By Alan Z. Segal, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
In this retrospective review and meta-analysis of reported cases of cerebral amyloid angiopathy (CAA), the investigators suggested that the risk of intracerebral hemorrhage can be quantified by the type of symptoms the patient presents with, but there remain many questions around the accuracy of diagnosis of CAA without pathological verification.
Sanchez-Caro JM, Martinez de Ubago IL, de Celis Ruiz E, et al. Transient focal neurological events in cerebral amyloid angiopathy and long-term risk of intracerebral hemorrhage and death: A systematic review and meta-analysis. JAMA Neurol 2022;79:38-47.
Cerebral amyloid angiopathy (CAA) is a well-recognized cause of intracerebral hemorrhage (ICH). “Amyloid spells” are short-lived neurological symptoms, which may be difficult to distinguish from transient ischemic attacks (TIAs).
According to the classic version of this phenomenon (recognized initially by Steven M. Greenberg in 1993), positive sensory symptoms spread in a Rolandic pattern, from the lips to the fingertips and hand (known as a “cheiro-oral” distribution). A classic case of this, in which a 69-year-old woman was treated with warfarin after “failing” multiple antiplatelet regimens as the result of recurrent events, was presented as a New England Journal of Medicine Clinical Pathological Conference (NEJM CPC) in 1996.1 As a resident following the case, I had the pleasure of providing clinical follow-up, which was included in the publication.
The specific cause of transient spells related to CAA is unknown. The prevailing theory suggests that microhemorrhages in the cerebral cortex set off cortical spreading neuronal depression, similar to migraine aura. In the current report, a more widely inclusive definition of “amyloid spells,” referred to as transient focal neurological events (TFNEs), is proposed, with a wider constellation of clinical phenomena. As the authors noted, misdiagnosis of TFNEs as TIAs can lead to improper treatment with antithrombotic medication, as demonstrated in the NEJM CPC, potentially exacerbating, rather than treating, the problem.
The authors studied 26 patients in a retrospective review from 2010 to 2020 derived from their own experience at tertiary referral centers in Madrid and Barcelona, Spain. The remainder of the cohort (n = 222) were abstracted from a review of cases reported in the literature, with a total study sample of 248.
Spells were characterized according to symptom type: sensory (74%), motor (43%), language/speech (40%), visual (7%), and headache (10%). The authors suggested this distribution mitigates against the classic sensory description, since 26% of patients had no sensory complaint and among the 74% who had sensory symptoms, less than half of these had isolated sensory-only events. They also observed that many patients had “negative” symptoms (sensory loss or motor weakness) as opposed to “positive” complaints, such as tingling numbness. Based on these results, the authors concluded their data “render the classical concept of positive sensory spreading episodes obsolete.”
Other notable baseline characteristics in the cohort included hypertension in 41%, previous ICH in 15%, and antithrombotic therapy in 20%. A smaller number of patients had a history of dyslipidemia (18%) with only 12% treated with statin therapy (which has been associated with hemorrhagic stroke).
The authors used the modified Boston Criteria to determine the level of certainty of the CAA diagnoses, with the vast majority (n = 142) having possible CAA and 96 having probable CAA. Only seven had probable CAA with supporting pathology and three had definite CAA (autopsy-proven disease).
The major finding of the study was that there was a statistically significant association between two factors and subsequent ICH. Motor TFNEs produced a risk ratio of 2.08 and antithrombotic use produced a risk ratio of 3.61. Symptomatic lobar ICH occurred in 75/248 patients (39%). The authors cautioned there may have been an overestimation of ICH risk, since patients with ICH, previously thought to have TIAs, could be reclassified as CAA with TFNEs, strengthening the connection retrospectively.
Death occurred in 31 patients (16%). Not surprisingly, lobar hemorrhage increased the risk of death threefold, while the presence of cortical superficial siderosis (known to be a bad prognostic factor in CAA) also led to tripling the mortality risk.
COMMENTARY
This study raises more questions than it answers. Not surprisingly, antithrombotic therapy poses a danger of ICH in patients with TFNEs suspicious for underlying CAA. But the authors do not address the issue of antiplatelet therapy, which would be more commonly prescribed in TIA patients, rather than antithrombotic treatment. The study does not provide insight into the risk of single antiplatelet therapy or, more importantly, the risk of dual antiplatelet therapy, typically with short-term aspirin and clopidogrel followed by aspirin or clopidogrel monotherapy. Large trials, such as POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke), support this regimen in minor stroke and TIA, with proven benefit regardless of any possible CAA-TFNE misdiagnosis.2
Furthermore, it is less clear why motoric CAA-related TFNEs raise ICH risk. The authors suggested that, because CAA has a posterior predilection, patients with motor TFNEs must have more extensive disease, affecting anterior (pre-central) as well as posterior sensory regions. The authors also suggested sensory TFNEs may be more likely to be diagnosed as CAA-related TFNEs when, in fact, they were “mimics,” since sensory symptomatology can be nonspecific. Logically, if sensory events suspected to be CAA-related TFNEs actually were not such, they would not be associated with ICH risk.
However, the uncertainty is far more concerning. Not only can it be questioned whether TFNEs actually were CAA-related, there can be questions whether the majority of this cohort who has “possible” CAA actually had CAA at all. Lobar hemorrhage also can be caused by hypertension, which was present in 40% of this population. Without a gold standard to diagnose CAA in the absence of pathology, and without a hard and fast conclusion that TFNEs are CAA-related, it becomes highly speculative to draw any conclusions about specific subsets of TFNEs and the risk of ICH.
Similar uncertainty persists in the management of patients with atrial fibrillation (AF) and possible CAA. Although there is no definitive answer, patients with AF and high stroke risk (calculated according to CHADS2 score) may benefit from anticoagulation despite cortical microbleeds, while others with high bleeding risk (with prior lobar ICH or cortical siderosis) may more appropriately avoid anticoagulation, even in the presence of AF.
REFERENCES
- Greenberg SM, Edgar MA. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 22-1996. Cerebral hemorrhage in a 69-year-old woman receiving warfarin. N Engl J Med 1996;335:189-196.
- Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018;379:215-225.
