnormality Protein 45 mg/dl or WBC count 8 (100) 48/66 (73) 5 cells/mm 3 Protein 70 mg/dl or WBC count 8 (100) 38/65 (58) 10 cells/mm 3 ESR, median (range) mm/hour 7 (2 41) 10 (0 110) Cerebral angiography findings consistent 0/4 76/83 (92) with vasculitis CNS histologic specimens consistent 8/8 (100) 23/41 (56) with vasculitis CNS biopsy specimen with amyloid angiopathy 4/8 (50) 5/41 (12) * Except where indicated otherwise, values are the number (%). PCNSV primary central nervous system vasculitis; MRI magnetic resonance imaging; CSF cerebrospinal fluid; WBC white blood cell; ESR erythrocyte sedimentation rate. Defined as the presence of at least 1 of the following: fatigue, anorexia, weight loss, or fever. needed to clearly define subsets of PCNSV. Lack of a criterion standard for diagnosis of PCNSV and case selection bias are possible reasons for the differences reported in these studies. In addition, as with most vasculitic syndromes, PCNSV is probably heterogeneous in disease severity and treatment requirements. To determine the clinical features and spectrum of PCNSV, we reviewed the medical records of all patients with a possible diagnosis of CNS vasculitis seen at the Mayo Clinic in Rochester over a 21-year period. We identified 101 patients meeting the criteria for diagnosis of PCNSV (7). In this report, we describe the clinical characteristics of a subset of 8 patients with a biopsy-proven diagnosis of PCNSV who were found to have prominent gadolinium leptomeningeal enhancement on magnetic resonance imaging (MRI). These patients had relatively mild symptoms at presentation, a good response to therapy, and a favorable neurologic outcome. PATIENTS AND METHODS Patients. Using the Mayo Clinic medical records linkage system, a list of all patients with a possible diagnosis of CNS vasculitis between January 1, 1983, and December 31, 2003, was generated. To maximize case ascertainment, we reviewed the records of all patients in whom there was evidence of vasculitis involving the CNS. The Mayo Clinic Institutional Review Board approved this study. Patients were considered to have definite PCNSV if brain or spinal cord biopsy showed vasculitis (intramural destructive inflammation) or if angiograms showed changes highly suggestive of vasculitis (e.g., segmental narrowing, dilatation, or occlusion affecting multiple cerebral arteries in the absence of proximal vessel changes of atherosclerosis; a neuroradiologist s opinion was also needed to indicate that the findings were consistent with a diagnosis of vasculitis), provided there was no other condition present that could explain the findings. We excluded patients with evidence of vasculitis in organs other than the CNS, those with evidence of other diseases such as connective tissue disorders (e.g., lupus erythematosus), and those with an underlying infection that might be associated with vasculitis (such as varicella-zoster virus infections) or that might mimic vasculitis. We also excluded patients with other diseases that might mimic PCNSV, such as tumors, and patients whose results suggested cerebral vasoconstriction syndromes (8). In cases in which the initial review of the diagnosis was uncertain, 2 rheumatologists (CS and GGH) and 1 neurologist (RDB) adjudicated the case by again reviewing the complete medical record and reaching a consensus.

3 PCNSV WITH LEPTOMENINGEAL ENHANCEMENT 597 Table 2. Clinical characteristics and MRI findings in the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI* Brain MRI Patient/ age/sex 1/63/F Clinical symptoms at presentation Confusion, cognitive decline, headache, aphasia, visual field defect Leptomeningeal enhancement Diffuse over the left cerebral hemisphere and the right frontal and temporal regions 2/60/M Aphasia with alexia Mild diffuse (right to left hemisphere) 3/78/M 4/64/M 5/57/M 6/39/M 7/30/M 8/39/F Decreased level of consciousness, confusion, cognitive decline, dizziness, fatigue, anorexia with weight loss Confusion, cognitive decline, personality change, headache, ataxia Confusion, cognitive decline, amnestic syndrome, aphasia, headache, papilledema Confusion, lower extremity weakness and numbness, bladder and stool incontinence, headache, ataxia Confusion, amnestic syndrome, personality change, headache, vomiting Ataxia, headache, dysarthria, vertigo, vomiting, fatigue Mild overlying the posterior parietal and occipital lobes Diffuse over both cerebral hemispheres and the cerebellum Prominent linear over both cerebral hemispheres, basal ganglia, and pons Diffuse over both cerebral hemispheres and posterior fossa Diffuse Prominent in the cerebellum and brainstem None Other lesions Intracerebral hemorrhage, confluent T2 abnormality of the white matter None Multiple infarcts, patchy T2 abnormality of the white matter Confluent T2 abnormality of the white matter None None Intracerebral hemorrhages * MRI magnetic resonance imaging; PCNSV primary central nervous system vasculitis. Assessments. Between 1983 and 2003, a total of 101 patients who fulfilled the diagnostic criteria for PCNSV (7) were seen at the Mayo Clinic in Rochester. A standard data collection form was completed in all cases. The form included information about clinical manifestations at presentation and during followup visits, comorbid medical conditions, laboratory investigations, including CSF analysis, and radiologic images (from computed tomography, MRI, magnetic resonance angiography [MRA], and cerebral angiography). Brain or spinal cord biopsy results or autopsy results (or both) were collected. In addition, information on treatment regimens, response to treatment, presence and number of relapses, followup functional status, and cause of death was noted when available. In some instances, outcome information was obtained by correspondence after the patient s last visit to the Mayo Clinic. In the sense that all patients meeting the criteria were included, the 101 patients form a consecutive series. The modified Rankin scale (9) was used to evaluate the functional status at presentation and at the last followup visit. The modified Rankin scale is a standardized, commonly used scale that measures disability or dependence in activities of daily living in stroke victims. The scale consists of 6 possible scores, from 0 to 5, in which 0 no symptoms; 1 no significant disability, despite symptoms; 2 slight disability; 3 moderate disability; 4 moderately severe disability; and 5 severe disability. CNS tissue was examined histologically for a diagnosis in 49 of the 101 cases. Vasculitis was found in 29 of 47 biopsy specimens (62%), and CNS tissue from 2 postmortem cases showed vasculitis. Of the 29 positive biopsy specimens, 27 were brain tissue and 2 were spinal cord tissue. Histologic patterns in positive specimens varied: 18 had a granulomatous inflammatory pattern (accompanied by vascular deposits of A4 amyloid peptide in 8), 8 had a lymphocytic pattern, and 5 had an acute necrotizing pattern. All the biopsy and postmortem specimens were reviewed by 2 pathologists (CG and DVM). To assess the effect of treatment, we used the treating physician s overall opinion about the response to the therapy provided. Statistical analysis. Differences between the groups with and without meningeal enhancement were tested using Wilcoxon s 2-sample rank sum test for numeric characteristics and Fisher s exact test for categorical characteristics. For hypothesis testing, P values less than 0.05 were considered significant. RESULTS Demographic and clinical features and associated conditions. Eight of the 101 patients (7.9%) had evidence of prominent gadolinium meningeal enhancement on MRI at diagnosis. Table 1 lists the demographic characteristics, clinical manifestations, and other findings in these 8 and the 93 other patients. Six of the 8 were male. The median age at diagnosis was 58 years (range years). The time from onset of symptoms

4 598 SALVARANI ET AL Table 3. Laboratory and pathology results in the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI* CSF Patient WBC count, cells/mm 3 Protein, mg/dl Pathology findings Open brain biopsy: granulomatous, leptomeningeal, and intraparenchymal, marked angiocentric inflammation; presence of -amyloid deposits First open brain biopsy: granulomatous, leptomeningeal, and intraparenchymal, marked angiocentric inflammation; presence of -amyloid deposits Second open brain biopsy: same findings as in the first Open brain biopsy: lymphocytic, leptomeningeal, marked angiocentric inflammation Open brain biopsy: granulomatous, leptomeningeal, and intraparenchymal, marked angiocentric inflammation; presence of -amyloid deposits and infarct Open brain biopsy: granulomatous, leptomeningeal, and intraparenchymal, marked angiocentric inflammation; presence of -amyloid deposits Open brain biopsy: granulomatous, leptomeningeal, and intraparenchymal, marked angiocentric inflammation Open brain biopsy: granulomatous, leptomeningeal, marked angiocentric inflammation Open brain biopsy: infarct, no evidence of vasculitis Cauda equina biopsy: necrotizing, marked angiocentric inflammation, infarct * See Table 1 for definitions. to diagnosis was 1 month in 4 of the 8 patients, with a median of 37 days (range days). Table 2 describes the manifestations and MRI findings in each of the 8 patients. Cognitive disorder, headache, and focal manifestations were the most common symptoms at presentation. Constitutional symptoms were present in 2 patients (anorexia with weight loss and fatigue in patient 3 and fatigue in patient 8). Symptoms related to spinal cord involvement were documented in 2 patients: patient 6 had spinal cord and cerebral symptoms at presentation, and patient 8 had spinal cord disease 8 months after the development of symptomatic brain involvement. Other significant medical disorders were noted in 4 patients, including 1 with hypothyroidism, 1 with diabetes, 1 with B cell chronic lymphocytic leukemia/small lymphocytic lymphoma, and 1 with Crohn s disease. Laboratory investigations and CSF results. Table 3 shows the details of the CSF examination findings obtained at diagnosis. Results of the CSF examination were abnormal in all 8 patients; the median CSF protein level was mg/dl (range ), and the median CSF white blood cell (WBC) count was 60 cells/mm 3 (range 2 446). Lumbar puncture was performed after the brain MRI in 4 patients (median 1 day; range 1 8 days) and before the brain MRI in the other 4 (median 7 days; range 4 12 days). Radiology results. Conventional cerebral angiography was performed in 4 of the 8 patients. Brain MRA was performed in 2 of these 4 and in 2 other patients. Thus, 6 of the 8 (75%) underwent cerebral angiography or brain MRA (or both) at presentation, but none of the findings were suggestive of vasculitis. Brain MRI at presentation showed prominent leptomeningeal contrast enhancement in all 8 patients (Figure 1 and Table 2). In 5 of them it was diffuse; in 3, it was more localized. In 1 patient (patient 5), linear enhancement was distributed over both cerebral hemispheres, basal ganglia, and pons; in a second (patient 8), the enhancement was prominent in the cerebellum and brainstem. In 4 patients, leptomeningeal enhancement was the only MRI finding; in 4 others, there were associated parenchymal abnormalities such as multiple infarcts, intracerebral hemorrhages, and patchy or confluent white matter T2 abnormalities. Biopsy results. Table 3 also shows the pathology results. Nine open brain biopsies and 1 cauda equina biopsy were performed. All 8 patients underwent at least 1 open brain biopsy; 1 patient (patient 2) underwent 2 brain biopsies (the second was performed 3 years after the first), and 1 patient underwent both brain and cauda equina biopsies (patient 8). Open brain biopsy showed evidence of vasculitis in 7 patients. The inflammatory infiltration was granulomatous (Figure 2) in 6 of these 7

5 PCNSV WITH LEPTOMENINGEAL ENHANCEMENT 599 Figure 1. Magnetic resonance images (MRIs) showing prominent leptomeningeal contrast enhancement. A, MRI at symptom onset showed diffuse, asymmetric, nodular, and linear leptomeningeal enhancement, with minimal involvement of the dura. B, Fluid-attenuated inversion recovery (FLAIR) MRI showed scattered areas of increased T2 signal within the white matter bilaterally, with abnormal FLAIR T2 signal apparent in the sulci. C, MRI after treatment showed resolution of the abnormal contrast enhancement and abnormal T2 signal within the sulci. D, FLAIR T2 image showed development of mild generalized cerebral atrophy.

6 600 SALVARANI ET AL Figure 2. Histologic findings in a patient with leptomeningeal granulomatous vasculitis. A, Destructive vasculitis with well-formed granulomas involved the small vessels of the leptomeninges (hematoxylin and eosin stained; original magnification 200). B, Enlarged view. Arrows indicate multinucleated giant cells (original magnification 400). patients and lymphocytic in 1. In the other patient (patient 8), findings from the open brain biopsy did not include evidence of vasculitis, but necrotizing angiitis was seen in the biopsy specimen from the cauda equina. The inflammation was markedly angiocentric in all patients. In 5 of the 7 with abnormal brain biopsy results, both leptomeningeal and parenchymal involvement were observed, but 2 had only leptomeningeal involvement. Four patients had vascular deposits of amyloid with deposition of -amyloid peptide. Both brain biopsies from patient 2 showed similar findings. Evidence of ischemic changes and infarct was seen in 3 biopsies from 2 patients (patients 4 and 8). Treatment and outcome. Table 4 shows the details of treatment, followup MRI, and status of the patients at the last followup visit. The median duration of followup was 24 months (range 1 87 months). Treatment of all patients included prednisone. The median starting dosage of oral prednisone was 60 mg/day (range mg/day). In 4 patients, oral prednisone therapy was preceded by a course of methylprednisolone pulse therapy (1 gm/day for 4 6 days). The median duration of oral prednisone therapy was 5 months (range 1 45 months). In 4 patients (patients 1, 3, 5, and 8), therapy was started with prednisone alone and in the other 4, therapy was started with prednisone plus cyclophosphamide. Patient 8 was treated with prednisone and cyclophosphamide for a recurrence 3 months after stopping prednisone treatment. Thus, 4 patients received monthly pulse intravenous injections of cyclophosphamide, and a fifth received daily oral cyclophosphamide. The median duration of treatment with cyclophosphamide was 12 months (range 1 17 months). Three patients (38%) had a relapse or recurrence. Patient 1 had a recurrence characterized by headache, confusion, and expressive aphasia 6 years after the suspension of initial therapy. At the time of the recurrence, brain MRI revealed the reappearance of meningeal enhancement. The patient was treated again with prednisone alone, resulting in complete remission of neurologic and MRI findings. Patient 6 had 2 relapses characterized by the presence of mild headache and confusion, MRI evidence of meningeal enhancement, and CSF abnormalities similar to those found at first diagnosis. With treatment, there was an improvement of symptoms and complete resolution of meningeal enhancement and CSF abnormalities that persisted to the last visit 31 months later. Patient 8 had a recurrence involving the spinal cord 3 months after stopping prednisone therapy but improved within days when therapy was restarted. In summary, all 8 patients responded to therapy with glucocorticoids or to glucocorticoids plus immunosuppressive therapy, generally within the first 2 3 weeks. However, in 1 patient, a delayed response was observed, with response noted only after 3 months of therapy. A rapid response to therapy was also noted in patients with relapses as described above. Four patients underwent followup brain MRIs and had a complete resolution of meningeal enhancement by a median of 12 weeks (range 2 24 weeks) after initiation of treatment. The outcome

7 PCNSV WITH LEPTOMENINGEAL ENHANCEMENT 601 Table 4. Patient Treatment, outcome, and followup duration among the 8 patients with PCNSV with gadolinium meningeal enhancement on MRI* Treatment Followup MRI findings for leptomeningeal enhancement Status Findings at last followup visit Modified Rankin score Followup duration, months 1 Prednisone for 13 months Resolution Improved Prednisone for 7 months; oral cyclophosphamide Not available Improved 0 37 for 12 months 3 Methylprednisolone pulse, 1 gm/day for 5 days; Not available Improved 3 2 prednisone for 1 month 4 Prednisone for 2 months; cyclophosphamide Resolution Improved 1 15 for 14 months (1.7 gm/month IV) 5 Prednisone for 19 months Resolution Improved Methylprednisolone pulse for 4 days (1 gm/day); Resolution Improved 2 61 prednisone for 45 months; cyclophosphamide for 17 months (1 gm/month IV); mycophenolate mofetil for 12 months; etanercept for 31 months 7 Methylprednisolone pulse for 4 days (1 gm/day); Not available Improved 1 1 prednisone for 1 month; cyclophosphamide for 1 month (1 gm/month IV) 8 Methylprednisolone pulse for 6 days (1 gm/day); Not available Improved 3 14 prednisone for 3 months; cyclophosphamide for 1 month (1 gm/month IV), started for a recurrence 3 months after stopping the first course of prednisone therapy * PCNSV primary central nervous system vasculitis; MRI magnetic resonance imaging; IV intravenous. Modified Rankin scale ranges from 0 to 5, with scores as follows: 0 no symptoms; 1 no significant disability, despite symptoms; 2 slight disability; 3 moderate disability; 4 moderately severe disability; and 5 severe disability. After the onset of symptoms. during followup was favorable among all patients. None had permanent major neurologic dysfunction at the last visit. Five patients had total recovery, and 3 had recovery with residual slight or moderate disability. The median Rankin score at the last visit was 1 (range 0 3), compared with a median score of 2 (range 1 4) at presentation. None of the 8 patients died during the followup period. However, patient 5 died suddenly subsequent to his last followup visit. The circumstances and cause of death were unknown. Comparison of patients with and those without meningeal enhancement. Table 1 compares the 8 cases of PCNSV with prominent meningeal enhancement and those of the other 93 without enhancement for whom information was available. Histologic evidence of vasculitis and of amyloid angiopathy was significantly more frequent in the 8 patients with meningeal enhancement than in the other 41 patients without enhancement who underwent biopsies (P 0.02 and P 0.03, respectively). The frequency of cerebral angiography showing evidence of vasculitis was significantly higher in the 83 patients without meningeal enhancement who had this test performed (P 0.001). CSF abnormalities (protein 70 mg/dl or WBC count 10 cells/mm 3 ) were significantly more frequent in the 8 patients with meningeal enhancement than in the other 65 patients without enhancement who had CSF results available (P 0.02). Patients with meningeal enhancement were older at diagnosis, were more frequently male, had a more acute clinical onset with a shorter median period from onset of symptoms to diagnosis, and more frequently had a cognitive disorder as the presenting finding; however, these differences were not significant. At presentation, the Rankin scores were 4in2of the 8 patients (25%) with leptomeningeal enhancement and 20 of the 93 (22%) without prominent enhancement. At the last visit, the Rankin scores were 4 in none of the 8 patients with leptomeningeal enhancement but in 13 of the 93 patients (14%) without enhancement. At the last followup, 1 of the 8 patients (12%) with leptomeningeal enhancement and 16 of the 93 (17%) without enhancement had died. When the 8 patients with meningeal enhancement were compared with the other 23 patients who had positive CNS biopsy findings but no prominent enhancement, no significant clinical differences were found. The median Rankin score at presentation was 2 in the 8 patients with meningeal enhancement and in the other 23 with positive CNS biopsy results; at the last visit, it

8 602 SALVARANI ET AL was 1 in the 8 patients with meningeal enhancement and remained at 2 in the 23 with positive CNS biopsy findings but no prominent enhancement. DISCUSSION As part of an analysis of 101 consecutive patients with PCNSV seen at our institution over a 21-year period (7), we noted that in 8 patients MRI examination showed prominent gadolinium enhancement of the meninges. After review of the clinical features of the 8 patients, it became apparent that, although not identical in all respects, they exhibited several similar features, including a male predominance, a rapid clinical onset, the frequent presence of cognitive dysfunction at presentation, and the absence of findings of vasculitis on cerebral angiography or brain MRA (or both). Brain or spinal cord biopsy showed evidence of small-vessel vasculitis in all involved parenchyma or leptomeninges (or both), and it was frequently granulomatous in appearance. Half of the patients had vascular amyloid deposits with A4 amyloid peptide. The median age of the 8 patients at diagnosis was older than that of those without meningeal enhancement. CSF abnormalities were present in all patients at diagnosis, whereas the ESR was normal in all but 1. All patients had a good clinical response to corticosteroid therapy (alone or combined with immunosuppressive agents, most commonly cyclophosphamide), with resolution of MRI enhancement and an overall favorable course. A trend toward better outcomes in the 8 patients at last visit was not significant, perhaps because of the small number of patients. When the 8 patients were compared with the 23 whose CNS biopsies were positive, a small trend toward less disability at last visit in the 8 patients was not significant. The typical MRI findings in PCNSV are multiple bilateral T2 and fluid-attenuated inversion recovery high-signal abnormalities in the cortex and deep white matter (10). Rarely, findings on conventional MRI may be normal (11). Leptomeningeal enhancement may represent diffuse inflammation and vasculitis in these structures. Leptomeningeal enhancement has been reported previously in 4 patients as the most prominent initial MRI abnormality, which was isolated or associated with parenchymal lesions (12 15). The characteristics of these patients were similar to the characteristics of our patients, including normal angiographic findings but pathologic evidence of granulomatous angiitis affecting mainly the small leptomeningeal vessels. Acute onset of mental status changes was the predominant presenting finding, and the neurologic status and MRI findings in these patients normalized or improved markedly with aggressive treatment (corticosteroids plus cyclophosphamide). MRI evidence of meningeal enhancement has also been reported in patients with antineutrophil cytoplasmic autoantibody positive vasculitis, particularly in Wegener s granulomatosis (16 18). However, these patients usually have a pachymeningeal pattern of meningeal enhancement, and leptomeningeal enhancement has been reported to occur infrequently (16,17). Neurosarcoidosis and infections are also causes of meningeal enhancement (19 21). The findings required to make a diagnosis of neurosarcoidosis are the presence of the disease in another organ, involvement of the cranial nerves (in particular, the optic nerve), and histologic confirmation with evidence of granulomas and absence of the classic changes of vasculitis in the CNS (19,20). A diagnosis of Wegener s granulomatosis, infection, or neurosarcoidosis was excluded in our patients on the basis of isolated CNS involvement, clinical, laboratory, and radiologic findings, and histologic characteristics. Four of our patients had associated cerebral amyloid angiopathy (CAA). In our entire clinical series of 101 patients with PCNSV (8), CAA was significantly more frequent in patients with meningeal enhancement than in those without. Although PCNSV and CAA are generally considered to be unrelated, cases with granulomatous CNS vasculitis and CAA have been described (22 25). This association is unlikely to be fortuitous, and it has been proposed to represent a distinct entity that is a variant of PCNSV (24). As in our patients, angiographic evidence of vasculitis was not found in the few patients previously described in the literature with CAA/ PCNSV who underwent angiography (22 24). Furthermore, as noted in the cases presented here, some patients with CAA/PCNSV had MRI evidence of prominent meningeal enhancement, which, when diffuse, raised concerns about carcinomatous or inflammatory meningitis (21,23). The earlier patients, similarly to ours, had a sustained and rapid clinical improvement and resolution of radiologic lesions with therapy. Therefore, patients presenting with CAA/PCNSV and meningeal enhancement seem to have a less progressive disease, which is responsive to treatment, with a prognosis that is apparently unaffected by the presence of amyloid angiopathy. Our patients were different from the cases described by Calabrese and colleagues (4,26) as a subset of PCNSV with a favorable course (benign angiopathy of the CNS). Ours were pathologically documented as having PCNSV, but available angiographic and MRA

9 PCNSV WITH LEPTOMENINGEAL ENHANCEMENT 603 findings were negative. All of our patients had CSF abnormalities, and the course was not monophasic as described in the series reported by Calabrese and colleagues. All of our patients had true vasculitis, whereas benign angiopathy of the CNS is a heterogeneous disorder that, in many patients, could be the result of a reversible vasoconstriction without underlying vasculitis. The medical literature on PCNSV is limited and difficult to analyze since much of the current understanding comes from small case series, individual case reports, and retrospective reviews of the literature. The strength of the present study is the identification of a clinical subset of patients who appear to have a less progressive disease in the context of the largest cohort of consecutive patients with PCNSV studied to date, with well-defined and uniform case ascertainment and clinical followup. ACKNOWLEDGMENT Editing, proofreading, and reference verification were provided by the Section of Scientific Publications at the Mayo Clinic. AUTHOR CONTRIBUTIONS Dr. Brown had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Salvarani, Brown, Meschia, Giannini, Hunder. Acquisition of data. Salvarani, Brown, Christianson, Meschia, Giannini, Miller, Hunder. Analysis and interpretation of data. Salvarani, Brown, Calamia, Christianson, Huston, Meschia, Giannini, Miller, Hunder. Manuscript preparation. Salvarani, Brown, Calamia, Christianson, Huston, Meschia, Hunder. Statistical analysis. Brown, Christianson. Funding assistance. Brown, Calamia. REFERENCES 1. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system: report of 8 new cases, review of the literature, and proposal for diagnostic criteria [review]. Medicine (Baltimore) 1988;67: Calabrese LH, Duna GF, Lie JT. 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