Cerebral Arteriopathy and Ischemic Stroke in a Pediatric MYH11 Patient

Abstract

Objectives:

Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2.

Methods:

A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI.

Results:

A 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed “broomstick-like” straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall.

Discussion:

This case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.

INTRODUCTION:

Arteriopathy is the leading cause of childhood acute ischemic stroke.¹ The identification of genetic syndromes that may have a phenotype with cerebral arteriopathy is important for stroke diagnosis, clinical management, and family counseling. The α-smooth muscle actin isotype 2 (ACTA2) mutation has been associated with prominent vascular and brain parenchymal changes that increase the risk of acute ischemic stroke. Other smooth muscle cell (SMC) genetic mutations such as MYH11, have been associated with familial thoracic aortic aneurysm dissection and patent ductus arteriosus (PDA).² We present a case of a 12-year-old girl with a MYH11 mutation who exhibited a phenotype characteristic of ACTA2 arteriopathy and presented with acute ischemic stroke.

CASE PRESENTATION:

A 12-year-old girl with history of PDA presented with left hemi-neglect, hemiplegia, and dysarthria (National Institute Health stroke scale = 16). A CT angiogram showed a right middle cerebral artery occlusion. Thrombolysis with alteplase (0.9 mg/kg) was administered after two hours of symptom onset. Since symptoms did not improve after the infusion of the bolus of alteplase, mechanical thrombectomy (MT) was performed after 2.5 hours of symptom onset. TICI2b was achieved after four passes and a thrombus was retrieved with the last MT. She improved after the procedure and was discharged to acute rehabilitation.

A comprehensive stroke workup that included a hypercoagulable panel, a transesophageal echocardiogram, an electrocardiogram, and cardiac telemetry was negative. A lower extremity ultrasound did not show deep venous thrombosis. Despite MT, a brain MRI showed infarction of the right middle cerebral artery territory and some characteristics specific to ACTA2 mutation (figure, panel B).

Figure.

Comparison of the diagnostic angiogram of the MYH11 patient and control. Compared to the control (panel A, red dotted line), the internal carotid artery has a decreased curvature (panel B, red dotted line). The distal branches of the anterior cerebral artery have an irregular rectilinear course (panel B, arrow). The proximal posterior cerebral artery has a small area of stenosis (panel B, arrowhead). Proximal middle cerebral artery irregular notches are visualized on digital substraction angiography (panel C, arrows) and narrowing of the origin of the anterior temporal artery (panel C, arrow). Fluid-attenuated-inversion-recovery imaging at 10-month after the stroke shows a large area of cystic encephalomalacia (panel D) and a V-shaped anterior corpus callosum (Panel D, arrowhead). A 7T-MRI acquired 6-months after the stroke shows thickening of the arterial wall on coronal T1 and T1+Gd imaging (panels E and F, arrows) and areas of focal hyperintensity (T1) and mild middle cerebral artery enhancement (T1+Gd) in sagittal views (panels G and H, arrows). Time-of-flight imaging shows the rectilinear shape and course of the posterior cerebral arteries on 7T-MRI (panel I, arrowheads).

She had a family history of thoracic aortic dissections: mother at 27 and maternal cousin at 20 years old. A three-generation pedigree showed that the maternal grandmother, mother, maternal cousin, and 16-year-old sister carry the same pathogenic splice site mutation: MYH11 IVS32G>A. DNA sequencing and copy number variation analysis for ACTA2 mutations were negative.

Five and ten-months post-stroke she experienced two episodes suggestive of transient ischemic attacks: worsening left hemiparesis while showering and after exercise. Both episodes resolved without evidence of new strokes on MRI. Electroencephalograms performed each time were negative for seizures.

A high-resolution 7T MRI performed three and six months after the stroke showed thickening of the right MCA wall. An area of T1 hyperintensity was suggestive of focal dissection (figure, panels E–H). Time-of-flight imaging and digital subtraction angiography showed “straightening” of the cerebrovasculature (figure, panels A, B, and I).

DISCUSSION:

Patients with MYH11 mutations commonly have thoracic aortic aneurysms, PDA and SMC dysfunction syndrome, and do not present with acute ischemic stroke. This SMC arteriopathy is not characterized by a specific cerebrovascular phenotype. The case described in this report exhibits characteristics that resemble another SMC mutation: ACTA2. The phenotypic characteristics of ACTA2 Arg179 pathogenic variants include abnormal straightening of the cerebrovasculature.³ We identified similar “broomstick-like” arterial segments in the vascular imaging of this patient (figure, panels A, B, and I). ACTA2 patients may also have brain parenchyma abnormalities such as a “V-shaped” anterior corpus callosum and cystic-like white matter lesions.^3,4 The case described in this report also exhibited these parenchymal abnormalities (figure, panel D). SMC dysfunction and “stiffer” vessels of ACTA2 patients lead to reduced cerebral autoregulation.³ The patient experienced recurrent episodes of stroke-like symptoms after being exposed to situations of increased vascular demand such as showering and exercise. The onset of symptoms on these circumstances suggests impairment of vascular autoregulation. In this case report a patient with a MYH11 mutation exhibited a similar phenotype to patients with ACTA2 mutations: straightening of the cerebrovasculature, brain parenchymal changes and decreased tolerance to increased vascular demand due to poor autoregulation.

The right middle cerebral artery on digital subtraction angiography showed “notches” with a banding pattern of the entire arterial segment (figure, panel C). This has been described in children with focal arteriopathies and acute ischemic stroke.⁵ Additionally, 7T-MRI showed thickening of the vascular wall, similarly described in patients with ACTA2 mutations.⁶ T1 imaging also showed hyperintensity of the distal MCA six months after the stroke, which is highly suggestive of a focal dissection (figure, panels E–H).⁷ We hypothesize that the SMC dysfunction due to a MYH11 mutation can lead to focal cerebral steno-occlusive arteriopathy, and increased vascular rigidity. MT may be more challenging as patients may be prone to develop dissections. However, it is unclear if the dissection was the result of the SMC vasculopathy or if it was a complication of MT in the setting of an underlying vasculopathy. MT should be performed with extreme caution in pediatric patients with suspected underlying arteriopathy.

Only one report has documented a MYH11 mutation in a two-year old girl with acute ischemic stroke and moyamoya-like vasculature. This patient had a novel missense mutation in the MYH11 gene.⁸ Initially the patient had straightening of the arterial circulation, and later developed a “moyamoya” pattern of collaterals as result of progressive occlusion of the proximal middle cerebral arteries. Based on our 7T-MRI imaging, it could be possible that some MYH11 and ACTA2 patients progress into complete MCA occlusions as result of neointimal cellular hyperplasia and thickening of the arterial wall with increased collagen deposition, which leads to luminal stenosis and stroke.⁶ In the case described in this manuscript, the arterial wall was thickened and arteries were straightened. This presentation suggests a monogenic form of focal cerebral steno-occlusive arteriopathy which may lead to acute ischemic stroke.