MCV = mean corpuscular volume; AST = aspartate aminotransferase; ESR = erythrocyte sedimentation rate; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; HIV = human immunodeficiency virus; CSF = cerebrospinal fluid.
Cerebral amyloid angiopathy associated with primary angiitis of the central nervous system: Report of 2 cases and review of the literature
Article first published online: 3 JUN 2003
Copyright © 2003 by the American College of Rheumatology
Arthritis Care & Research
Volume 49, Issue 3, pages 421–427, 15 June 2003
How to Cite
Schwab, P., Lidov, H. G. W., Schwartz, R. B. and Anderson, R. J. (2003), Cerebral amyloid angiopathy associated with primary angiitis of the central nervous system: Report of 2 cases and review of the literature. Arthritis & Rheumatism, 49: 421–427. doi: 10.1002/art.11049
- Issue published online: 3 JUN 2003
- Article first published online: 3 JUN 2003
- Manuscript Accepted: 1 DEC 2002
- Manuscript Received: 10 JUL 2002
- The Arthritis Foundation
Cerebral amyloid angiopathy (CAA) is a common pathologic entity in the elderly characterized by β-4 (“senile”) amyloid deposition in the media of small- to medium-sized cortical and leptomeningeal arteries (1). It is, for the most part, asymptomatic but may present with an otherwise unexplained lobar hemorrhage or with progressive dementia. The degree and extent of amyloid involvement of the vessels is variable, and severe in only a minority of cases. An associated inflammatory infiltrate is not characteristic. Primary angiitis of the central nervous system (PACNS), on the other hand, is by definition a central nervous system (CNS) vasculitis occurring in isolation and not secondary to an infection (e.g., herpes zoster), a lymphoproliferative tumor, or a systemic connective tissue disease (2, 3). Over the past 20 years, 16 cases of CAA occurring in apparent association with florid vasculitis have been reported, primarily in the neurology literature (4–17). The angiocentric inflammation in those cases has been speculated to be in reaction to the amyloid present in the vessel wall rather than a fortuitous association, and these cases have been proposed to represent a distinct entity and a variant of PACNS (18). In this article, we report 2 patients who presented with a mass-like intracranial lesion and were found to have CAA associated with PACNS upon brain biopsy. These histopathologic findings led to referral to rheumatologists who were called upon to guide management. We describe the clinical presentation, radiographic features, brain biopsy results, and treatment courses of these 2 patients; compare them with the cases previously reported in the literature; and summarize the features and current understanding of the association between these 2 entities.
Case report 1
FK is a 74-year-old white man who presented for evaluation of seizure and growing right temporal lesion. He was in his usual state of health until 2 months prior to admission when he experienced a generalized tonic-clonic seizure. Computed tomography (CT) scan of the brain showed a small right temporal lesion speculated at that time to be due to trauma related to the seizure. After experiencing a second seizure 1 month later, a repeat CT showed an increase in the size of the lesion noted previously, as well as possible meningeal enhancement.
His history was significant for 1-month difficulty with both short-term and long-term memory, decreased sense of balance, behavioral changes, and headaches. He denied visual changes or jaw claudication. His medical history was significant for the following: non–insulin-dependent diabetes mellitus complicated by diabetic retinopathy, chronic renal insufficiency, neuropathy, hypertension, coronary artery disease with stable angina and mild left ventricular systolic dysfunction, previous history of hyperthyroidism treated with radioactive iodine, B12 deficiency, and prostate cancer treated with local radiation therapy. His medications included phenytoin, aspirin, amlodipine, carvedilol, fluvastatin, glipizide, and isosorbide dinitrate. He had a 65 pack per year history of smoking, drank 1 glass of wine daily, and was a retired salesman.
On examination, his blood pressure was 170/60 mm Hg. His general examination including his joints and skin was normal. Neurologically, he was alert, but oriented to name and place only, and appeared confused with a short attention span. His strength and deep tendon reflexes were normal except at his right biceps and triceps, where they were diminished presumably due to a long-standing cervical radiculopathy. His plantar responses were extensor.
Results of his laboratory tests are as listed in Table 1. Of note, his erythrocyte sedimentation rate (ESR) was 107 mm/hour. Cerebrospinal fluid (CSF) was clear and colorless with 1 white blood cell and 24 red blood cells, a normal glucose level, and an elevated protein level of 50 gm/dl. CSF Gram stain and routine cultures were negative. A magnetic resonance imaging (MRI) study of his brain revealed diffuse leptomemingeal enhancement bilaterally with decreased signal in the adjacent tissues, indicating edema (Figure 1A).
|Patient 1 (FK)||Patient 2 (MB)|
|White blood cell count, per mm3||5||7.7|
|Blood urea nitrogen, mg/dl||36||9|
|Total protein, gm/dl||6.7||8|
|Hepatitis B and C panel||Negative||Negative|
|CSF||Clear, colorless||Clear, colorless†|
|WBC, per mm3||1||26|
Because of concern for carcinomatous meningitis, a temporal lobe biopsy was performed. Fragments of gliotic cerebral cortex and white matter were obtained. Examination of small- to medium-sized blood vessels in both the leptomeninges and brain parenchyma revealed marked perivascular inflammatory cuffs and, in some instances, true vasculitis. Additionally, scattered microhemorrhages of various ages were seen adjacent to or around the blood vessels. The inflammatory infiltrate consisted predominantly of CD68-positive immunoreactive macrophages and of a sparse lymphocytic component. Occasional multinucleated cells as well as hemosiderin-laden macrophages, indicating remote hemorrhage, were seen. The walls of the involved blood vessels had a thick hyaline appearance, some with evidence of disruption of the external elastic lamina and some to the point of apparent occlusion. No definite granulomas were identified. Immunohistochemistry for β-amyloid showed strong reactivity in the blood vessel walls, as well as in senile plaques in the parenchyma and perivascular locations (Figures 2A–D).
Dexamethasone was given perioperatively and tapered over the next few days, and the rheumatology service was consulted. Further evaluation revealed no evidence of a systemic vasculitis. After an initial 1 gram of intravenous methylprednisolone, the patient was transferred to a rehabilitation facility on dexamethasone (4 mg 4 times daily, orally). This was tapered over the course of the next 30 days. Shortly thereafter he was readmitted for continued confusion and hallucinations at which time his ESR was 40 mm/hour. After receiving 1 course of pulse methylprednisolone, it was elected not to continue corticosteroids. He has since made a slow but gratifying recovery. Currently, more than 1 year postoperatively, he has returned to his baseline cognitive level although occasionally displaying lapses in judgment. His gait has much improved but remains wide-based. He has had no recurrent seizures.
Case report 2
MB is a 70-year-old woman who was admitted for evaluation of a transient episode of confusion and a right temporal mass. Seven months prior to admission she began having daily bitemporal headaches. She was evaluated at that time with an MRI of her brain, an ophthalmologic examination, and a temporal artery biopsy, which were all normal. On the day of admission, she experienced a period of altered sensation with olfactory hallucinations followed by a period of confusion and poor memory. Her medical history was significant for hypertension, osteoporosis, and depression. Her medications included moexipril, hydrochlorothiazide, sertraline, estrogen, and alendronate. Her occupational and social history were unremarkable, as was her system review.
On examination she was afebrile. Her blood pressure was 150/80 mm Hg. Her general examination and neurologic examination were essentially normal. An MRI of her brain revealed a slightly enhancing T2-bright infiltrative lesion in the right temporal lobe with mild mass effect (Figures 1B and C). The differential diagnosis included a low-grade tumor, and a biopsy of the leptomeninges and underlying brain was performed. Mild to moderate inflammation consisting of lymphocytes and CD68-positive macrophages was noted in the perivascular spaces and in walls of medium-sized vessels. A few indistinct granulomas were identified in the leptomeninges. The walls of medium-sized vessels had hyaline changes and showed immunoreactivity for β-amyloid. There was mild gliosis of the cortical gray matter and subcortical white matter. In addition, scattered senile plaques were present (Figures 3A–C). Gram stain, mycobacterial, and fungal stains, and cultures did not show any microorganisms.
Given the histopathologic findings, a rheumatologic evaluation was obtained. Further history and physical examination showed no features suggestive of a systemic vasculitis. Laboratory tests results are listed in Table 1. Of significance was an elevated ESR of 116 mm/hour.
After having received dexamethasone intravenously perioperatively, the patient denied any further headaches and was fully oriented. She was discharged home on prednisone 1 mg/kg in divided doses or 20 mg 3 times a day and phenytoin for postoperative seizure prophylaxis. On close outpatient followup, she continued to do well. Six weeks after presentation, repeat ESR was normal at 19 mm/hour, and repeat MRI showed expected postsurgical changes in the right temporal lobe as well as a marked reduction in the extent of the signal abnormality and the degree of mass effect seen previously. Based on these findings prednisone was tapered rapidly.
Four weeks later, while taking 30 mg of prednisone, she was readmitted with fevers up to 105°F and rigors. Physical examination and evaluation for infectious causes were unrevealing. CSF was clear and colorless and had an elevated protein level of 129 gm/dl with a normal glucose level, 26 white blood cells with 6% polymorphonuclear cells, 68% lymphocytes, 23% monocytes, 1% eosinophils, 2% atypical lymphocytes, and 6 red blood cells. Routine, mycobacterial, fungal, and viral stains and cultures as well as cytology on the CSF were negative. Despite broad spectrum intravenous antibiotics, her fever persisted. After phenytoin was discontinued because of the possibility of a drug-induced fever, the patient experienced a tonic-clonic seizure. Another MRI of her brain revealed recurrence of the infiltrative mass of the posterior temporal lobe with confluent peripheral enhancement.
A craniotomy was performed for resection of the enlarging mass. The specimen was largely composed of floridly inflamed leptomeninges with evidence of reactive fibroblastic proliferation. In contrast to the earlier biopsy, eosinophils were noted. Only small amounts of underlying cortical parenchyma were seen and were necrotic, suggesting ischemic injury. Although the inflammatory process dominated the picture, β-amyloid immunoreactive vessels could still be identified in the necrotic cortex (Figures 3D and E). A cerebral angiogram was normal.
Perioperative dexamethasone was continued. She was discharged home on prednisone (1 mg/kg daily) with plan for a very slow taper. Twelve months after her initial admission, oral cyclophosphamide was briefly added as a steroid-sparing agent but discontinued after febrile neutropenia developed. Eighteen months after her initial presentation, she is living semi-independently, has developed short-term memory deficits, and continues to take a moderate dose of prednisone. Her MRI shows interval cortical atrophy but no evidence of recurrent inflammation.
We report 2 patients, both in their early 70s, who presented with confusion, headaches, and seizures, as well as an elevated ESR and CSF protein level. MRI in both cases showed T2-bright signal abnormalities in the temporal lobe, which were associated with varying degrees of enhancement and mass effect, raising concern for a neoplastic process (Table 2). The findings in the first case suggested carcinomatous or inflammatory meningitis; and in the second case, a primary brain neoplasm or focal inflammatory process was suspected. On brain biopsy, however, both were found to have marked perivascular granulomatous inflammation in association with congophilic or amyloid angiopathy. Neither patient had evidence of infection, tumor, or systemic vasculitis. Neither had clinically evident lobar hemorrhages, although pathologically the first patient did have evidence of microhemorrhages at various stages, a characteristic feature of congophilic angiopathy. Both were treated initially with steroids at high doses and experienced rapid improvement of their symptoms, as well as an improvement in their sedimentation rates. We hypothesize that our second patient had a relapse manifested by high fevers and recurrence of focal leptomeningeal inflammation related to the very rapid prednisone taper.
|Patient 1 (FK)||Patient 2 (MB)|
|Duration of illness before diagnosis, months||2||7|
|Clinical features||Seizure, cognitive changes, unsteady gait||Headache, seizure|
|MRI of brain||Ill-defined right temporal lesion with diffuse leptomeningeal enhancement||Temporoparietal mass-like lesion with leptomeningeal enhancement|
Our patients share similarities with the 16 patients with PACNS in association with CAA previously reported in the literature (4–17). Fountain and Eberhard (14) recently reviewed most of these cases and compared them with cases of PACNS alone and CAA alone. These patients were in their late 50s to early 70s, presented predominantly with subacute mental status changes, confusion, or seizures and often had headaches and an unsteady gait. Similar to our patients, 4 of the 16 presented with an intracranial mass-like lesion mimicking a neoplasm. When compared with patients with PACNS alone, patients with PACNS/CAA were also predominantly male but tended to be older. Where reported, ESR was elevated in 5 of 8 (5, 9, 14–16) cases and improved in response to immunosuppressive therapy in both cases that provided followup values. On CSF analysis, they had a consistent elevation in CSF protein and occasionally had xanthochromia resulting from microhemorrhages, the latter being a feature of CAA and not of PACNS. Angiographic evidence of concentric narrowing of the vessels as seen in PACNS was not found in any of the few patients with CAA/PACNS who had an angiogram (14). Consistent with this pattern, the angiogram performed on our second patient was also normal.
PACNS refers to a CNS vasculitis affecting primarily the CNS and not associated with a systemic rheumatic disease, infection, neoplasm, or amyloid. Although used synonymously with granulomatous angiitis of the CNS, the term PACNS is preferable because the inflammation involving the small- to medium-sized vessels may be nongranulomatous (2). In contrast, granulomatous inflammation in giant cell or temporal arteritis involves large arteries and characteristically spares the cerebral vessels beyond the dura. Wilkinson and Russell (19) defined anatomic distribution of giant cell arteritis by reviewing 12 autopsies of patients dying with giant cell arteritis. They found that all patients had temporal and cervical vertebral inflammation but that none demonstrated involvement of the intracranial arteries, common carotid arteries, or cervical part of the internal carotid arteries. PACNS and PACNS/CAA are therefore distinct from giant cell arteritis in that, by definition, they involve the CNS.
CAA results from β-4 or “senile” amyloid deposition in the media of small- to medium-sized vessels in the brain (1). Amyloid plaques can also be seen throughout the brain parenchyma. It usually occurs sporadically but can be associated with Alzheimer's disease; rare familial cases have also been reported. Unlike systemic amyloidosis, it is isolated to the brain and does not result from longstanding inflammation or an associated monoclonal gammopathy. In one study reviewing 784 autopsy cases, moderate to severe CAA was found in 2.3% of patients aged 65–74 years, 8% of those between 75 and 84 years, and 12.1% of those older than 85 years. It is for the most part clinically silent but typically presents as lobar hemorrhage in a normotensive patient. Smaller hemorrhages can also be detected and may result in transient neurologic symptoms, subclinical seizures, or progressive dementia. Short of postmortem examination, the diagnosis can be suspected in patients greater than 60 years of age presenting with multiple cerebral hemorrhages without an identifiable cause. Gradient echo MRI looking for areas of old hemorrhages can be a helpful additional diagnostic study (1, 20). The pathophysiology of CAA is not known, but a relationship to apolipoprotein E (apoE) allelic variation has been proposed. The epsilon 4 allele has been associated with a greater chance of amyloid deposition, whereas the epsilon 2 allele has been associated with a greater risk of the amyloid-laden vessels to rupture, resulting in hemorrhages (21).
Perivascular inflammation in CAA is characteristically not seen, although immunohistochemical analyses in one study detected activation of monocyte and macrophage lineage cells (22). This is in contrast to CAA associated with PACNS where inflammatory cells including macrophages and lymphocytes infiltrate the vessel walls and perivascular spaces. The opinion in the literature is that the association between CAA and PACNS is not coincidental (14). First, although accurate estimations of the prevalence of CAA and PACNS are not available, it appears, based on an estimate of the number of cases reported in the literature, that they occur together more often than would be predicted by chance alone (14). Although cerebral amyloid is quite common, it rarely affects patients in their late 60s to early 70s to a severe degree (1). Second, the granulomatous inflammation and amyloid deposits strikingly colocalize to the same vessels in the cerebral cortex and leptomeninges. In the case of MB, for example, vascular inflammation and amyloid deposits were both more marked in the leptomeninges than in the cortex. It is not known whether β-amyloid in these patients is the byproduct of chronic inflammation of the vessels (13), or whether the inflammation is in reaction to the amyloid deposited in the vessel walls (18), or whether both CAA and PACNS result from the same immunologic disturbance (14). Mandybur and Balko (13) reported improvement of both the inflammatory infiltrate and degree of amyloid deposition in one patient treated with corticosteroids and cyclophosphamide, suggesting that the degree of amyloid deposition reversed after treatment of the inflammatory process. However, the effect of immunosuppression on the pathogenesis of isolated CAA is not known and may be independent of its antiinflammatory effect. On the other hand, the finding of amyloid fragments engulfed within macrophages strongly suggests that the inflammation may represent a foreign body reaction to the amyloid deposits in the vessel walls (18). It is unclear why these few patients should mount an inflammatory response to the amyloid-laden vessels, because nearly all patients with CAA do not have an associated vasculitis. One might speculate that these particular patients have a predisposition, possibly genetic and related to apoE allelic variation, to fragment their vessels, resulting in “exposure” of the β-amyloid peptide. In studies of Alzheimer's disease, β-amyloid has been shown to bind the first complement component C1q and could therefore result in complement activation and recruitment of an inflammatory infiltrate (23).
Based on the few existing case reports alone, it is not possible to draw firm conclusions on the natural history of CAA/PACNS and its appropriate treatment. It is well recognized that patients with CAA should avoid anticoagulation or antiplatelet agents, given their tendency to develop intracranial hemorrhages. To date, no therapy is available to reverse amyloid deposition or prevent its further progression in CAA. New immunotherapeutic approaches based on vaccination with β-amyloid 1–42 peptide or monoclonal antibodies against β-amyloid are being studied in animal models and early clinical trials for the treatment of Alzheimer's disease in which β-amyloid has been shown to be an important pathogenic component of plaques (24). The applicability of this approach to CAA remains to be evaluated. A rationale exists for treatment focused on abating the inflammatory process. The choice and degree of antiinflammatory or immunosuppressive treatment should be guided by the severity of each patient's clinical presentation, progress on followup evaluation, and comorbidities. Treatment of the cases reported in the literature has included prednisone alone, cyclophosphamide alone, prednisone and cyclophosphamide in combination, surgical resection alone, and no treatment (Table 3). Outcome has varied from full recovery to progressive clinical deterioration or death from infectious complications related to immunosuppression.
|Author and year||Age/sex||ESR, mm/hour||Treatment||Length of followup||Outcome||Mode and time of diagnosis|
|Reid and Maloney 1973||55/F||—||None||4 years||Death||Autopsy|
|Probst and Ulrich 1985||59/F||—||None||9 years||Death 6 days after VP shunt||Autopsy|
|Murphy and Sima 1985||66/M||—||Surgical resection||9 months||Doing well, residual hemianopsia||Surgery, upon presentation|
|Shintaku et al 1986||69/M||—||None||4 months||Death||Autopsy|
|Briceno et al 1987||55/F||—||Surgical resection||4 months||Doing well, mild EHL weakness||Surgery, upon presentation|
|Ginsberg et al 1988||73/M||35–59||Steroids||1 year||Doing well||Biopsy, 1 month after symptom onset|
|Yamazaki et al 1988||70/M||12||None||10 months||Death from SIADH||Autopsy|
|Gray et al 1990||82/M||10||Steroids and antibiotics||2.5 months||Death||Autopsy|
|Le Coz et al 1991||51/F||—||Surgical resection||13 years||Doing well||Surgery, 2 months after symptom onset|
|Mandybur and Balko 1992||62/F||—||Steroids and oral cyclophosphamide||8 months||Death from CMV pneumonia||Biopsy, 1 month after symptom onset|
|Fountain and Eberhard 1996||66/M||1||Steroids and oral cyclophosphamide||20 months||Stable dementia with mild aphasia||Biopsy, 4 months after symptom onset|
|69/F||87||Steroids and oral cyclophosphamide||6 months||Death from aspiration pneumonia||Biopsy, 4 months after symptom onset|
|Fountain and Lopez 1999||71/M||70||Oral cyclophosphamide||22 months||Doing well||Biopsy, 5 months after symptom onset|
|Streichenberger et al 1999||67/W||—||Prednisone||33 days||Death from tonic-clonic seizure||Autopsy|
|NEJM CPC 2000||63/M||15–70||Cyclophosphamide||13 months||Slow neurologic deterioration||Biopsy, 26 days after symptom onset|
Because all described patients either underwent biopsy or came to autopsy, a bias toward patients with a worse prognosis may exist. Additionally it is notable that 2 of the patients who were not treated lived 4 and 9 years, respectively, following onset of their neurologic symptoms (4, 5), although one cannot be certain that their initial neurologic presentation corresponded to the onset of CAA/PACNS because their diagnosis was only established at autopsy. It is also interesting that 3 patients did well after surgical resection alone, an intervention that may not be considered therapeutic for such a global disease. Taken together, these observations suggest that CAA/PACNS is different from PACNS. Its clinical course may be less rapidly progressive and therefore may not require aggressive therapy with long-term immunosuppression using steroids and cyclophosphamide. Based on a few case reports, corticosteroids and cyclophosphamide used alone or in combination appear to be effective in the treatment of CAA/PACNS (Table 3), but given their risk for potentially fatal infectious complications, their use should be individualized based on severity of presentation and close followup. If initially elevated, ESR may be a useful measure to monitor along with clinical progress and radiographic improvement. Further genetic and immunologic studies are needed to elucidate the pathogenesis and rational treatment of this entity. Rheumatologists should be aware of it as part of the spectrum of CNS vasculitis, as they might be called upon to guide its management.
- 17Giant cell angiitis of the central nervous system with amyloid angiopathy: a case report and review of the literature. Clin Exp Pathol 1999; 46: 311–7., , , , .