Imaging pearls of pediatric Behçet’s disease

Accepted Manuscript Title: Imaging Pearls of Pediatric Behc¸et’s Disease Authors: Osman Melih Topcuoglu, Elif Dilara Topcuoglu, Cetin Murat Altay, Sinan Genc PII: DOI: Reference:

S0720-048X(17)30263-2 http://dx.doi.org/doi:10.1016/j.ejrad.2017.06.016 EURR 7876

To appear in:

European Journal of Radiology

Received date: Revised date: Accepted date:

19-4-2017 18-6-2017 21-6-2017

Please cite this article as: Topcuoglu Osman Melih, Topcuoglu Elif Dilara, Altay Cetin Murat, Genc Sinan.Imaging Pearls of Pediatric Behc¸et’s Disease.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.06.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Imaging Pearls of Pediatric Behçet's Disease

Title: Imaging Pearls of Pediatric Behçet's Disease Review article Authors 1. Osman Melih Topcuoglu, MD Yeditepe University Medical School, Department of Radiology 34718, Atasehir, Istanbul, Turkey Conflict of interest: None Disclosures: None E-mail: [email protected] 2. Elif Dilara Topcuoglu, MD Umraniye Education and Research Hospital, Department of Radiology 34764, Umraniye, Istanbul, Turkey Conflict of interest: None Disclosures: None E-mail: [email protected] 3. Cetin Murat Altay, MD Kecioren Education and Research Hospital, Department of Radiology 06380, Kecioren, Ankara, Turkey Conflict of interest: None Disclosures: None

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E-mail: [email protected]

4. Sinan Genc, MD Dr. Behçet Uz Children’s Education and Research Hospital, Department Pediatric Radiology 35210, Konak, Izmir, Turkey Conflict of interest: None Disclosures: None E-mail: [email protected]

Correspondence to Osman Melih Topcuoglu, MD Yeditepe University Medical School, Department of Radiology 34718, Atasehir, Istanbul, Turkey Tel: +905073573777 Fax: +902165784800 E-mail: [email protected]

Highlights: 1. Pediatric Behçet’s disease is difficult to diagnose. 2. Imaging can play a pivotal role in diagnosis of pediatric Behçet’s disease. 3. New diagnostic criteria includes imaging findings now.

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Abstract Objective: To emphasize the diverse diagnostic imaging findings of pediatric Behçet's disease and to define the fundamental imaging clues for pulmonary, vascular, gastrointestinal and central nervous system involvements of Behçet's disease in pediatric age group. We also aim to list the major imaging differences of Behçet's disease in childhood and adulthood. Conclusion: The diagnosis of pediatric Behçet’s disease is challenging. Imaging can narrow the differential diagnosis by using some substantial clues and prevent diagnostic delays. Key Words: Behcet’s disease; Behçet’s disease; vasculitis; pediatric; rheumatologic; imaging

Introduction

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Overview Behçet’s disease (BD) is a systemic auto-inflammatory disease affecting all sized vessels and is therefore classified as a variable vasculitis. It has unknown origin that was first demonstrated by a Turkish dermatologist, Dr Hulusi Behçet in 1937 [1]. BD typically presents in the 2nd to 4th decades of life and although the incidence of juvenile or pediatric onset (before the age of 16 years) is rare [2-4]; it is rising gradually due to clinical and radiological awareness. As usually seen in auto-inflammatory diseases, the course of BD is recurrent and prognosis is uncertain. The clinical spectrum is also quite heterogeneous because of the systemic involvement of the disease and symptoms are seen according to the involved organ/system. Male and female children are affected almost equally [3, 5, 6] however; severe uveitis, vasculitis and mortality are more frequent in males whereas, genital aphtosis and erythema nodosum are more common in females [7-11]. In this current review we discuss the diverse diagnostic imaging findings and fundamental imaging clues for pulmonary, vascular, gastrointestinal and central nervous system involvements of Behçet's disease in pediatric age group and list the main differentials and major imaging differences in childhood and adulthood. Epidemiology Geographic distribution is observed in pediatric BD along the Silk Road (the area between the Far East and the Mediterranean region) similar with the adult onset BD [12] because of the similar genetic backround. Prevalance in Northern China and Iran is nearly 100/100,000, in Turkey 80/100,000, in Turkish-German population 77/100,000 and in Western Europe; 0.1 to 15.9/100,000 [13-18]. Thus, in addition to genetics, sex and country of residence, it can be clearly understood that ethnicity

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plays a pivotal role in the development of BD. Pediatric cases are 3.3% to 26% of all BD patients [14, 19]. Genetics Viral and/or bacterial infections, environmental factors and auto-immune basis have been speculated as predisposing reasons for BD [20]. However; pediatric BD has a strong genetic component because of the increased frequency of HLA-B51 allele in children with BD [21, 22]. There is also an increased prevalance in familial cases (9% to 42%) although it is not autosomal dominantly inherited [23, 24]. The most important genes and susceptibility loci associated with BD are ERAP1, IL23R and IL10 which are the same genes postulated in the development of psoriasis, inflammatory bowel disease and spondyloarthritis [25]. Besides these, TLR 2 and TLR 4 also have an act in the immune system activation. After all these complex genetic backround and pathologic mechanisms; the eventual scenario is similar: neutrophil activation by natural killer cells, monocytes and T-helper-17 cells causing multi-systemic vasculitis [12]. Pathophysiology BD is a type of chronic relapsing vasculitis that affects any type and size of vessel [26]. Activated neutrophils provoke the release of superoxide radicals and lysosomal enzymes which lead to inflammatory vasculitis starting from the vaso vasorum of the tunica media with loss of elastic fibers. That intense inflammatory reaction of the vessel wall leads to luminal thrombosis or dilatation and aneurysm formation [27]. Clinical history The typical clinical history for a pediatric BD initial presentation usually includes non-specific oral ulcers and fever of unknown origin. The clinical symptoms generally depends on the affected organ or system. Genital aphtosis, cutaneous signs

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including acneiform lesions and erythema nodosum, chest pain, cough, ocular sings, arthralgia, gastrointestinal and neurological features can be seen with decreasing incidence [12]. Diagnosis International Study Group defined the most commonly used diagnostic criteria for BD in 1990 with a sensitivity and specificity of 85% and 96%, respectively (Table 1) [28]. Recurrent oral ulcers are obligatory according to those criteria and also at least two of the listed skin lesions must be positive. Its relative low sensitivity caused delayed diagnoses for the significant number of the patients in the pediatric age group, resulted in complications. In 2014, international study group revised the criteria for BD (Table 2) to prevent delayed diagnoses [29] and finally in 2015, criteria specific to pediatric BD have been defined (Table 3) [12]. Pathergy test, which is a hypersensitivity reaction of the skin to the needle prick, has been excluded from the new criteria of pediatric BD [12] and the sensitivity was increased because of the added neurological and vascular symptoms. Indeed, most of the time, very few symptoms are observed in children [12], making the diagnosis of pediatric BD challenging, but some pivotal radiologic findings, described in the current review, can aid to diagnose pediatric BD and narrow the differential diagnosis in addition to physician’s experience. Those group of patients with non-specific oral ulcers and fever of unknown origin seek for a treatment from one clinic to another all the time and if the diagnosis delays, untreated BD has the potential for a massive hemoptysis and eventual asphyxia due to the ruptured pulmonary arterial aneurysm or massive pulmonary emboli secondary to deep vein thrombosis of the legs or vena cava inferior thrombosis. Functional damages and clinical deterioration are also observed in children related to untreated neurological and ocular involvements. Therefore, to

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prevent diagnostic delays is the most important goal in BD especially in the pediatric age group. Imaging modalities The selected radiologic modality depends mostly on the clinical symptom. Chest radiography is the first choice imaging modality in a child with respiratory symptoms. It can demonstrate hilar or mediastinal enlargements indicating aneurysms of thoracic aorta or pulmonary arteries, or parenchymal non-specific focal radio-opacities. It can also be utilized for monitoring treatment response. Although radiation is an important issue for a pediatric patient, with the rapid development of the CT technology, it is now possible to obtain a pediatric chest CT with significantly lessened radiation doses [30]. Chest CT and CT-angiography enable to evaluate both vascular structures as thoracic aorta and pulmonary arteries/veins, and pulmonary parenchyma simultaneously [31]. CT angiography is the preferred imaging modality in a child with cardiovascular symptoms. Digital subtraction angiography is usually not necessary because it does not show vessel walls and associated inflammatory findings. A cardiac MR may be useful for suspected cardiac manifestations. In a child with gastrointestinal symptoms, ultrasonography, barium studies and abdominal CT should be used. Ultrasonography and CT demonstrate bowel wall thickening and mesenteric inflammation, and barium studies with double contrast technique show mucosal or deep ulcers. Cranial CT and especially MR are the preferred imaging techniques in a child with neurological symptoms for detection of central nervous system vascular or parenchymal involvement. The frequency of occurrence, sex predominance and key imaging features of the involved body part in pediatric Behçet’s disease are summarized at Table 4.

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Pulmonary involvement Pulmonary involvement is seen in approximately 1 to 10% of the patients with BD [32, 33]. BD primarily affects pulmonary arteries in children and this involvement is usually multifocal and bilateral [12]. Intense inflammatory reaction in the walls of pulmonary arteries secondary to vasculitis, leads to thrombosis and/or aneurysm formation (Figure 1). Preferential pulmonary arterial wall thickening is related to the inflammation mediated by activated neutrophils within the vaso vasorum of the tunica media. BD is the most frequent cause of pulmonary artery aneurysm and the aneurysms can be saccular or fusiform and located mostly in the lower or main pulmonary arteries [34]. As a result, the classic clinical symptoms include cough, dyspnea, hemoptysis and chest pain. The fundamental imaging clue is the inflammatory pulmonary arterial vessel wall thickening leading to luminal dilatation or luminal narrowing and parenchymal infarction. In the course of the disease; parenchymal hemorrhage, subpleural nodules or cavities, pleural effusion and mediastinal lymphadenopathy can also be detected [35]. Nodular lesions are generally observed in the acute phase of pulmonary arterial involvement and they are usually peripherally located and bilateral, and mostly detected as subpleural opacities representing hemorrhage, necrosis and infarction [35]. Pleural effusions may accompany parenchymal infarctions. Most of them are disappeared during follow-up. Pulmonary arterial emboli which is a rare entity for children, traumatic aneurysms and mycotic aneurysms due to syphilis or tuberculosis, are the main differential diagnoses. However, these pathologies generally lack vessel wall thickening and the clinical history is completely different. In addition, Hughes-Stovin syndrome (HSS), a kind of vasculitis affecting veins and arteries both, causes pulmonary artery aneurysms with vessel wall thickening. But, although a cut off point for the measurement of the wall

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thickening does not exist, the inflammatory thickening in HSS is not as significant as in BD [36]. Also lack of oral or genital ulcers in HSS may aid for discrimination [37]. Cardiovascular involvement Cardiovascular involvement is fortunately less commonly seen in children compared to adults and the incidence is approximately 5% to 20% in pediatric BD cases [12]. Venous thrombosis is the most frequent vascular involvement especially in the deep veins of the legs [38]. Thrombosis of the inferior vena cava, cervical veins and hepatic veins (Budd-Chiari syndrome) are seen. Arterial complications are most commonly seen in pulmonary arteries as mentioned above. It is the leading reason for mortality. In children, males are more frequently affected than females (M/F; 6/1) [39]. The fundamental imaging clue is the arterial or venous vessel wall thickening leading to luminal dilatation (aneurysm or pseudo-aneurysm formation), luminal narrowing or occlusion/thrombosis (Figures 2, 3, 4, 5 and 6). Presenting symptoms are observed due to the involved vessel or organ. In the differential list, arterial dissection is an important situation that affects mostly cranio-cervical arteries with a characteristic clinical history of post-traumatic stroke or transient ischemic attack and neck or head pain [40]. Secondly, thrombophilia can also promote venous thrombosis or arterial dissection and must be in the differential list. Occasionally, thromboses may be idiopathic and are therefore a diagnosis of exclusion. The aorta, the sinuses of Valsalva and also the coronary arteries are involved in BD vasculitis [41]. Aneurysms of those structures can easily be detected with cardiac MR or coronary CT angiography. Although the cardiac manifestations are rare in children, they can cause fatal complications. Intra-cardiac thrombus, pericarditis, pericardial effusions and myocarditis can be seen in the course of the disease [42].

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Gastrointestinal involvement Gastrointestinal symptoms including mostly abdominal pain and discomfort, occur approximately in the 40% of children with BD [43]. Mucosal or deep aphthosis and ulcerations, bleeding, GI perforation can be seen secondary to bowel wall vasculitis [20]. Although the entire GI tract from mouth to anus may be involved, the ileum and colon are most frequently affected [20]. There are some important key findings that can strongly suggest BD. There is usually bowel wall thickening leading to luminal narrowing and non-specific mesenteric fat infiltration (Figure 7). Concentric wall thickening is a pivotal sign for an intestinal ulcer and ulcer formation is the most characteristic finding for the gastrointestinal involvement in BD [42]. CT is a useful modality and sometimes the involved intestinal segment seems as a polypoid masslike lesion, even it can require surgical exploration (Figure 7C) [20]. For detection of mucosal or deep ulcers, barium studies with double contrast might be helpful in addition to endoscopic evaluation. Differentiation from inflammatory bowel diseases (IBD) is a real challenge because of their similar clinical and radiological findings. However, gastrointestinal perforation is more common in BD than IBDs [20]. Central nervous system involvement Neuro-Behçet’s disease (NBD) affects 5% to 30% of the children with BD [43-45]. NBD can be the first presentation and also can be the sole involvement in the course of the disease [46]. Male predominance is generally observed. There are two main manifestations; first, cerebral vein thrombosis (Figure 8) and secondly, parenchymal involvement which is usually in the form of meso-diencephalic meningo-encephalitis (Figures 9 and 10) [47, 48]. Dural sinus thrombosis is more frequently detected in children whereas, parenchymal involvement is indeed more common in adults [45]. The major differences of BD in children and adults are summarized at Table 5.

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Headache, epilepsy, papilledema, hemiparesis, cranial nerve palsies (especially the 6th nerve), psychiatric disturbances and ataxia may be clinical presentations [45]. Dural sinus thrombosis in a child, which is a pivotal imaging clue, should remind the physicians about BD. Although less commonly seen in children, typical brain stem involvement as meso-diencephalic extension and/or hemorrhagic lesions and/or patchy enhancement should also make think BD. However, similar imaging patterns can be detected in infectious meningo-encephalitis and it should be considered in the differential diagnosis. Multiple sclerosis, thrombophilia and other vasculitides must also be in the differential list. Muco-cutaneous involvement Although it is very rarely seen in the pediatric age group, recurrent oral ulcers are also a common classical finding in children with BD and they are non-specific and similar to other simple oral ulcers [12]. On the other hand, genital ulcers are far less frequently seen in children with BD. Necrotic folliculitis and acneiform lesions, erythema nodosum and a positive patergy test which is no longer obligatory now, are other muco-cutaneous findings for pediatric BD. Joint involvement Recurrent arthralgia is more frequent than arthritis in children and it can be in the form of oligo- or poly-arthritis. Approximately 50% of the children with BD present joint symptoms [43]. Imaging findings usually interfere with a variety of diseases but in the form of arthritis typical synovial hypertrophy and synovitis can be detected [4951]. Eye involvement The most frequent and characteristic finding is the bilateral posterior uveitis and retinal vasculitis. However, papilledema is the most common ophthalmological

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finding [48]. There is a male predominance and eye involvement in pediatric BD is more severe in males [52, 53]. It is mostly seen after the age of 10. There is no reported specific imaging finding for the eye involvement. Treatment There is no FDA-approved treatment for pediatric BD [12]. The objective of the treatment is generally to reduce the inflammation. Colchicine is used for preventing recurrent oral and genital ulcerations. Intermittent utilization of steroids also may aid relieving ulcerations. Immunosuppressives including azathioprine, cyclosporine and cyclophosphamide are usually used for severe ocular, vascular and neurologic involvements. TNF-α inhibitors are effectively used in patients unresponsive to conventional immunosuppresants [54]. Anti-interleukins, and phosphodiesterase-4 inhibitors are can also be used in selective involvements of pediatric BD [55, 56]. For the treatment of BD thromboses, usage of anti-coagulants or immunosuppressive agents still remains as a dilemma [57]. Conclusion The diagnosis of Behçet’s disease in children is challenging. However, imaging can aid much to narrow the differential diagnosis by using some crucial hints and prevent diagnostic delays and complications, although there is no best method of imaging.

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Figure legends

Fig. 1 —A 15-year-old boy with Behçet’s disease and hemoptysis. Axial (A) and coronal oblique (B) chest CT images show severe inflammatory wall thickening in both lower lobe pulmonary arteries (long arrows) and an occluded segment on the right side (short arrows).

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Fig. 2 — Abdominal pain in a 16 year-old male patient with Behçet’s disease. Axial CT images (A and B) show arterial wall thickening and aneurysmatic dilatations (arrows) in both internal iliac arteries. 3D reconstruction image (C) also reveals the bilateral internal iliac artery aneurysms (arrows). Following the endovascular treatment, 3D reconstruction image (D) demonstrates occluded aneurysms and bilateral stents.

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Fig. 3 — Vomiting and diarrhea in a 17-year-old boy with Behçet’s disease. Coronalreformatted (A) and axial (B and C) abdominal CT images show significant vessel wall inflammation leading to thickening and thrombus formation along the course of the inferior vena cava (arrows in A and B) and right iliac vein (arrow in C).

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Fig. 4 — Ankle swelling in a 15-year-old girl with Behçet’s disease. Sagittal (A) reformatted lower extremity CT angiography image shows intense inflammatory vessel wall thickening (star) on the posterior and caudal part of the posterior tibial artery and the aneurysm (arrow). 3D-reconstructed (B) CT angiography image shows the aneurysm (arrow) clearly on the posterior tibial artery.

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Fig. 5 — Hematuria in a 9-year-old boy with Behçet’s disease. Non-contrast coronaloblique CT image reveals a relatively hyperdense thrombus (arrow) in the right renal vein and enlarged right kidney due to edema (arrow heads).

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Fig. 6 — Hematuria in a 15-year-old boy with Behçet’s disease. Contrast-enhanced coronal-oblique CT image reveals inflammatory wall thickening (long arrows) and an aneurysm (arrow) on the superior division of the left renal artery.

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Fig. 7 — Diarrhea and abdominal pain in a 16-year-old boy with Behçet’s disease. Axial ultrasonography image (A) shows bowel wall thickening (white arrows) and increased mesenteric echogenity (black arrows). Contrast-enhanced abdominal CT scans (B and C) show mass-like wall thickening in the distal ileal segments (long arrows in B and C) and fat stranding (short arrow in B) adjacent to involved bowel. There is also free fluid (stars in C) in the left paracolic gutter and between intestinal loops.

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Fig. 8 — Acute headache and bilateral papiledema in a 12-year-old boy with Behçet’s disease. Axial T2-weighted (A and B) images reveal thrombi in the superior sagital (arrow in A) and right tranverse (arrow in B) sinuses.

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Fig. 9 — Seizure and left hemiparesis in a 16-year-old boy with Behçet’s disease. Coronal T2-weighted (A) image shows diffuse and expansile T2 signal increase in the meso-diencephalic junction and pons (arrows). Contrast-enhanced coronal T1weighted (B) image shows heterogeneous enhancement in the pons and mesencephalon (arrows).

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Fig. 10 — Vomitting and syncope in a 4-year-old boy with Behçet’s disease. Axial T2 weighted (A) image reveals hypo-intense nodular lesion in the right anterior part of the pons (arrow). Axial contrast-enhanced T1-weighted (B) image shows mild nodular enhancement (arrow) in the same region. DWI with B=1000 (C) and ADC map (D) images demonstrate diffusion restriction in a larger area.

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Table 1. International study group classification criteria for Behçet’s disease in 1990.  recurrent oral ulcers + at least two of the followings o recurrent genital ulcers o eye lesions (uveitis or retinal vasculitis) o skin lesions (erythema nodosum, papulopustular lesions, or acneiform nodules) o a positive pathergy test

Table 2. International study group classification criteria for Behçet’s disease in 2014. Clinical finding

Score

Oral aphtosis

2

Genital ulcers

2

Ocular signs (anterior or posterior uveitis,

2

retinal vasculitis) Skin lesions (necrotic folliculitis and acneiform

1

lesions, erythema nodosum) Neurological involvement

1

Vascular involvement (arterial or large vein

1

thrombosis, phlebitis) Positive pathergy test (extra criterion)

1

Diagnosis of Behçet’s disease ≥ 4

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Table 2. International study group classification criteria for pediatric Behçet’s disease in 2015. Clinical finding

Score

Oral aphtosis (at least 3 attacks/year)

1

Genital ulcers (characterictically with scar)

1

Ocular signs (anterior or posterior uveitis,

1

retinal vasculitis) Skin lesions (necrotic folliculitis and acneiform

1

lesions, erythema nodosum) Neurological involvement (not isolated

1

headache) Vascular involvement (arterial or venous

1

thrombosis, arterial aneurysm) Diagnosis of Behçet’s disease ≥ 3

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Table 4. Frequency of occurrence, sex predominance and key imaging features of the involved body part in pediatric Behçet’s disease. Involved body part

Percentage (%) Sex

Pulmonary system

1-8

Key imaging features

M=F Pulmonary arterial wall thickening and aneurysm formation or thrombosis

Cardiovascular

5-20

M>F Arterial or venous vessel wall thickening

5-30

M>F Cerebral vein thrombosis and parenchymal

system Central nervous system

involvement in the form of mesodiencephalic meningo-encephalitis

Gastrointestinal system

40

M>F Bowell wall thickening and mesenteric fat infiltration indicating ulcer formation2 Polypoid masslike lesions

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Table 5. The major differences of Behçet’s disease in children and adults. The involved system or

Childhood

Adulthood

Gastrointestinal and

GI symptoms are more

Genital ulcers are more common.

genitourinary system

common.

Central nervous system

CNS involvement mainly

clinical feature

CNS involvement mainly consists of

consists of venous thrombosis meso-diencephalic parenchymal

Severity and sex

and cranial nerve palsy.

involvement.

Male gender have more

Increased involvement of

severe disease.

organ/systems. Younger than 25 years at disease onset and male gender have more severe disease.

Morbidity and mortality

Overall morbidity and

Vasculitic complications and overall

mortality are less common.

morbidity and mortality are more common.

Musculoskeletal system

Arthralgia is more common.

Arthritis is more common.

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