Curr Cardiol Rep (2014) 16:533 DOI 10.1007/s11886-014-0533-0
STROKE (AB SINGHAL, SECTION EDITOR)
Advances in Primary Angiitis of the Central Nervous System Michael Lucke & Rula A. Hajj-Ali
# Springer Science+Business Media New York 2014
Abstract Primary angiitis of the central nervous system (PACNS) is a rare idiopathic inflammatory syndrome targeting the vessels of the brain and spinal cord. Clinical presentation is variable, insidious, and non-specific; headache and encephalopathy are the most common symptoms. Multiple strokes affecting numerous vascular territories may be seen, and both focal and diffuse neurologic dysfunction may be present. Cerebrospinal fluid (CSF) analysis is crucial; a normal CSF along with normal brain parenchymal imaging carries a high negative predictive value in excluding PACNS. The role of imaging continues to evolve, and most patients have abnormal vascular imaging; however, the specificity of imaging for PACNS has historically been poor. Cerebral and meningeal biopsy is a valuable tool in confirming the diagnosis and excluding mimics. PACNS generally responds to immunosuppressive therapy. Failure to respond should prompt evaluation for an alternative diagnosis. Given the rarity of this disorder, exclusion of mimics such as the reversible cerebral vasoconstriction syndromes (RCVS) and infectious processes is essential. Keywords Primary angiitis . Central nervous system . Reversible cerebral vasoconstriction syndrome . Amyloid B-related angiitis . Aseptic meningitis This article is part of the Topical Collection on Stroke M. Lucke Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected] R. A. Hajj-Ali (*) Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]
Abbreviations ABRA Amyloid B-related angiitis CNS Central nervous system CSF Cerebrospinal fluid HRMRI High-resolution-3-tesla magnetic resonance imaging HSV Herpes simplex virus MRA Magnetic resonance angiography MRI Magnetic resonance imaging PACNS Primary angiitis of the central nervous system RCVS Reversible cerebral vasoconstriction syndrome VZV Varicella zoster virus
Introduction Primary angiitis of the central nervous system (PACNS) is a rare vasculitis confined to the brain and spinal cord that may result in focal and diffuse neurologic symptoms. Expanding cohort data have advanced the understanding of the range of subsets of PACNS, and developments in neuroimaging have contributed to further differentiating PACNS from mimicking conditions. The pathogenesis of PACNS remains poorly understood. While no clear genetic links have been identified for PACNS in adults, a recent publication has linked loss of function mutations in CECR1 gene encoding adenosine deaminase 2 to recurrent strokes in children and polyarteritis nodosa-type phenotypes[1]; this mutation has not been studied in PACNS. Unlike secondary causes of central nervous system (CNS) vasculitis, PACNS lacks systemic involvement and laboratory markers of inflammation are frequently normal. Diagnostic criteria for PACNS have been proposed by Calabrese and Mallek in 1988 [2]. Included in these criteria are the presence of an otherwise unexplained neurologic or psychiatric defect, the presence of classic angiographic or
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histopathologic features of angiitis within the CNS, and the exclusion of mimicking conditions. Typical PACNS findings of ischemic stokes, diffuse white matter disease, and less frequently mass lesions often present diagnostic dilemmas. Early recognition and treatment is important as immunosuppressive therapies can improve outcomes. Equally as essential is excluding mimicking conditions which can be worsened by the use of immunosuppressive treatments. The rarity of PACNS and the absence of specific serologic or imaging testing highlight the need for a high clinical suspicion and consideration of a broad differential. Reversible cerebral vasoconstrictive syndrome (RCVS) is the most common diagnostic mimic. Additionally, chronic meningitis after infectious or secondary to neoplastic disorders must be excluded. CSF studies of PACNS reveal evidence of inflammation and aseptic meningitis formula and play a crucial role in differentiating PACNS from RCVS. Recent advances in neuroimaging may further aide in differentiating these disorders. Despite advances, angiography and other imaging techniques have limitations, and biopsy remains the gold standard for diagnosis.
Clinical Manifestations PACNS can occur at any age including childhood, but peaks around 50 years of age. The presentation of disease is highly variable but should be considered in patients with cerebral ischemia affecting different vascular territories in association with inflammatory changes in the CNS. Headache is the most common symptom but may vary substantially in quality and intensity. A typical presentation is insidious onset of headaches with cognitive impairment. Cognitive dysfunction, behavioral changes, and encephalopathic symptoms may be present. Cerebrovascular accidents and transient ischemic attacks are common and frequently affect multiple territories through the involvement of different vessels. An acute thunderclap headache is highly unlikely to indicate a diagnosis of PACNS and is much more typical of RCVS. Unexplained intracranial hemorrhage should also prompt evaluation for RCVS. Constitutional symptoms, extracranial organ dysfunction, and elevated acute-phase reactants raise the likelihood of systemic illnesses or secondary process rather than PACNS.
Differential Diagnosis The diagnosis of PACNS remains challenging and requires a multidisciplinary approach to investigate a broad differential. Thromboembolic and atherosclerotic sources must be excluded early prior to consideration of PACNS. Atherosclerotic disease is the most common cause of cerebral angiographic abnormalities, and although infarcts are generally seen in only one territory, multiple vascular territories may be affected.
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Infections can also mimic all aspects of PACNS (Table 1). In particular, varicella zoster virus (VZV) can closely mimic PACNS. All cases of suspected PACNS should be tested for VZV; even without prior history of a rash. Additionally, antivaricella zoster virus immunoglobulin should be measured, as this is more sensitive indicator of VZV vasculopathy [3••, 4]. Human immunodeficiency virus, hepatitis C, syphilis, and tuberculosis may also mimic PACNS, and patients should be evaluated for these infections. Secondary CNS vasculitis due to systemic autoimmune diseases should be considered in the setting of extracranial symptoms. Granulomatosis with polyangiitis, Behçet’s syndrome, systemic lupus erythematosus, Sjögren’s syndrome, and sarcoidosis are among systemic inflammatory conditions which may present with diffuse and focal neurologic deficits (Table 1). High levels of acute-phase reactants increase the likelihood of a systemic inflammatory or infectious process. Primary intravascular CNS lymphoma, intravascular lymphoma, and lymphomatoid granulomatosis can mimic the radiographic findings of PACNS. A brain biopsy can help identify these disorders. Encephalopathy is a frequent feature of PACNS, and workup of these patients should include evaluation for paraneoplastic conditions and antibody-mediated inflammatory brain diseases including NMDAR encephalitis and voltage-gated potassium channel antibodies with limbic encephalitis [5]. Abnormal angiographic findings may help distinguish PACNS from these conditions.
Reversible Cerebral Vasoconstriction Syndromes The most frequent mimic of PACNS is RCVS (Table 2), a non-inflammatory vasospastic syndrome characterized by acute onset of severe headaches with or without neurologic symptoms and evidence of reversible vasoconstriction. This disorder frequently affects young women without other risk factors for stroke. Subarachnoid and intracerebral hemorrhage may occur, and RCVS should be suspected in young women with unexplained hemorrhagic stokes. The onset is often spontaneous, but about half of cases are triggered by drugs or occur in the postpartum state [6••]. Identification of precipitating drugs is crucial to mitigate further risk. Common vasoconstrictive drug exposures correlated with RCVS include nasal decongestants, marijuana, serotonergic drugs, sumatriptan, cocaine, amphetamines, hormonal agents, and high-dose caffeine. The pathology of this condition is secondary to a transient disturbance in cerebral vascular tone with sympathetic overactivity. Plasma levels of endothelin-1, a potent vasoconstrictor, have been shown to be significantly elevated during vasoconstrictive attacks with RCVS [7•]. Headache is the only symptom in a majority of cases. Headaches are typical sudden and severe, and patients may have
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Table 1 Frequent mimics of PACNS Frequent mimics of PACNS Reversible cerebral vasoconstrictive syndrome
Infections
Induced Cocaine Marijuana Hormonal shifts Sympathomimetic agents Selective serotonin reuptake inhibitors Viral VZV Human immunodeficiency virus HSV
Idiopathic
Bacterial Syphilis Lyme Tuberculosis
Fungal
Inflammatory diseases Systemic lupus erythematosis Sjogren’s syndrome Sarcoidosis
Malignancies Hodgkin and non-Hodgkin lymphomas Leukemia Paraneoplastic vasculitis
Secondary CNS Vasculitis Systemic vasculitis Granulomatosis with Polyangiitis Microscopic polyangiitis Behcet’s syndrome Thrombotic disorders Premature intracranial atherosclerosis
recurrent thunderclap headaches over weeks. Focal neurologic deficits may occur and may persist in a minority of patients [8••], but the clinical outcome is usually benign. Initial imaging studies may be normal in RCVS; however, over 80 % will ultimately have abnormal imaging. Convexity subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and large watershed region infarcts may be seen. Typical angiographic findings are tapered arterial narrowing followed by normal or distended arteries, often with bilateral hemisphere involvement that may be more striking and diffuse than those seen with PACNS. RCVS can be associated with cervical artery dissection in a minority of patients [9].
Angiographic abnormalities typically resolve within 2– 3 months [3••]. CSF analysis plays an essential role in differentiating PACNS from RCVS (Table 2). In RCVS, there is no evidence of inflammatory changes in the CSF which is in marked contrast to the pleocytosis expected in PACNS. Likewise, brain biopsy does not reveal inflammatory changes or vasculitis in RCVS cases. Treatment of RCVS utilizes vasodilatory agents, with calcium channel blockers often selected as a first line agent, although there is no evidence that such treatment prevents stroke or hemorrhagic complications. There is no role for
Table 2 Discriminating PACNS from RCVS Discriminating PACNS from RCVS
Gender Disease onset Disease course Provocative vasospastic event CSF High-resolution MRI Hemorrhagic stoke Biopsy findings Treatment
PACNS Trend to male Chronic, insidious Chronic, responds to immunosuppression No Elevated WBC, total protein Vessel wall enhancement Very rare Vasculitis Prednisone, cytotoxic therapy
RCVS Female Acute, thunderclap headaches Self-limited trigger identified in 50 % of cases Normal Minimally enhancing/non-enhancing Common No vasculitis Calcium channel blockers, avoidance of precipitating agent
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immunosuppression, and use of steroids may worsen the clinical course.
Diagnostic Assessments There is no one test to diagnose PACNS. The Calabrese and Mallek criteria remain widely utilized when suspicion for PACNS arises. The diagnosis is made on a combination of history, imaging findings, CSF analysis, and brain pathology. All of these aspects are often required to make a diagnosis and assist in excluding PACNS mimics.
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can differentiate between RCVS and central nervous system vasculitis. In a series of seven patients, the three patients without arterial wall enhancement had resolution of lesions within 3 months consistent with RCVS, while the four patients with enhancement had persistent or progressive arterial narrowing. Three of these four patients were diagnosed with central nervous system vasculitis, with cocaine vasculopathy being diagnosed in the fourth [12]. Cases of vessel wall enhancement with gadolinium MR without leptomeningeal enhancement should also prompt evaluation for viral invasion of the vessel wall and has been described in herpes simplex virus associated vasculitis [13].
Imaging Cerebrospinal Fluid Analysis An abnormal brain magnetic resonance imaging (MRI) is the main modality for initial evaluation and is abnormal in nearly all cases in contrast to RCVS, where imaging is often normal upon presentation and can remain normal in 20 % of the cases. In fewer than 5 % of cases, PACNS may present as a solitary cerebral mass with vasculitis confirmed by pathology. Spinal cord involvement is uncommon but present in approximately 5 % of case. Suspicion for PACNS often arises in the setting of strokes of unknown etiology with or without abnormal cerebral vascular imaging. Cerebral angiography can be normal, particularly in the granulomatous variety that affects distal small vessels. If abnormal, typical findings include alternating areas of stenosis and dilation of multiple vessels in both hemispheres; however, this is a non-specific finding and can be found in multiple other entities. No pattern of vessel involvement on a cerebral angiography is specific for PACNS, even when typical findings of alternating stenosis and dilation are noted. Extensive involvement of mid-sized vessels on both sides of the hemisphere points to a more likely diagnosis of RCVS. Magnetic resonance angiography (MRA) has been increasingly used as an investigation prior to proceeding with an angiogram. However, like angiography, MRA may be inadequate to detect vasculitic changes of small vessels involved in PACNS. An emerging imaging study to identify PACNS is highresolution-3-tesla magnetic resonance imaging with contrast (HRMRI). The ability of HRMRI to define the intracranial vessel wall can help distinguish RCVS from PACNS (Fig. 1, Table 2). Additionally, HRMRI imaging has also been shown to be more specific than 1.5T imaging in detecting stenosis [10]. An analysis of 26 patients with a diagnosis of RCVS or CNS vasculitis that underwent HRMRI at the Cleveland Clinic showed that enhancement of the vessel wall occurred mainly in the CNS vasculitis group and minimally in the RCVS group [11••]. Preliminary results from Mandel et al. also show that the 3T MR
Abnormal CSF findings occur in 80–90 % of pathologically documented cases of PACNS [2, 3••]. CSF analysis is consistent with aseptic meningitis with mild lymphocytic pleocytosis and mildly elevated total protein level. White blood cell count is commonly in the range of 10–20 cells/ μL, and the median protein level is approximately 120 mg/dL [14]. Oligoclonal bands and elevated IgG synthesis may be seen. In contrast, CSF in RCVS is normal unless there are abnormalities attributable to concomitant intracranial or subarachnoid hemorrhages. As initial analysis of the CSF cannot differentiate PACNS from viral infections, inclusion of viral studies from CSF in suspected cases is a routine practice.
Pathology Cerebral and meningeal biopsy remains the gold standard for diagnosis. Biopsy can not only assist in the identification of angiitis when clinically suspected but also in excluding infectious and malignant mimics. Several subsets of disease may be identified by pathology. Granulomatous, diffuse lymphocytic and necrotizing patterns may be seen on the histopathology of leptomeningeal and parenchymal arterial vessels. A series of 46 patients with PACNS who underwent biopsy showed no statistically significant difference in disease aggressiveness or response among these three histologic patterns [15]. However, it should be noted that the number of cases in different pathologic groups in this series was too low for robust statistical comparisons. Cerebral biopsy carries a 1 % risk of neurologic deficit; however, pathology is often essential in obtaining the correct diagnosis and avoiding inappropriate treatment. Amyloid B-related angiitis (ABRA), caused by amyloid-β peptide deposition in the brain leading to vessel wall breakdown, is a subset of PACNS with distinctive features. These patients tend to present at an older age, are
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Fig. 1 HRMRI brain axial section post gadolinium contrast: Vasculitis patient (a) shows vessel wall enhancement and thickening (arrow) while RCVS patient (b) shows minimal wall enhancement (arrow). (Reproduced with permission from Current Science Inc.: Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep. 2013;15(8):346) [24]
more likely to present with mass like lesions, and commonly present with gadolinium leptomeningeal enhancement on MRI [16, 17••]. A 2013 systemic review identified 98 cases reported in the literature, with a mean age of 67 years. Of the cases, 70 % had Apo E genotype e4/e4 [18]. Autoantibodies to Aβ 1–42 have recently been identified in patients with ABRA [19], providing clues for differentiating this subtype from other forms of PACNS. As PACNS displays segmental vessel involvement, there is a high false negative rate for brain biopsies, and a negative biopsy does not exclude a diagnosis of PACNS. Open or stereotactic biopsies should be directed toward radiographically involved area and include leptomeningeal sampling, when possible. If the radiographic region is inaccessible, biopsy should be directed toward the non-dominant temporal lobe tip. Low sensitivities of 53–63 % have been reported [20]; however, sensitivity is improved when targeting a radiographically abnormal area [15]. The presence of vasculitis on biopsy should not preclude evaluation for infectious etiologies and stains, and cultures for occult infections should be included in histological samples.
Prognosis The expectation for recovery has improved with increasing identification of PACNS and appropriate use of immunosuppressive regimens. Symptoms due to active inflammation such as headache and altered cognition are expected to improve with immunosuppressant therapy. Patients with recurrent infarcts and rapid progression are at an elevated risk for progression and require more aggressive treatment. Conversely, identification of permanent deficits is paramount to prevent unwarranted escalations in therapy. Modified Rankin scores have commonly been used as response criteria.
Treatment Randomized control data to guide treatment recommendations is lacking. Immunosuppressive regimens developed for other systemic small vessel vasculitides are commonly employed, with the choice of agents guided by the degree of neurologic dysfunction. High-dose prednisone at doses starting at 1 mg/kg in combination with oral cyclophosphamide 2 mg/kg is a commonly used regimen. A review of a cohort of 163 patients at the Mayo Clinic reported a favorable response to both high-dose prednisone alone (60 mg/day median initial dose) and prednisone plus cyclophosphamide (median dose 150 mg/day). The patients with cyclophosphamide plus prednisone had a significantly decreased rate of relapse [21•]. Treatment responses in ABRA have been reported to be similar to the granulomatous form of PACNS. In a 2013 review, 78 % of patients treated with steroids for ABRA showed partial or complete improvement [18]. Treatment is initiated for 3–6 months until remission at which point long-term maintenance regimen is started with azathioprine or mycophenolate mofetil. Methotrexate has generally been avoided due to potential poor penetrance to the CNS. Data on long-term outcomes of patients with PACNS is scarce. Reported data from a French cohort indicate a high disease relapse rate, with a median diagnosis to relapse interval of 19 months [22]; however, it was not clear whether relapses occurred when treatment was withdrawn or not. Our experience supports a strategy of using long-term maintenance therapy after initial induction treatment. Rituximab has been used with success to treat CNS involvement of other vasculitides and has been used with anecdotal success in PACNS with lymphocytic vasculitis. Two patients in the French PACNS COVAC’ cohort received rituximab with subsequent improvement in symptoms. One patient was treated with 375 mg/m2 weekly for four doses as initial therapy while the second was treated with rituximab due to a lack of response to cyclophosphamide [23].
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Antiplatelet drugs as well as anticoagulants for patients with ischemic stroke may be considered, but to date, there is no evidence that these therapies affect outcome. Appropriate infectious prophylaxis and osteoporosis prophylaxis should be initiated with long-term steroid use. Failure to respond to immunosuppressive regimens should prompt reevaluation for alternative etiologies. Serial MRI imaging and repeat lumbar puncture analysis can be helpful in guiding immunosuppressive therapy. New lesions or neurologic deficits while on therapy should prompt reinvestigation and consideration of opportunistic infections and medication side effects.
Conclusion While advances in recognizing PACNS and its mimics including RCVS have progressed, there remains a lack of randomized control studies and limited long-term data. Angiographic findings may raise a suspicion for PACNS but are neither sensitive nor specific. Advances in HRMRI may be of assistance in further differentiating PACNS from RCVS (Table 2). The diagnosis of PACNS should not be based on angiography alone; CSF analysis is essential, and pathologic confirmation is usually required. Brain biopsy remains a useful intervention with a low complication rate to confirm a diagnosis as well as exclude other etiologies such as infection and lymphoma. Patients respond well to immunosuppressive regimens, and a lack of response should prompt reevaluation of the diagnosis.
Compliance with Ethics Guidelines Conflict of Interest Michael Lucke and Rula A. Hajj-Ali declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2.
Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911–20. 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. Medicine (Baltimore). 1988;67(1):20–39.
Curr Cardiol Rep (2014) 16:533 3.•• Hajj-Ali RA, Singhal AB, Benseler S, Molloy E, Calabrese LH. Primary angiitis of the CNS. Lancet Neurol. 2011;10(6):561–72. This review provides a throughout description of PACNS disease subsets in childhood and adult disease, as well as discussion of diagnostic assessments and mimicking conditions. 4. Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. 2008;70(11):853–60. 5. Twilt M, Benseler SM. The spectrum of CNS vasculitis in children and adults. Nat Rev Rheumatol. 2011;8(2):97–107. 6.•• Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11(10):906–17. This review covers the clinical features and precipitants of RCVS, neuroimaging findings, and approach to diagnosis and treatment of RCVS. 7.• Calabrese, LH, Uchino K, et al. Endothelin-1 plays a role in the pathogenesis of reversible cerebral vasoconstriction syndrome [Abstract.] Arthritis Rheum 2013; 1657. This series demonstrating that plasma endothelin −1 levels are significantly elevated in RCVS compared to controls yields new insights into the pathogenesis of RCVS. 8.•• Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011;68(8):1005–12. A large retrospective analysis describing the epidemiology, clinical features, laboratory results, imaging findings, and treatments of RCVS. 9. Mawet J, Boukobza M, Franc J, et al. Reversible cerebral vasoconstriction syndrome and cervical artery dissection in 20 patients. Neurology. 2013;81(9):821–4. 10. Cosottini M, Canovetti S, Pesaresi I, et al. 3-T magnetic resonance angiography in primary angiitis of the central nervous system. J Comput Assist Tomogr. 2013;37(4):493–8. 11.•• Obusez EC, Hui F, Hajj-Ali RA, Cerejo R, Calabrese LH, Hammad T, Jones SE. High-resolution MRI vessel wall imaging: spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis. Am J Neuroradiol. 2014 Apr 10( In press) This retrospective analysis of 26 patients establishes HR-MRI as a tool in differentiating vessel wall patterns of CNS vasculitis and RCVS. 12. Mandell DM, Matouk CC, Farb RI, et al. Vessel wall MRI to differentiate between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis: preliminary results. Stroke. 2012;43(3):860–2. 13. Guerrero WR, Dababneh H, Hedna S, Johnson JA, Peters K, Waters MF. Vessel wall enhancement in herpes simplex virus central nervous system vasculitis. J Clin Neurosci. 2013;20(9):1318–9. 14. Salvarani C, Brown Jr RD, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62(5):442–51. 15. Miller DV, Salvarani C, Hunder GG, et al. Biopsy findings in primary angiitis of the central nervous system. Am J Surg Pathol. 2009;33(1):35–43. 16. Molloy ES, Singhal AB, Calabrese LH. Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system. Ann Rheum Dis. 2008;67(12):1732–5. 17.•• Salvarani C, Hunder GG, Morris JM, Brown Jr RD, Christianson T, Giannini C. Abeta-related angiitis: Comparison with CAA without inflammation and primary CNS vasculitis. Neurology. 2013;81(18): 1596–603. This series of patients established over 25 years characterizes the unique features of ABRA as a distinct subset of PACNS. 18. Danve, A, Deodhar, A. Systematic review of amyloid beta-related angiitis: a treatable cause of vasculitis affecting central nervous system. [Abstract.] Arthritis Rheum 2013; 1659. 19. Hermann DM, Keyvani K, van de Nes J, et al. Brain-reactive betaamyloid antibodies in primary CNS angiitis with cerebral amyloid angiopathy. Neurology. 2011;77(5):503–5.
Curr Cardiol Rep (2014) 16:533 20.
Salvarani C, Brown Jr RD, Hunder GG. Adult primary central nervous system vasculitis. Lancet. 2012;380(9843):767– 77. 21.• Salvarani, C, Teresa, C, et al. Primary central nervous system vasculitis: treatment and course. [Abstract.] Arthritis Rheum 2013; 1660. An analysis of a 163 patient cohort over a 29 year period lending new insights into the outcomes of immunosuppressive therapy for PACNS. Most patients with PACNS show a favorable response with cyclophosphamide and prednisone as the core treatment regimen.
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de Boysson H, Zuber M, Naggara O, et al. Revised primary angiitis of the central nervous system: description of the first 52 adults enrolled in the French COVAC’ cohort. Arthritis Rheum. 2014. dE Boysson H, Arquizan C, Guillevin L, Pagnoux C. Rituximab for primary angiitis of the central nervous system: report of 2 patients from the french COVAC cohort and review of the literature. J Rheumatol. 2013;40(12):2102–3. Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep. 2013;15(8):346.
STROKE (AB SINGHAL, SECTION EDITOR)
Advances in Primary Angiitis of the Central Nervous System Michael Lucke & Rula A. Hajj-Ali
# Springer Science+Business Media New York 2014
Abstract Primary angiitis of the central nervous system (PACNS) is a rare idiopathic inflammatory syndrome targeting the vessels of the brain and spinal cord. Clinical presentation is variable, insidious, and non-specific; headache and encephalopathy are the most common symptoms. Multiple strokes affecting numerous vascular territories may be seen, and both focal and diffuse neurologic dysfunction may be present. Cerebrospinal fluid (CSF) analysis is crucial; a normal CSF along with normal brain parenchymal imaging carries a high negative predictive value in excluding PACNS. The role of imaging continues to evolve, and most patients have abnormal vascular imaging; however, the specificity of imaging for PACNS has historically been poor. Cerebral and meningeal biopsy is a valuable tool in confirming the diagnosis and excluding mimics. PACNS generally responds to immunosuppressive therapy. Failure to respond should prompt evaluation for an alternative diagnosis. Given the rarity of this disorder, exclusion of mimics such as the reversible cerebral vasoconstriction syndromes (RCVS) and infectious processes is essential. Keywords Primary angiitis . Central nervous system . Reversible cerebral vasoconstriction syndrome . Amyloid B-related angiitis . Aseptic meningitis This article is part of the Topical Collection on Stroke M. Lucke Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected] R. A. Hajj-Ali (*) Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]
Abbreviations ABRA Amyloid B-related angiitis CNS Central nervous system CSF Cerebrospinal fluid HRMRI High-resolution-3-tesla magnetic resonance imaging HSV Herpes simplex virus MRA Magnetic resonance angiography MRI Magnetic resonance imaging PACNS Primary angiitis of the central nervous system RCVS Reversible cerebral vasoconstriction syndrome VZV Varicella zoster virus
Introduction Primary angiitis of the central nervous system (PACNS) is a rare vasculitis confined to the brain and spinal cord that may result in focal and diffuse neurologic symptoms. Expanding cohort data have advanced the understanding of the range of subsets of PACNS, and developments in neuroimaging have contributed to further differentiating PACNS from mimicking conditions. The pathogenesis of PACNS remains poorly understood. While no clear genetic links have been identified for PACNS in adults, a recent publication has linked loss of function mutations in CECR1 gene encoding adenosine deaminase 2 to recurrent strokes in children and polyarteritis nodosa-type phenotypes[1]; this mutation has not been studied in PACNS. Unlike secondary causes of central nervous system (CNS) vasculitis, PACNS lacks systemic involvement and laboratory markers of inflammation are frequently normal. Diagnostic criteria for PACNS have been proposed by Calabrese and Mallek in 1988 [2]. Included in these criteria are the presence of an otherwise unexplained neurologic or psychiatric defect, the presence of classic angiographic or
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histopathologic features of angiitis within the CNS, and the exclusion of mimicking conditions. Typical PACNS findings of ischemic stokes, diffuse white matter disease, and less frequently mass lesions often present diagnostic dilemmas. Early recognition and treatment is important as immunosuppressive therapies can improve outcomes. Equally as essential is excluding mimicking conditions which can be worsened by the use of immunosuppressive treatments. The rarity of PACNS and the absence of specific serologic or imaging testing highlight the need for a high clinical suspicion and consideration of a broad differential. Reversible cerebral vasoconstrictive syndrome (RCVS) is the most common diagnostic mimic. Additionally, chronic meningitis after infectious or secondary to neoplastic disorders must be excluded. CSF studies of PACNS reveal evidence of inflammation and aseptic meningitis formula and play a crucial role in differentiating PACNS from RCVS. Recent advances in neuroimaging may further aide in differentiating these disorders. Despite advances, angiography and other imaging techniques have limitations, and biopsy remains the gold standard for diagnosis.
Clinical Manifestations PACNS can occur at any age including childhood, but peaks around 50 years of age. The presentation of disease is highly variable but should be considered in patients with cerebral ischemia affecting different vascular territories in association with inflammatory changes in the CNS. Headache is the most common symptom but may vary substantially in quality and intensity. A typical presentation is insidious onset of headaches with cognitive impairment. Cognitive dysfunction, behavioral changes, and encephalopathic symptoms may be present. Cerebrovascular accidents and transient ischemic attacks are common and frequently affect multiple territories through the involvement of different vessels. An acute thunderclap headache is highly unlikely to indicate a diagnosis of PACNS and is much more typical of RCVS. Unexplained intracranial hemorrhage should also prompt evaluation for RCVS. Constitutional symptoms, extracranial organ dysfunction, and elevated acute-phase reactants raise the likelihood of systemic illnesses or secondary process rather than PACNS.
Differential Diagnosis The diagnosis of PACNS remains challenging and requires a multidisciplinary approach to investigate a broad differential. Thromboembolic and atherosclerotic sources must be excluded early prior to consideration of PACNS. Atherosclerotic disease is the most common cause of cerebral angiographic abnormalities, and although infarcts are generally seen in only one territory, multiple vascular territories may be affected.
Curr Cardiol Rep (2014) 16:533
Infections can also mimic all aspects of PACNS (Table 1). In particular, varicella zoster virus (VZV) can closely mimic PACNS. All cases of suspected PACNS should be tested for VZV; even without prior history of a rash. Additionally, antivaricella zoster virus immunoglobulin should be measured, as this is more sensitive indicator of VZV vasculopathy [3••, 4]. Human immunodeficiency virus, hepatitis C, syphilis, and tuberculosis may also mimic PACNS, and patients should be evaluated for these infections. Secondary CNS vasculitis due to systemic autoimmune diseases should be considered in the setting of extracranial symptoms. Granulomatosis with polyangiitis, Behçet’s syndrome, systemic lupus erythematosus, Sjögren’s syndrome, and sarcoidosis are among systemic inflammatory conditions which may present with diffuse and focal neurologic deficits (Table 1). High levels of acute-phase reactants increase the likelihood of a systemic inflammatory or infectious process. Primary intravascular CNS lymphoma, intravascular lymphoma, and lymphomatoid granulomatosis can mimic the radiographic findings of PACNS. A brain biopsy can help identify these disorders. Encephalopathy is a frequent feature of PACNS, and workup of these patients should include evaluation for paraneoplastic conditions and antibody-mediated inflammatory brain diseases including NMDAR encephalitis and voltage-gated potassium channel antibodies with limbic encephalitis [5]. Abnormal angiographic findings may help distinguish PACNS from these conditions.
Reversible Cerebral Vasoconstriction Syndromes The most frequent mimic of PACNS is RCVS (Table 2), a non-inflammatory vasospastic syndrome characterized by acute onset of severe headaches with or without neurologic symptoms and evidence of reversible vasoconstriction. This disorder frequently affects young women without other risk factors for stroke. Subarachnoid and intracerebral hemorrhage may occur, and RCVS should be suspected in young women with unexplained hemorrhagic stokes. The onset is often spontaneous, but about half of cases are triggered by drugs or occur in the postpartum state [6••]. Identification of precipitating drugs is crucial to mitigate further risk. Common vasoconstrictive drug exposures correlated with RCVS include nasal decongestants, marijuana, serotonergic drugs, sumatriptan, cocaine, amphetamines, hormonal agents, and high-dose caffeine. The pathology of this condition is secondary to a transient disturbance in cerebral vascular tone with sympathetic overactivity. Plasma levels of endothelin-1, a potent vasoconstrictor, have been shown to be significantly elevated during vasoconstrictive attacks with RCVS [7•]. Headache is the only symptom in a majority of cases. Headaches are typical sudden and severe, and patients may have
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Table 1 Frequent mimics of PACNS Frequent mimics of PACNS Reversible cerebral vasoconstrictive syndrome
Infections
Induced Cocaine Marijuana Hormonal shifts Sympathomimetic agents Selective serotonin reuptake inhibitors Viral VZV Human immunodeficiency virus HSV
Idiopathic
Bacterial Syphilis Lyme Tuberculosis
Fungal
Inflammatory diseases Systemic lupus erythematosis Sjogren’s syndrome Sarcoidosis
Malignancies Hodgkin and non-Hodgkin lymphomas Leukemia Paraneoplastic vasculitis
Secondary CNS Vasculitis Systemic vasculitis Granulomatosis with Polyangiitis Microscopic polyangiitis Behcet’s syndrome Thrombotic disorders Premature intracranial atherosclerosis
recurrent thunderclap headaches over weeks. Focal neurologic deficits may occur and may persist in a minority of patients [8••], but the clinical outcome is usually benign. Initial imaging studies may be normal in RCVS; however, over 80 % will ultimately have abnormal imaging. Convexity subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and large watershed region infarcts may be seen. Typical angiographic findings are tapered arterial narrowing followed by normal or distended arteries, often with bilateral hemisphere involvement that may be more striking and diffuse than those seen with PACNS. RCVS can be associated with cervical artery dissection in a minority of patients [9].
Angiographic abnormalities typically resolve within 2– 3 months [3••]. CSF analysis plays an essential role in differentiating PACNS from RCVS (Table 2). In RCVS, there is no evidence of inflammatory changes in the CSF which is in marked contrast to the pleocytosis expected in PACNS. Likewise, brain biopsy does not reveal inflammatory changes or vasculitis in RCVS cases. Treatment of RCVS utilizes vasodilatory agents, with calcium channel blockers often selected as a first line agent, although there is no evidence that such treatment prevents stroke or hemorrhagic complications. There is no role for
Table 2 Discriminating PACNS from RCVS Discriminating PACNS from RCVS
Gender Disease onset Disease course Provocative vasospastic event CSF High-resolution MRI Hemorrhagic stoke Biopsy findings Treatment
PACNS Trend to male Chronic, insidious Chronic, responds to immunosuppression No Elevated WBC, total protein Vessel wall enhancement Very rare Vasculitis Prednisone, cytotoxic therapy
RCVS Female Acute, thunderclap headaches Self-limited trigger identified in 50 % of cases Normal Minimally enhancing/non-enhancing Common No vasculitis Calcium channel blockers, avoidance of precipitating agent
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immunosuppression, and use of steroids may worsen the clinical course.
Diagnostic Assessments There is no one test to diagnose PACNS. The Calabrese and Mallek criteria remain widely utilized when suspicion for PACNS arises. The diagnosis is made on a combination of history, imaging findings, CSF analysis, and brain pathology. All of these aspects are often required to make a diagnosis and assist in excluding PACNS mimics.
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can differentiate between RCVS and central nervous system vasculitis. In a series of seven patients, the three patients without arterial wall enhancement had resolution of lesions within 3 months consistent with RCVS, while the four patients with enhancement had persistent or progressive arterial narrowing. Three of these four patients were diagnosed with central nervous system vasculitis, with cocaine vasculopathy being diagnosed in the fourth [12]. Cases of vessel wall enhancement with gadolinium MR without leptomeningeal enhancement should also prompt evaluation for viral invasion of the vessel wall and has been described in herpes simplex virus associated vasculitis [13].
Imaging Cerebrospinal Fluid Analysis An abnormal brain magnetic resonance imaging (MRI) is the main modality for initial evaluation and is abnormal in nearly all cases in contrast to RCVS, where imaging is often normal upon presentation and can remain normal in 20 % of the cases. In fewer than 5 % of cases, PACNS may present as a solitary cerebral mass with vasculitis confirmed by pathology. Spinal cord involvement is uncommon but present in approximately 5 % of case. Suspicion for PACNS often arises in the setting of strokes of unknown etiology with or without abnormal cerebral vascular imaging. Cerebral angiography can be normal, particularly in the granulomatous variety that affects distal small vessels. If abnormal, typical findings include alternating areas of stenosis and dilation of multiple vessels in both hemispheres; however, this is a non-specific finding and can be found in multiple other entities. No pattern of vessel involvement on a cerebral angiography is specific for PACNS, even when typical findings of alternating stenosis and dilation are noted. Extensive involvement of mid-sized vessels on both sides of the hemisphere points to a more likely diagnosis of RCVS. Magnetic resonance angiography (MRA) has been increasingly used as an investigation prior to proceeding with an angiogram. However, like angiography, MRA may be inadequate to detect vasculitic changes of small vessels involved in PACNS. An emerging imaging study to identify PACNS is highresolution-3-tesla magnetic resonance imaging with contrast (HRMRI). The ability of HRMRI to define the intracranial vessel wall can help distinguish RCVS from PACNS (Fig. 1, Table 2). Additionally, HRMRI imaging has also been shown to be more specific than 1.5T imaging in detecting stenosis [10]. An analysis of 26 patients with a diagnosis of RCVS or CNS vasculitis that underwent HRMRI at the Cleveland Clinic showed that enhancement of the vessel wall occurred mainly in the CNS vasculitis group and minimally in the RCVS group [11••]. Preliminary results from Mandel et al. also show that the 3T MR
Abnormal CSF findings occur in 80–90 % of pathologically documented cases of PACNS [2, 3••]. CSF analysis is consistent with aseptic meningitis with mild lymphocytic pleocytosis and mildly elevated total protein level. White blood cell count is commonly in the range of 10–20 cells/ μL, and the median protein level is approximately 120 mg/dL [14]. Oligoclonal bands and elevated IgG synthesis may be seen. In contrast, CSF in RCVS is normal unless there are abnormalities attributable to concomitant intracranial or subarachnoid hemorrhages. As initial analysis of the CSF cannot differentiate PACNS from viral infections, inclusion of viral studies from CSF in suspected cases is a routine practice.
Pathology Cerebral and meningeal biopsy remains the gold standard for diagnosis. Biopsy can not only assist in the identification of angiitis when clinically suspected but also in excluding infectious and malignant mimics. Several subsets of disease may be identified by pathology. Granulomatous, diffuse lymphocytic and necrotizing patterns may be seen on the histopathology of leptomeningeal and parenchymal arterial vessels. A series of 46 patients with PACNS who underwent biopsy showed no statistically significant difference in disease aggressiveness or response among these three histologic patterns [15]. However, it should be noted that the number of cases in different pathologic groups in this series was too low for robust statistical comparisons. Cerebral biopsy carries a 1 % risk of neurologic deficit; however, pathology is often essential in obtaining the correct diagnosis and avoiding inappropriate treatment. Amyloid B-related angiitis (ABRA), caused by amyloid-β peptide deposition in the brain leading to vessel wall breakdown, is a subset of PACNS with distinctive features. These patients tend to present at an older age, are
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Fig. 1 HRMRI brain axial section post gadolinium contrast: Vasculitis patient (a) shows vessel wall enhancement and thickening (arrow) while RCVS patient (b) shows minimal wall enhancement (arrow). (Reproduced with permission from Current Science Inc.: Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep. 2013;15(8):346) [24]
more likely to present with mass like lesions, and commonly present with gadolinium leptomeningeal enhancement on MRI [16, 17••]. A 2013 systemic review identified 98 cases reported in the literature, with a mean age of 67 years. Of the cases, 70 % had Apo E genotype e4/e4 [18]. Autoantibodies to Aβ 1–42 have recently been identified in patients with ABRA [19], providing clues for differentiating this subtype from other forms of PACNS. As PACNS displays segmental vessel involvement, there is a high false negative rate for brain biopsies, and a negative biopsy does not exclude a diagnosis of PACNS. Open or stereotactic biopsies should be directed toward radiographically involved area and include leptomeningeal sampling, when possible. If the radiographic region is inaccessible, biopsy should be directed toward the non-dominant temporal lobe tip. Low sensitivities of 53–63 % have been reported [20]; however, sensitivity is improved when targeting a radiographically abnormal area [15]. The presence of vasculitis on biopsy should not preclude evaluation for infectious etiologies and stains, and cultures for occult infections should be included in histological samples.
Prognosis The expectation for recovery has improved with increasing identification of PACNS and appropriate use of immunosuppressive regimens. Symptoms due to active inflammation such as headache and altered cognition are expected to improve with immunosuppressant therapy. Patients with recurrent infarcts and rapid progression are at an elevated risk for progression and require more aggressive treatment. Conversely, identification of permanent deficits is paramount to prevent unwarranted escalations in therapy. Modified Rankin scores have commonly been used as response criteria.
Treatment Randomized control data to guide treatment recommendations is lacking. Immunosuppressive regimens developed for other systemic small vessel vasculitides are commonly employed, with the choice of agents guided by the degree of neurologic dysfunction. High-dose prednisone at doses starting at 1 mg/kg in combination with oral cyclophosphamide 2 mg/kg is a commonly used regimen. A review of a cohort of 163 patients at the Mayo Clinic reported a favorable response to both high-dose prednisone alone (60 mg/day median initial dose) and prednisone plus cyclophosphamide (median dose 150 mg/day). The patients with cyclophosphamide plus prednisone had a significantly decreased rate of relapse [21•]. Treatment responses in ABRA have been reported to be similar to the granulomatous form of PACNS. In a 2013 review, 78 % of patients treated with steroids for ABRA showed partial or complete improvement [18]. Treatment is initiated for 3–6 months until remission at which point long-term maintenance regimen is started with azathioprine or mycophenolate mofetil. Methotrexate has generally been avoided due to potential poor penetrance to the CNS. Data on long-term outcomes of patients with PACNS is scarce. Reported data from a French cohort indicate a high disease relapse rate, with a median diagnosis to relapse interval of 19 months [22]; however, it was not clear whether relapses occurred when treatment was withdrawn or not. Our experience supports a strategy of using long-term maintenance therapy after initial induction treatment. Rituximab has been used with success to treat CNS involvement of other vasculitides and has been used with anecdotal success in PACNS with lymphocytic vasculitis. Two patients in the French PACNS COVAC’ cohort received rituximab with subsequent improvement in symptoms. One patient was treated with 375 mg/m2 weekly for four doses as initial therapy while the second was treated with rituximab due to a lack of response to cyclophosphamide [23].
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Antiplatelet drugs as well as anticoagulants for patients with ischemic stroke may be considered, but to date, there is no evidence that these therapies affect outcome. Appropriate infectious prophylaxis and osteoporosis prophylaxis should be initiated with long-term steroid use. Failure to respond to immunosuppressive regimens should prompt reevaluation for alternative etiologies. Serial MRI imaging and repeat lumbar puncture analysis can be helpful in guiding immunosuppressive therapy. New lesions or neurologic deficits while on therapy should prompt reinvestigation and consideration of opportunistic infections and medication side effects.
Conclusion While advances in recognizing PACNS and its mimics including RCVS have progressed, there remains a lack of randomized control studies and limited long-term data. Angiographic findings may raise a suspicion for PACNS but are neither sensitive nor specific. Advances in HRMRI may be of assistance in further differentiating PACNS from RCVS (Table 2). The diagnosis of PACNS should not be based on angiography alone; CSF analysis is essential, and pathologic confirmation is usually required. Brain biopsy remains a useful intervention with a low complication rate to confirm a diagnosis as well as exclude other etiologies such as infection and lymphoma. Patients respond well to immunosuppressive regimens, and a lack of response should prompt reevaluation of the diagnosis.
Compliance with Ethics Guidelines Conflict of Interest Michael Lucke and Rula A. Hajj-Ali declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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