Autonomic Dysfunction in the Setting of CADASIL Syndrome

The patient was asymptomatic and normotensive during the episodes of bradycardia. The patient had not yet resumed any antihypertensives. An echocardiogram was unremarkable with a left ventricular ejection fraction of 55 to 60%, normal anatomy, and no significant pericardial effusion. Carotid artery duplex examination demonstrated patent vessels with anterograde vertebral flow bilaterally. Due to the unknown cause of the bradycardia, the patient was discharged with a 14-day ambulatory cardiac monitor, advised to continue statin, aspirin, and lisinopril, and given a referral to continue with outpatient physical therapy and occupational therapy.

The patient’s ambulatory cardiac monitoring showed dominant sinus rhythm, with the HR in the range of 40 to 170 bpm with an overall average 70 to 80 bpm. The patient’s HR spent 5% of the recording time under 50 bpm and 14% of the time > 100. There was no evidence of heart block. No symptoms were recorded per the patient’s symptom diary during the entire 2 weeks of monitoring. Further follow-up showed that the patient presented to a primary care practitioner 1 month later with similar symptoms and was sent to the ED of an outside hospital without admission. The ECG was again unremarkable, demonstrating only sinus bradycardia with normal T waves, QT interval, without ST elevations or depressions. About 3 weeks later, the patient presented to the ED again with chest pain and was discharged with a diagnosis of atypical chest pain possibly related to anxiety without findings consistent with acute coronary syndrome (ACS).

Discussion

This patient with CADASIL syndrome and significant stroke history with cardiac symptoms demonstrates 3 important discussion points: the difficulty of early diagnosis, high rates of morbidity/mortality, and the need for further research into the cardiac effects of CADASIL syndrome. Due to this patient’s bradycardic episodes while being monitored on telemetry, it is possible that the cause of the strokelike symptoms was a TIA, secondary to decreased perfusion pressure, explaining the lack of acute ischemia on imaging. With regards to the history of thyroid dysfunction, this particular episode of bradycardia was unlikely to be related as the thyroid-stimulating hormone was reflective of subclinical hyperthyroidism with T4 levels within normal limits.

This case demonstrates a potential link between CADASIL syndrome and autonomic dysfunction. Similar to general stroke patients, patients with CADASIL syndrome are at an increased risk of hypoperfusion injury secondary to cardiovascular and autonomic dysfunction. This raises a question of initial and surveillance screening tests on diagnosis of CADASIL syndrome. It may be appropriate to obtain routine echocardiogram and ECG and other arrhythmia screening tests in these patients, especially during or following an ischemic episode. However, more evidence is required to support creation of a formal recommendation.

In a study of cardiac rhythm abnormalities in a half-million adults, 1.57% of women aged 55 to 64 years were found to have rhythm abnormality with 0.27% having a bradyarrhythmia.¹⁹ In the setting of neurologic disease, ECG changes such as arrhythmias and repolarization changes are regularly noted.²⁰ However, it is unlikely that the bradycardia would be causing the brain lesions. In CADASIL syndrome, there is relative sparing of the occipital, orbitofrontal subcortical white matter, subcortical fibers, and cortex. Specifically, within CADASIL syndrome, a study of 23 patients showed no ECG changes regarding infarction/ischemia, conduction disturbances, or arrhythmias compared with that of controls.²¹

Further research into the cardiac effects of CADASIL syndrome is needed. As CADASIL syndrome is primarily a disorder of the vasculature, the disease has potential to affect the heart in addition to the brain.¹ This theory is well supported by the embryologic effects of the NOTCH3 receptor pathways, which are responsible for the development of the cardiovascular system.²² Anecdotal evidence supports this theory as few case reports have been published that describe various cardiac abnormalities in patients with CADASIL syndrome, including myocardial infarction (MI), conduction abnormalities, and arrhythmias.^{2, 23-25}

There have only been 2 published studies regarding investigations into CADASIL syndrome and cardiac disease. The first paper was a case-control study that investigated ECG changes in the setting of CADASIL syndrome. The study found no evidence for MI, ischemia, conduction disorder, or arrhythmias in patients with CADASIL syndrome.²¹ Unfortunately, this study was underpowered and limited in scope, only investigating a single ECG recording from 23 patients with CADASIL syndrome in a single clinic.²¹ Other cardiac markers, such as echocardiogram, stress test, and contractility, and longitudinal cardiac outcomes were not investigated in this study.²¹ The second paper was also a case-control study by Rufa and colleagues that investigated HR variability and other ECG changes during a 10-minute rest recording on 23 patients with CADASIL syndrome and compared the results to 22 age- and gender-matched patients in good health.¹¹

This study found reduced HR variability and an increased ratio of low-frequency to high-frequency variability, which the authors claimed demonstrates autonomic dysfunction in patients with CADASIL syndrome.¹¹ Rufa and colleagues concluded that patients with CADASIL syndrome are at higher risk for cardiac arrhythmias.¹¹ This study also found no evidence for MI, ischemia, conduction disorder, or arrhythmias in the patients with CADASIL syndrome compared with that of age-matched controls.¹¹ Similar to the first paper, this study is underpowered, only looks at a single timepoint recording, and uses incomplete and indirect measurements of cardiac function.

There is a need for a longitudinal review of cardiac outcomes in the CADASIL syndrome population to determine whether these patients require additional surveillance or prophylaxis. While the variability in HR of our patient cannot be definitively attributed solely to CADASIL syndrome, the subsequent admissions demonstrate that long-term monitoring may be warranted.

Conclusions

CADASIL syndrome is an autosomal dominant NOTCH3 signaling disease that affects the small vessel vasculature and leads to early ischemic events, headache, dementia, and death. CADASIL syndrome is frequently misdiagnosed due to insidious onset and vague presenting symptoms. Delay in diagnosis often results in nonoptimized medical management. Current guidelines recommend following poststroke protocol and minimizing individual risk factors by using antiplatelet, antihypertensive, and dyslipidemia medications. This case demonstrates a classic presentation of CADASIL syndrome with lesser described cardiac symptoms. Few cases of unusual cardiac symptoms in the setting of CADASIL syndrome have been reported. The relationship between cardiovascular disease and CADASIL syndrome is not well described. Further research is needed to elucidate any links between CADASIL syndrome and cardiovascular disease and to optimize management for these patients.