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.

Table 1.

Cerebral arteriopathies

Intracranial atherosclerosis Small-vessel diseases from chronic hypertension, diabetes (lipohyalinosis and leukoaraiosis) Inflammatory/immunological vasculitis (e.g. giant cell arteritis, Takayasu arteritis, primary angiitis of the CNS, polyarteritis nodosa, scleroderma, systemic lupus erythematosus, Behçet's’s disease, Churg–Strauss syndrome, Kohlmeier–Degos disease, Eale’s retinopathy, Spatz–Lindenberg disease, vasculitic cerebral amyloid angiopathy) Infectious arteritis (e.g. tuberculosis, syphilis, cysticercosis, herpes zoster, HIV, bacterial meningitis) Reversible cerebral vasoconstriction syndromes (Call–Fleming syndrome, benign angiopathy of the CNS, postpartum angiopathy, and cerebral vasoconstriction associated with vasoactive drug use, recurrent thunderclap headaches, etc) Posterior reversible encephalopathy syndrome Moyamoya disease Intracranial cerebral artery dissection Transient cerebral arteriopathy of childhood Genetic, inherited and developmental anomalies (e.g. Fabry’s disease, fibromuscular dysplasia, dolichoectasia, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal-recessive arteriosclerosis with subcortical infarcts and leukoencephalopathy (CARASIL), sickle cell disease, COL4A1 mutation, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), Osler–Weber–Rendu syndrome, Ehlers–Danlos syndrome type IV, Marfan syndrome, neurofibromatosis type 1, retinal vasculopathy with cerebral leukodystrophy (RVCL), pseudoxanthoma elasticum, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), osteogenesis imperfecta)

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 CT- or MR- angiography, 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 medium-vessel cerebral arteriopathy, who developed clinical worsening within days of presentation. RCVS was suspected, but conditions such as PACNS and Moyamoya disease could not be excluded. On the basis of the idea that nimodipine may reverse RCVS-associated vasoconstriction and thereby prevent clinical decline, all patients received intra-arterial nimodipine treatment. Patients eventually diagnosed with RCVS showed prompt reversal of vasoconstriction with intra-arterial nimodipine, unlike those eventually diagnosed as PACNS, Moyamoya, and intracranial atherosclerosis. The authors (8) propose that in suspected RCVS patients with clinical worsening, the vasodilator response to intra-arterial nimodipine could be used a diagnostic test to confirm RCVS and exclude mimics. Given the historic difficulties in diagnosing medium-sized cerebral arteriopathies and the potential impact of accurate diagnosis on subsequent management, these results are relevant. However, over 95% of RCVS patients have benign clinical outcome despite initial clinical or angiographic progression (9–12). It is important to consider instances in which an interventional diagnostic procedure may be warranted, the diagnostic accuracy, efficacy, and safety of such procedures, and the appropriate steps in diagnosing RCVS and other medium-vessel arteriopathies.

Linn et al. (8) suspected RCVS on the basis of headache and angiographic abnormalities. Only five of nine patients were ultimately diagnosed with RCVS, showing how difficult it can be to diagnose arteriopathies in the acute setting. Historically, it has been challenging to distinguish RCVS from mimics such as PACNS because of overlapping features such as headache and angiographic irregularities (13–14). Recent studies characterizing RCVS (9–12) and PACNS (15–16) suggest that diagnostic accuracy in the acute setting can be enhanced by considering specific characteristics of the presenting headache, the clinical setting, and brain and vascular imaging findings. Patients with RCVS invariably have a dramatic presentation with recurrent and severe thunderclap headaches; brain imaging can be normal or shows ‘watershed’ territory infarcts, convexity subarachnoid hemorrhages, lobar hemorrhages, and reversible brain edema; and cerebral angiography shows smoothly tapered segmental arterial narrowing (sausage-on-a-string appearance) of the circle of Willis arteries and their branches. Further, RCVS frequently occurs in specific clinical settings (e.g. the post-partum state), and cerebrospinal fluid examination results are invariably normal. Patients with PACNS typically have insidious-onset subacute headaches and encephalopathy; 97% have abnormal brain imaging findings, including scattered small-vessel infarcts, white matter changes and leptomeningeal enhancement; and less than a third develop proximal-vessel angiographic abnormalities. Other arteriopathies such as Moyamoya disease and intracranial atherosclerosis are not associated with recurrent thunderclap headaches, and they often have characteristic imaging features, for example the cigar-like narrowing of the intracranial internal carotid artery with a ‘puff of smoke’ appearance of the lenticulostriate collateral pathways (Moyamoya disease), or calcifications and irregular focal stenosis of 1–2 proximal arteries (intracranial atherosclerosis).

Given the above, it is likely that most patients with RCVS can easily be diagnosed acutely, without the need for follow-up angiography to document reversibility. The problem of distinguishing RCVS from mimics will therefore only apply to a minority with atypical features. In such patients, an interventional diagnostic procedure can only be justified if urgent diagnosis is imperative for management, for example if RCVS still needs to be excluded before proceeding to brain biopsy or immunosuppressive therapy for PACNS. Linn et al. (8)’s results suggest a diagnostic role for intra-arterial nimodipine infusion. However, the retrospective nature and small sample size of this study, the reliance on follow-up angiography alone for final diagnosis in all but one patient, and the potential for irreversible vasoconstriction due to secondary inflammation in some RCVS patients (17) suggest the need for further studies to determine the diagnostic accuracy of this procedure.

Many authors including Linn et al. (8) have proposed a therapeutic role for intra-arterial approaches such as the application of nimodipine or other calcium-channel blockers, milrinone, or balloon angioplasty, in patients with probable RCVS (18–22). The efficacy of such procedures may be overestimated because most RCVS patients do well despite initial angiographic or clinical progression. The vasodilator response to calcium-channel blockers can be transient and followed by ‘rebound’ vasoconstriction, and opening the artery incurs the risk of reperfusion injury, brain edema, and hemorrhage (18). Hence at present it seems reasonable to withhold intervention if the only markers for progression are isolated recurrent headaches, minor worsening of the neurological examination, or angiographic progression without clinical change. Simple observation with pain control is usually adequate in most patients, and oral calcium-channel blockers may reduce the frequency and intensity of headaches. Only in RCVS patients judged to have ‘significant’ clinical worsening despite conservative management, as in the study under discussion (8), should interventional strategies be considered. Of course, waiting too long may render any intervention ineffective, and therefore much depends on clinical experience and judgment.

The study by Linn et al. (8) emphasizes the need to develop non-invasive tools to diagnose cerebral arteriopathies in the acute setting. Advanced MRI techniques may provide clues to diagnosis; for example, high-resolution 3-Tesla MRI may be useful to distinguish inflammatory from atherosclerotic or other cerebral arteriopathies (23), and contrast-enhanced MRI findings of vessel wall thickening and enhancement may suggest vasculitis (24). Cerebral vasoreactivity tests may prove useful for diagnosing RCVS (12). A prospective multicenter collaborative study pooling clinical, laboratory, radiographic, and pathological data of patients with acute cerebral arteriopathies is needed to validate existing preliminary diagnostic criteria (13), develop diagnostic and prognostic biomarkers, and lay the foundation for treatment trials (25). The fact that Linn et al. (8) accumulated nine patients with arteriopathy-associated clinical worsening within 2.5 years, and that recent publications reported relatively large numbers of arteriopathy cases at single centers (9–12,15–16), suggest that prospective studies and clinical trials are feasible.