r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 3 4 4 – 3 4 9 Available online at www.sciencedirect.com Original article Neurological manifestations of Behc¸et’s disease: Evaluation of 40 patients treated by cyclophosphamide Les manifestations neurologiques de la maladie de Behc¸et : e´tude de 40 patients traite´s par cyclophosphamide E.H. Ait Ben Haddou a,1,*, F. Imounan a,1, W. Regragui a, O. Mouti b, N. Benchakroune e, R. Abouqal c,d, A. Benomar a,c,d, M. Yahyaoui a aService de neurologie B et de neuroge´ne´tique, hoˆpital des spe´cialite´s, ONO, CHU de Rabat-Sale´, BP 6444, Rabat-Instituts, Rabat, Maroc b Private practice, rue Oukaimidine, immeuble 61, n810, Rabat, Maroc cCentre de recherche en e´pide´miologie clinique et essais the´rapeutiques (CRECET), faculte´ de me´decine et de pharmacie, Rabat, Maroc d Laboratoire de biostatistiques et de recherche en clinique e´pide´miologique (LBRCE), faculte´ de me´decine et de pharmacie, Rabat, Maroc eService d’ophtalmologie B, hoˆpital des spe´cialite´s, ONO, CHU de Rabat-Sale´, BP 6444, Rabat-Instituts, Rabat, Maroc i n f o a r t i c l e Article history: Received 6 July 2011 Received in revised form 10 September 2011 Accepted 20 September 2011 Published online 1 December 2011 Keywords : Cerebral deep venous system thrombosis Cyclophosphamide Meningo-encephalitis Myelopathy Neurobehc¸et disease Mots cle´s : Thrombose veineuse ce´re´brale profonde Cyclophosphamide Me´ningoence´phalite Mye´lopathie Neurobehc¸et a b s t r a c t Introduction. – Neurological manifestations in Behc¸et’s disease represent between 4 to 49% of systemic manifestations and remain, in the long term, the leading cause of morbidity and mortality. Methods. – Retrospective series of 40 severe Neurobehc¸et cases fulfilling the International Study Group criteria for Behc¸et’s disease were consecutively recruited over a period from June 2004 to December 2010. All patients had clinical and ophthalmologic examinations; they underwent laboratory and imaging investigations. They received corticosteroids and cyclophosphamide as initial bolus of 600 mg/m2 of BSA in the 1st, 2nd, 4th, 6th and 8th day followed by a bolus of 600 mg/m2 BSA every 2 months for 2 years. Antithrombotic therapy was given to patients with cerebral deep venous thrombosis. Patient follow-up and toler- ance to treatment were analyzed. Results. – The average age at diagnosis was 34 � 13 years, with a sex-ratio of 1.78. The clinical presentation was dominated by the meningoencephalitis in 48.8% of cases, cerebral deep venous thrombosis in 43.6% of cases and myelopathy in 7.7% of cases. The 40 patients receiving cyclophosphamide bolus, despite two aggravated cases, evolved positively with clinical improvement and good tolerance. Conclusion. – The demographic and clinical aspects of our series are similar to those reported in the literature. In contrast to previously reported cases of a poor prognosis in severe neurobehc¸et’s disease, our study suggests that immediate and aggressive treatment by cyclophosphamide may ameliorate the prognosis. However, a multicenter study is needed to confirm the possible efficacy of cyclophosphamide and further assess the long-term tolerance. # 2011 Elsevier Masson SAS. All rights reserved. * Corresponding author. E-mail address :
[email protected] (E.H. Ait Ben Haddou),
[email protected] (F. Imounan). 1 E. Ait Ben Haddou et F. Imounan ont contribue´ de fac¸on e´gale a` ce travail. 0035-3787/$ – see front matter # 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neurol.2011.09.006 nife tati cas die 20 in re´s aly en ´nin thie ave´ to em orm m mi r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 3 4 4 – 3 4 9 345 1. Introduction Behc¸et’s disease (BD) is a multisystem relapsing inflammatory disorder of unknown cause. Neurologic involvement in Behc¸et (NB) disease was first reported by Knapp in 1941 (Araji and Desmond, 2009). The first paper which described the pathology of neurologic manifestations of Behc¸et disease was reported in 1944 (Araji and Desmond, 2009). The neurological involvement in BD is either caused by primary neural parenchymal lesions (neuro-Behc¸et’s syndrome [NB]) or is secondary to major r e´ s u m e´ Introduction. – Les ma 4 a` 49 % des manifes Me´thodes. – Quarante d’e´tude pour la mala juin 2004 au de´cembre de cyclophosphamide lants ont e´te´ administ traitement ont e´te´ an Re´sultats. – L’aˆ ge moy e´tait domine´ par la me (43,6 %) et la mye´lopa excepte´ deux cas aggr clinique et une bonne Conclusion. – Contrair et agressif dans les f Cependant, une e´tude cyclophosphamide et vascular involvement (vasculo-Behc¸et’s syndrome [VB]) (Araji and Desmond, 2009). It is one of the most serious causes of long- term morbidity and mortality in BD. Although BD is rare in neurological practice in most countries, it is commonly mentioned in the differential diagnosis of inflammatory or demyelinising central nervous system diseases. Neurological manifestations represented between 4 to 49% of manifestations of BD (Haghighi et al., 2005). The most common manifestation of NB consists of different combinations of cranial nerve palsy, dysarthria, unilateral or bilateral pyramidal tract signs, ataxia with or without consciousness disturbance (Borhani, 2009). Less common central nervous system manifestation includes hemiparesis, cognitive–behavioral changes, emotional chan- ges, extrapyramidal signs and seizures. At the time of a neurologic attack, typical neuroradiologic findings have been defined. Polymorphonuclear pleocytosis and/or absence of IgG oligoclonal bands are suggestive of NBD. The presence of worse prognostic factors should be considered when treatment is initiated. The presence of abnormal cerebrospinal fluid (CSF) and parenchymal involvement, especially of the brainstem, justifies more aggressive treat- ment (Bowirrat and Radi, 2010). Some NBD patients have an insidious onset of the disease with primary progressive central nervous system dysfunction, and others may display symp- toms attributable to intracranial hypertension associated with dural venous sinus thrombosis (Bowirrat and Radi, 2010). In most cases of NB, corticosteroids should be given as infusion of intravenous methyl prednisolone followed by a slowly tapering course of oral steroids (Araji and Desmond, 2009). Immunosuppressive agents should be used in cases of severe form of NB such as meningoencephalitis, a myelopathy and cerebellar deep venous system thrombosis. In most series, the most used immusupressant were azathioprine and methotrexate (Ghayad et al., 2009). Cyclophosphamide (CPM) is only reported in only sporadic cases, and used in second intention (Borhani, 2009). stations neurologiques de la maladie de Behc¸et repre´sentent entre ons et restent la principale cause de morbimortalite´. de Neurobehc¸et remplissant les crite`res du groupe international de Behc¸et, ont e´te´ recrute´s conse´cutivement sur une pe´riode de 10. Les patients ont rec¸u des corticoı¨des et 600 mg/kg par m2 par SC traveineux tous les deux mois pendant deux ans. Les anticoagu- en cas de thrombose veineuse ce´re´brale. Le suivi et la tole´rance au se´s. e´tait de 34 � 13 ans, avec un sex-ratio de 1,78. Le tableau clinique go-ence´phalite (48,8 %), la thrombose veineuse ce´re´brale profonde (7,7 %). Les 40 patients ayant rec¸u un bolus de cyclophosphamide, s, ont e´volue´ positivement sous traitement avec une ame´lioration le´rance. ent a` la litte´rature, notre e´tude sugge`re que le traitement imme´diat es se´ve`res par cyclophosphamide peut ame´liorer le pronostic. ulticentrique est ne´cessaire pour confirmer l’efficacite´ possible de eux e´valuer la tole´rance a` long terme. # 2011 Elsevier Masson SAS. Tous droits re´serve´s. This study was conducted to describe the clinical and prognostic aspects of neurologic involvement in BD among patients and evaluate tolerability of CPM in NB patients during 24 months. 2. Patients and methods 2.1. Data collection During 5 years from June 2004 to December 2010, 40 severe forms of NB cases satisfied the diagnostic criteria of the international study group of BD (International Study Group for Behcet’s disease, 1990), managing in our neurologic and neurogenetics department of Rabat Hospital (Morocco), were retrospectively and consecutively recruited and followed over the period of 24 months. Twenty-four males and 16 females were included in our study. The age ranged between 14 and 69 years old. The time interval relapsing between onset of the disease and appearance of neurologic symptoms was recor- ded. The skin pathergy test was performed on all patients. Cardiac examination was performed whenever we have cardiac symptoms. All patients received an ophthalmic examination for admission to the service. Patients who had papilleoedema and exacerbation of uveitis were followed regularly in neuroophtalmology consultation. The 40 patients 3). During the study no patients with cardiac involvement. 3.2. Treatment and evolution For the 40 patients put on induction cure of CPM followed by maintenance courses of 600 mg/m2 per BSA every 2 months: 31 patients improved immediately after the 2nd month of treatment; therapeutic benefit was maintained throughout the follow-up. Seven patients remained stationary. The aggravation was noted in two patients with myelopathy syndrome; one of them had a progressive myelopathy, neurologic examination revealed 0/5 strength in lower extremities, with bilateral sensory deficit and bladder dys- function in the initial examination, the other patient had an acute myelopathy associated with cerebral deep venous system thrombosis: patient had a flaccid tetraplegia, cons- ciousness disorder, swallowing disorders. r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 3 4 4 – 3 4 9346 who had evidence of NBD underwent laboratory and imaging investigations. Computed tomographic scan was performed on all patients, magnetic resonance on 32 patients, and lumbar puncture on 37 cases. The severe forms of BD were defined by patients presenting severe meningoencephalitis, myelopathy and patients who had cerebral deep venous system thrombosis. All patients were treated with colchicine. Ophthalmic topical weren’t used in our series. All patients received infusions of 120 mg/8 h per 6 days of methyl prednisolone followed by 1 mg/kg per day of oral prednisone during 1 month, then progressive degression: degression of 10 mg every 2 months until a dose of 20 mg and a degression of 5 mg every 2 months until effective dose of 10 mg in 15 patients and 5 mg in 25 patients. There was no accidental discovery of central venous thrombosis in MRI. In fact, all patients with a clinical symptom suggestive of cerebral deep venous thrombosis were confirmed by MRI angiography. For the neurological symptoms caused by VD, the antithrombotic therapy was implemented to patients with cerebral deep venous system thrombosis, they received anticoagulants 0.1 UI/kg per day of low weight molecular heparin (LWMH), followed by antivitamin K during 1 year. 2.2. Treatment and evolution For 40 patients with severe forms of NB, CPM was adminis- tered as induction therapy at a dose of 600 mg/m2 at the 1st, 2nd, 4th, 6th and 8th day. Then, maintenance courses of 600 mg/m2 of body surface area (BSA) were administered every 2 months. Lack of availability of uromitexan, oral and parenteral hydration has been advocated for the cure. All patients received a report before each cure: a blood count, a urine culture and a liver report. Evolution under treatment: The criteria of the treatment evolution were established as follow: � improved cases: patients with complete regression of neurological signs; � stationary cases: patients who have effects and persistence of clinical signs; � aggravated cases: patients with aggravation of neurological signs and/or have risk to relapse. The tolerance was assessed by: � a questionnaire on the occurrence of adverse effects; � a biological assessment systematically administered before each bolus to detect hematologic or hepatic toxicity. 3. Results 3.1. Demographic and clinical characteristics of the population study Our study is a retrospective series of 40 NB cases. The average age at diagnosis was 34 � 13 years. The age at onset was between 14 and 69 years (mean 32.6). There was a slight male predominance (62% versus 38%) with a sex-ratio = 1.78. All cases had oral aphtae, 30 cases had genital ulcerations which representing 75% of the cases. The skin pathergy test was positive in 75% of the patients tested. The clinical syndrome was dominated by meningoence- phalitis in 48.8% of cases, cerebral deep venous system thrombosis was present in 43.5% of cases and, however, the myelopathy was only in 7.7% of cases. The most frequent neurologic manifestations were cranial nerve palsies (65%), severe headache (62.5%), pyramidal signs (62.5%), hemiparesis (62.5%), cerebellar signs (22.5%) convulsive disorders (12.5%), tetraparesis (12.5%), paraparesis (10%) and mild cognitive impairment (2.5%) of cases (Table 1). All patients received a fundus examination, which was normal in 37.5% of cases; it’s showed uveitis in 42% of cases, and papillary oedema in 20% of cases. With regard to CSF results, it was normal in 35% cases, 16 patients had predominantly lymphocytic pleocytosis, five had hyper pro- teionorrachia, and five patients had high pression. Computed tomography scan was normal in five patients, with 12 patients showing a low-density lesion in the brainstem, 14 patients having a cerebellar edema, and six patients show dural sinus thrombosis. Magnetic resonance imaging was performed on 32 patients, it was normal in 5% of cases, showed the brainstem lesions in 60% of cases and showing cerebral venous system thrombosis in 20% of the cases (Table 2, Figs. 1– Table 1 – Neurological manifestations observed among our patients. Manifestations neurologiques observe´es chez nos patients. Manifestations n (%) Severe headache 25/40 (62.5) Cognitive derangement 1/40 (2.5) Cranial nerve palsies 26/40 (65) Cerebellar signs 9/40 (22.5) Pyramidal signs 25/40 (62.5) Convulsions 2/40 (5) Muscle strength Paraparesis 4/40 (10) Hemiparesis 25/40 (62.5) Tetraparesis 5/40 (12.5) During all the duration of the study, most patients tolerated the cumulative doses of 12 g of CPM. Fig. 2 – Venous angiography. Thrombosis of rosenthal vein. Angioscanner veineux. Thrombose de la veine basilaire de Rosenthal. Table 2 – Results of ophthalmic examination, CT scan, MRI, and CSF examination in 40 patients with NBD. Re´sultats de l’examen ophtalmologique, du scanner, de l’IRM et analyse du LCR chez 40 patients pre´sentant un neuro- behc¸et. Explorations n (%) Fundus examination Normal 15/40 (37.5) Papilledema 8/40 (20) Uveitis 17/40 (42.5) CT scan Normal 5/40 (12.5) Cerebral edema 12/40 (30) Low density lesion in brainstem 17/40 (42.5) Sinus thrombosis 6/40 (15) MRI Normal 2/40 (5) Brainstem lesions 24/40 (60) Cerebral deep venous system thrombosis 8/40 (20) Not perfomed 6/40 (15) CSF Normal 14/40 (35) Mainly lymphocytic pleocytosis 16/40 (40) Hyperprtenorachy 5/40 (12.5) r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 3 4 4 – 3 4 9 347 It is worth mentioning that we had two transitional alopecia cases and one amenorrhea case after the 10th bolus in a woman High pression 5/40 (12.5) MRI: magnetic resonance imaging; CSF: cerebrospinal fluid; CT scan: computed tomography scan. who was in premenauposal. The analysis of blood count before each bolus did show no leucopenia, no lymphopenia. There was no case of infection. The liver report was normal in all patients. There were no cases of hemorrhagic cystitis. Fig. 1 – Cerebral MRI coronal T2-weighted image. Extensive T2W hyperintense lesions of the brain stem, thalamus and right internal capsule. IRM ce´re´brale : coupe coronale en se´quence T2. Hypersignal T2 diffus en plage du tronc ce´re´bral, du thalamus et de la capsule interne. 4. Discussion In the present study, we were interested in clinical and evolutionary aspects analyzing of Neurobehc¸et’s disease and the evaluate tolerability of CPM in the treatment of neurolo- gical manifestations in BD. Araji and Desmond reported that the BD sex-ratio was of 2.8 more in men than in women (Araji and Desmond, 2009), which were obtained from our series. The average age of our patients was 34 years which matching to the age of onset of NB (Araji and Desmond, 2009). Fig. 3 – Cervical magnetic resonance imaging: sagittal T2- weighted sequence: hyperintensity of the spinal cervical C1-C2. Imagerie par re´sonance magne´tique cervicale : coupe sagittale en se´quence ponde´re´e T2 : hypersignal de la moelle cervicale C1–C2. r e v u e n e u r o l o g i q u e 1 6 8 ( 2 0 1 2 ) 3 4 4 – 3 4 9348 The diagnosis of neurological involvement in BD is done mainly by clinical means; the ancillary investigations noted below help to suggest alternatives, and especially infective complications of treatment, but there is no diagnostic test for NBD (Araji and Desmond, 2009). The site most often involved in NBD is the parenchyma, including meningoencephalitis, myelopathy and deep veins thrombosis which presented 80% in retrospective series (Ghayad et al., 2009). However, non parenchymal symptoms, including veins thrombosis and aneurysms were rare; and were about 18% of NBD cases in the studies (Ghayad et al., 2009). The prevalence of cerebral veins thrombosis is higher in patients who have had previous venous thromboses elsewhere (Bank and Weart, 1984). The most common symptoms, in our series, were parenchymal involvement in (56.5% cases), with meningoencephalitis in 48.8% of the cases. Cerebral deep veins system thrombosis representing 43.5% of the cases, while the myelopathy was present in only 7.7% of the cases. No validated score for the clinical and follow-up evaluation of NBD exist. Blood count and biochemical screening are used to identify the nature and severity of the systemic disorder and to identify signs of a superimposed infective complication. CSF constituents are altered in around 70–80% of patients with parenchymal complications. CSF protein is modestly raised in most cases, sometimes to over 1 g/dl and oligoclonal bands are usually absent. Patients with cerebral veins thrombosis (CVT) or intracranial hypertension have normal CSF constituents. In our series, CSF was normal in 35% cases, it showed predominantly lymphocytic pleocytosis in 40%, and hyper proteionorrachia in 12.5% of cases. We have treated the 40 patients, who have responded to a high dose of CPM and founded that 31 patients have achieved durable recovery with a follow-up extending to 24 months. It is worth mentioning that in our series, we systematically used immunosuppressive treatment for meningoencephalitis and myelitis, and then, we added anticoagulants in case of cerebral deep venous system thrombosis. We have used also an initial high dose of CPM, like 600 mg/m2 per BSA. However, our patients received only of 5 g during 8 days. Then, maintenance courses of 600 mg/m2 are administered every 2 months. After administration of the induction doses, patients showed a start of remission within a month, maintenance of remission required bimonthly pulses of CPM for 24 months. Even though, we could not come up with an objectively score to evaluate the disability and the outcome. The strength of our study is based on the fact that we use the CPM as a first intention treatment. Thirty-one patients have a complete remission after 6 months of CPM treatment and maintained it during the study. Corticosteroids have been significantly minimised. All our patients have reached 10 mg to 24 months follow-up. Two patients remained stationary and the aggravation was noted in two patients with myelopathy syndrome; associated in one of them with cerebral deep veins system thrombosis. Reviewing the literature, the most reports showed a diversity of NB treatment, corticosteroids should be given as infusions of intravenous methylprednisolone: 1 g i.v. daily for up to 7 days followed by prednisone 0.5 to 1 mg/kg per day for acute attacks. Therefore, preventive treatment for early relapses consists of prednisone which must be very gradually tapered over 2 to 3 months (Fresco and Siva, 2000), followed by a slowly tapering course of oral steroids (Araji and Desmond, 2009). However, there is controversy about the choice of immunosuppressant therapy as an adjuvant to corticoste- roids; immunosuppressive agents or tumor necrosis antago- nists should be used at the same time or later depending on the nature of the disease, its severity, the response to steroids, and whether the patient has had previous attacks (Araji and Desmond, 2009). In the retrospectives series, immunosup- pressive therapy was not used until the second attack occurs, or if the disease is aggressive (Araji and Desmond, 2009). Similarly, no treatment trial has been undertaken cerebellar veins thrombosis. For dural sinus thrombosis associated with Behc¸et disease, concurrent use of corticosteroids and anti- coagulants is suggested (Bank and Weart, 1984). Either intravenous unfractionated heparin or subcutaneous low- molecular-weight heparin can be used (Siva, 2001). Some neurologists prefer not using anticoagulants, choosing instead to give steroids and immunosuppressant alone. Others prefer to use anticoagulants, but recent data showed that immuno- suppressant were underused (Araji and Desmond, 2009). Several immunosuppressive agents were previously reported, such as azathioprine, CPM, chlorambucil, thalidomide and methotrexate (Boone et al., 1986; Hamuryudan et al., 1997; Hamuryudan et al., 2001). For patients with parenchymal Neurobehc¸et’s disease without any poor prognostic factor, azathioprine or methotrexate and corticosteroids are recom- mended as the first line treatment. For high-risk patients, intravenous CPM and corticosteroids are recommended (Bowirrat and Radi, 2010). Only clinical cases were reported (Andrews et al., 2007). In our series, the aggravation was noted in two patients with myelopathy syndrome, these two cases were comparable to previous reports identifying that presence of myelopathy is a factor associated with a poor response to CPM. Regarding tolerance and side events, it is interesting to note that our patients have received 12 g of the mean cumulative during the following up. However, Radis reported that the cumulative toxic dose was around 80 g (Radis et al., 1995), side events were recorded in three patients, two of them have reversible alopecia and the second has a definitive amenorrhea after 10th bolus. There were no cases of hemorrhagic cystitis (Rodo´ et al., 2001). 5. Conclusion The demographic and clinical aspects of our series are similar to those of the literature. In contrast to previous reports of a poor prognosis in NBD, our study suggests that immediate and aggressive treatment with CPM therapy may ameliorate the prognosis in patients with mild to moderate NBD by increasing survival and decreasing the disability and mortality in this patient series. However, a multicenter study is needed to confirm the possible efficacy of CPM and further assess the long-term tolerance. 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