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Central Nervous System Vasculitis
Stephan A. Mayer
Vasculitis affecting the central or peripheral nervous system often presents major diagnostic and therapeutic challenges for physicians because of its variable clinical manifestations and the lack of specific diagnostic tests other than biopsy. Central nervous system (CNS) vasculitis comprises a heterogeneous group of inflammatory diseases that affect leptomeningeal and parenchymal blood vessels of the brain with different but frequently overlapping clinical and pathologic manifestations.
The histopathologic changes of CNS vasculitis essentially consist of an inflammatory infiltrate within the vessel wall associated with necrosis, vessel occlusion and infarction, and in some cases, hemorrhage. The cases of CNS vasculitis are protean: It may occur as an idiopathic primary autoimmune process or within the context of systemic to autoimmune disease, as a reaction to an infection such as varicella-zoster or a neurodegenerative process such as amyloid angiopathy, after drug exposure (e.g., cocaine), as a manifestation of radiation exposure, and in the setting of malignancy. Although the precise pathogenesis often remains obscure, in all cases, the immune system plays a central role, and immunosuppressive agents are the cornerstones of treatment.
There are several different classifications for CNS vasculitis. Some classifications are based on the size of the affected vessels (small, medium, large), whereas other classifications are based on histologic features (e.g., granulomatous, lymphomatous, or leukocytoclastic inflammation) or immunologic markers (e.g., the association with antineutrophil cytoplasmic antibodies, or ANCAs, with some forms of vasculitis). CNS vasculitis can also be further broadly classified into primary and secondary vasculitis depending on whether the process is confined to the CNS or is part of a systemic illness.
In 2012, the International Chapel Hill Consensus Conference proposed a revised nomenclature system that groups different vasculitides by taking in consideration multiple factors including size of vessels and whether the vasculitis involves a single organ or is part of a more systemic condition (Table 42.1
PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM
Primary angiitis of the central nervous system (PACNS) is associated with select inflammation and destruction of small- and medium-sized arteries of the brain parenchyma, spinal cord, and leptomeninges, resulting in symptoms and signs of CNS dysfunction. The term angiitis is synonymous with vasculitis and refers to involvement of blood vessels on both the arterial and venous sides of the circulation. PACNS is also frequently referred to as primary central nervous system vasculitis.
The annual incidence rate of PACNS is 2.4 cases per 1 million person-years. The disease affects patients of all ages, peaking at 50 years of age, with a 2:1 male predominance.
The etiology and pathogenesis of PACNS is unknown. Infectious agents such as herpes zoster virus, West Nile virus, and varicellazoster virus have been proposed as possible causes or triggers.
Three main histopathologic patterns are generally seen: granulomatous, lymphocytic, and necrotizing vasculitis. In lymphocytic PACNS, immunohistochemical staining reveals predominant infiltration by memory T cells in and around small cerebral vessels, signifying an antigen-specific immune response occurring in the wall of cerebral arteries.
Due to diffuse involvement of the CNS, the clinical manifestations are variable and nonspecific, with a clinical course ranging from hyperacute to stepwise to chronic and insidious. Mental obtundation and decreased cognition are the most frequent clinical presentations, usually evolving subacutely as a progressive encephalopathy. Other symptoms may include headaches, seizures, and focal neurologic deficits due to ischemic stroke or cerebral hemorrhage. Signs and symptoms of systemic vasculitis, such as peripheral neuropathy, fever, weight loss, or rash, are by definition lacking in PACNS.
AMYLOID β-RELATED ANGIITIS
-related angiitis (ABRA) is a form of CNS vasculitis in which perivascular β
-amyloid is thought to act as a trigger for inflammation mediated by CD68+ macrophages and CD3+ T lymphocytes. The condition develops in patients with symptomatic or asymptomatic amyloid angiopathy (see also Chapter 38
), which presents as dementia, gait disorder, and progressive brain hemorrhages (both microbleeds and parenchymal intracerebral hemorrhage). Patients with ABRA often exhibit altered mental status and respond to immunosuppressive treatment. Common CSF findings include an elevated protein and a lymphocytic pleocytosis. MRI often demonstrates T2 hyperintense lesions extending through the cortical white matter and often gray matter, suggestive of breakdown of the blood-brain barrier and a reversible leukoencephalopathy. Cerebral angiography shows beading in a minority of patients, perhaps due to involvement of exclusively medium- and small-sized vessels. In every case on brain biopsy, microglia, macrophages, and T cells surround amyloid-laden vessels. After initiating antiinflammatory treatment consisting of steroids or cyclophosphamide
for a duration ranging from 2 weeks to several months, a majority of patients with ABRA show improvement. However, some patients relapse, and other patients do not improve or progressively decline.
CENTRAL NERVOUS SYSTEM VASCULITIS ASSOCIATED WITH SYSTEMIC VASCULITIS
GIANT CELL (TEMPORAL) ARTERITIS
Giant cell arteritis (GCA), also known as temporal arteritis because of its predilection for superficial temporal artery involvement, is a large-vessel granulomatous vasculitis. The disease usually affects the aorta or its major branches, with a predilection for the branches of the cervical internal and external carotid arteries and the vertebral arteries. The intracranial vessels are generally spared. GCA is often linked with polymyalgia rheumatica in terms of its systemic manifestations, ESR elevation, and response to steroid therapy.
GCA has an annual incidence that is highest among white individuals, ranging between 10 and 20 cases per 100,000 among persons older than 50 years of age. The incidence is markedly lower in persons of Asian or African descent in the range of 1 case per 100,000. Although GCA almost never occurs before age 50 years, the incidence increases thereafter, reaching its peak incidence between the ages of 70 and 80 years.
Although the etiology of GCA is unknown, there appears to be an interplay between increasing age, a genetic predisposition, and infectious triggers that involves both the cellular and humoral immune system, resulting in an acute vascular inflammatory state. Current literature regarding the molecular basis of GCA suggests that activated dendritic cells, residing in the vessel wall, play an important role in the pathophysiology by initiating the pathogenic cascade, recruiting T cells and macrophages to form granulomatous infiltrates.
GCA is a panarteritis, including all the arterial layers. Thrombosis may develop at sites of active inflammation. Fibrosis, scarring, and narrowing or occlusion of the arteries develops secondary to the inflammation, tissue injury, and repair process.
GCA is classically characterized by a combination of five features:
Age older than 50 years,
A localized new-onset headache,
Tenderness over the temporal artery,
An elevated ESR (≥50 mm/h), and
Biopsy revealing a necrotizing arteritis with a predominance of mononuclear cells or a granulomatous process with multinucleated giant cells.
The presence of three of the above five criteria is associated with 94% sensitivity and 91% specificity for the diagnosis of GCA. GCA typically presents with a constellation of constitutional symptoms, headache and tenderness over the temporal artery, jaw claudication, visual symptoms, and symptoms of polymyalgia rheumatica (diffuse myalgias and body aches). Because intracranial vascular involvement is rare in GCA, transient ischemic attacks (TIAs) and stroke are usually secondary to embolism or flow failure related to cervical vertebral or internal carotid lesions.
Neurologic manifestations arise in approximately 30% of patients, with more than half being peripheral neuropathies, followed by one-third with TIA or stroke, one-third with ophthalmologic symptoms, and one-fifth with neuro-otologic syndromes. Ophthalmologic symptoms can include transient monocular blindness (i.e., retinal TIA or amaurosis fugax) due to internal carotid artery stenosis or sustained unilateral visual loss due to anterior ischemic optic neuropathy or occlusion of the central retinal artery (see also Chapter 9
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