Primary Angiitis of the Central Nervous System – Diagnosis and Management

Abstract

Primary angiitis of central nervous system (PACNS) is a rare idiopathic disorder affecting blood vessels of brain, spinal cord, and meninges, consequently leading to infarct and less frequently hemorrhage. CNS vasculitis can also occur as part of systemic vasculitis or secondary to autoimmune diseases or infections. The clinical manifestations of PACNS are non-specific and no single laboratory investigation or neuroimaging finding can reliably diagnose this condition. Histopathological evidence of transmural inflammation of blood vessels of CNS is the gold standard, but is generally pursued subsequent to conventional angiogram (CA) because of its invasive nature. The differentials of PACNS are exhaustive and include systemic vasculitis, secondary vasculitis, non-inflammatory intracranial vasculopathies, demyelination, and neoplasm. These alternative conditions can often be distinguished by history, examination, immunological testing, cerebrospinal fluid analysis, and neuroimaging. CA can detect vasculitic changes in the large to medium cerebral arteries but the specificity is low. Recent advancements in vessel wall imaging techniques have further enabled the distinction of various intracranial vasculopathies from CNS vasculitis. The disease has considerable morbidity and fatality unless timely treatment with immunosuppressive agents is initiated. Induction therapy with glucocorticoids and cyclophosphamide followed by azathioprine, mycophenolate mofetil, or methotrexate as maintenance therapy is the cornerstone of management. Biological agents such as rituximab and anti-tumour necrosis factor alpha inhibitors (infliximab and etanercept) may be used in refractory cases. This review discusses the approach to the diagnosis, determinants of outcome, and management.

INTRODUCTION

Primary angiitis of central nervous system (PACNS) (synonyms, primary central nervous system vasculitis and primary central nervous system angiitis) is a rare idiopathic vasculitis restricted to the brain, spinal cord, and meninges.[1,2] Harbitz first described this entity in 1922 as an “unknown form of angiitis in the central nervous system (CNS).”[3] “Isolated angiitis of the CNS,” “granulomatous angiitis of the CNS,” “cerebral granulomatous angiitis,” “idiopathic granulomatous angiitis of the CNS,” “non-infectious granulomatous angiitis of the CNS,” and “giant-cell arteritis of the CNS” are some of the earlier nomenclature used for PACNS.[2,4,5] Inflammation of the cerebral blood vessels can occur in systemic inflammatory disorders and infections and is referred to as secondary vasculitis that needs to be excluded before diagnosing PACNS.[6,7]

Transmural inflammation of cerebral blood vessels with subsequent parenchymal infarct and necrosis is the pathological hallmark of this condition.[5,8] The exact mechanisms triggering immune-mediated cascade and the perpetuating pathophysiological processes damaging the cerebral blood vessels are uncertain.[7] A majority of affected patients manifest with recurrent vascular events, cognitive decline, headache, and seizures. Very rarely, intracranial hemorrhage, tumour-like mass lesions, or myelopathy can occur.[9,10,11,12] The disease can present acutely or as subacute or chronic progressive disease course or can have a relapsing and remitting course similar to inflammatory demyelinating disorders of CNS.[13] Unless treated aggressively with immunosuppressive medications, symptoms tend to progress leading to significant morbidity and mortality.[14,15]

Considerable advancements have been made in the diagnostic and therapeutic aspects of PACNS during the past decade based on the experience from four large observational studies and many case series.[9,11,16,17,18] In an appropriate clinical setting, angiographic and/or tissue evidence of vasculitis is needed after excluding alternative causes for the diagnosis of PACNS.[19] High-resolution magnetic resonance vessel wall imaging (HRVWI) is a promising novel modality that can support the diagnosis of PACNS.[1,20,21] Treatment of PACNS was mostly dependent on glucocorticoids in the earlier times but now, induction therapy with glucocorticoids and cyclophosphamide (CYC) followed by maintenance therapy with azathioprine (AZA), mycophenolate mofetil (MMF), or methotrexate (MTX) is the standard practice.[2,17] Newer immunomodulatory agents such as tumour necrosis factor alpha (TNFα) inhibitors and rituximab have been tried with good response in refractory cases.[9,16,17,22] In light of the recent updates, this review shall focus on the diagnostic aspects, applicability of vessel wall imaging, and current therapeutics in PACNS in adults.

EPIDEMIOLOGY

PACNS is a very rare disease and regional or worldwide epidemiological data on its incidence and prevalence are scarce. One study had estimated the average annual incidence rate of PACNS to be 2.4 cases per 1,000,000 person-years in Olmsted County, Minnesota, United States of America.[10]

The disease can affect people of any age but usually occurs in the fourth or fifth decades of life.[7,14] In the US cohort, the median age of onset was 50 years compared to 36 years from an Indian study that suggests a possible geographical and racial variability.[10,11] A male preponderance was noted in the French and Indian cohort; however, female to male ratio was more in the US cohort.[9,10,11] The age-standardized survival in PACNS patients compared to the general population is significantly reduced.[10]

PATHOGENESIS

The exact sentinel event triggering the immunological cascade and the molecular mechanisms behind the preferential involvement of cerebral arteries is unknown.[23] The critical event could be the activation of immune system by pathogen-derived antigens.[24] Varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and mycoplasma infection has been postulated as the inciting events and the downstream inflammatory pathways driven by molecular mimicry.[7] However, there are no substantial evidence supporting this hypothesis.[24,25] There is also insufficient evidence to attribute to either immune complexes or antibody-mediated pathogenic process in PACNS unlike in systemic autoimmune disorders.[24] Alternate complement pathway activation similar to antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis has been proposed in a small study that has a definite therapeutic implication.[26]

Transmural destructive inflammation of the arteries is the pathological marker for CNS vasculitis; veins and venules are less frequently affected.[5,24] Venous sinuses of the CNS, other organs, and peripheral nervous system are spared in PACNS. The affected blood vessel shows infiltration by inflammatory cells consisting of T and B lymphocytes and plasma cells leading to vessel wall destruction. The stenosis and occlusion of vessels because of intimal proliferation, fibrosis, and thrombi can engender infarction.[2,6,7] Destruction and necrosis of vessel wall can cause rupture of vessels and hemorrhage.[2,6] Histological patterns can vary in PACNS and consist of granulomas, fibrinoid necrosis, or only lymphocytic infiltration.[7,14,24]

CLINICAL FEATURES

Neurological manifestations in PACNS are non-specific. Steno-occlusive lesions of the cerebral arteries result in ischemia and infarcts. The infarcts may be focal, multifocal, or diffuse depending on the size and number of vessels affected.[9] The type of vessels involved can be classified into large, medium, and small-sized vessels. Large arteries are constituted by intra-cranial internal carotid arteries and proximal part of anterior, middle, and posterior cerebral arteries. The second divisions and subsequent branches that are well appreciated in the conventional angiography (CA) are termed medium-sized vessels. Small-sized arteries are not detected in CA and their involvement is usually diagnosed based on biopsy evidence.[9,16,27]

Strokes, acute or subacute encephalopathy, and relapsing and remitting illness are the three common types of presentation in PACNS.[13] Patients often manifest as acute onset focal neurological deficits because of transient ischemic attacks or strokes. Large and medium size vessel involvement usually presents as stroke. When there is extensive involvement of small vessels, it can lead to encephalopathy-like presentations, cognitive dysfunction, and seizures.[9,10,16] In the largest series reported so far, headache was the commonest symptom (59.5%), followed by cognitive dysfunction (54%), persistent neurological deficit or ischemic stroke (40.5%), seizures (20.2%), and intracranial hemorrhage (9.8%). Systemic manifestations of fatigue, anorexia, weight loss, arthralgia and fever, a predominant feature in systemic inflammatory disorders, and infections were less frequently reported.[16] Articular, dermatological, renal, pulmonary, and peripheral nervous system involvement direct away from PACNS. Headaches often precedes stroke, seizures, or encephalopathy by a few days or weeks.[9] Thunderclap headache at onset should steer the clinician towards a diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) unless the vasculitic changes persist in angiogram even after 3 months of onset.[28] Spinal cord involvement and tumour-like mass lesions are rare manifestations of PACNS.[9,11] Some patients can progress rapidly with a fulminant and potentially fatal course refractory to standard treatment.[15,22]

DIFFERENTIAL DIAGNOSIS

The differentials for PACNS are vast and include systemic vasculitis, vasculitis secondary to autoimmune disorders, infections, and neoplastic process [Box 1].[4,13,24] Systemic involvement and elevated acute phase reactants may suggest infections, immune-mediated disorders, or malignancy. Detection of antinuclear antibodies (ANA), antiphospholipid antibodies, ANCA, cryoglobulins, and rheumatoid factor indicates autoimmune disorders or systemic vasculitis. Serological testing for human immunodeficiency virus, hepatitis B and C viruses, rapid plasma reagin, anti-varicella zoster IgG antibody, and cerebrospinal fluid (CSF) analysis including broad-based polymerase chain reaction for viruses, bacteria, and mycobacterium and various microbiological stains can detect infectious causes.[2,23,29] Computed tomography (CT) of chest, abdomen, and pelvis and CSF for malignant cytology and flow cytometry are helpful to rule out neoplastic processes such as carcinomatous meningitis and lymphoma.[9,23]

Box 1.

Causes of secondary central nervous system (CNS) vasculitis

Systemic vasculitis involving CNS Giant-cell or temporal arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schönlein purpura, and Behcet disease Vasculitis secondary to immune-mediated disorders Systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, Sjogren syndrome, mixed connective tissue disorders, inflammatory bowel disease, and dermatomyositis Infections Bacterial—Listeria monocytogenes, Borrelia burgdorferi, Mycoplasma pneumoniae, Rickettsia, Treponema pallidum, and Mycobacterium tuberculosis Viral—Varicella zoster virus, cytomegalovirus, parvovirus B19, Human immunodeficiency virus, Hepatitis C virus, and Hepatitis B virus Fungal—Aspergillosis, coccidioidomycosis, and mucormycosis Parasites—Cysticercosis, toxoplasmosis, and malaria Septic emboli from infective endocarditis and pyogenic meningitis Other inflammatory disorders Sarcoidosis, Susac syndrome, and Amyloid beta-related angiitis Drugs Cocaine, amphetamines, methamphetamines, ecstasy, and ephedrine Malignancy Hodgkin’s lymphoma, non-Hodgkin lymphoma, intravascular lymphoma, and paraneoplasia

Non-inflammatory intracranial vasculopathies can mimic angiographic pattern of CNS vasculitis [Box 2] and high-resolution vessel wall imaging may be useful in differentiating these entities.[13,20,30,31,32] RCVS is the notable mimicker of CNS vasculitis and should be excluded as glucocorticoids can be deleterious in the former.[33,34] Intravascular large B-cell lymphoma can present as cognitive decline and can have initial response to steroids. They are characterized by growth of large neoplastic cells within the lumen of blood vessels that can be confirmed by biopsy.[35] Clinical manifestations of cognitive impairment, seizures, headache, and focal deficits are also seen in cerebral amyloid angiopathy associated with inflammation and can be differentiated from PACNS by demonstrating Aβ amyloid deposits in biopsy.[36]

Box 2.

Angiographic mimics of vasculitis

Reversible cerebral vasoconstriction syndrome Intracranial atherosclerotic disease Fibromuscular dysplasia Radiation vasculopathy Subarachnoid hemorrhage Eclampsia Hypertension Migraine Drugs (cocaine, amphetamines, and ephedrine) Marfan’s syndrome Ehlers-Danlos syndromes Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) Sneddon syndrome (progressive, noninflammatory cerebral arteriopathy, and livedo) Intravascular lymphoma Moyamoya disease and syndrome Sickle cell disease

INVESTIGATIONS

There is no single clinical, laboratory, or radiological finding that can confidently diagnose PACNS.[13] It is prudent to consider PACNS in a patient who has headache, focal neurological deficits, encephalopathy, and dementia. The first step is to obtain magnetic resonance imaging (MRI) of brain for lesions consistent with PACNS.[27,37] The second step is to demonstrate the presence of vasculitis by either CA or by biopsy. The third step is to rule out systemic vasculitis, autoimmune disorders, and infections by appropriate investigations.[19]

Laboratory parameters

The routine blood investigations, such as blood counts, renal and liver function tests, and serum electrolytes, are usually normal in PACNS.[24] C-reactive protein levels are normal; however, one quarter can have mild elevation. Serum immunological profile is usually negative; however, low titres of ANA without anti-dsDNA antibody positivity or features of systemic lupus erythematosus has been reported in PACNS.[9,29] Anti-thyroid peroxidase antibodies and antithyroglobulin antibodies are done to exclude Hashimoto's encephalopathy.[38]

CSF analysis

CSF may show modest elevation in proteins, cells, or both in three-fourth cases of PACNS. The median leukocyte count reported was 6/mm³ (range 0–250) and the median protein concentration was 0.5 mg/ml (range 0.1–4.10). CSF analysis is mainly useful to exclude the possibility of infectious and neoplastic etiology.[5,9] Marked cellular reaction (>250/mm³), polymorphonuclear predominance and hypoglycorrhachia of CSF indicate infectious etiology.[30]

Neuroimaging

CT scan of brain can detect single or multiple infarcts and intracerebral hemorrhages. However, MRI brain is preferable to CT scan in suspected CNS vasculitis because of its much better resolution of parenchymal and meningeal lesions.[37] It is also used to document the extent and nature of lesions and to assess the treatment response.[24]

MRI is abnormal in nearly all cases of PACNS [Figure 1a-i]. The French Vasculitis group extensive account of the MRI abnormalities in PACNS. The majority (92%) had evidence of subacute and chronic infarcts. Acute infarcts at the time of diagnosis were seen in 75% and almost half had both acute and subacute/chronic infarcts. Infarcts were more often bilateral and supratentorial; but single arterial territory infarcts and infratentorial infarcts can also occur.[27] Subcortical white matter, deep grey matter, deep white matter, and cerebral cortex are involved.[2] Diffuse small vessel changes resulting in ischemic demyelination can be seen in the periventricular locations. Two-third patients had at least one hemorrhagic manifestation of which majority had parenchymal hemorrhages. One-quarter had cortical subarachnoid hemorrhage that could be confused with RCVS; however, associated features such as leptomeningeal enhancement can argue in favor of PACNS.[27,33] The parenchymal hemorrhage could be because of hemorrhagic transformation of the infarct or direct parenchymal bleed.[27] Bleeding results from rupture of weakened vessel wall because of the vasculitic process or it might be related to reperfusion injury from steno-occlusive disease or their complex interplay.[24,27] Very rarely, intraventricular hemorrhage is reported.[12,27] Presence of microbleeds and leptomeningeal enhancement are other important findings.[11,27] Parenchymal enhancement is usually present in the vicinity of ischemic lesions or outside (non-ischemic). Therefore, the pattern of gadolinium uptake can provide a diagnostic clue for PACNS. Large tumor-like lesions with or without hemorrhages and myelopathy are other rare findings.[11,24,27]

Figure 1.

Magnetic resonance imaging of brain and high-resolution MR vessel wall imaging. MR brain imaging showing (a and b) acute infarcts in left middle cerebral arteries (MCA) territory (c) multiple bihemispheric lesions (d) grade 3 Fazeka small vessel ischemic changes (e and f) tumour-like lesion presentation (g) parenchymal enhancement (h) pontine hemorrhage and (i) multiple cortical microbleeds. High-resolution MR vessel wall imaging showing (j) concentric thickening of left internal carotid artery in T1W sequences (k) with concentric vessel wall enhancement after gadolinium injection and (l) concentric thickening and enhancement of right MCA (arrow head) and basilar artery (arrow)

Multiple or confluent lesions as in CNS vasculitis can occur in many conditions [Box 3].[1,29,37] The individual findings in MRI are non-contributory, but the constellation of the imaging findings such as multiple disseminated lesions, parenchymal hemorrhages, and parenchymal and leptomeningeal enhancement can increase the diagnostic certainty in PACNS.[27]

Box 3.

Conditions mimicking MRI patterns of primary angiitis of central nervous system

Systemic vasculitis

Secondary vasculitis Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Fabry disease Mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome Inflammatory CNS demyelinating disorders—Acute disseminated encephalomyelitis, Multiple sclerosis, Neuromyelitisoptica spectrum disorder, and Myelin oligodendrocyte antibody-associated demyelination Neoplasm —Gliomatosis cerebri, CNS lymphoma Cardio-embolic stroke Small vessel diseases Emboli from atrial myxoma Cerebral amyloid angiopathy (CAA), CAA-related inflammation (CAARI), and Amyloid beta-related angiitis Posterior reversible encephalopathy syndrome

Magnetic resonance angiogram (MRA)

Large- and medium-sized vessel involvement is identifiable on MRA. The time of flight-MRA (TOF MRA) at 3T has better spatial resolution for intracranial arteries when compared to contrast-enhanced MRA for detection of vasculitis. This technique when combined with routine MRI can detect arterial stenosis, occlusions, fusiform dilatations, and beading pattern in multiple vessels.[27,39] The diagnostic yield from TOF MRA is around 75%; however, the sensitivity is lower when compared to CA as the stenotic distal lesions can be missed in TOF MRA.[9,24,27] TOF MRA could be an alternative to CA for demonstrating angiographic evidence of vasculitis in large-medium vessels as a non-invasive option and for disease monitoring.[2,27]

CA

Conventional four vessel digital subtraction angiography (CA) is important for the diagnostic confirmation of PACNS. Stenosis of blood vessels is the commonest finding and it can involve multiple regions in single or multiple vessels and can be bilateral [Figure 2]. Abrupt cut off of the vessels suggests occlusion. Fusiform dilatations can also be seen; however, micro-aneurysms are rare. Alternate areas of narrowing and ectasia give rise to “string of beads pattern,” a classical description of vasculitis.[19,30] Luminal irregularity, delayed contrast enhancement, early venous filling, attenuation of distal branches, and collateral formation are other findings. Blood vessels of the anterior circulation are more often affected than that of posterior circulation.[4]

Figure 2.

Conventional angiogram findings in primary angiitis of central nervous system. Conventional angiogram showing (a) stenosis of vessels (b) stenosis (arrow) of left proximal middle cerebral artery followed by fusiform dilatation (arrow head) (c) string of bead appearance (d) stenosis of multiple vessels in right internal carotid artery injection (e) mild stenosis involving pericallosal (thick arrow) and callosomarginal (thin arrow) arteries and vessel wall irregularities (circle) and (f) multiple aneurysms in the posterior circulation (arrow)

The diagnostic yield of CA ranges from 70 to 88%.[9,11,16] False negative angiography despite biopsy evidence of CNS vasculitis occurs when the vasculitic process is confined to very small arteries (<500 μm in diameter) that are beyond the resolution of CA.[9,16] CA has a specificity and positive predictive value of less than 30% for diagnosing PACNS as many conditions can mimic similar angiographic appearance.[13,30,39,40]

Biopsy

Biopsy is still regarded as the gold standard for the diagnosis of PACNS not only because it can confirm the presence of CNS vasculitis but also for excluding other causes.[14,41] Cerebral amyloid angiopathy (CAA), amyloid beta-related angiits, intravascular lymphoma, infections, CNS lymphoma, progressive multifocal leukoencephalopathy, Alzheimer's pathology, tauopathy, demyelination, and small vessel disease are the alternate conditions encountered when biopsied for PACNS.[14,32,41]

Biopsy can be negative because of two main reasons – segmental nature of the inflammation (skip lesions) and when disease is confined to large vessels that are not sampled in biopsy. The diagnostic yield increases when the biopsy is taken from a radiologically abnormal area (targeted biopsy) and an ideal biopsy sample should consist of cortex, leptomeninges, dura, and white matter.[14] Neuronavigation techniques can be used for the selection of biopsy site. If targeted biopsy is not possible in situations where there is no easily accessible area or if the abnormality is in eloquent cortex, then biopsy can be done from non-dominant frontal lobe or temporal pole (blind biopsy). These sites have low risk for causing neurological deficits.[4,14] The complications include parenchymal hematoma at surgical site, post-operative meningitis, and permanent neurological deficits.[11,24] However, there is a strong argument in favor of biopsy in recent times because the postoperative risks are very low (0.03–2%.) compared to complications of long-term immunosuppressive therapy.[13,32]

Transmural inflammation with destruction of the vessel wall of the cerebral arteries is required for histopathological diagnosis of PACNS [Figure 3]. Perivascular inflammation alone or infiltration of the parenchyma away from the vessels favors a secondary vasculitis or other infective or inflammatory process.[14,24] Apart from vessel involvement, parenchymal changes, such as infarcts and hemorrhages are seen. Among the different patterns of vasculitis, granulomatous pattern is the more frequent and is delineated by well-formed granulomas, multinucleated giant cells, and mononuclear inflammation.[24] The second common pattern is the lymphocytic vasculitis characterized by predominant lymphocytic infiltration with occasional plasma cells.[14,25] Less frequent is the necrotizing vasculitis characterized by transmural fibrinoid necrosis predominantly involving the small vessels.[14]

Figure 3.

Histopathological pattern in primary angiitis of central nervous system. Lymphocytic vasculitis pattern demonstrating transmural lymphocytic infiltration of intraparenchymal (a, arrow) and leptomeningeal (b, arrow) blood vessels. Parenchyma showing hemorrhage (c,*) and multiple blood vessels with fibrinoid necrosis (c, arrows) and magnified image of an intraparenchymal blood vessel with fibrinoid necrosis suggestive of necrotising vasculitis (d) (a–d: Hematoxylin and eosin stain; magnification b: ×400; a, d: ×250; c: ×100). (Courtesy: Dr Rajalakshmi P, Associate Professor, Department of Pathology, SCTIMST, Thiruvananthapuram)

Vessel wall imaging

HRVWI, a non-invasive tool that can detect vessel wall changes, has emerged as a novel promising tool to differentiate various intracranial vasculopathies that share similar angiographic appearance. It can image large intracranial arteries; but smaller size and deeply located vessels pose technical challenge.[20,42] Concentric vessel wall thickening and enhancement is the distinctive feature seen in PACNS [Figure 1j-l]. Absent or negative remodeling is the other finding usually observed.[43] Eccentric thickening and enhancement are infrequent and may suggest intracranial atherosclerotic disease (ICAD).[20,42] Lesional juxta luminal T2 hyperintensity with surrounding hypointensity that corresponds to the atherosclerotic plaque is rather a specific finding that differentiates ICAD from RCVS and PACNS. Concentric wall thickening with no or mild enhancement favors RCVS.[21,42,44]

DIAGNOSIS

It has been more than 30 years since Calabrese and Mallek put forth the diagnostic criteria [Box 4] for PACNS, but the diagnosis still remains a challenge for the clinicians.[19] Because of the low specificity of angiography, Birnbaum and Hellman[30] brought in definite and probable diagnosis of PACNS to indicate the diagnostic certainty giving more weightage to the tissue diagnosis. Definite diagnosis of PACNS requires confirmation of vasculitis on histopathology from meningocortical biopsy. In the absence of tissue evidence, probable diagnosis of PACNS is entertained if there are high probability findings on an angiogram and if MRI and CSF findings are consistent with PACNS.[30] A diagnostic algorithm for PACNS is depicted in Figure 4. Despite well-laden diagnostic criteria, the median time to reach the diagnosis of PACNS is 15 weeks and even longer for biopsy-proven cases.[9]

Box 4.

Calabrese and Mallek’s[19] diagnostic criteria for primary angiitis of central nervous system (PACNS)

The following three criteria have to be met for the definite diagnosis of PACNS:- History and clinical features of an acquired neurological deficit that remains unexplained after a proper initial basic evaluation consisting of blood counts, blood biochemistry, CSF studies, neuroimaging, and serological tests. Either classic angiographic or biopsy features of angiitis of the central nervous system. No evidence of systemic vasculitis or any other condition to which the angiography or histopathology could be attributed.

Figure 4.

Flow chart depicting investigative approach in primary angiitis of central nervous system. ACE = angiotensin converting enzyme, CNS = central nervous system, CT = computed tomography, CSF = cerebrospinal fluid, ELISA = enzyme-linked immunosorbent assay, HCV = hepatitis C Virus, HIV = Human immunodeficiency virus, MRI = magnetic resonance imaging, PACNS = primary angiitis of CNS, PCR = polymerase chain reaction, TOF = Time of flight

TREATMENT

There are no randomized controlled trials to provide evidence-based treatment for PACNS.[13] The current treatment practice is largely derived from large cohort studies [Table 1], case series, and case reports and is also influenced by the guidelines followed in systemic vasculitis. Treatment consists of induction and maintenance phases and glucocorticoids and immunosuppressive agents form the mainstay.[2,45] Achieving remission is the goal of induction therapy, whereas prevention of relapse is the intent of maintenance therapy.[2,17] For induction therapy, a combination of glucocorticoids and CYC is given for a period of 6 months. Pulse intravenous methylprednisolone 1g/day (30 mg/kg/day in children) for a period of 3–5 days followed by oral prednisolone at a dose of 1mg/kg/day is started.[24] Oral prednisolone at full dose is continued for 4–6 weeks that is followed by slow taper over a period of 6 months. Glucocorticoids at low dose can be maintained for a period of 1–2 years as decided by the treating physician depending on the clinical response along with the other immunosuppressive agents as maintenance therapy.[17] CYC dose is given either as intravenous infusions every month for 6 months at a dose of 750 mg/m² or orally at a dose of 2 mg/kg/day.[2] AZA, MMF, or MTX are given as maintenance therapy.[17,31] AZA is prescribed at 2–2.5 mg/kg/day in two divided doses, MMF 2–3 g/day (800–1200 mg/m²/day in children) in two divided doses, and MTX 20–25 mg/week.[46] A recent study has shown that patients on maintenance therapy with one of these agents had less relapse and better functional outcome compared to those without maintenance therapy.[17] The duration of maintenance therapy is uncertain and de-escalation of therapy is planned based on the clinical response and neuroimaging.

Table 1.

Comparison of three large cohorts of adult PACNS

Parameters	Salvarani et al.[10] 101 patients*	Salvarani et al.[16] 163 patients	de Boysson et al.[9] 52 patients	de Boysson et al. [17] 112 patients	Sundaram et al.[11] 45 patients
Study design	Retrospective single centre, Mayo Clinic, USA	Retrospective single centre, Mayo Clinic, USA (updated cohort)	Retrospective and prospective; French multi-center study	Retrospective and prospective; French multi-center study	Retrospective single centre, SCTIMST, India
Median age of onset (range), years	47 (17-84)	48 (17-85)	43.5 (18-79)	47 (18-81)	36 (19-70)
Sex (male/female)	43/58	72/91	30/22	60/52	31/14
Median time between onset and diagnosis (range)	0.1 year	0.1 (0.0-5.2) year	15 (1-417) weeks	NA	103 (12-1893) days
Angiography positive	76/84 (94%)	113/129 (88%)	38/48 (79%)	68 (61%)	30/42 (71.4%)
Biopsy positive	31/49 (63%)	58/81 (72%)	19/31 (61%)	33 (29%)	19/29 (65.5%)
CSF, abnormal	66/75 (88%)	100/123 (81.3%)	33/49 (67%)	73/104 (70%)	25/42 (60%)
Cell count, median cells/ml (range)	5 (0-535)	NA	6 (0-250)	9 (0-425)	5 (0-60)
Median total proteins median, mg/dl (range)	72 (15-1,034)	NA	50 (10-410)	70 (10-410)	45.5 (18-131)
MRI, abnormal	90/101 (97%)	NA	51/51 (100%)	108 (96%)†	44/44 (100%)
Induction therapy
Glucocorticoids	43 (42.6%)	75 (46%)	7 (13.5%)^	20 (17.9%)	31 (69%)
Glucocorticoids + Cyclophosphamide	46 (45.5)	72 (44%)	43 (82.7%)	89 (79.5%)‡	11 (24%)
Maintenance therapy	NA	AZA (11), MMF (11), and MTX (3)	AZA (22), MMF (1), and MTX (1)	AZA (41), MTX (7), and MMF (4)	AZA (3)
Duration of follow up, median (range)	13 months (0-13.7 years)	12 months (0-13.7 years)	35 (range 2-148) months	53 (0-198) months	33.1 (0.7-356) months
Mortality	17 (16.8%)	25 (15.3%)	3 (6%)	9 (8%)	7 (15.6%)
Relapse	26 (25.7%)	44 (27%)	14 (27%)	38 (34%)	25 (55.6%)
Outcome with different modes of treatment (GCs vsGCs + CYC)	No significant difference	No significant difference in disability; relapses occurred more frequently in patients who received GCs alone when compared with those treated with GC and CYC	No difference in relapse	Maintenance therapy was associated with prolonged remission (OR, 4.32; P=0.002) and better functional status at last follow-up (OR, 8.09; P<0.0001)	No significant difference in relapse or disability
Predictors of relapse	NA	Treatment with GCs only	Seizures and meningeal enhancement on MRI	Gadolinium-enhanced lesions in MRI	Higher NIHSS at admission and normal angiogram

AZA=Azathioprine, CYC=cyclophosphamide, EEG=electroencephalography, mRS=modified Rankin Scale, MRI=magnetic resonance imaging, MTX=methotrexate, MMF=Mycophenolatemofetil, NIHSS=National Institutes of Health Stroke Scale, GCs=glucocorticoids. *Included patients with a beta amyloid-related angiitis. ^{^}One patient received Rituximab and one patient received only cyclophosphamide without GC. ^†MRI showing white matter changes. ^‡3 patients received Rituximab for induction therapy

Some patients can progress despite appropriate therapy and treatment with alternate immunomodulatory agents may be considered. Rituximab, an anti CD20 monoclonal antibody, and TNFα inhibitors such as Infliximab and Etanercept have been tried in a few cases with encouraging results.[22,46] Rituximab dose for induction therapy is either 375 mg/m²/week for four doses or 750 mg/m² (or 1000 mg) every 2 weeks for 2 doses. CD19/CD20 cell count has to be monitored, and based on the repopulation of these cells, subsequent doses can be planned (usually given once in every 6 months).[5,22] Sometimes a combination therapy of glucocorticoids, CYC, and Rituximab may be needed in rapidly progressive PACNS.[2] Relapses are also treated with increasing the dose of glucocorticoids; however, adverse effects limit the dose escalation and prolonged duration of glucocorticoid therapy.[5]

OUTCOME

The paradigm shift in the management of the PACNS with early aggressive induction therapy has improved the outcome in PACNS. The relapse, morbidity, and mortality have significantly reduced with the above regimen. Use of oral immunosuppressive agents for maintenance after induction therapy has resulted in prolonged remission.[17]

To assess the response to treatment, the following parameters need to be monitored during each follow up visit –presence of relapse, disability (modified Rankin Scale – mRS), clinical improvement and treatment-related adverse effects. Relapse is defined as recurrence of new symptoms or worsening of existing symptoms other than headache after a period of inactive disease. Progression of existing lesions or appearance of new lesions on subsequent MRI brain is also considered as a relapse.[10,11] Escalation of therapy is warranted if there is relapse.[16]

The reported relapse rate is approximately 25–30% but can be as high as 55%.[9,11,16] Small vessel vasculitis and presence of gadolinium-enhanced lesions are associated with increased risk for relapse.[46,47] Studies have shown that oral maintenance therapy, lower mRS, and headaches at disease onset predicted good outcome (mRS ≤3).[9,11,46] One quarter of patients had poor outcome at 6-month follow up and in them, baseline mRS >2 or National Institutes of Health Stroke Scale >4 predicted poor outcome at 6 months.[11]The mortality has significantly reduced in PACNS and is in the range of 6–16%.[9,11]

CONCLUSIONS

PACNS is a rare disease with heterogeneous clinical, imaging, and histologic features. This review highlighted the systematic approach towards the diagnosis and therapy of PACNS including the concept of induction and maintenance therapy. Treatment of rapidly progressive PACNS subtype is challenging and the use of newer biological agents needs to be explored. Pathophysiological basis of PACNS is abstruse and research to unearth the mechanistic process underlying this condition thereby enabling targeted therapeutics is the way ahead. The benefits of a prospective multicentric research network for PACNS focusing on diagnosis, treatment, and outcome predictors cannot be overemphasized.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.