Case studies
Case 5: Spontaneous ICH in the elderly
This is the most severe subtype of stroke, causing death or severe disability in at least 60% of affected individuals (Case 5). Most often in the complication of chronic progressive cerebral small-vessel disease, there is evidence that genetic factors play a role in its pathogenesis. ICH can be more common within families, although not in a clear familial pattern, suggesting that either genetic or shared environ- mental exposures are at play. ICH is frequently cat- egorized according to the location within the brain in which the hematoma arises (Figure 13.3). Hem- orrhages centered in the basal ganglia, thalamus, brain stem, and cerebellum are frequently consid- ered the manifestation of the so-called hypertensive vasculopathy, although factors other than hyperten- sion contribute to their pathogenesis including advancing age, alcohol exposure, and a prior history of stroke. Hemorrhages arising at the cortical–sub- cortical junctions are termed “lobar” in location, and these are most often attributable to underlying CAA, a common small-vessel vasculopathy of the elderly. Chronic hypertension, as well as alcohol abuse and the presence of a prior stroke also play a role in lobar hemorrhage occurrence. Strikingly, the risk of both lobar and nonlobar hemorrhage is elevated in individuals with a history of ICH in a fi rst-degree relative [114].
(a)
(d)
(b)
(e)
(c)
(f)
Fig. 13.3 CT characteristics of intracerebral hemorrhage (ICH). Hematoma location on CT scan of the head is frequently used to characterize location and suggest the etiology of ICH: (a) right basal ganglia; (b) pontine; (c) left thalamic; (d) cerebellar; (e) bilateral lobar;
and (f) occipital lobar ICH.
Case 5
An 83-year-old man with a history of coronary artery disease, status post coronary artery bypass grafting, atrial fi brillation (on warfarin),
hypertension, and hyperlipidemia was brought to the emergency ward (EW) by the EMS after being involved in a car accident. He was reportedly in his usual health until the morning of this admission, when he drove to a local mall with his wife. As per his wife’s report, he showed no signs of illness until he drove onto the highway, where he initially acted
“confused,” looked around in distress, mumbled incomprehensibly, and then suddenly accelerated toward the shoulder, where he collided with the construction blocks left behind. A bystander called 911, and upon arrival, the patient was found to be confused and agitated, with incomprehensible speech, and not moving his right side well. In the
EW, he was found to have Wernicke aphasia, right homonymous hemianopsia, and right upper more than right lower extremity weakness. Urgent noncontrast head CT demonstrated left temporal hematoma, ~20 cc in size, without intraventricular extension or evidence of extensive edema or mass effect. Coagulation testing showed an international normalization ratio (INR) of 3.4, and the patient received an urgent reversal of anticoagulation with IV vitamin K administration followed by infusion of fresh frozen plasma. His repeat INR at 6 hours was 1.6, and head CT at 24 hours showed only slightly more of hematoma expansion (fi nal volume of 25 cc). His clinical exam was stable and improved signifi cantly with regard to motor function. He was discharged to a rehabilitation facility on day 5 with persistent hemianopsia and residual Wernicke-like aphasia.
Differential diagnosis and diagnostic approach Although current standards of acute management of ICH do not require an intensive diagnostic evalua- tion other than to exclude underlying AVM, second- ary prevention strategies may be informed by the distinction of lobar from nonlobar ICH, along with the confi rmation of underlying CAA. Using the Boston Criteria, clinicians can make the diagnosis of probable CAA using clinical and neuroimaging cri- teria alone. These criteria are, in fact, suffi ciently sensitive and specifi c for clinical decision making and have been validated in pathological case series.
Lobar and nonlobar ICHs appear to differ markedly in their risks for recurrence. Up to 10% of lobar ICH survivors have recurrent lobar ICH per year, whereas the rate for nonlobar ICH is closer to 2–4% per year [115]. Accumulating evidence demonstrates that control of hypertension can substantially reduce the risk of recurrent nonlobar hemorrhages and may offer benefi t for patients with lobar ICH. Warfarin may increase the risk of recurrent ICH in survivors of lobar and nonlobar ICH, and the decision to anti- coagulate ICH survivors is therefore one that requires careful attention to risks and benefi ts [116].
Role of genetic variation in disease risk, course and biology
The gene for APOE, well-established as a risk factor for AD, is also a confi rmed risk factor for CAA [117]. Of the three common alleles, e4 and e2 appear to be associated with risk of CAA-related ICH, in contrast to their relationship to AD risk, where e4 is the risk allele, but e2 is actually protective. Patients with pathologically confi rmed CAA-related ICH have higher frequencies of e2 and e4, as do cohorts of individuals with probable CAA by clinical/neuro- imaging criteria. Furthermore, in prospective cohort studies of lobar ICH survivors, the possession of e2 or e4 appears roughly to double the annual risk of recurrent lobar ICH [117].
Genetic counseling and prognosis
Currently, there is no role for genetic testing in bedside decision making for ICH survivors or those at risk for spontaneous ICH. Although APOE geno- type is a risk factor for CAA-related ICH, it is neither sensitive nor specifi c for the diagnosis of CAA. The clinical/neuroimaging-based Boston Criteria are far
more useful in this regard. Although APOE may help differentiate those lobar ICH survivors who are at highest risk for recurrent ICH, the absence of any specifi c preventative strategies for lobar ICH recur- rence makes this information of limited clinical utility. Furthermore, when deciding whether to offer anticoagulation to survivors of ICH who also have atrial fi brillation, currently identifi ed genetic markers of bleeding risk do not appear to confer a risk of ICH suffi ciently high to warrant routine genetic testing for patients at average risk of throm- boembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin- ICH do not support the use of these tests for with- holding anticoagulation in patients with atrial fi brillation [118].
Discoveries, prior to the GWASs era, that common DNA sequence variants in CYP2C9 and VKORC1 play a substantial role in determining an individual’s warfarin dose requirement led to the initiation of randomized clinical trials and an update of the US Food and Drug Administration label for Coumad- inTM/warfarin, suggesting that clinicians consider genetic testing before initiating warfarin [119].
Although these discoveries represent a crucial fi rst step toward the application of genetic information to make anticoagulation safer, it is clear that identi- fying an individual patient’s risk for hemorrhage on anticoagulation, or thromboembolism in atrial fi brillation (and other diseases), will require many more genetic discoveries. Ongoing whole genome association studies of ICH currently being con- ducted by the International Stroke Genetics Consor- tium offer the promise of identifying additional genetic risk factors for ICH and bleeding on warfa- rin. Perhaps, combining novel genetic risk factors with APOE as well as those known to modulate bleeding risk on warfarin may become a helpful bedside approach for screening patients for antico- agulation, whether or not they have had an ICH.
Conclusion
Prevention and treatment of stroke remain among the major challenges in clinical medicine [91].
Although single-gene disorders associated with stroke have been well characterized, disease-specifi c therapies are still limited, and frequently, healthcare
providers are left with little to offer our patients beyond genetic counseling and diagnosis [34]. In addition, single-gene disorders are associated with only a small proportion of all strokes, even those that occur predominantly in the young. The discov- ery of the genetic variants that contribute to the risk of multifactorial stroke, on the other hand, could offer a promise of tackling this problem on a much greater scale [15]. Sets of genetic markers are already being evaluated for risk prediction in cardiovascular disease [20] and prostate [120] and breast cancers [121]. In stroke, such clinical risk assessment could open doors to a new era of primary and secondary prevention, in which individualized risk prediction can clarify bedside decision making for primary and secondary prevention. Furthermore, a major lesson from the initial results of GWASs in other complex diseases is to expect the unexpected: associated genetic variants are generally outside of genes once considered “candidates” and frequently outside of any gene altogether. Unraveling the links between these new genetic risk factors may hold the greatest
hope for fi nally gaining control of the public health epidemic that cerebrovascular disease represents, because it is in these unexpected links that new mechanisms and, ultimately, new drug targets will be found. For now, clinicians are advised to con- tinue to focus on rigorous treatment of all modifi - able risk factors for stroke and to offer thoughtful, competent genetic counseling before obtaining genetic tests in their patients. Systematic genetic screening of individuals at risk for stroke will require further study.