Autonomic Dysfunction in the Setting of CADASIL Syndrome

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited cause of stroke. CADASIL syndrome is a nonsclerotic angiopathy resulting from a mutation of the NOTCH3 gene on chromosome 19p13, encoding a receptor expressed by vascular smooth muscle cells.¹ This mutation results in migraine, recurrent ischemic stroke, affective disorders, and dementia, with migraine often manifesting earliest.^2,3

The onset of stroke symptoms occurs typically in ages ≥ 60 years with some patients experiencing stroke as early as in their 30s.^1,4 Presentation varies among patients even within the same family.⁵ CADASIL syndrome is frequently mistaken for other more common neurologic conditions due to the low prevalence of CADASIL syndrome, reported to be between 2 and 5 per 100,000.^3,6 The cumulative nature of multiple ischemic episodes seen in 85% of symptomatic individuals leads to disability. Dementia is often hallmarked as one of the features of end-stage CADASIL syndrome.⁷ Extent and severity of brain tissue damage are shown to be the most critical factors of clinical symptoms.⁸ There is no specific treatment for CADASIL syndrome other than addressing risk factors.⁹

Symptoms are traditionally described to be limited to the central nervous system (CNS); however, reports of other organ system effects exist. Twenty-six percent of premature mortality relating to CADASIL syndrome is sudden unexpected death, which several authors have postulated could be attributed to cardiac events.^10,11

The NOTCH3 gene encodes a protein expressed during gastrulation and in the CNS during embryological development. The expression of this protein decreases with time and has limited expression in adulthood.¹² The pathophysiology of CADASIL syndrome includes myriad changes, including cerebral vessels narrowed by intimal thickening due to expansion of the extracellular matrix, degeneration of smooth muscle cells of the cerebral vessel walls, and osmiophilic material deposition in patients with CADASIL syndrome.¹³ Granular osmiophilic material in the vascular basal lamina can be observed on electron microscopy of patients with CADASIL syndrome and are used for diagnostic purposes.¹⁴

CADASIL syndrome often presents a diagnostic dilemma for physicians and is easy to misdiagnose in the early stages. The diagnostic dilemma arises given the subacute onset of CADASIL syndrome with vague early presenting symptoms, such as headache, prior to more specific findings (ie, multiple early strokes or transient ischemic attacks [TIA]). Patients presenting with CADASIL syndrome may be misdiagnosed with other neurologic conditions, including migraine or multiple sclerosis (MS).¹⁵ Especially in the case of MS, lesions visible on magnetic resonance imaging (MRI) may be differentiated by the higher rates of temporo polar lesions seen in CADASIL syndrome in comparison with those in MS.³

It is important to consider CADASIL syndrome in patients presenting at a young age with stroke due to the compounding effects of multiple ischemic episodes and subsequent motor/sensory and neuropsychologic deficits. This necessitates increasing awareness of CADASIL syndrome in the neurologic and radiologic community and the importance of educating families of patients on the importance of being evaluated. This diagnostic dilemma can lead to delay in appropriate therapy and control of related modifiable risk factors, including hypertension, hyperlipidemia, etc. Delays in initiation of anti-stroke pharmacotherapy can lead to additional morbidity and mortality in these patients.

The radiology of CADASIL syndrome is unique and particularly important due to the possible confusion with MS. MRI is an important tool in the evaluation of the cerebral pathology of CADASIL syndrome, revealing white matter and microangiopathic signal abnormalities, indicative of ischemic infarcts, lacunar strokes, and diffuse leukoencephalopathy.^13,16 MRI lesions are often seen in the basal ganglia, thalamus, external capsule, and pons.⁷ The lesions also are seen in the periventricular region, explaining its misperception as MS.¹⁷ In addition, cerebral microhemorrhages have been seen. To further differentiate these lesions, the anterior temporal lobe should be observed for gliosis or hyperintensities, which correlates with CADASIL syndrome.¹⁸ Location of hyperintensity in the temporal lobes, relative sparing of the occipital/orbitofrontal white matter, corpus callosum, subcortical u-fibers, and cortex is helpful in differentiating from other etiologies, such as microvascular white matter ischemic disease, MS, and mitochondrial encephalopathy with lactic acidosis and strokelike symptoms (MELAS).

Case Presentation

A patient aged > 50 years presented to the emergency department (ED) due to numbness of the right perioral area, gait difficulties, difficulty speaking, and increasing right lower extremity weakness with no numbness or paresthesia. The patient’s medical history is relevant for CADASIL syndrome, hypertension, prior cerebrovascular accident, recurrent TIAs, multinodular goiter with a history of radioactive iodine treatment, and neurogenic bladder controlled with oxybutynin since age 30 years. The patient had a significant stroke history: the first stroke occurred at age 36 years and 3 more strokes at ages 38, 44, and 53 years and 4 TIAs over that period. This patient reported no recent headache or memory changes and had no history of smoking, alcohol, or recreational drug use. Family history was pertinent for the mother’s death secondary to stroke, with a history of multiple strokes beginning at a young, undetermined age and no major motor, sensory, or neuropsychologic deficits prior to her death. A sister and first cousin had been diagnosed with MS.

On triage in the ED, stroke alert was called but tissue plasminogen activator was not given due to time eligibility. The patient’s numbness and weakness were improved within 7 hours, but she continued to have difficulty with dysarthric speech and unsteady gait following this incident. Antihypertensive medications were discontinued on admission to allow for permissive hypertension to improve cerebral blood flow. A brain MRI revealed bilateral increased T2 fluid-attenuated inversion recovery (FLAIR) signal in the anterior temporal lobes, confluent increased T2 FLAIR signal in the periventricular/deep white matter, bilateral basal ganglia chronic lacunar infarcts, and several chronic microbleeds (Figure 1). There was no evidence for an acute infarct on the MRI. Recrudescence of prior stroke symptoms secondary to CADASIL syndrome was suspected as a primary diagnosis with a differential of TIA.

Starting the second day of admission, the patient had intermittent sinus bradycardia with the lowest heart rate (HR) in the range of 40 beats per minute (bpm) while awake with an unchanged neurologic examination. Each episode was transient, lasting less than an hour per staff documentation. The electrocardiogram (ECG) on admission demonstrated normal sinus rhythm in the range of 70 to 80 bpm.