Spectrum of Transient Focal Neurological Episodes in Cerebral Amyloid Angiopathy
Multicentre Magnetic Resonance Imaging Cohort Study and Meta-Analysis
Background and Purpose—Transient focal neurological episodes (TFNE) are recognized in cerebral amyloid angiopathy (CAA) and may herald a high risk of intracerebral hemorrhage (ICH). We aimed to determine their prevalence, clinical neuroimaging spectrum, and future ICH risk.
Methods—This was a multicenter retrospective cohort study of 172 CAA patients. Clinical, imaging, and follow-up data were collected. We classified TFNE into: predominantly positive symptoms (“aura-like” spreading paraesthesias/positive visual phenomena or limb jerking) and predominantly negative symptoms (“transient ischemic attack–like” sudden-onset limb weakness, dysphasia, or visual loss). We pooled our results with all published cases identified in a systematic review.
Results—In our multicenter cohort, 25 patients (14.5%; 95% confidence interval, 9.6%–20.7%) had TFNE. Positive and negative symptoms were equally common (52% vs 48%, respectively). The commonest neuroimaging features were leukoaraiosis (84%), lobar ICH (76%), multiple lobar cerebral microbleeds (58%), and superficial cortical siderosis/convexity subarachnoid hemorrhage (54%). The CAA patients with TFNE more often had superficial cortical siderosis/convexity subarachnoid hemorrhage (but not other magnetic resonance imaging features) compared with those without TFNE (50% vs 19%; P=0.001). Over a median period of 14 months, 50% of TFNE patients had symptomatic lobar ICH. The meta-analysis showed a risk of symptomatic ICH after TFNE of 24.5% (95% confidence interval, 15.8%–36.9%) at 8 weeks, related neither to clinical features nor to previous symptomatic ICH.
Conclusions—TFNE are common in CAA, include both positive and negative neurological symptoms, and may be caused by superficial cortical siderosis/convexity subarachnoid hemorrhage. TFNE predict a high early risk of symptomatic ICH (which may be amenable to prevention). Blood-sensitive magnetic resonance imaging sequences are important in the investigation of such episodes.
- cerebral amyloid angiopathy
- cerebral microbleeds
- intracerebral hemorrhage
- superficial cortical siderosis
Sporadic cerebral amyloid angiopathy (CAA) is a common age-related cerebral small vessel disease characterized by the progressive deposition of amyloid-β in the wall of cortical and leptomeningeal small arteries.1 CAA is a common cause of spontaneous lobar intracerebral hemorrhage (ICH) and cognitive impairment in the elderly.1
Another characteristic clinical presentation associated with CAA is with transient focal neurological episodes (TFNE), sometimes termed “amyloid spells.”2–4 Most published cases describe recurrent, stereotyped, spreading paraesthesias, usually lasting several minutes.2,3 The recognition of TFNE is of clinical importance because they may have diagnostic value as the most common clinical presentation of CAA other than ICH and may precede symptomatic ICH,5 a risk that could be reduced by avoiding antithrombotic use after misdiagnosis as a transient ischemic attack. The available evidence on TFNE in CAA consists of only case reports and small case series (<10 patients),2,3,6–8 which may be subject to publication bias, limiting their generalizability.
Our aims were to determine the prevalence, clinical features, neuroimaging correlates, and future ICH risk associated with CAA-related TFNE in a multicenter CAA cohort. We hypothesized that TFNE are common in CAA and that they signify a high risk of future symptomatic ICH. We pooled our results with all previously published studies identified in a systematic review.
Subjects and Methods
We included consecutive patients with CAA diagnosed at 4 stroke centers over defined time periods. The hospitals were University College London Hospitals NHS Foundation Trust (London) (March 2003–September 2011), Addenbrooke's Hospital (Cambridge) (July 2002–March 2010), Cliniques Universitaires Saint Luc (Brussels) (December 2003–April 2010), and Université Catholique de Louvain (August 2005–March 2009). At participating centers, magnetic resonance imaging (MRI) scanning is routine for all cases of suspected CAA, unless there are contraindications. Our inclusion criteria were: possible, probable, or definite CAA, defined according to the Boston criteria (Supplementary Table I);9 and a clearly documented history of transient (≤24 hours), fully resolving, focal neurological episodes with no known alternative explanation other than CAA (eg, structural brain lesion, atrial fibrillation, extracranial or intracranial stenosis). We classified TFNE into 2 categories: (1) predominantly positive focal symptoms (“aura-like” spreading paraesthesias, positive visual phenomena, or limb jerking); and (2) predominantly negative focal symptoms (“transient ischemic attack–like” sudden-onset limb weakness, dysphasia, or visual loss). We excluded patients without an adequate medical history or imaging, those not meeting the criteria for CAA, and those with nonfocal transient symptoms (eg, generalized seizures, confusion, disorientation).
Cases were ascertained using multiple overlapping methods from prospective clinical databases and radiological reports; 172 patients with possible (n=54), probable (n=115), probable with supportive pathology (n=2), or definite (n=1) CAA were included. Two patients were excluded because of an alternative explanation of TFNE (1 with significant carotid stenosis, 1 with sepsis), 2 because an adequate history was not available, and 11 because episodes were not focal.
Demographic and clinical data were collected using standardized forms. Follow-up information on recurrent cerebrovascular events (including ICH) was obtained from prospective databases and medical records.
MRI Acquisition and Analysis
The MRI protocol was standardized in each hospital. Imaging was at 1.5-T field strength for all patients and included T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and T2*-weighted gradient-recalled echo sequences. For some patients, susceptibility-weighted imaging and diffusion-weighted imaging were available. All MRI scans were performed after the TFNE. Images were reviewed blinded to clinical data. Hemorrhagic lesions, ischemic lesions (chronic or acute), and white matter changes (leukoaraiosis) were recorded according to predefined standardized criteria. The presence and distribution of cerebral microbleeds (CMB) were evaluated on T2*-weighted gradient-recalled echo images using the Microbleed Anatomic Rating Scale.10 Previous symptomatic ICH was defined as a symptomatic stroke syndrome associated with imaging evidence of a corresponding ICH (>5 mm in diameter).11 Asymptomatic previous ICH (>5 mm in diameter) was noted. Convexity subarachnoid hemorrhage (cSAH) was defined as linear hypointensity in the subarachnoid space affecting ≥1 cortical sulci of the cerebral convexities on T2* gradient-recalled echo/susceptibility-weighted imaging sequences with corresponding hyperintensity in the subarachnoid space on T1-weighted and/or fluid-attenuated inversion recovery images. Cortical superficial siderosis was defined as linear residues of blood products in the superficial layers of the cerebral cortex showing a characteristic “gyriform” pattern of low signal on T2* gradient-recalled echo images without corresponding hyperintense signal on T1-weighted or fluid-attenuated inversion recovery images. The distribution of superficial siderosis and cSAH was classified as focal (restricted to ≤3 sulci) or disseminated (≥4 sulci).12 Leukoaraiosis was assessed with the 4-step simplified Fazekas rating scale from 0 to 3 (0, no lesions; 1, focal lesions; 2, early confluent; 3, confluent).13 All MRI lesions in the cerebral location corresponding to the clinical features of the TFNE were documented. For patients with a symptomatic ICH after their TFNE, we determined whether the location of the recurrent ICH corresponded to the likely anatomic origin of preceeding TFNE.
Systematic Review: Search Strategy, Selection Criteria, and Data Extraction
We undertook a systematic review of all published cases of sporadic CAA with clearly documented TFNE and no known alternative explanation other than CAA. Articles published in full in any language were identified through a search of PubMed and Embase (January 1970–October 2011; Supplementary Table II). Reference lists from all included articles also were searched for relevant publications. We extracted and used individual patient data from each study when available (including follow-up data on ICH).
Survival analysis was used to examine the time to symptomatic ICH from the start of TFNE using Kaplan-Meier analysis. Cox proportional hazard analyses and log rank tests were used to compare the time to symptomatic ICH according to whether patients had experienced predominantly positive or negative symptoms. The proportional hazards assumption was tested to ensure that there was no evidence of nonproportionality (P>0.2). Multivariable Cox proportional hazards analyses were performed after adjusting for gender and age. Other statistical tests were used as indicated: continuous variables were compared using Student t test (normally distributed) or Mann-Whitney U test (non-normally distributed) and categorical variables using χ2 tests or Fisher exact test.
All statistical tests were 2-sided. Analyses were performed using Stata 11.2 (StataCorp LP). We prepared this report according to STROBE guidelines for observational studies.14
Multicenter Cohort Study
We identified 172 patients with CAA; of these, 25 (definite CAA=1; probable CAA with supporting pathology=2; probable CAA=18; possible CAA=4; 14.5%; 95% confidence interval [CI], 9.6%–20.7%) had a history of TFNE, meeting the study inclusion criteria (Table 1).
Clinical Features of the Episodes
Thirteen patients (52%) had predominantly positive (“aura-like”) symptoms; 12 (48%) had predominantly negative (“transient ischemic attack-like”) symptoms (Supplementary Table III). The most common positive symptom was transient paraesthesias (with or without numbness) in 8 patients (32%); a gradual spread to continuous body parts was described in 5 of these. Sensory symptoms affected the mouth or hand in all cases, and both regions in 4 cases. Four patients (16%) had limb-jerking episodes and 4 (16%) patients had visual disturbances involving monocular blurred vision, flickering, or flashing lights, transient “zig-zags” (teichopsia), or visual loss. Four (16%) patients had focal weakness and 7 (28%) had dysphasia. Most participants (17/25; 68%) had multiple (≥2) stereotyped episodes. The episodes typically lasted <10 minutes and in 70% of the patients they lasted <30 minutes. In 7 patients (28%), antiplatelets or anticoagulants were started after TFNE.
Neuroimaging Findings and Correlation With Symptoms
All except 1 patient (with pathologically proven CAA) had a brain MRI undertaken after the TFNE (Supplementary Table I); the median time from the episodes to MRI was 7 days (interquartile range, 6.5–30 days). Nineteen patients (76%) had evidence of lobar ICH: 9 patients (36%) had evidence of acute lobar ICH, whereas 10 patients (40%) had evidence of chronic lobar ICH. Only 1 patient had a previous cortical infarct. Multiple strictly lobar CMB were present in 14 patients (58%), cortical superficial siderosis, or cSAH in 14 cases (58%). Diffusion-weighted imaging was available in 17 patients (71%) and susceptibility-weighted imaging was available in 10 patients (42%). Among patients with diffusion-weighted imaging, 7 (41%) were scanned within 2 weeks of the start of TFNE; acute ischemia was noted in only 1 of these patients. In 23 patients (92%; patients 1–4, 6–16, and 18–25) the clinical features of the TFNE could be anatomically correlated with hemorrhagic cortical or cortico-subcortical radiological lesions (Figures 1, 2). Interictal electroencephalography was obtained in 5 patients (patients 1, 8, 13, 17, and 25) and did not show any epileptiform features.
Pathological samples were available in 3 of the 25 patients (patients 5, 17, and 18); hematoxylin and eosin staining and immunohistochemical detection of amyloid-β revealed moderate to severe CAA without vasculitis. In patient 5, who presented with multiple recurrent episodes of sudden numbness of the right hand, a biopsy of the left temporal lobe revealed multiple cortical microinfarcts, Alzheimer-type pathology, and severe CAA (without vasculitis).
Risk of Future ICH
Follow-up data were available in all except 1 patient with TFNE over a median duration of 14 months (interquartile range, 4–35 months), during which 12 of 24 patients (50%) had symptomatic spontaneous lobar ICH; 3 had multiple consecutive ICH. Only 1 patient had an ischemic stroke. For 7 patients with ICH after TFNE (58%), the subsequent ICH was in a cortical area corresponding to the likely origin of their TFNE (based on the clinical presentation). Kaplan-Meier ICH analysis indicated that within 2 months of the TFNE, 37.5% (95% CI, 21.6%–59.7%) of the patients experienced a symptomatic ICH (Figure 3A). Patients with a subsequent ICH did not differ from those without future ICH, either in clinical and imaging characteristics or in antiplatelet or anticoagulant use (data not shown).
Characteristics of CAA Patients With TFNE vs Those Without TFNE
Patients with and without TFNE were not significantly different in age, prevalence of vascular risk factors, antithrombotic use, or previous history of symptomatic lobar ICH (Table 2). Among neuroimaging characteristics, only the prevalence of superficial cortical siderosis was significantly higher in patients with TFNE compared with those without (50% vs 19%; P=0.001). Disseminated cortical superficial siderosis (≥4 sulci) was more than twice as common in CAA patients with TFNE compared with those without (33% vs 14%; P=0.005). There were no significant differences in other neuroimaging findings (acute ischemic lesions, leukoaraiosis, cSAH, presence of multiple lobar CMB, presence of ICH, or CMB count) between patients with and without TFNE.
Systematic Review and Meta-Analysis
We included 21 studies in the systematic review containing data on 68 patients with CAA-related TFNE (Supplementary Figure I). Fifteen studies (6 case series and 9 case reports; n=43) had adequate follow-up data. This population was similar in age, gender, and proportion of cases with a history of symptomatic ICH to our multicenter cohort.
A meta-analysis of these 15 studies showed a future risk of symptomatic ICH of 17.2% (95% CI, 8.5%–32.7%) at 2 months (Figure 3B). Once these data are pooled with our cohort, the 2-month risk of symptomatic ICH increases to 24.5% (95% CI, 15.8%–36.9%; Figure 3C). Patients with negative symptoms had a similar risk of future ICH as patients with positive symptoms (hazard ratio, 0.91; 95% CI, 0.40–2.08; P=0.83). There was a borderline significant lower risk of future ICH among patients with previous symptomatic ICH compared with those without (hazard ratio, 0.47; 95% CI, 0.22–1.01).
Previously published studies had a significantly higher proportion of “aura-like” positive spreading sensory disturbances compared with our multicenter cohort (82% vs 36%; P<0.0001; Figure 4).
In our multicenter cohort study we found TFNE in 14% of patients with CAA. Our study confirms previous reports that CAA-related TFNE are mostly recurrent, stereotyped, and brief (usually <30 minutes).2,3 However, unlike published studies, in which “aura-like” sensory episodes seem to be most frequent, in our cohort negative symptoms were just as common. This difference might reflect previous publication bias in favor of CAA cases with spreading sensory phenomena not typical of transient ischemic attacks. All episodes of aura-like sensory symptoms in our cohort (n=8) involved the face or hand; 3 involved the corner of the mouth and the hand consistent with a cortical cheiro-oral syndrome. In 2 of these, cortical siderosis/cSAH were present over the frontal or parietal lobes, whereas the third case had multiple lobar CMB. Although the numbers of cases was small, the cheiro-oral pattern may be rather characteristic of sensory CAA-related TFNE.
The clinical features of the episodes indicate a cortical rather than a subcortical origin; moreover, they were often correlated anatomically with hemorrhagic MRI lesions, including CMB, superficial cortical siderosis, and lobar ICH. Thus, TFNE are probably related to the hemorrhagic rather than the ischemic components of CAA; possible mechanisms include focal seizure-like activity or migraine aura-like cortical spreading depression, as suggested by previously published small case series.2,3,15 Twenty-three patients in our cohort had hemorrhagic imaging findings in a neuroanatomical location, corresponding to their TFNE symptoms; 8 had superficial cortical siderosis, reflecting previous episodes of acute bleeding in the subarachnoid space of adjacent cortical sulci. Three other recent case series also have emphasized the possible role of nontraumatic cSAH in CAA-related TFNE.6,8,16 Our finding that superficial cortical siderosis was significantly more common in CAA patients with TFNE than in those without (P=0.001) provides strong evidence that this pattern of bleeding is likely to be an important cause of TFNE.
Nevertheless, a role for ischemic lesions in CAA-related TFNE cannot be ruled out by our study: small (apparently asymptomatic) ischemic lesions have been detected in vivo in clinically probable CAA,17 and “microinfarcts” are a frequent neuropathological finding in the brains of patients with CAA.1 Because not all cases in our study had diffusion-weighted imaging soon after the onset of TFNE, we may have underestimated the contribution from small acute ischemic lesions.
We report a strikingly high early risk of symptomatic lobar ICH (37.5% at 2 months) after CAA-related TFNE, which we confirmed in a meta-analysis of our data with all published studies. We found only a borderline difference in the risk of ICH among patients with previous symptomatic ICH compared with those without, suggesting that TFNE, rather than simply the presence of CAA with previous symptomatic ICH (with a known recurrent ICH risk of ≈10% per year1) are an independent marker of high early future ICH risk. TFNE in CAA thus may be a clinical marker for cerebral areas of focally active and severe CAA pathology, with more vascular leakage leading to an increased risk of future ICH. This is supported by our finding of a significantly higher prevalence of superficial cortical siderosis in CAA patients with TFNE, because superficial siderosis is hypothesized to result from recurrent bleeding into the subarachnoid space, leading to subpial accumulation of blood-breakdown products. However, the role of superficial siderosis as a prognostic imaging marker of increased ICH risk in CAA requires further study.
Although in 58% of patients with ICH after TFNE the new hematoma was located in a cortical area corresponding to the likely origin of their TFNE (based on the clinical presentation), further work is needed to establish whether this apparent clustering of ICH in brain regions implicated by TFNE symptoms is greater than predicted by chance.
Our study has several potential limitations. We may have underestimated the true prevalence of CAA-related TFNE because of the retrospective study design; further large prospective studies with systematic enquiry about previous TFNE are needed. Some of our CAA cohort may have been misdiagnosed because of the imperfect specificity of the Boston criteria (particularly the “possible CAA” category).9 MRI was performed at different times from TFNE onset; this, combined with the lack of availability of acute diffusion-weighted imaging sequences in all cases, may have influenced the detection of hemorrhagic over ischemic lesions. We also acknowledge the potential for referral, selection, and publication bias in the cases identified in the systematic review. Our multicenter cohort results might not be generalizable to all CAA patients, but only to those presenting to vascular neurology services and those in whom other possible causes of transient focal neurological symptoms have been excluded. Although this study includes the largest number of CAA-related TFNE cases to date, we did not have sufficient statistical power to definitively determine potential predictors for ICH. Finally, an important question is whether CAA patients with TFNE have an increased risk of future symptomatic ICH compared with those without TFNE, but the retrospective design and focus on outcome after TFNE in our study meant that we were unable to undertake this comparison.
We have shown that TFNE are common in CAA and signify a very high early future risk of ICH. Hence, their diagnosis has important clinical implications. Our findings clearly suggest a key role for T2* gradient-recalled echo MRI (or other blood-sensitive sequences) in the investigation of patients with unexplained TFNE, especially in individuals without known risk factors for transient ischemic attack. The very high early risk of lobar ICH after TFNE in CAA may be an opportunity to commence preventive strategies. We suggest clinicians should discontinue and avoid administering antiplatelets or anticoagulants in cases of TFNE with imaging evidence of CAA, even if the episodes seem clinically likely to be ischemic. Because TFNE were observed in patients without a history of symptomatic ICH, they also may prove to be a useful diagnostic marker of CAA, potentially allowing diagnosis earlier in its disease course.1
Sources of Funding
Supported by Greek State Scholarship Foundation (A.C.); Samantha Dickson Brain Tumour Trust and Brain Research Trust (H.R.J.); and Department of Health/Higher Education Funding Council for England (Clinical Senior Lectureship Award), British Heart Foundation and the Stroke Association (D.J.W.). Part of this work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.657759/-/DC1.
- Received March 16, 2012.
- Accepted June 13, 2012.
- © 2012 American Heart Association, Inc.
- Charidimou A,
- Gang Q,
- Werring DJ
- Greenberg SM,
- Vonsattel JP,
- Stakes JW,
- Gruber M,
- Finklestein SP
- Beitzke M,
- Gattringer T,
- Enzinger C,
- Wagner G,
- Niederkorn K,
- Fazekas F
- Knudsen KA,
- Rosand J,
- Karluk D,
- Greenberg SM
- Gregoire SM,
- Chaudhary UJ,
- Brown MM,
- Yousry TA,
- Kallis C,
- Jager HR,
- et al
- Kidwell CS,
- Greenberg SM
- Linn J,
- Halpin A,
- Demaerel P,
- Ruhland J,
- Giese AD,
- Dichgans M,
- et al
- von Elm E,
- Altman DG,
- Egger M,
- Pocock SJ,
- Gotzsche PC,
- Vandenbroucke JP,
- et al
- Kumar S,
- Goddeau RP Jr.,
- Selim MH,
- Thomas A,
- Schlaug G,
- Alhazzani A,
- et al
- Gregoire SM,
- Charidimou A,
- Gadapa N,
- Dolan E,
- Antoun N,
- Peeters A,
- et al