Primary Angiitis of the Central Nervous Systems

Vasculitis, referred to as angiitis, that affects the central nervous system (CNS) is one of the most formidable diagnostic and therapeutic challenges for physicians because the clinical manifestations of CNS vasculitis are highly variable, the CNS is a common target of many forms of systemic vasculitis and may also be the sole target of vasculitis, and specific noninvasive tests are lacking and material for pathophysiologic investigation is limited. Despite these challenges, we have witnessed a great progress in our understanding of the disease, and its subsets. Our ability to recognize and diagnose the mimics of CNS vasculitis have improved dramatically. Correct diagnosis still requires a high degree of suspicion coupled with knowledge of other diseases that can masquerade as vasculitis.

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Definition

A primary vasculitis limited to the CNS is referred to as primary angiitis of the CNS (PACNS). A generalized systemic vasculitic process can also involve the CNS, and in such cases, it is referred to as secondary vasculitis of the CNS. Secondary vasculitis is not discussed in this chapter.

The earliest reports of PACNS described the disease as fatal and progressive, limited to the CNS, and characterized by rich granulomatous vasculitis. The disease was named granulomatous angiitis of the CNS (GACNS), and it remained a rare diagnostic entity until the 1980s. Increasing reports of successful treatment with cyclophosphamide and glucocorticoids as well as the use of angiography for the diagnosis of PACNS heightened the interest in the diagnosis. In 1988, Calabrese and Mallek1 proposed criteria for the diagnosis of PACNS (Box 1).
Box 1: Proposed Criteria for Primary Angiitis of the Central Nervous System1
The presence of an acquired and otherwise unexplained neurologic deficit
• With presence of either classic angiographic or histopathologic features of angiitis within the CNS
• And no evidence of systemic vasculitis or any condition that could elicit the angiographic or pathologic features

Adapted from 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;67:20-39.

In the 1990s, we and others began to question whether PACNS is a homogeneous disease or whether different clinical subsets exist. A subset diagnosed on the basis of angiography and with a predictably more benign outcome requiring less–intensive therapy was identified and originally named benign angiopathy of the CNS (BACNS). Later on, it became clear that the pathophysiologic basis of BACNS is characterized by vasospasm and closely resembles other vasospastic disorders such as Call–Fleming syndrome, postpartum angiopathy, migrainous vasospasm, and drug–induced arteritis. The term reversible cerebral vasoconstriction syndromes (RCVS) have unified BACNS and other similar phenotypes under the same clinico–radiological syndromes.2 In our practice, RCVS represents a major mimic of PACNS and it will discussed in this chapter.

Over the years, it became clear that PACNS is not uniform but rather a heterogeneous disease with multiple presentations. Mass–like presentation occurs in 5% of the cases.3 The diagnosis is usually unexpected and is ascertained after pathologic findings of vasculitis in the excised mass. Other subsets include, spinal cord involvement in 5% of cases,4 leptomeningeal enhancement disease, and beta–related amyloid angiopathy, which is mostly seen in older patients.5

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Prevalence

Primary angiitis of the CNS was first described in the mid–1950s. By 1986, only 46 cases had been reported in the English–language medical literature. Since 1975, an increasing number of cases have been described, and over 500 cases were reported through 2007. Primary angiitis of the CNS affects patients of all ages but peaks around 50 years of age and is most common in males. A retrospective analysis of 101 cases revealed that the average annual incidence of PACNS is 2.4 cases per 1 million person–years.6 Recently, CNS vasculitis was found to be one of the common misdiagnoses of patients with sporadic Creutzfeldt–Jakob disease, when a brain biopsy was used in the work up of dementia.7 Today, although PACNS is still uncommon, its specter is often raised in patients with neurologic problems of obscure origin, making its diagnostic approach a relevant clinical issue.

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Pathophysiology

Primary angiitis of the CNS is a heterogeneous disease with different clinical subsets of unknown etiology and pathogenesis. The pathologically defined entity, GACNS, is primarily a leptomeningeal and cortical vasculitis involving the small and medium leptomeningeal and cortical arteries. Pathologic findings include classic granulomatous angiitis with Langhans’ or foreign body giant cells, necrotizing vasculitis, or a lymphocytic vasculitis. The initial event that primes the inflammatory cells is not known. However, the final pathway of inflammation leads to occlusion of the involved blood vessel, thrombosis, and, ultimately, ischemia and necrosis of the territories of the involved vessels. Limited data suggest an association with systemic viral illnesses or a state of altered host defense and PACNS. Duna and colleagues8 analyzed 168 reported cases of PACNS and found that 29 of these were associated with an illness characterized by an immunosuppressive state, including corticosteroid therapy, lymphoproliferative or myeloproliferative disorders, and human immunodeficiency virus (HIV) infection. In addition, a variety of pathogens have been documented in association with CNS arteritis, including varicella zoster virus (VZV), HIV, and cytomegalovirus.9–11

It is likely that in the setting of altered host defense mechanisms or in a predisposed patient, a pathogen escapes immune defense mechanisms and induces arteritis. In support of this hypothesis is the well–defined clinical syndrome of post–herpes zoster ophthalmicus contralateral hemiplegia. In this syndrome, a contralateral hemiplegia occurs weeks to months after VZV infection of the trigeminal ganglion and nerve, apparently resulting from the retrograde spread of VZV to intracranial vessels. Viral particles have been identified in the cytoplasm and nuclei of smooth muscle cells within the walls of affected vessels. Human immunodeficiency virus infection has been similarly described in such a setting.10,12

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Signs and Symptoms

The clinical signs and symptoms of PACNS are nonspecific and reflect the diffuse and often patchy nature of the pathological process. The course of the illness is also variable with presentations ranging from hyperacute to chronic and insidious. In patients with the disease variant GACNS, characterized by a presentation of chronic meningitis and a small–vessel distribution, signs or symptoms might precede diagnosis by 3 years or more.6,13

The most common symptoms of PACNS are headaches, followed by neurologic deficits. The headache varies in description, intensity, and pattern. It is usually chronic and insidious. We believe that thunderclap headaches are not a feature of PACNS and their presence should indicate a diagnosis of RCVS.2 Other symptoms include cognitive impairment, stroke, and transient ischaemic attacks occurring in 30% to 50% of patients with PACNS (Box 2).6,13 Strokes are usually multiple and vary in age. Cranial nerve can be rarely affected, in addition to myelopathy, seizures, and ataxia.