Internal carotid artery dissection in a patient with Ehlers-Danlos syndrome type IV: diagnosis and management

Ehlers-Danlos syndrome (EDS) type IV, also known as vascular EDS, is an inherited connective tissue disorder with an estimated prevalence of 1/100,000 to 1/250,000. In EDS type IV, vascular complications may affect all anatomical areas, with a preference for largeand medium-sized arteries. Dissections of the vertebral and carotid arteries in their extraand intra-cranial segments are typical. The authors report the case of a patient with EDS type IV for whom the diagnosis was established based on clinical signs and who developed internal carotid artery dissection at the age of 44 years. In the absence of a specific treatment for EDS type IV, medical interventions should focus on symptomatic relief, prophylactic measures, and genetic counseling. Invasive imaging techniques are contraindicated, and a conservative approach to vascular complications is usually recommended.

she was discharged and started clinical follow-up with a vascular surgeon, who suspected a connective tissue congenital disease and referred the patient to a geneticist, who established the clinical diagnosis of EDS type IV.
Her family history was relevant, as her brother had a brain aneurysm diagnosed at 17 years, a maternal aunt had an ischemic stroke at 40-45 years, and her maternal grandmother died suddenly due to cardiac arrest at the age of 36 years.Her medical history included umbilical hernia surgery at 21 years of age, resection of uterine leiomyomata at 35 years of age, and operation of varicose veins in the lower limbs at 37 years.
Color Doppler ultrasound showed a thin band a two-phase turbulent flow in left ICA, with hypoechoic material in its lumen filling more than 60% of the diameter of the segment evaluated (Figure 2).She underwent magnetic resonance angiography (MRA) to examine cervical vessels, and results revealed stenosis of about 80% to 90% of the proximal segment of the left ICA, about 2.5 cm above its emergence (Figure 3).
The investigation continued by using other imaging methods and, because the patient was allergic to iodinated contrast, angiography with carbon dioxide was chosen.The scan showed an image compatible

INTRODUCTION
Internal carotid artery (ICA) dissection is a condition that results from the infiltration of blood into the vessel wall.It may affect the subintimal and medial layers and lead to artery stenosis or occlusion, or the sub-adventitial layer, which leads to aneurysm formation. 1Dissections, which usually affect the superior cervical segment of the extracranial ICA and the supraclinoid segment of its intracranial portion, are often caused by trauma 1 .Other possible causes include fibromuscular dysplasia, fibroelastic changes of the intima, cystic fibrosis of the media and connective tissue diseases, such as the Ehlers-Danlos syndrome 1.The Ehlers-Danlos syndrome (EDS) comprises a heterogeneous set of at least 11 syndromes with specific clinical and genetic characteristics resulting from defects in the synthesis or the structure of several types of collagen 2 .The vascular form of the disease is called EDS type IV, which is an inherited dominant autosomal disorder caused by mutations in gene COL3A1, located in 2q32.2, which encodes the pro-alpha 1 chain (III) of the fibrillar collagen type III 3-5.The estimated prevalence of EDS type IV is about 1:100,000 to 1:250,000 in the general population, and there is no ethnic or sex predilections 3,4.Clinically, EDS type IV is characterized by important vascular involvement and a mean life expectancy of 48 years 4 .Vascular complications may affect all anatomic areas, with a preference for large-and medium-sized arteries, and dissections of vertebral and carotid arteries in intra-and extracranial segments are typical events.
EDS type IV is very rare and physicians are not familiar with it.Therefore, the diagnosis is usually made after a catastrophic vascular complication or during autopsy 4 .This report describes a case of EDS type IV in a patient whose most obvious clinical sign was hemiplegia due to spontaneous dissection of the internal carotid artery.The authors also discuss the diagnosis and management of this syndrome in this specific case.

CASE REPORT
A white, married, 44 years old, woman with no history of pregnacy was seen in the emergency department presenting with dysarthria, hemiplegia and hemiparesia of sudden onset in the upper and lower right extremities.Based on symptoms and imaging studies, a diagnosis of ischemic stroke (IS) was made, and she was treated conservatively in an intensive care unit for one week.After that time, with an intimal flap in the bulbar portion of the left ICA and narrowing up to about the beginning of the petrous segment, findings associated with acute dissection of the left ICA.In addition, there was a saccular dilatation measuring 0.5 cm of diameter at about 1.5 cm from the carotid bifurcation, which was suggestive of a pseudoaneurysm (Figure 4).
She has been followed up by a vascular surgeon in the outpatient service, and has been taking antiplatelet agents (clopidogrel, 75 mg/day).At every 6 months, she undergoes ultrasound scanning because of her bicuspid aortic valve; abdominal ultrasound to evaluate the abdominal aorta; and ultrasound scanning of the carotid arteries.She also undergoes treatment with a speech therapists and a physiotherapist due to the sequelae of the ischemic stroke.She was seen by a geneticist, underwent non-directive genetic counseling, and received information about prophylactic measures, risks associated with pregnancy and the and inherited characteristics of EDS type IV.criteria (thin and translucent skin, characteristic facial features and fragility of arterial walls) and at least three minor criteria (joint hypermobility, early onset of varicose veins and family history of sudden death), but she has not had access to specific genetic tests to this date.An American study analyzed a series of 31 cases of EDS type IV and found that 24 patients (77.3%) underwent biochemical tests, 11 (35.5%) had molecular tests and 7 (22.7%)had a clinical diagnosis 12 .
The diagnosis of EDS type IV may be suggested by any ischemic stroke in a young individual 13,14, as the syndrome is usually suspected only after vascular complications 7,9.Intracranial hemorrhages affect 4% of the patients with EDS type IV, and half of these cases are caused by the rupture of previously detected intracranial aneurysms 15 .In a series of 31 patients with EDS type IV, 25% had complications that affected the carotid arteries, and 2 patients had dissections 12 .ICA dissections are clinically characterized by a triad of headache (frontal, orbital or peri-orbital), neck pain and partial ipsilateral Horner syndrome (ptosis and myosis).However, carotid dissection is unilateral in most cases, and the patient rarely presents with the classical triad 1 .About 50% to 95% of the patients with ICA dissection are estimated to have a subsequent stroke.A Brazilian study with 48 patients conducted from 1997 to 2003 found that the mean time interval from symptom onset to ischemic focal deficit was four to five days 16 .
In cases of ICA dissection, the diagnosis of EDS type IV is important for the vascular diagnosis and should define treatment.Defects in collagen type III synthesis make patients highly susceptible to artery or vein ruptures that are difficult to repair surgically 9,12.Therefore, invasive imaging studies 3,17, such as intra-arterial digital subtraction angiography, the reference standard in the investigation of ICA dissection 1,18, are contraindicated.Several non-invasive vascular imaging techniques may be helpful in establishing a diagnosis: extracranial and transcranial Doppler ultrasound and color-coded duplex ultrasound; computed tomography (CT); magnetic resonance (MR); and magnetic resonance angiography (MRA).Ultrasound studies have a joint sensitivity of 95%, but are limited for the visualization of distal ICA dissections.MRI and MRA provide better visualization of morphology and blood flow in the carotid arteries, but also have disadvantages, such as a tendency to overestimate the degree of stenosis, the production of artifacts due to swallowing or patient movements, and a lower capacity to detect acute hematomas 1,16,18 .When

DISCUSSION
The clinical diagnosis of EDS type IV is usually made according to the criteria defined in 1997 during the Villefranche Conference 6-9, shown in Table 1.The presence of two or more major diagnostic criteria suggests the diagnosis, and biochemical or molecular genetic tests should be performed for confirmation. 2iochemical tests evaluate collagen type III by means of electrophoresis of proteins in fibroblasts cultured in material collected for skin biopsy 9 .Molecular tests evaluate DNA directly, and include the complete sequencing of the COL3A1 gene (reference criterion for laboratory investigation because it detects 95% of the mutations that cause the disease 4 ) and the analysis of deletions and insertions more frequently associated with the disease using different techniques, such as polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) 10.In clinical practice, it is very difficult to perform genetic tests to confirm EDS type IV.Currently, biochemical and molecular tests to identify EDS type IV are performed by only 18 laboratories registered in GeneTests, an American site sponsored by the National Center for Biotechnology Information (NCBI), an association of international laboratories that conduct genetic tests approved by the Food and Drug Administration (FDA) 10.In Brazil, despite the National Comprehensive Health Care Policy for Clinical Genetics of the Brazilian Unified Health System, most patients with genetic diseases do not have access to medical geneticists or the necessary genetic testing 11 .The patient in this case report had a clinical diagnosis because she met three major Specifically, the clinical management of patients with EDS type IV should include the adoption of general prophylactic measures: the elimination of intense physical activity, violent sports or diving; the awareness of the vascular risks of pregnancy (maternal death is about 12%); and, ideally, the use of contraception 3 .As EDS type IV is an autosomal dominant trait, patients should receive genetic counseling and be aware that the risk of recurrence for their offspring is 50% [3][4][5] .

CONCLUSION
Vascular surgeons should keep in mind the possibility of EDS type IV and its severe vascular complications.Patients with this disease require special care before, during and after operation.combined, non-invasive vascular imaging studies are the best option for patients with EDS type IV 3,12,17 .
In the case reported here, Doppler ultrasound, MRA and carbon dioxide angiography confirmed ICA dissection, and the patient did not have to undergo surgery.Studies in the literature suggest that the risk of weakening arterial walls during surgery is high because of the fragility of vessels in patients with EDS type IV.Standard vascular sutures usually lead to tearing, and the best choices for these patients are arterial ligatures, as long as they do not compromise the blood supply to the organ, or a carotid bypass.Other precautions include the delicate and atraumatic handling of the artery and the use of soft, coated clamps or occlusion balloons instead of standard clamps 1,3,9,12 .However, no conclusive data about the use of stents are available 12 .
In general, patients that had spontaneous ICA dissection should receive prolonged anticoagulation treatment with heparin and warfarin for 3 to 6 months to prevent artery-to-artery embolism, and the treatment should be discontinued when there is full arterial recanalization 1,16 .In a small percentage of cases, recanalization is not achieved after six months, and surgical revascularization may be used 1 .In patients with EDS type IV, treatment should be conservative whenever possible, and surgery should be limited to unavoidable, life-threatening situations 3,12,17 .Minimally symptomatic aneurysms should not be operated on electively unless there are signs of rapid expansion and imminent rupture 12 .Patients with aneurysms treated conservatively should be examined at intervals of 3 to 6 months using non-invasive vascular imaging techniques 12 .When there is no aneurysm, the usefulness of routine vascular screening is controversial 3 , but some authors recommend a yearly follow-up visit for a careful physical examination, echocardiogram, carotid and abdominal ultrasound, as well as chest and abdominal CT and MRI in case there are incidental findings 3,12 .
Several studies have compared anticoagulants and antiplatelet agents for cases of cervical artery dissections, and both medications seem to have similar results 19 .Additionally, a recent multicenter study with patients with EDS type IV showed that the use of celiprolol, a β(1)-adrenoceptor antagonist with a β(2)-adrenoceptor agonist action, reduces the incidence of dissection or arterial ruptures threefold 20 .Although celiprolol was approved for use in Brazil in 1996, 21 it is not easily found in the market in this country 22 , and it is usually imported, which complicates its use by patients.

Figure 1 .
Figure 1.Patient in reported case.Thin facial features, thin lips, thin skin and paucity of subcutaneous tissue.

Figure 2 .
Figure 2. Doppler ultrasound scan of carotid artery shows hyperechoic material in left ICA lumen (arrow) and narrow area of two-phase, turbulent flow (*).

Figure 3 .
Figure 3. MRA of cervical vessels shows narrowing of left ICA segment (arrow).