A 60-year-old woman, healthy and highly functioning at baseline, was in her usual state of health when she developed new-onset headache in a bilateral temporoparietal distribution. This was gradual in onset, associated with nausea and vomiting, and without photophobia or phonophobia. She was noted to be disoriented to time, place, and person by her family. She also rapidly developed auditory hallucinations, which prompted admission to an outside hospital. She was afebrile and hemodynamically stable. Kernig's and Brudzinski's signs were negative. Neurologic examination was nonfocal. A noncontrast computed tomography (CT) scan of the brain showed hypodensities with mild mass effect involving both posterior temporal lobes and left frontal subcortical white matter. Magnetic resonance imaging (MRI) of the brain (Figure 1) showed signal changes in the same locations with smaller areas of signal abnormality and localized mass effect involving the subcortical white matter of the frontal lobes and superior cerebellar vermis. Gradient-echo imaging demonstrated multiple tiny punctate areas of hemosiderin deposition in the brain bilaterally without focal intracranial hemorrhage or ischemia. She was empirically treated with acyclovir, ceftriaxone, and vancomycin for suspected meningoencephalitis. Cerebrospinal fluid (CSF) analysis showed 3 white blood cells (WBCs)/high-power field (hpf), 15 red blood cells (RBCs)/hpf, protein 16 mg/dl, and glucose 48 mg/dl. Herpes simplex virus (HSV) polymerase chain reaction (PCR) was negative. Electroencephalogram (EEG) showed right temporal and parietal sharp waves but no epileptogenic activity. Blood, CSF, and urine cultures returned negative, after which antibiotics were discontinued. She was treated symptomatically and headaches improved, but did not resolve completely. She was dismissed home and returned to work 2 weeks later.
Four days later, she relapsed with severe headaches and disorientation. She was hospitalized and a repeat MRI (Figure 1) showed areas of leptomeningeal enhancement and multiple white matter lesions with T2 hyperintensity, patchy enhancement, and restricted diffusion. Repeat lumbar puncture showed 1 WBC/hpf, 8 RBCs/hpf, glucose 52 mg/dl, and protein 65 mg/dl. CSF studies were negative or normal for angiotensin-converting enzyme level, syphilis, Whipple's disease, Lyme, HSV, West Nile virus, and enterovirus PCR. Serologic studies for Western, Eastern, and California equine viral encephalitis were negative, as were CSF bacterial, mycobacterial, and fungal cultures. The erythrocyte sedimentation rate was 26 mm/hour and the C-reactive protein level was 1 mg/liter. Laboratory studies were normal or negative, including a complete blood cell count, liver and kidney functions, antinuclear antibody (ANA), extractable nuclear antigen (ENA) panel, antineutrophil cytoplasmic antibodies, lupus anticoagulant, and antiphospholipid antibodies. Chest/abdomen/pelvis CT and mammogram were also normal. The patient subsequently developed auditory hallucinations again and had new findings of peripheral vision loss on the left side and formed visual hallucinations. A neuroophthalmology evaluation confirmed left homonymous hemianopia. EEG showed periodic lateralized epileptiform discharges over the right temporoparietal areas. Although hemodynamically stable, her confusion and disorientation continued to worsen. She underwent a right temporal lobe brain biopsy that was interpreted as being suggestive of vasculitis. She was treated with methylprednisolone intravenously 1 gm daily for 3 days with a remarkable resolution of all of her clinical symptoms. She was also started on levetiracetam for abnormalities on EEG and trimethoprim/sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis. She returned to her baseline and was dismissed home on an oral steroid taper a week later. She did well clinically for 2 months until she was down to prednisone 10 mg daily. At that point, her headaches returned and she presented to our center for reevaluation.
Her medical history was pertinent for asthma, seasonal allergies, gastroesophageal reflux disease, hypertension, hyperlipidemia, and hypothyroidism, all of which were in good control at the onset of her current illness.
Family and social history
She was happily married, had 6 children, and was a school teacher by profession. She was a lifelong nonsmoker and denied alcohol or illicit drug use. She had no relevant family history of autoimmune disease or neurologic disorders.
Her medications included levothyroxine for hypothyroidism, omeprazole for gastroesophageal reflux disease, fluticasone propionate, and as needed, albuterol inhalers for asthma, lisinopril and hydrochlorothiazide for hypertension, loratadine and mometasone nasal spray for seasonal allergies, and simvastatin for hyperlipidemia. She was not taking any herbal supplements or other over-the-counter drugs.
Review of systems
The patient denied fever, chills, night sweats, or weight loss. She also denied any prior history of skin rash, photosensitivity, alopecia, oral/nasal/genital/cutaneous ulcers, sicca symptoms, arthralgias or arthritis, inflammatory eye symptoms, pleurisy, pericarditis, hemoptysis, epistaxis, or recurrent sinusitis. She did not have cough, chest discomfort, or shortness of breath. She denied any numbness or tingling in the extremities and did not have any focal motor weakness or movement disorder. She did not have any seizures. She denied vision changes, scalp tenderness, jaw claudication, carotidynia, and upper or lower extremity claudication.
The patient was awake, alert, and in no acute distress. She weighed 83.3 kg and was 157 cm tall (body mass index 33.8 kg/m2). She was afebrile, had a blood pressure of 126/72 mm Hg, a respiratory rate of 12 breaths/minute, and a heart rate of 80 beats/minute. The head, eye, ear, nose, and throat examination was unremarkable. She did not have any oral or nasal ulcers. Her mucous membranes were moist and her salivary pool was adequate. There was no lymphadenopathy or thyromegaly. The cardiovascular examination showed a regular rhythm without murmurs, rubs, or gallops. There were no bruits over the large vessels of the upper or lower extremities. The lungs showed good air entry bilaterally without any wheezing, rubs, or crackles. The abdomen was nontender and without organomegaly. There was no evidence of rheumatologic skin rash, cutaneous nodules, synovitis, or joint deformities. Neurologic examination revealed intact cranial nerves, normal proximal and distal strength in the upper and lower extremities, and preserved biceps, triceps, patellar, and Achilles tendon reflexes. Proprioception, vibration, temperature, and fine sensations were intact. Mini-mental status examination was normal. A comprehensive ophthalmology examination was negative.
Laboratory and radiologic evaluation
Laboratory results from her prior hospital admission were reviewed and additional tests were repeated. These were noncontributory and are summarized in Table 1. A repeat MRI (Figure 1) showed a marked decrease in the nonspecific foci of T2 signal hyperintensity in hemispheric white matter bilaterally compared to prior MRIs. MR angiogram showed no focal stenosis or aneurysm in the head/neck. Abundant punctate foci of hemosiderin deposition were seen on susceptibility weighted imaging (SWI) consistent with cerebral amyloid angiopathy (CAA) (Figure 1). The areas of greatest signal abnormality seen on prior MRI scans correlated with regions demonstrating the greatest concentration of amyloid angiopathy as demonstrated with SWI. Areas of previous restricted diffusion showed evidence of laminar necrosis.
The patient is a 60-year-old healthy woman who developed rapidly progressive new-onset bilateral temporoparietal headaches, disorientation, and visual and auditory hallucinations with abnormal brain MRI findings and suspicion of “vasculitis” on a brain biopsy. Her condition was steroid responsive but relapsed with steroid taper.
Evaluation of vasculitis is one of the most daunting diagnostic and therapeutic challenges for physicians. Rheumatologists are often called upon by neurologists to assist in the management of patients with vasculitis involving the central nervous system (CNS) that may be primary or secondary to systemic inflammatory disease, infection, or malignancy. It can also have many mimics (Table 2). The following conditions were primarily considered in the differential diagnosis of our patient.
Table 2. Differential diagnosis and mimics of CNS vasculitis*
CNS = central nervous system; HIV = human immunodeficiency syndrome; AIDS = acquired immunodeficiency syndrome; CAA-I = cerebral amyloid angiopathy–associated vascular/perivascular inflammation.
PACNS is rare vasculitis of unknown etiology with angiitis of the leptomeningeal and parenchymal arteries and veins exclusively confined to the brain and rarely the spinal cord. It was originally described in the 1950s as a highly fatal disease, with only 46 cases reported until 1986. With the advent of angiography, many more cases have been reported, but some may represent reversible cerebral vasoconstriction syndromes that can appear similar on angiography. In 1988, Calabrese and Mallek (1) proposed the criteria for diagnosis as the presence of an acquired, otherwise unexplained neurologic deficit with either classic angiographic or histopathologic features of angiitis within the CNS without evidence of systemic vasculitis or any condition that could elicit the angiographic or pathologic features. Patients may present with subacute to chronic headaches, encephalopathy, seizures, stroke/transient ischemic attacks (recurrent), ataxia, and behavioral and cognitive deficits. The average age at presentation is 45 years, and there is a slight male preponderance (1). There are no diagnostic laboratory studies. These are done mainly to rule out infections, malignancy, connective tissue disease (CTD), or systemic vasculitides. Inflammatory markers are usually normal and elevated markers raise concern for a systemic process. CSF is often abnormal and shows lymphocytic pleocytosis with elevated protein. EEG is of low yield and may show nonspecific slowing without epileptiform activity. MRI is usually abnormal and may show leptomeningeal enhancement, acute infarcts, hemorrhages, or nonspecific white matter hyperintensities. Normal MRI is very uncommon. Angiography is often normal or nondiagnostic; the classic pattern of alternating stenoses and dilatations with vessels demonstrating a “beading pattern” is rarely seen and may be nonspecific. The gold standard for diagnosis is a cerebral biopsy from an involved area demonstrating granulomatous inflammation. Vasculitis can be focal and segmental in distribution, but is often multifocal with “skip lesions” along an affected blood vessel with multiple associated foci of infarction or hemorrhage. PACNS had a dreadful prognosis until 1983, when Cupps et al (2) reported successful treatment with corticosteroids and cyclophosphamide. Our patient had a clinical presentation and biopsy suggestive of PACNS, but was older compared to most adults who develop this condition.
Infections are great mimics of vasculitis and must be actively searched for when biopsy suggests a vasculitic process. CNS and systemic vasculitis have been reported with bacteria, viruses, fungi, protozoa, and Rickettsia. The organism may be angioinvasive or vascular inflammation may result from host defense with secondary damage to host tissues. The infection can often be occult and localized to the brain or CSF only. Detection requires a high degree of suspicion in conjunction with awareness of the risk factors and epidemiologic characteristics of the patient. Syphilis can mimic vasculitis and present as an ischemic stroke in a young person (3), as Treponema pallidum invades vessels in the subarachnoid space and causes thrombosis and infarction. These patients often have prior untreated sexually transmitted diseases or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. HSV can cause meningoencephalitis and can mimic vasculitis clinically or on MRI. Varicella-zoster virus (VZV) causes cerebral angiitis that tends to affect older age groups (4), is more localized than PACNS, and is often preceded by a herpes zoster skin rash. Segmental unilateral involvement of vessels in the middle cerebral artery distribution on cerebral angiography is characteristic and diagnosis is confirmed by a positive VZV PCR in the CSF or by the presence of a higher VZV antibody titer in the CSF compared to serum. Hepatitis C (5), Borrelia burgdorferi (6), Bartonella (7), Mycobacterium tuberculosis (8), and cysticercosis (9) have also been reported to cause CNS vasculitis. Our patient was tested extensively for infections and determined negative for tuberculosis, hepatitis C, syphilis, and HIV. She had no prior history of sexually transmitted disease. CSF PCR for Lyme, HSV, and VZV was also negative.
CNS manifestations occur in many patients with systemic vasculitides. The diagnosis of CNS involvement is often presumed on the basis of neurologic symptoms and signs occurring in the setting of a systemic vasculitis. It can be difficult to confirm CNS involvement without biopsy, as it often affects small vessels that are beyond the resolution of conventional angiograms. The CNS may be involved in up to 8% of patients having granulomatosis with polyangiitis (Wegener's) (10) and may present with confusion, headaches, stroke, visual loss, or seizures. CNS involvement is also reported with polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome (11). Of patients with Behçet's disease, 10–49% can have CNS involvement where vasculitis has a venous predominance, and can present with ischemic stroke (12). Vasculitis affecting the intracranial vessels is exceedingly rare in patients with Takayasu arteritis or giant cell arteritis. Our patient did not have any clinical features of the above systemic vasculitides and her antimyeloperoxidase and proteinase 3 antibodies were negative.
CNS involvement is seen many CTDs, particularly systemic lupus erythematosus (SLE) (13) and others, including Sjögren's syndrome, rheumatoid arthritis, mixed CTD, and dermatomyositis. The diagnostic approach to a patient with neurologic dysfunction in the setting of CTD is also fraught with the dilemma of whether the particular abnormality is due to CTD-associated organ dysfunction or a secondary phenomenon (infection, medication side effects, or metabolic abnormality). SLE is associated with a bland vasculopathy with small-vessel hyalinization, thickening, thrombus formation (14), and microinfarcts (15). Frank vasculitis is very rare but can be dramatic and often fatal (16). Antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, and cardiogenic emboli all need to be considered in the differential diagnosis of patients with SLE and neurologic dysfunction (17). Rheumatoid CNS vasculitis is rare and may present with seizures, hemiparesis, cranial nerve palsy, blindness, hemispheric dysfunction, cerebellar ataxia, or dementia (18, 19). In Sjögren's syndrome, mononuclear cell infiltrates can lead to vasculopathy of small leptomeningeal and cortical vessels causing neurologic manifestations (20). However, frank vasculitis on imaging is seen in <20% of affected patients, with an even lesser number confirmed histologically. Our patient did not have any clinical manifestations of CTD, and her autoantibody screen (ANA, ENA profile) and complement levels were normal or negative.
CNS vasculitis has been reported with Hodgkin's and non-Hodgkin's lymphoma and angioimmunolymphoproliferative lesions (21). The lymphoproliferative disease can present outside the CNS or be restricted to the CNS. Clinical presentation can be similar to PACNS and pathology can be indistinguishable from widespread granulomatous angiitis (22). Mass lesions and spinal cord involvement raise the suspicion for lymphoproliferative disease. In the right setting, appropriate immunohistochemical staining for B cell and T cell markers should be performed to help rule this out. Our patient did not have any constitutional symptoms, weight loss, or lymphadenopathy. She had imaging of the chest, abdomen, and pelvis that did not reveal a malignancy, and CSF did not show any blasts or malignant cells. Suspicion was low for lymphoproliferative disease in her case.
Other miscellaneous possibilities
There are several other mimics of vasculitis. Reversible cerebral vasoconstriction syndromes are a group of disorders that are characterized by acute-onset severe recurrent headaches, with or without additional neurologic signs and symptoms, normal CSF, and prolonged but reversible (in 4–12 weeks) vasoconstriction of the cerebral arteries (23). However, a brain biopsy (if performed) would not show vasculitis in cases of reversible cerebral vasoconstriction syndrome, as was seen in our patient. A number of vasoactive drugs (including sympathomimetics, cocaine, heroin, amphetamines, and phenylpropanolamine) can cause neurologic deficits associated with abnormalities on cerebral angiogram, and screening for these substances may be indicated in select cases.
The MRI findings raised suspicion for interval improvement of an inflammatory process related to CAA. Review of the outside brain biopsy slides confirmed an inflammatory reaction consisting of reactive T lymphocytes in the perivascular areas with a single multinucleated giant cell, reactive astrocytes, gliosis, and amyloid plaques (Figure 2). Immunohistochemical staining of the cerebral cortex and white matter showed presence of amyloid β (Aβ) colocalizing to areas of vascular inflammation consistent with Aβ-related angiitis (ABRA). The patient's prednisone was increased to 20 mg daily with a slow taper. Mycophenolate mofetil was started and titrated up to a dose of 1,000 mg twice daily. She did develop visual hallucinations 1 month later with the presence of epileptogenic activity on EEG, both of which resolved after increasing the dose of levetiracetam.
PACNS is a rare, albeit severe, vasculitis of unknown etiology commonly involving the brain, and rarely the spinal cord (24). CAA is a vasculopathy characterized by deposition of Aβ peptide (ABP) in the media and adventitia of small to medium-sized arteries primarily in the cerebral cortex and leptomeninges. PACNS and CAA have been regarded as unrelated disorders, although a small subset of patients harbor a combination of both entities and yet exhibit unique features of their own.
CAA is common, occurring in 23–57% of the asymptomatic elderly (25) on histopathology examination and more than 90% of patients with Alzheimer's disease in whom it tends to be severe. Aβ is produced from amyloid precursor protein in the brain and removed by degradation through metallopeptidases, absorption into the bloodstream via low-density lipoprotein receptor–related protein or P-glycoprotein on endothelial cells, or drainage along the vessel walls (26–28). The pathogenesis of CAA is unclear, but defects in the described clearance mechanisms may cause amyloid to accumulate in excess in the cerebral vessel walls. The presence of the ε4 allele of apolipoprotein (Apo) has been found to predispose to vascular accumulation of ABP in comparison to parenchymal deposition (29). CAA is associated with recurrent, multifocal, lobar intracranial hemorrhage (30) in the normotensive elderly. In others, it is associated with dementia (27) and transient stereotypical neurologic symptoms (31). It is now being considered as a trigger for CNS vasculitis. A clinical trial of Aβ42 immunotherapy for Alzheimer's disease (32, 33) was terminated early when 6% of the vaccinated patients developed a subacute meningoencephalitis and postmortem findings confirmed inflammation surrounding Aβ containing blood vessels in 2 patients (33, 34). This generated suspicion for Aβ-triggered vascular inflammation contributing to their neurologic decline and death, similar to cases now known to have ABRA.
There is a unique subset of patients that present at an earlier age than patients with CAA, but with features of PACNS. Interestingly, radiologic findings are distinct and neuropathology shows evidence of CAA-associated vascular/perivascular inflammation (CAA-I). This entity has come to be better known as ABRA. Of the cases reported, most have been responsive to immunosuppression, making it a treatable form of cerebral amyloidosis. It is being increasingly recognized as a treatable form of encephalopathy in the elderly. Recognition requires clinical suspicion, imaging studies, and confirmation using specific immunohistochemical staining for ABP.
ABRA is a rare form of CNS vasculitis, presumed to be an inflammatory response to Aβ deposition in the walls of blood vessels. Other terms used for ABRA include PACNS associated with CAA, amyloid angiopathy with granulomatous angiitis of the CNS, cerebral amyloid inflammatory vasculopathy, and CAA associated with giant cell arteritis, all emphasizing the association between CAA and coexisting vascular inflammation. ABRA affects patients younger (mean age 67 years) than those with CAA (mean age 76 years), but older than those with PACNS (mean age 45 years) (35, 36). There is no known sex predilection. Clinical presentation includes acute or subacute onset of headache, cognitive and behavioral changes (most common symptom at presentation in up to 76%) (31), seizures, hallucinations, and focal neurologic deficits (transient ischemic attack and stroke). A small proportion presents with features of increased intracranial pressure (nausea, vomiting, and papilledema).
There are no specific diagnostic laboratory tests or serologies. An extensive evaluation must be undertaken to exclude infections, malignancy, autoimmune CTDs, or systemic vasculitides. Inflammatory markers often are elevated, but are nonspecific. Apo ε4/ε4 genotype may be found (noted in 10 of 14 patients tested) (37, 38); CSF shows elevated protein and mild to moderate lymphocytic pleocytosis (31), and its analysis is necessary to exclude infections (such as tuberculosis, HSV, fungal, and partially treated bacterial infections) and neoplastic processes. MRI is the imaging modality of choice and shows asymmetric or symmetric, confluent, or patchy T2-weighted or fluid-attenuated inversion recovery hyperintensities with or without edema, without infarcts, and in some cases, leptomeningeal or parenchymal enhancement (31, 39). It may show a mass lesion that can be confused with a glioma or lymphoma. SWI is most critical in differentiating ABRA from PACNS, as it shows multiple cortical/subcortical microbleeds or evidence of old lobar hemorrhages related to CAA. Cerebral angiograms may be normal or equivocal (39). EEG may show nonspecific focal or generalized slowing and rarely epileptiform discharges. Definitive diagnosis can be established only on brain biopsy with evidence of perivascular, transmural, or intramural vascular inflammation (lymphocytic, granulomatous, or necrotizing; with or without multinucleated giant cells) in the brain or leptomeningeal vessels. There is striking colocalization of vascular amyloid deposits with the inflammatory response on immunohistochemical staining for Aβ. Biopsy should be taken from a radiologically involved area for best yield, but may be nondiagnostic due to sampling error given the patchy nature of vasculitis.
The major differential diagnoses for ABRA include infections (particularly tuberculosis, neurosyphilis, progressive multifocal leukoencephalopathy, neuroborreliosis), neurosarcoidosis, autoimmune demyelinating disease (acute disseminated encephalomyelitis), and malignant processes (gliomatosis cerebri, lymphoma, and carcinomatous meningitis). Hypertensive encephalopathy can result in microhemorrhages in the thalamus, brainstem, cerebellum, or basal ganglia in comparison to lobar distribution in ABRA.
There is no standard therapy, and treatment is based on experience from previous case series. High-dose corticosteroids (oral or pulsed intravenously) may be given initially until a clinical and radiologic response is achieved followed by additional immunosuppressive therapy that needs to be individualized. Cyclophosphamide has been used most often (19 cases) (31), but there are reports of successful use of methotrexate (2 cases), azathioprine (1 case), and mycophenolate mofetil (2 cases). Response to therapy is noted within 1–3 weeks after treatment is initiated and may be variable. Most patients respond favorably, but some may have a relapsing–remitting course or relentless progression and death despite aggressive immunosuppressive therapy (36). The optimal duration of immunosuppression is uncertain but should be individualized based on the clinical and radiologic disease course. Relapse can occur with reduction or cessation of therapy and usually responds to reintroduction of immunosuppression.
In 2007, Kinnecom et al (37) suggested making a diagnosis of probable CAA-I noninvasively on the basis of typical clinical and radiologic findings without requiring a biopsy. Chung et al (31) then comprehensively reviewed findings from all 72 cases of ABRA published in the literature until 2010 and proposed diagnostic criteria for “probable” and “definite” CAA-I. Per the authors, “probable CAA-I” can be diagnosed in a patient age >40 years with typical clinical and radiologic features (as described above). If infection is ruled out with a fair amount of certainty, a trial of immunosuppressive therapy without brain biopsy in selected patients with probable CAA-I is reasonable (40), keeping in mind the ongoing diagnostic uncertainty. “Definite CAA-I” requires tissue evidence of CAA-I. Brain biopsy should be reconsidered in patients with probable CAA-I who fail to respond to empiric high-dose corticosteroid therapy within 3 weeks (31).
Our patient had clinical features of PACNS but imaging suggestive of CAA. ABRA was confirmed on histopathologic examination with immunohistochemical staining of a brain biopsy. Biopsy evaluation of patients with CNS vasculitis should include staining for amyloid to distinguish ABRA from PACNS.
In conclusion, although rare and probably underrecognized, ABRA appears to be a distinct entity with a characteristic presentation. Patients with ABRA may be misclassified as PACNS if vascular Aβ is not specifically sought by specialized immunohistochemical staining techniques. It may be overlooked on imaging if an MRI sequence with high sensitivity for hemosiderin deposition, such as SWI, is omitted from the scanning protocol. There are many unanswered questions about the pathophysiology of ABRA. A better understanding of the condition will be important for developing disease biomarkers and more effective therapy. In addition, it may lead to better insight into Aβ-related meningoencephalitis associated with Alzheimer's disease immunotherapy. Rheumatologists must consider ABRA in the differential diagnosis of patients presenting with clinical features of CNS vasculitis.
Amyloid β–related angiitis.
The patient has done well clinically on the regimen with corticosteroids and mycophenolate mofetil. She has been able to taper prednisone down to 8 mg daily and continues to remain in remission at 9 months of followup with no recurrence of symptoms or MRI changes.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Makol 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 conception and design. Makol, Petty, Warrington.
Acquisition of data. Makol, Parisi, Petty, Watson.