Vascular Ehlers-Danlos syndrome presenting in the ICU as aneurysmal subarachnoid haemorrhage
- 1 Intensive Care Department, Hospital Garcia de Orta EPE, Almada, Portugal
- 2 Neuroradiology, Hospital Garcia de Orta EPE, Almada, Portugal
- Correspondence to Dr Filipe André Gonzalez; filipeandregonzalez@gmail.com
Abstract
Vascular Ehlers-Danlos syndrome is caused by mutations of COL3A1 gene coding for type III collagen. The main clinical features involve a propensity to arterial tears leading to several life-threatening conditions and intensive care unit admission. We, herein, report the case of a 34-year-old woman presenting with an aneurysmal subarachnoid haemorrhage. Endovascular coil treatment was attempted; however, the procedure was complicated by dissection of the left iliac artery and abdominal aorta. Hospital management was marked by a series of vascular and haemorrhagic complications. These events, together with some distinctive physical features and medical history, raised the suspicion of vascular type of Ehlers-Danlos syndrome. Neurological evolution was not favourable, and the patient evolved to brain death. Genetic testing was available postmortem and identified a mutation in the COL3A1 gene. This case illustrates the importance of medical history and clinical suspicion for diagnosis, which often goes unnoticed until major complications occur.
Background
The Ehlers-Danlos syndromes (EDSs) comprise a group of heterogeneous hereditary connective tissue disorders caused by mutations in genes coding for various procollagen types of enzymes involved in the synthesis and processing of collagen. Typically, EDS present with joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. However, EDSs are heterogeneous and over the years, up to 14 clinical phenotypes have been described.1 2 The vascular EDS, previously known as EDS type IV, is inherited as an autosomal dominant trait and is caused by heterozygote mutations of COL3A1 gene located on the long arm of chromosome 2 and coding for type III procollagen. These mutations are particular within each family and make molecular prenatal diagnosis possible for families in which the mutation is known. However, sporadic cases of vascular EDS without a family history of the disease occur in about 50% of patients since the rate of de novo mutations is high.3
The prevalence of vascular EDS is 5%–10% of all EDS types, whose prevalence is estimated between 1/10 000 and 1/25 000. The diagnosis is mainly based on characteristic clinical features and can be complemented by laboratory studies, documenting a deficit in type III collagen or identifying a mutation on the COL3A1 gene. Once type III collagen is constituent of arterial walls, vascular EDS’s main clinical features involve a propensity to arterial tears manifested from easy bruising to arterial dissections, which can lead to several life-threatening conditions.4 Additionally, it is also present in the skin and hollow organs such as digestive tract walls and uterus with colonic perforations and obstetric complications also being common among affected patients. Most patients have distinct facial features characterised by prominent cheek-bones and sunken cheeks along with a small chin and thin nose and lips. The skin appearance is also peculiar, being abnormally thin and translucent with highly visible subcutaneous vessels. Although these are the most common features encountered in patients, the disease is heterogeneous and clinical features vary, reflecting the heterogeneity of mutations responsible for the disease phenotype likewise.3
The arterial complications can affect all anatomical areas with a tendency towards thoracic and abdominal arteries of both large size and medium size. Arteries of the head and neck are also frequently stricken and result in significant morbidity and mortality. Carotid-cavernous fistulae and dissections of vertebral and carotid arteries on their intracranial or extracranial segments are common.3 4 Therefore, vascular EDS should be considered in young patients with ischaemic stroke or intracranial haemorrhage. The prevalence of intracranial haemorrhage is higher than in the general population and is often the result of a ruptured aneurysm which is a common finding in these patients. This disease increases not only the risk of life-threatening vascular complications but also the potential for catastrophic surgical and radiological complications caused by a significant increase in vascular fragility. Hence, when managing arterial complications of vascular EDS, specifically ruptured cerebral aneurysms, it is important to consider each invasive interventions’ risk and benefit. Diagnostic arteriography is contraindicated and both endovascular and surgical treatments of ruptured aneurysms are hazardous procedures.5
About half of intracranial haemorrhages are a consequence of previously identified aneurysms, while the rest can be presented as an unpredictable event or even as the initial disease presentation, making clinical suspicion and differential diagnosis of critical importance, as it can determine significant changes in the management of these patients.3 5
We, herein, report a case of a 34-year-old woman, with an undiagnosed vascular EDS, who presented with a life-threatening subarachnoid haemorrhage due to a ruptured intracranial aneurysm, managed with endovascular treatment and followed by a number of vascular and pulmonary complications. Early diagnosis of vascular EDS can alter patient management; hence, the importance of clinical suspicion for its diagnosis which often goes unnoticed until major complications occur.
Case presentation
A 34-year-old woman presented to the emergency department (ED) with a sudden intense headache, followed by a generalised tonic-clonic seizure witnessed in the ED. A head-CT was promptly requested, which identified subarachnoid haemorrhage with tetraventricular bleeding and hydrocephalus. CT-angiogram showed an intracranial aneurysm of the anterior communicating artery (figure 1). The patient’s consciousness deteriorated from a Glasgow Coma Scale score of 15 to 4, and an emergent surgical procedure was performed to place an external ventricular drain. In the postoperative period, the patient was admitted to the intensive care unit (ICU) under sedation and mechanical ventilation.
Head-CT showing subarachnoid haemorrhage with tetraventricular bleeding and an aneurysm of the anterior communicating artery on CT-angiogram (arrow) with 3D reconstruction (circle).
As a medical history, the patient had a psychiatric condition treated with benzodiazepines and antipsychotic drugs. Past surgical interventions included an abdominal exploratory laparotomy, 7 years ago, due to purulent peritonitis with an undetermined origin, complicated by paralytic ileus and colonic perforation needing a Hartmann’s procedure, with later intestinal transit reestablishment. The patient also had a recent surgical procedure to remove varicose veins of the lower limbs and a caesarean section in 2009, both without complications.
Investigations
On the first 48 hours of ICU admission, arteriography was achieved to perform endovascular coil treatment of the intracranial aneurysm. After puncture of the femoral artery, fluoroscopy imaging suggested a dissection of iliac arteries with extravascular extravasation of contrast media complicating the procedure (figure 2). Consequently, the procedure was interrupted prematurely and coiling of the aneurysm was not completed. The CT-angiogram conducted post angiography confirmed a dissection of the left iliac artery with extravasation of contrast contained in the arterial wall and dissection of the abdominal aorta with rupture of the adventitia layer and extravascular haemorrhage, without active bleeding (figure 3). A conservative strategy with close surveillance was adopted, and a following CT scan, 4 days after the procedure, showed no evolution of the dissection or haemorrhage, but showed a large de novo hepatic hematoma.
Angiography showing extravascular extravasation of contrast and dissection of left iliac artery.
CT showing arterial dissection of left iliac artery and abdominal aorta with retention of contrast post-DSA (A and B) and CT-angiogram without active bleeding (C and D).
A predisposition to vascular fragility was noticed during the ICU stay, as complications of the endovascular procedure, as well as a tendency to bruising, skin ecchymosis and spontaneous or minor trauma-related haematoma formation during bed mobilisations. Considering the vascular fragility along with some distinctive physical features, such as a thin face with prominent cheekbones and clearly visible subcutaneous vessels in the thorax and lower abdomen, the hypothesis of a connective tissue disorder was considered. According to the clinical features and personal medical history, EDS, particularly the vascular type, was the most plausible cause despite the absence of suggestive family medical history. Genetic testing was ordered to investigate the hypothesis of vascular EDS and identified a heterozygote variant in the COL3A1 gene (c.3256-43T>G) which had previously been reported in another patient with vascular EDS.
Outcome and follow-up
The neurological evolution was not favourable and was marked by refractory intracranial hypertension and central hyperthermia. Although the intracranial aneurysm treatment was not achieved through endovascular coiling, given the clinical suspicion of vascular EDS, surgical therapy for aneurysm resection was not considered feasible because of the high probability for a fatal outcome due to potential intraoperative and postoperative complications. The patient’s clinical condition further deteriorated with the occurrence of cerebral vasospasm, complicating the subarachnoid haemorrhage, which resulted in cerebral ischaemia in the right anterior and middle cerebral territory (figure 4). Considering the poor neurological prognosis, surgical control of intracranial hypertension was not achieved and the patient further evolved to brain death 9 days after admission.
Follow-up head-CT conducted a week after the initial bleeding evidencing areas of cerebral ischaemia in the right anterior and middle cerebral territories determining midline shift.
The genetic testing ordered to investigate the hypothesis of vascular EDS was only available postmortem. The mutation identified, although previously reported in another patient with vascular EDS, is not registered on the population databases and so clinical significance remains uncertain. Family members of the patient were referenced to a genetic consultation.
Discussion
This case illustrates the importance of clinical suspicion for the diagnosis of vascular EDS. Given the rarity of the disease and paucity of relevant clinical manifestations during childhood, with easy bruising often being disregarded and characteristic facial features only deemed relevant in retrospect, the disease goes unnoticed until complications occur and diagnosis is considered on a vessel or hollow organ rupture.6 7
Spontaneous colonic perforations are common in early adulthood and most of which affect the sigmoid colon but also the small intestine to a lesser extent.8 Obstetric complications are of concern in female patients arising typically during pregnancy or immediate postpartum period. Uterine rupture or haemorrhage after delivery are more frequent in women with vascular EDS and can lead to fatal outcomes.6 Looking at the medical history of our patient, one can infer that complications frequently encountered at patients with vascular EDS are present and could have arisen the clinical suspicion to investigate the diagnosis earlier. Apart from the physical appearance, the presence of a previous abdominal complication, particularly with a perforation of the sigmoid colon, is a major diagnostic criteria in vascular EDS.2 Our patient had a history of a pregnancy without any complications, however as most complications are related to labour itself, the delivery by caesarean for an unknown motive could have hindered the potential hazards.
The arterial complications are indeed the major cause of mortality among patients with vascular EDS and affect up to 80% of patients by the age of 40 years. In our case, a subarachnoid haemorrhage due to a previously unknown ruptured aneurysm was the fatal complication of the disease. The detection of a vascular lesion threatening vital prognosis can lead to the decision of a planned surgical procedure which is safer when performed outside the emergency context. However, the haemorrhagic risk is elevated in these patients and the decision for surgical treatment is rarely made in the absence of symptoms. So, the value of a regular vascular check-up often leads to unnecessary anxiety and no changes in therapeutic approach.3 In the case of arterial rupture, surgery is often necessary as a life-saving intervention despite the increased rate of complications.
For an aneurysmal subarachnoid haemorrhage, treatment is warranted despite high morbidity and mortality. The literature is conflicting regarding the choice between endovascular or surgical treatment of an intracranial aneurysm in patients with vascular EDS. Endovascular treatment itself carries the risk of arterial dissection and bleeding, and mortality can be as high as in surgical intervention. However, some successful cases of endovascular coiling have been described.5 9 In the case of our patient, endovascular approach was associated with extensive arterial dissection and treatment was not achieved due to early complications during the procedure. At the time of the endovascular technique, the diagnosis of our patient was not suspected yet and previous knowledge of the disease might have changed our approach. Some authors postulate that a surgical approach to aneurysm resection might be achieved without permanent morbidity. Thus, timely diagnosis can influence patient management, especially in the presence of a vascular complication.
In the absence of suggestive family history, the diagnosis is often made in face of a major complication or, not uncommonly, postmortem. However, since there is a high rate of spontaneous mutations, about half of patients have no family history of the disease. Genetic testing confirms the diagnosis by identifying specific mutations in COL3A1 gene. An elevated number of mutations in COL3A1 gene have been described in association with vascular EDS and mutations are particular to each family.6 So, although the mutation identified in our patient was not reported in population databases, it had previously been described in another patient with vascular EDS and along with clinical features justified the diagnosis. Because it was identified only postmortem, other studies such as secretion of collagen III by skin fibroblasts to clarify clinical significance of this mutation were not conducted.
Once identified a mutation in COL3A1 gene, a familial genetic study should be completed because it can influence patient management in the face of disease complications and can elucidate genotype–phenotype correlations. In the absence of disease complications, and since there is no proven specific treatment for vascular EDS, medical intervention should focus on symptomatic treatment and prophylactic measures.10
Learning points
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Vascular Ehlers-Danlos syndrome is a rare condition involving a propensity to arterial tears which can lead to a number of life-threatening conditions and intensive care unit admission.
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The disease and initial clinical features often go unnoticed until major complications occur.
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Clinical suspicion is of crucial importance to make the diagnosis.
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Knowledge of the disease may influence medical approach and decisions regarding treatment of potential complications.
Ethics statements
Acknowledgments
We thank Sara Lança, assistant physician at Intensive Care Department, Hospital Garcia de Orta for conception and revision of the manuscript.
Footnotes
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Contributors All authors contributed to the writing of the article and were involved with the patient’s care. IP: conception of the article, revising intellectual content and drafting of the manuscript. RV: writing of the initial draft. FC: participated in revision of the case and selection of relevant images. FAG: revising and preparation of the final manuscript. All authors read and approved the final manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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