Case Report: Cerebral venous thrombosis revealing celiac disease

Celiac disease (CD) is an autoimmune enteropathy resulting from intolerance of an individual genetically predisposed to gluten. It has a large clinical polymorphism ranging from a classic digestive clinical presentation due to the malabsorption syndrome to extra-intestinal symptoms. Among the hematologic abnormalities, venous thromboembolic disease (VTE) has been reported, and they are most often located in the abdomen or lower limbs, but the cerebral localization was exceptionally described. We report a case of CD revealed by cerebral thrombophlebitis. A 44-year-old patient with no medical history and no drug intake, presented with hemiplegia followed by a status epilepticus in a context of apyrexia, initially hospitalized in intensive care. Magnetic imaging resonance displayed a cerebral venous thrombosis of the sigmoid sinus requiring anticoagulant treatment, then transferred to our department for the etiological investigation. On questioning, the patient reported chronic diarrhea and weight loss with no other associated symptoms. The examination revealed an underweight patient with pale conjunctiva, improvement of her deficit symptoms, and no other abnormalities. Laboratory tests noted biological signs of malabsorption. The thrombophilia assessment revealed a protein C deficiency with a slight increase in anticardiolipin antibodies and anti-Beta 2 glycoprotein 1 antibodies. Immunological tests noted positives anti-transglutaminase and IgA anti-endomysium antibodies. Duodenal biopsy demonstrated villous atrophy. After ruling out the other causes of VTE, the diagnosis of cerebral venous thrombosis secondary to CD was retained. Early diagnosis and treatment of CD improves the quality-of-life for patients and may spare them various long-term or even fatal complications.


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Introduction
Celiac disease (CD) is an autoimmune enteropathy resulting from intolerance of an individual genetically predisposed to gluten. It affects 0.6-1.0% of the world population. 1 It has a large clinical polymorphism ranging from a classic digestive clinical presentation due to the malabsorption syndrome; diarrhea and abdominal pain; to extra-intestinal symptoms. 2 It requires lifelong adherence to a gluten-free diet.
Among the hematologic abnormalities, venous thromboembolic disease (VTE) has been reported in the literature, with a 25% higher risk in patients with CD compared with the general population. 3 VTE is most often located in the abdomen or lower limbs, but the cerebral localization has been exceptionally described. 4 Here, we report a case of CD revealed by cerebral venous thrombosis discovered while exploring a status epilepticus. This clinical situation remains exceptional and unusual during CD.

Case report
A 44-year-old Tunisian female patient, housewife, with no medical history and no drug intake, presented with hemiplegia followed by a status epilepticus in a context of apyrexia, initially hospitalized in intensive care. Neuroimaging displayed a cerebral venous thrombosis of the superior sagittal sinus ( Figure 1) requiring anticoagulant treatment (low-molecular -weight -heparin 100 IU/kg Â 2/24 h followed by Warfarin for 6 months. After treatment, the patient was transferred to our department of Internal Medicine for the etiological investigation. On examination, the patient reported chronic diarrhea and weight loss with no other associated symptoms. Physical examination revealed an underweight patient (BMI:16.9) with pale conjunctiva, improvement of hemiparesis, and no other abnormalities. Laboratory tests noted biological signs of malabsorption. [(Hemoglobin: 10 g/dl (normal range > 12 g/dl), Albumin: 17.9 g/L, cholesterol: 2.8 mmol/l (normal range < 5,1 mmol/l).] Thrombophilia assessment revealed a protein C deficiency 57% (normal range: 70-120%), a slight increase in anticardiolipin antibodies 11 IU/ml (normal range <7 UI/ml) and anti-Beta 2 glycoprotein 1 antibodies 18 IU/ml (normal range <

REVISED Amendments from Version 1
I would like to express my sincere thanks to the reviewers for their constructive comments and suggestions for improving the manuscript.
This versions respond to the reviewer's advices and includes the rest of thrombophilia assessment which is negative factor 2 mutation and lupus anticoagulant, and immunological test which is negative antinuclear antibodies.
I mentioned that protein C deficiency has been reported in previous studies related to CD and due to vitamin K deficiency and particularly malabsorption.
I added two new paragraphs about thromboembolic and cardiovascular complications associated with CD and a proportion of CD is nowadays found while screening in-at risk groups.
Any further responses from the reviewers can be found at the end of the article 8 IU/ml) in two tests with 12 weeks apart, normal levels of protein S, antithrombin III and homocysteinemia, and negative factor II mutation, factor V Leiden and lupus anticoagulant. Immunological tests noted positive anti-transglutaminase >50 IU/ml (normal range < 8 U/ml) and anti-endomysium antibodies at 0.6 g/L (normal range < 0.2 g/L) with negative antinuclear antibodies.
From examination and laboratory results, VTE was diagnosed and CD as the cause was suspected. Duodenal biopsy demonstrated villous atrophy, meaning that the diagnosis of CD could be retained after ruling out the other causes of VTE as the neoplastic aetiologies; gynaecologic examination didn't show a lesion, neither chest radiography or colonoscopy.
The outcome of the patient was deemed favorable with anticoagulant therapy (low-molecular weight Heparin followed by Warfarin for 6 months without bleeding complications), combined with a gluten-free diet during the follow-ups over a period of 3-years in our outpatient consultation.

Discussion
CD is defined as a chronic immune-mediated small intestinal enteropathy caused by gluten intolerance in genetically predisposed individuals. 5 The activation of both the innate and adaptive response of the immune system, following the ingestions of gluten leads to damage to the proximal mucosa of the small intestine, resulting in the malabsorption of nutrients and the appearance of extra-intestinal manifestations.
CD is a systemic disorder, with different forms of clinical manifestations, from a classic digestive clinical presentation to extra-intestinal symptoms. The intestinal form of CD is more commonly found in the pediatric population 6 and rarely in adults. It includes diarrhea, which is a common presenting sign, in addition to malabsorption symptoms.
Nevertheless, extra-intestinal manifestations are being increasingly recognized, most likely due to better awareness of atypical presentations. They can include chronic fatigue, anemia, osteoporosis, recurrent aphthous stomatitis, elevated liver enzymes, joint or muscle pain, epilepsy, peripheral neuropathy, and infertility 7 Therefore, it is reported that extraintestinal manifestations may appear before the diagnosis of CD, as shown in our case.
It has been recognized that chronic inflammation is also an independent risk factor for VTE as the consequence of inflammatory cytokines and oxidative stress on the coagulation cascade is demonstrated. 8 Our patient presented a deficiency of protein C; which has been reported in previous studies related to CD and due to vitamin K deficiency and particularly malabsorption, 9 results in the over activity of coagulation factors V and VIII thus increasing the risk for thrombotic events. 9 We noted also a slight increase in anticardiolipin antibodies and anti-Beta 2 glycoprotein 1 antibodies but it didn't respond to antiphospholipid syndrome criteria which was reported to be associated to CD 10 and as shown in several studies where a higher prevalence of autoantibodies among patients with CD, including anti-phospholipid antibodies (see review of studies in 9 ). It is possible that these anti-phospholipid antibodies might also contribute to hypercoagulability.
VTE as a presentation of CD is unusual and rarely reported, especially since this thrombosis is located in the cerebrum and its first manifestation is a status epilepticus.
In fact, other central nervous system manifestations were reported more associated to CD than cerebral thrombosis, including cerebellar ataxia, peripheral neuropathy, seizures, headache, cognitive impairment, and psychiatric symptoms. 11 Seizures are nonspecific and can simply be a consequence of cerebral thrombosis. 12,13 In addition, thromboembolic manifestations and cardiovascular disease events represent serious extraintestinal manifestations of CD due to malabsorption (vitamin B12 deficiency, vitamin B6 deficiency, folic acid deficiency, vitamin D deficiency, and carnitine deficiency), chronic inflammation, endothelial dysfunction, thrombocytosis, protein C and S deficiency, thrombophylic autoantibodies and atherosclerosis. 14 So a thrombosis assessment should be considered in patients with CD.
The seriousness of these manifestations show that malabsorption syndrome should be systematically investigated to explore any symptoms due to systemic complications of malabsorption, for early diagnosis and better prognosis. 15 These factors must be investigated and corrected by a gluten free diet. 16 Furthermore, a long diagnostic delay may increase the risk of poor clinical response. 17 A significant proportion of CD are found while screening in-at risk groups such as, type 1 diabetes T1D, autoimmune thyroidal and liver diseases, IgA deficiency, family risk, and Down, Turner, and Williams syndromes. 15 Early diagnosis and treatment of CD improves the quality-of-life for patients and may spare them various long-term or even fatal complications like thromboembolic diseases.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.

Consent
Written informed consent for publication of the clinical details and associated images was obtained from the patient.
The presence of antiphospholipid antibodies in this patient should also be discussed: simple positivity of these autoantibodies already reported during CD, or an authentic antiphospholipid syndrome associated with CD (venous thrombosis + positive anticardiolipin antibodies and anti-Beta 2 glycoprotein 1 antibodies). The association of these two autoimmune diseases remains a possible eventuality! 1 Is the control of these autoantibodies carried out at 12 weeks?
The possible origin of protein C deficiency must also be discussed: a real thrombophilia? protein loss through diarrhea? or the received anticoagulant treatment (Warfarin)?
Bibliography: the list of bibliographic references is not well selected. Indeed, to support the discussion, the cases reporting CVT and CD, in particular the inaugural forms and associated with epilepsy, may be cited and used in the discussion: [refs 2-6] Likewise, the very latest update on thromboembolic and cardiovascular complications associated with CD should be cited in the list of bibliographic references and used to discuss the different possible mechanisms of thrombogenesis during this disease 7 .

5.
As a minor remark the article should also mention that a significant proportion of celiacs are nowadays found while screening in-at risk groups such as Graves disease, type 1 diabetes etc (2). And these patients are without any symptoms but they benefit from treatment (Kurppa et al., 2014).
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