Diagnostic challenges in RCVS, PACNS, and other cerebral arteriopathies

In the field of vascular neurology, few conditions pose greater diagnostic and therapeutic challenges than the intracranial cerebral arteriopathies (Table 1). They are a common cause of secondary headaches (vascular headaches), and perhaps the most common cause of stroke, accounting for 20–35% of strokes in young adults (1–2) and over 50% in children (3). In older adults, intracranial atherosclerosis alone accounts for 10–50% of stroke (4), and lipohyalinotic small-vessel disease another 15%. Intracranial arteriopathies can be classified according to etiology or the affected age group. From the diagnostic standpoint it is convenient to classify them according to the size of the affected artery as medium-vessel or small-vessel; the former induce abnormalities visible on transfemoral angiography, whereas the latter affect distal small vessels that are beyond the current resolution of angiography. Some arteriopathies, such as the reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS), can affect both the medium and the small vessels. The diagnosis of small-vessel cerebral arteriopathies requires a high level of clinical suspicion, astute interpretation of imaging findings, and a detailed examination of the skin, eye, or other organ systems. They are often disclosed by the presence of recurrent small-vessel infarcts in patients with chronic headaches, skin lesions, known systemic infections, or MRI findings of scattered small-vessel infarcts or micro-hemorrhages with or without white matter lesions. Several small-vessel arteriopathies (e.g. CADASIL (5); see Table 1) have established diagnostic criteria or can be confirmed with specialized tests, such as skin or brain biopsy, or genetic, immunological, or microbiological tests. Some small-vessel arteriopathies can be comfortably diagnosed with clinical-imaging correlation, for example lipohyalinotic small-vessel disease in patients with chronic hypertension, a lacunar stroke syndrome, and a corresponding small cerebral infarction in the distribution of a ‘penetrator’ artery. Others such as PACNS continue to pose diagnostic challenges because definitive diagnostic tests such as brain biopsy are often false-negative, and tests such as cerebrospinal fluid examination and angiography have low specificity (6). Medium-vessel cerebral arteriopathies are typically disclosed when CTor MRangiography, performed during the routine evaluation of stroke or headache, reveal arterial irregularities. Alternately, they are suggested by clinical clues such as recurrent thunderclap headaches; stroke in the setting of recent headache, infection, stereotyped transient ischemic attacks, recent pregnancy, or illicit drug use; or imaging findings of unilateral deep border zone infarcts (7). Once arterial irregularity is documented, it becomes imperative to determine the etiology in order to initiate appropriate therapy. Unfortunately, in the absence of validated diagnostic criteria or confirmatory tests for most medium-sized arteriopathies, the approach remains variable and uncertain. Older adults are usually assumed to have intracranial atherosclerosis if they have vascular risk factors or calcified proximal cerebral arteries. In children, the diagnosis is particularly challenging given the need for serial angiography or advanced imaging (e.g. 3-Tesla MRI) to diagnose conditions such as transient cerebral arteriopathy and intracranial dissection that are more common in childhood. Young adults with intracranial arterial irregularities typically undergo a battery of expensive diagnostic tests, most of which have relatively low sensitivity and specificity, often culminating in a brain biopsy or empirical treatment for cerebral ‘vasculitis’, which is not without risks. Linn et al. (8) report a study of nine patients with headache, variable clinical deficits, and a mediumvessel cerebral arteriopathy, who developed clinical