Brachial artery aneurysm and bilateral posterior circulation strokes in a young child with tuberous sclerosis complex

Abstract

Although tuberous sclerosis (TS) may affect many organs, vascular manifestations involving medium- and large-size vessels are rare. We present a young child with known TS who presented with bilateral posterior circulation infarcts and subsequently was found to have right-hand ischaemia secondary to a thrombosed brachial artery aneurysm. A wound on his right middle finger failed to heal with conservative management, and digital subtraction angiography and MR angiogram demonstrated a lack of bypass target with microcollateral supply of the forearm only. The right middle digit ischaemia was initially managed with right middle finger disarticulation at the metacarpophalangeal joint, but the wound failed to heal and the patient proceeded to a thumb-sparing carpo-metacarpal amputation. Aneurysms, stenotic-occlusive disease and embolic stroke are rare but important complications of TS.

Background

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic condition characterised by multiorgan benign tumours or hamartomas formed due to inappropriate activation of mammalian target of rapamycin signalling.¹ TS has a prevalence of approximately 1 in 6000 to 10,000 worldwide.^{2 3} Prominent features include angiofibromas, hypomelanotic macules, cardiac rhabdomyomas, cortical tubers, glial tumours, renal angiomyolipomas and retinal hamartomas.⁴

Dysplastic proliferations of small blood vessels within angiomyolipomas that are associated with microaneurysms and risk of haemorrhage are frequent and well recognised.⁵ However, anomalies of medium- and large-size vessels are rare, yet associated with life- and limb-threatening complications.⁵ Aneurysm formation and stenotic-occlusive disease involving the aorta, intracranial vessels and peripheral arteries are very infrequent but important complications in individuals with TS, including young children. Extracranial artery aneurysms are exceedingly rare.⁶

The importance of cerebellar lesions in TS is increasingly recognised, and cerebellar involvement is associated with more severe clinical and neuroradiological phenotypes.⁷ Between 8% and 46% of individuals with TS have cerebellar tubers, dystrophy-like focal atrophy or hypoplasia and cerebellar abnormalities are typically associated with TSC2 variants. However, posterior circulation strokes have not been described in TS previously to our knowledge.

We present a young child with known TS who presented with bilateral posterior circulation infarcts and was subsequently found to have right-hand ischaemia secondary to a thrombosed brachial artery aneurysm. His ischaemia responded poorly to conservative management and necessitated a thumb-sparing carpo-metacarpal amputation of the right hand.

Case presentation

A young preschool-aged child with a known diagnosis of TS presented to the emergency department with suspected seizures described as extensor tonic stiffening associated with ataxia and vomiting. There was no history of recent illness or infection, and his medications and ketogenic dietary therapy had been stable. On examination, he was alert and afebrile with normal vital signs, including blood pressure. His head circumference was 47.7 cm (tracking between the 25th and 50th centile). His cranial nerve examination was normal although because of his pre-existing language delay, his speech was not assessed. His power and tone in all four limbs were normal, but his reflexes were generally diminished. His plantar responses were flexor bilaterally. His gait was mildly ataxic for age. No dysmetria or intention tremor was observed.

TSC had been diagnosed after he presented at 1 year of age with hypomelanotic macules and infantile spasms, and his brain MRI demonstrated multiple cortical tubers and subependymal nodules. He was found to have a maternally inherited pathogenic in-frame deletion variant in TSC2 (c.5238_5255del, p.His1746_Arg1751del). His infantile spasms were treated with vigabatrin and high-dose prednisolone with incomplete response, but subsequently abated on the ketogenic diet. Multiorgan surveillance on initial presentation demonstrated cardiac rhabdomyomas, a bicuspid aortic valve, dilatation of the ascending aorta and a small patent foramen ovale. His renal ultrasound scan and ophthalmological examination were normal. At 2 years of age, he had significant expressive and receptive language delay. He had double syllable consonant babble but no meaningful speech and similarly delayed social communication skills.

An acute brain MRI for suspected raised intracranial pressure demonstrated restricted diffusion in the posteroinferior right cerebellar hemisphere, posterosuperior and inferolateral left cerebellar hemisphere, and anterior superior right thalamus. The cerebellar lesions were associated with pial enhancement, and the findings were most consistent with multifocal infarction, suggestive of embolic pathophysiology (figure 1). MR angiogram demonstrated normal intracranial and neck vessels, with no evidence of dissection or thrombus (figure 2). An echocardiogram to evaluate the heart as a potential source of emboli demonstrated the multiple left and right ventricle rhabdomyomas were similar in size to 1 year prior, with a previously recognised bicuspid aortic valve and ascending aorta dilatation. There was no evidence of an intracardiac thrombus, and Holter monitoring showed sinus arrhythmia only. A thrombophilia screen did not demonstrate a prothrombotic disorder (table 1). The child was started on aspirin for secondary stroke prophylaxis.

Figure 1.

(A) T2-weighted axial image demonstrating T2 hyperintensities of the posteroinferior right and left inferolateral cerebellar hemispheres (white arrows). (B) T2-weighted axial image demonstrating T2 hyperintensity of the superior left cerebellar hemisphere (white arrow); a pre-existing cortical tuber is also evident (dashed white arrow). (C) T2-weighted axial image demonstrating new T2 hyperintensity of the anterior superior right thalamus, in addition to pre-existing cortical tubers (dashed white arrows). (D) Diffusion-weighted image demonstrating restricted diffusion of the superior left cerebellar hemisphere lesion (white arrow), which was confirmed on the apparent diffusion coefficient map (E) (white arrow). The thalamic and other cerebellar lesions demonstrated in images A–C similarly showed restricted diffusion. (F) T1-weighted MPRAGE sequence demonstrating pial enhancement of the inferior right and inferolateral left cerebellar lesions (white arrows).

Figure 2.

Reconstruction images of MR angiogram demonstrating anatomy and patency of the circle of Willis and intracranial vasculature (A) and neck vessels (B).

Table 1.

Results of coagulation studies and thrombophilia screen

Test	Result	Normal range
Activated partial thromboplastin clotting time (APTT)	30 s	25–37 s
Prothrombin ratio (PR)	0.9	0.8–1.2
Fibrinogen	4.4 g/L (H)	1.5–4.0 g/L
Dilute thrombin clot time (DTCT)	14 s (L)	15–20
Anti-thrombin assay	>120% (H)	80–120
Protein C (functional)	86%	70–120
Protein S (functional)	>110% (H)	65–110
Activated protein C (APC) resistance	2.3	>2.0
Prothrombin variant 20 210G>A	Negative

Over the next 2 days, his parents reported intermittent blue discolouration of his right hand and persistently reduced movement. He had macrodactyly of his right middle finger, but no other growth asymmetry. His right arm power, tone and reflexes were normal. His right hand was comparatively cool, and Buerger’s test was positive with rubor evident. His right brachial pulse was absent below the elbow. An ultrasound demonstrated expansion of the right brachial artery into a heterogeneous mass 2×2×3.8 cm with mixed echogenicity in keeping with a large, thrombosed aneurysm. He underwent a CT angiogram of the chest, abdomen and pelvis which showed a small and thready right subclavian artery, axillary artery and proximal portion of the brachial artery and a mixed density laminated thrombus in the medial right upper arm. Collateral vessels were seen around the shoulder girdle with faint enhancement of the radial artery and some distal hand branches, and no other aneurysms were identified. Aspirin was changed to prophylactic enoxaparin. Thrombolytic therapy was considered in a multidisciplinary setting, but considering anticoagulation is usually an effective treatment for limb ischaemia in small children, the risk of haemorrhagic transformation of his cerebellar infarcts and limited experience of thrombolytic therapy in young, preschool-aged children, the patient was managed conservatively.

The patient re-presented 3 weeks later with a dusky and swollen right middle finger associated with pain. A microcollect wound from his right middle finger during his earlier admission had failed to heal. On examination, the distal right middle finger was ischaemic to the level of the distal phalanx. Digital subtraction angiography and MR angiogram confirmed occlusion of the distal axillary artery, thrombosis of the proximal brachial pseudoaneurysm and only microcollateral supply of the forearm with no suitable bypass target evident (figure 3).

Figure 3.

Digital subtraction angiography demonstrating (A) occlusion of the distal axillary artery and brachial artery by the thrombosed pseudoaneurysm (black arrow), the profunda artery provides collateral supply to the forearm (white arrow) and (B) poor opacification beyond the distal humerus with relative absence of the radial and ulnar arteries. (C) MR angiogram demonstrating fusiform expansion and occlusion of the brachial artery with enhancement surrounding the aneurysm (white arrow). There is early filling of the vein which is dilated and tortuous indicating an underlying arteriovenous communication. (D) T1-weighted fat-saturated postcontrast image demonstrating T1 hyperintense clot within the brachial artery aneurysm (white arrow).

After stabilisation of the level of infarct, the patient underwent right middle finger disarticulation at the metacarpophalangeal joint. Despite wound washouts, debridement and antibiotics, healing of the amputated wound was poor and complicated by osteomyelitis. Repeat MR angiogram 6 months later showed static occlusion of the distal axillary artery and pseudoaneurysm with only a small vessel along the radial aspect of the wrist, which remained inadequate for an interposition graft, and the patient proceeded to a thumb-sparing carpo-metacarpal amputation.

Outcome and follow-up

Six months after his right transmetacarpal amputation, the child uses his right thumb-palmar grip to hold objects and feed himself. He continues to have physiotherapy input and has been referred to the Artificial Limb Centre. He continues to have a wide-based gait without ataxia in primary stance. He is averbal but can follow one-step commands. He demonstrates joint attention and enjoys symbolic play. His attention span is limited for his age, and he demonstrates early symptoms of attention deficit/hyperactivity disorder.

Discussion

We present a young boy presenting with two rarely described, severe complications of TSC: a thrombosed right brachial pseudoaneurysm with limb ischaemia and multifocal posterior circulation infarcts.

TSC affects nearly all organ systems, and the clinical manifestations depend on the target organ affected and the extent of damage brought about by the lesions.⁸ TSC is caused by mutations in the TSC1 or TSC2 genes which encode the intracellular proteins hamartin and tuberin, respectively. The hamartin-tuberin complex is an endogenous repressor of mechanistic target of rapamycin (mTOR) activity. mTOR is a central, anabolic, signalling pathway for cell proliferation, nutrient uptake and transcriptional and translational control. The enzymatic activity of the complex is encoded by TSC2, and TSC2 variants are associated with more severe neurological phenotypes.⁹

Vascular manifestations of TSC are well described with angiomyolipomas being the most common vascular abnormality.⁵ Angiomyolipomas result from overgrowth of small, thick-walled vessels, adipose tissue and smooth muscle. Aneurysms and stenotic-occlusive disease in medium to large vessels are infrequently described, especially in extracranial vessels.^{6 10} The abdominal aorta is the most common site for peripheral arterial aneurysms, and aneurysms in the axillary, subclavian and iliofemoral arteries have only rarely been reported.^{6 11–14} In most cases of axillary aneurysms reported to date, there has been adequate collateral supply for bypass and only one case of amputation has been reported to our knowledge.^12–15

The mechanism of arterial aneurysms is considered to be disruption of the vasa vasorum by vascular hamartomas.¹⁵ The histopathology of resected aneurysms shows fibroelastic intimal hyperplasia and atrophy of the medial smooth muscle and elastic fibres, attributed to ischaemia.

Vascular complications have been reported within TSC pedigrees, with one report of two monozygotic triplets presenting with carotid artery aneurysms.¹⁰ The triplet’s maternal grandmother had died from a ruptured intracranial aneurysm and was suspected to have TSC also. Screening has been recommended in all patients with TSC and palpable vascular masses, hypertension or abdominal pain. In the case reported, the child’s mother has had a normal vascular examination, recent MR brain and CT angiogram which have not identified any medium-large vessel disease.

Posterior circulation strokes have not been described in TS and the most common cause in children is vertebral artery dissection.¹⁶ Rhabdomyomas have been postulated as a cause for embolic stroke in TSC; however, most of the cases described were only imaged with CT, and therefore, this hypothesis has not been well substantiated.¹⁷ Most cardioembolic strokes occur in the anterior circulation, but approximately 10% of posterior circulation infarcts in adults have a cardioembolic source.¹⁸ Cerebellar tubers are an important differential diagnosis in children with TSC, especially children with a TSC2 mutation; however, in the case reported, the acute-onset cerebellar symptoms and signs, extent of restricted diffusion, presence of the thalamic infarct, reactive pial enhancement and evolution of the lesions favoured cerebellar embolic infarcts (figure 4). Investigations did not identify thrombophilia or an embolic source; however, the concomitant presentation of posterior cerebellar infarcts and thrombosis of his brachial artery aneurysm suggested that the child was in a hypercoagulable state prior to presentation. The ketogenic diet has been associated with reduced distensibility of blood vessels associated with raised cholesterol levels during the first 12 months of the diet; however, the child had been on the ketogenic diet for 11 months at the time of presentation, and his cholesterol levels were normal.¹⁹

Figure 4.

MRI of posterior circulation infarcts on 5 days after initial MRI. (A) T2-weighted axial image demonstrating reduced T2 hyperintensity and mild volume loss of the posterior inferior right cerebellar and lateral inferior left cerebellar hemispheres(white arrows). (B) T2-weighted axial image demonstrating reduced T2 hyperintensity of the anterior superior right thalamus (white arrow); cortical tubers are shown as previously. (C and D) Diffusion weighted and apparent diffusion coefficient axial images demonstrating resolution of diffusion restriction of the superior left cerebellar infarct(white arrows).

The case highlights rare but significant vascular manifestations of TS which occur in young children and throughout the lifespan of individuals with TS. Vascular manifestations may be particularly important to consider in young children starting the ketogenic diet. We describe the unusual presentation of posterior circulation embolic infarcts, the possibility of a cardioembolic source and important differentiating radiological features from cerebellar tubers which are relatively common in TS.

Learning points.

• Aneurysms and stenotic-occlusive disease can occur in medium to large vessels in young children with tuberous sclerosis (TS) and may require operative management.

• Posterior circulation embolic infarcts may arise from cardiac rhabdomyomas in TS and can be differentiated from cerebellar tubers based on radiological features.

• Vascular manifestations may be particularly important to consider in young children starting the ketogenic diet.

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