MD François Simon
email: fsimon05@gmail.com

Anthony Wolfe

Benjamin Guichard

Chloé Bertolus

Roman Hossein Khonsari

Paul Tessier facial reconstruction in 1970 Iran, a series of post-noma defects

Keywords: Barron-Tessier flap, Iran, noma, Paul Tessier, reconstruction

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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Introduction: Paul Tessier was a leading craniofacial surgeon who came to Iran in the late 1970s to reconstruct post-noma defects. He was invited by the Shah to apply his innovative techniques of facial reconstruction and restore some humanity after the extensive mutilation caused by noma. The invitation of world-known physicians to Iran was also part of a greater effort to boost and modernize Iran's health system (Wolfe, 1997;Watts, 2008;[START_REF] Guichard | Midface osteotomies lines: evolution by Paul Tessier, the second Tessier classification[END_REF]. Noma (from the Greek "'to devour'") is a severe infectious disease usually found in extreme sanitary conditions, such as many areas of rural Iran in the 1960s (Ronaghy and Nasr, 1970;[START_REF] Asadi-Lari | Public health improvement in Iran--lessons from the last 20 years[END_REF][START_REF] Movahedi | Trends and geographical inequalities of the main health indicators for rural Iran[END_REF]. Often preceded by a systemic infection (such as measles or malaria), it develops at a young age (peak age 1-4 years) and in conditions of malnutrition, poor local hygiene and medical isolation (Tempest, 1966;[START_REF] Bourgeois | The World Health Organization initiative on noma[END_REF][START_REF] Baratti-Mayer | Noma: an "'infectious"' disease of unknown aetiology[END_REF][START_REF] Marck | A history of noma, the "'Face of Poverty[END_REF][START_REF] Enwonwu | Noma (cancrum oris)[END_REF][START_REF] Feller | Noma (cancrum oris) in the South African context[END_REF]. Studies have established a link between noma and the country's economic development, especially the enforcement of public health policies [START_REF] Bourgeois | The World Health Organization initiative on noma[END_REF][START_REF] Marck | A history of noma, the "'Face of Poverty[END_REF][START_REF] Enwonwu | Noma (cancrum oris)[END_REF]. The disease mechanism is not clearly understood but multiple factors interact from bacterial or viral infection to capillary and arterial microthrombosis [START_REF] Baratti-Mayer | Noma: an "'infectious"' disease of unknown aetiology[END_REF]. Noma starts as a gingival ulcer and quickly evolves into major facial gangrene and death in 80% of cases (Tempest, 1966;[START_REF] Bourgeois | The World Health Organization initiative on noma[END_REF][START_REF] Baratti-Mayer | Noma: an "'infectious"' disease of unknown aetiology[END_REF][START_REF] Marck | A history of noma, the "'Face of Poverty[END_REF][START_REF] Enwonwu | Noma (cancrum oris)[END_REF]. The infection can be treated at an early stage with broad-spectrum antibiotics but most patients seek medical assistance at a late stage when extensive facial defects can only be reconstructed by surgery [START_REF] Bourgeois | The World Health Organization initiative on noma[END_REF][START_REF] Baratti-Mayer | Noma: an "'infectious"' disease of unknown aetiology[END_REF][START_REF] Enwonwu | Noma (cancrum oris)[END_REF].

Long term defects are very difficult to treat due to the fibrous and retracting scars which add to the initial tissue loss, mainly of the mouth and cheek. Patients suffer from social isolation following the great disfigurement and important functional complications, mainly

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3 maxillomandibular constriction due to muscular fibrosis or sometimes bony ankylosis and fusion (Tempest, 1966;[START_REF] Bourgeois | The World Health Organization initiative on noma[END_REF][START_REF] Baratti-Mayer | Noma: an "'infectious"' disease of unknown aetiology[END_REF][START_REF] Marck | A history of noma, the "'Face of Poverty[END_REF][START_REF] Enwonwu | Noma (cancrum oris)[END_REF]. Other consequences include severe dental malposition, salivary incontinence or speech impairment. Surgical reconstruction usually requires many procedures with stage by stage planning using local flaps and increasingly nowadays, free flaps (Tempest, 1966;[START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Marck | Surgical treatment of noma[END_REF][START_REF] Giessler | Noma: experiences with a microvascular approach under West African conditions[END_REF][START_REF] Marck | A history of noma, the "'Face of Poverty[END_REF].

Material and methods:

We recovered documents comprising accounts of consultation and surgical procedures (from the Tessier collection [START_REF] Guichard | Midface osteotomies lines: evolution by Paul Tessier, the second Tessier classification[END_REF], property of the Association Française des Chirurgiens de la Face), concerning a series of 23 patients operated on by Paul Tessier for post-noma defects in Iran (Tehran) in the late 1970s. Tessier wrote in detail (in a typed or handwritten format) the clinical description of the defects and each surgical technique used for the facial reconstruction, all cases had photographs of the original defects and sometimes of post-reconstruction. He was especially meticulous and from the very first consultation anticipated and planned out all the following steps (Fig. 1). During the procedures themselves he was also very precise in his notes and discussed step by step the different solutions to each problem he encountered.

From these documents, we classified the different types of defects using the Montandon classification [START_REF] Montandon | The surgical treatment of noma[END_REF] (Fig. 2), thus enabling us to separate patients with central (type II or III) or lateral (type I or IV) defects. We also studied the different surgical techniques sorting them according to the anatomical structure being reconstructed. Thereby we compared the techniques, their frequency and effectiveness first between themselves and then finally to the techniques described nowadays in the literature.

Results: A series of 14 female and nine male patients were operated on in Tehran from May 1974 to September 1978 with a mean age of 24 years (range: 6-54) at the time of surgery. The age at which the noma infection occurred was recorded in only nine cases, with a mean age of 7 years (range: 2-17). Based on this average, the year in which noma was contracted was calculated for all patients and showed a peak of incidence in the 1960s (from 1931 to 1973). All patients came from isolated rural areas and medical assistance for defect reconstruction was sometimes only sought years after the initial infection. The defects were classified using the Montandon classification (Fig. 2) showing a majority of type I (ten, 44%) affecting the lip and cheek and of type II (nine, 39%) affecting the upper lip and nose. Only one case (4%) was of type III affecting the lower lip and chin and three patients (13%) were type IV suffering from extensive facial defects. The defects were always unilateral, 12 on the left and 11 on the right (Table 1). Half the patients (n = 12, 52%) suffered from nose defects (Table 2). Up to seven had severe maxillomandibular constriction, due to bony fusion in one case (mandible to zygoma) and masseter fibrosis in the others. Another seven patients were found to have important bone defects (premaxilla in six cases and mandible in the other), one type IV patient had extensive premaxilla, zygoma, ethmoid and orbital floor bone defects. As many as 13 patients had previously been unsuccessfully reconstructed using tube pedicles which were sometimes kept by Tessier for vestibular reconstruction but otherwise always removed. Indeed, Tessier considered that they were useless for the reconstruction (neither functional nor esthetic) and hampered his own reconstruction model. Using solely local flaps and an average of three procedures per patient, all the reconstructions were successful (including patients after secondary surgery for partial flap necrosis), although no long-term follow-up was available. Tracheotomy was necessary in two cases. Tessier's preferred reconstruction technique for each anatomical structure can be found in Table 3. The nose was almost always reconstructed with nasofrontal flaps (ten cases) to remodel all types of defects ranging from the columella to the ala or the nose tip. The dorsum was reconstructed with iliac bone grafts in three cases and the nose floor or anterior palate were reconstructed with bone grafts (six cases) and septal grafts (three cases). When dealing with extensive type IV defects ranging from the cheek to the ala, the outer lining flap was often used to complement the reconstruction.

The outer cheek was reconstructed with a rotation flap (four cases), or with a frontotemporal flap (six cases), which was also used to correct the lower lip when possible. Submental island flaps were used twice and a retro-auricular-mastoidian flap and a direct left interior arm flap [START_REF] Kong Bok | Inner arm flap for the reconstruction of nasal and facial defects[END_REF] were used once. The inner cheek was reconstructed mainly using Barron-Tessier myocutaneous flaps (Fig. 3) for important defects (ten cases) and with mucosal flap in two less important cases.

Bone grafts were used in ten cases to support the soft tissue flaps and were always taken from the iliac bone mainly for premaxilla reconstruction. Skin grafts were also used in 13 cases to correct frontotemporal and nasofrontal flap harvesting sites.

Constriction was successfully treated in all cases, mostly by excision of masseter fibrosis and in one case by mandibular osteotomy due to bony fusion between the coronoid process and the zygoma. Teeth were extracted when necessary and a Le Fort I osteotomy was carried out in one case to correct a severe maxillary retrusion. Precise description of the surgical procedure is given in three cases: a patient with a central type II defect (case A, Fig. 3), with a lateral type IV defect (case B, Fig. 4) and lastly with another challenging type IV defect which was, in Tessier's own words "'la plus importante reconstruction hémi-faciale que j'ai entreprise en un seul temps'" (the largest hemi-facial reconstruction that I have undertaken in a single stage; case C, Fig. 2 and5).

Case A, a type II 19-year-old patient suffered important lesions to the upper lip, left corner of the mouth and nose, with columella, left ala, nose tip and dorsum defects. The patient had benefited at a younger age from numerous surgical procedures using tubed pedicle flaps which had to be replaced. Tessier first reconstructed the lip using a heterolabial flap for the left upper lip and the nose with a nasofrontal flap, reinforced by a bone graft. Skin was later grafted to the frontal donor-site. In a second stage, the patient benefited from a left commissuroplasty, Z-plasties of the scars and excision of excess tissue. In a final stage conchal cartilage graft to the left ala and Le Fort I osteotomy to correct maxillary retrusion was planned and the reconstruction was complete after five procedures.

Case B, a type IV 17-year-old patient also suffered from extensive noma sequellae with up to five attempted reconstructions using tube pedicle flaps, resulting in extensive cheek fibrosis continuing in the left lower and upper lip and major maxillomandibular constriction. The tube pedicle flaps were first removed by Tessier who then released the constriction with excision of masseter fibrosis. The left lip and corner of mouth were reconstructed using a masseter flap, the outer cheek using a frontotemporal flap and the inner cheek using a Barron-Tessier myocutaneous flap. Skin was grafted to the frontotemporal donor-site and the reconstruction was complete after two procedures.

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Case C was a 22-year-old patient with a complex type IV defect of the left side of the face with important cheek and nose defects (ala, columella) and severe constriction but most importantly a complete destruction of the left maxillary bone (including the orbital floor) and induced deformity of the left mandible. Extensive excision of scar tissue in the cheek and osteotomy of the mandible were necessary to partially lift the constriction. Tessier decided on a bold one-stage reconstruction using a temporal muscle flap reinforced by a fragment of the coronoid process to reconstruct the orbital floor (as described by Tessier in Fig. 5) and four different cutaneous local flaps to reconstruct the cheek and nose. A frontal flap was used to create a lateral nasal wall and a right frontotemporal flap to shape the nose. The cheek was reconstructed with a Barron-Tessier cervical flap for the inner lining and a left frontotemporal flap for the outer lining and finally skin was grafted to the large frontal donorsite. In a second stage Tessier grafted iliac bone to the maxillary and mandibular defects and the reconstruction was complete after four procedures.

Discussion: Tessier was an innovative surgeon who believed that all facial defects could be reconstructed using local or regional flaps after precise planning, following the precept of craniofacial autarchy (meaning that he considered the head and neck to be self-sufficient for reconstruction). Most of the techniques he introduced are still widely used today (Wolfe, 1997). All the previous reconstruction attempts in this series consisted of unsuccessful tubed pedicles and Tessier helped to develop the use of local flaps as an excellent functional and aesthetic solution to facial defects (Tempest, 1966;[START_REF] Adekeye | Cancrum oris: principles of management and reconstructive surgery[END_REF].

The study of patient defects enables us, like other authors (Tempest, 1966;[START_REF] Adams-Ray | Cancrum oris: functional and cosmetic reconstruction in patients with ankylosis of the jaws[END_REF][START_REF] Pittet | Clinical experience in the treatment of noma sequelae[END_REF][START_REF] Giessler | Microsurgical reconstruction of noma-related facial defects with folded free flaps: an overview of 31 cases[END_REF], to distinguish two main reconstruction issues, in central defects with the nose and premaxilla (type II) and in lateral defects with the cheek and jaw constriction (type I and IV). The lip and especially the upper lip was almost always concerned in both reconstructions.

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The lip was most often repaired with a heterolabial flap and commissuroplasty when necessary. This is consistent with most authors as it is the way to best preserve the lip fullness with continence and aesthetic result (Tempest, 1966;[START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Adams-Ray | Cancrum oris: functional and cosmetic reconstruction in patients with ankylosis of the jaws[END_REF]. In lateral defects Tessier often used tissue from the cheek to complete reconstruction of the lip, using either the outer lining (frontotemporal or cheek island or rotation flap) or the masseter muscle itself. This was an innovative technique which gave muscle support and thickness to a mutilated corner of mouth as in facial paralysis rehabilitation (Sawhney, 1977;[START_REF] Conley | The masseter muscle flap[END_REF][START_REF] Demir | Oral commissure reconstruction with split masseter muscle transposition and cheek skin flap[END_REF]. Also some teams now prefer the use of free flaps (mostly forearm) to reconstruct large defects of the lip, the functional results, especially continence, are always disappointing compared with muscle or heterolabial flaps [START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Giessler | Noma: experiences with a microvascular approach under West African conditions[END_REF][START_REF] A N U S C R I P T A C C E P T E D Accepted Manuscript 15 Giessler | Primary and secondary procedures in functional and aesthetic reconstruction of nomaassociated complex central facial defects[END_REF]. The use of the nasofrontal flap for the reconstruction of the nose has also been widely used in other teams in the 1970s and nowadays with excellent aesthetic results as can be seen in case A (Tempest, 1966;[START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Dean | One-stage reconstruction for defects caused by cancrum oris (noma)[END_REF]. Indeed no other local or free flap enables such an easy and effective reconstruction of the complex shape of the nose.

Repairing the cheek can be done with a large variety of methods either local or free flaps.

Most authors agree that cheek reconstruction ideally needs double lining, although some teams use only one thick musculocutaneous flap [START_REF] Adekeye | The versatility of pectoralis major and latissimus dorsi myocutaneous flaps in the reconstruction of cancrum oris defects of children and adolescents[END_REF][START_REF] Adams-Ray | Cancrum oris: functional and cosmetic reconstruction in patients with ankylosis of the jaws[END_REF][START_REF] Ahmad | Bipaddle pectoralis major myocutaneous flap in reconstructing full thickness defects of cheek: a review of 47 cases[END_REF][START_REF] Kang | Double continuous radial forearm flap for the reconstruction of full-thickness buccal cheek defect[END_REF]. Tessier always used the Barron-Tessier flap to rebuild the inner lining of the cheek and mostly temporofrontal rotation flaps for the outer lining. When possible he did a slit masseter transposition to the corner of the mouth as an intermediate layer for lip fullness as discussed previously. Tessier was one of the first to develop this local platysma island flap technique (Fig. 6) rather than other regional flaps with great donor-site morbidity such as the deltopectoral or inner arm flap [START_REF] Kong Bok | Inner arm flap for the reconstruction of nasal and facial defects[END_REF]; [START_REF] Adekeye | Cancrum oris: principles of management and reconstructive surgery[END_REF][START_REF] Adekeye | The versatility of pectoralis major and latissimus dorsi myocutaneous flaps in the reconstruction of cancrum oris defects of children and adolescents[END_REF]. This highly reliable flap has many advantages as it is very thin and comparable to native tissue, has no donor-site morbidity and is technically simple [START_REF] Futrell | Platysma myocutaneous flap for intraoral reconstruction[END_REF][START_REF] Cannon | Reconstruction of the oral cavity using the platysma myocutaneous flap[END_REF][START_REF] Coleman | The platysma musculocutaneous flap: experience with 24 cases[END_REF][START_REF] Hurwitz | The anatomic basis for the platysma skin flap[END_REF]Talmant, 1983;Tessier et al., 2011). The main drawback in this series was the partial necrosis where total reconstruction was needed in two cases (10%) compared with 0-8% in the literature [START_REF] Futrell | Platysma myocutaneous flap for intraoral reconstruction[END_REF][START_REF] Coleman | The platysma musculocutaneous flap: experience with 24 cases[END_REF]Talmant, 1983;Tessier et al., 2011).

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The use of local flaps for the outer lining of the cheek such as the frontotemporal or submental flap was more common and easily found in the literature (Tempest, 1966;[START_REF] Barthelemy | Prefabricated superficial temporal fascia flap combined with a submental flap in noma surgery[END_REF][START_REF] Behan | The cervico-submental keystone island flap for locoregional head and neck reconstruction[END_REF]. The comparison to the more recent techniques of cheek reconstruction using free flaps (mostly forearm or parascapular) seem to favor Tessier's simpler and more functional approach in native hospitals. Also, compared with radial forearm flaps which take three to four hours, the Barron-Tessier flap can be completed in one hour, which significantly reduces operation time. Different studies show a high short-term failure rate (10%) and an important long-term complication rate due to the lack of appropriate follow-up, which show that the complexity of the procedures associated with suboptimal native hospital conditions render free flaps more perilous to use in post-noma defects [START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Giessler | Noma: experiences with a microvascular approach under West African conditions[END_REF][START_REF] A N U S C R I P T A C C E P T E D Accepted Manuscript 15 Giessler | Primary and secondary procedures in functional and aesthetic reconstruction of nomaassociated complex central facial defects[END_REF][START_REF] Bouman | Early outcome of noma surgery[END_REF].

Indeed the strategy varies depending on whether the patient is operated on in a native hospital and in a one-stage or multi-stage planned operation. When treating post-noma defects, Tessier followed Tempest's principle of "'safe, sound and simple'" where the goal is to restore satisfactory function and especially limit constriction rather than multiply complex procedures trying to obtain a perfect aesthetic result (Tempest, 1966). This particularly makes sense because most procedures as is this series take place during missions in the native country with sometimes suboptimal conditions and very short follow-up. Some teams, on the contrary, M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 prefer to have the patients travel to their hospital, enabling them to use more complex procedures such as free flaps in a more secure environment [START_REF] Montandon | The surgical treatment of noma[END_REF][START_REF] Pittet | Clinical experience in the treatment of noma sequelae[END_REF]. Nowadays, more and more free flaps are being used in native countries while attempting one-stage free flap reconstructions [START_REF] Dean | One-stage reconstruction for defects caused by cancrum oris (noma)[END_REF], however, a noma follow-up study tends to confirm Tessier's approach and shows a long-term complication rate of 64% in free flaps and a significantly much higher rate of success with simple local procedures comparing different teams [START_REF] Bouman | Early outcome of noma surgery[END_REF].

The main limit of this series is the lack of long term follow-up especially concerning constriction which, as we have seen can reappear even after excellent initial results, although this is mainly due to a lack of physiotherapy [START_REF] Bisseling | Long-term results of trismus release in noma patients[END_REF][START_REF] Bouman | Early outcome of noma surgery[END_REF]. This series of patients also emphasizes the sanitary situation in rural areas of Iran in the 1960s which was much more extreme than one could think of nowadays [START_REF] Asadi-Lari | Public health improvement in Iran--lessons from the last 20 years[END_REF][START_REF] Movahedi | Trends and geographical inequalities of the main health indicators for rural Iran[END_REF]. Although Tessier's work was greatly needed the main battle was in the prevention of the disease. Statistics of children under five, during noma's peak of incidence, give a very good indication of nutrition and general health. Most of the population lived in rural areas (62% of the population in villages under 5000 inhabitants in 1970) with poor nutrition, lack of sanitation and understanding of basic health measures and isolated from medical assistance (Ronaghy and Nasr, 1970). Attempts to improve public health in rural areas started in 1964 with the creation of a "'health corps'" and in 1973 with the "'auxiliary health workers'" (Ronaghy and Nasr, 1970;Zeighami et al., 1977;[START_REF] Barzegar | Evaluation of rural primary health care services in Iran: report on vital statistics in West Azarbaijan[END_REF]. The first were young doctors who spent a few years in rural areas instead of their military service. The auxiliary health workers were trained for a few months to treat basic medical conditions and were sent to live within communities in remote rural areas where physicians were absent (Zeighami et al., 1977;[START_REF] Barzegar | Evaluation of rural primary health care services in Iran: report on vital statistics in West Azarbaijan[END_REF]. They were allowed to give basic medication (including antibiotics) and would refer more food supplementation instead of sole breast-feeding, and earlier disease treatment [START_REF] Barzegar | Evaluation of rural primary health care services in Iran: report on vital statistics in West Azarbaijan[END_REF].

Conclusion:

This paper shows the importance of planning in the reconstruction of post-noma defects. Tessier carefully anticipated all the stages using simple local flaps which did not require optimal medical conditions. He also preferred to operate in native Iranian hospitals (although he sometimes had patients brought to France) limiting the reconstruction to a few surgical stages which required short follow-up. This strategy proved to be successful in all cases of these series although the reconstruction of the cheek proved to be challenging with some partial necrosis of his Barron-Tessier platysma flaps. Moreover, the cases emphasize the destructive aspect of this disease and its link to extreme poverty, especially malnutrition and protein depletion. Its occurrence in Iran, a country which has nowadays a developed health system and strong health statistics for children under five, shows the efforts that have been made since the peak of incidence of these cases in the 1960s.

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  Concerning lip reconstruction, Tessier chose the heterolabial Abbe flap in 15 patients, mainly for the upper lip, completed by commissuroplasty in six patients. Masseter flaps were also used in four cases, when the muscle was strong enough and non-atrophic, for both the upper and a bilateral nasogenian flap for the upper lip was used once. When a frontotemporal flap was used for cheek reconstruction, Tessier also used it for the lips in four cases. To reconstruct a total or subtotal upper lip, Tessier combined a heterolabial Abbe flap and a cheek flap.

  Out of the 23 patients, partial flap necrosis occurred in five cases and only concerned the cheek reconstruction, Barron-Tessier flaps had been used in four of the cases and the direct M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 interior arm flap. A new procedure was necessary in two cases and the cheek was reconstructed using a frontotemporal and submental island flap.

  physicians in local towns. A 1981 study showed a decrease in the birthrate and of under-five death rates explained by better infant nutrition, such as earlier solid

Fig. 1 :

 1 Fig. 1: Example (case C) of the notes used by Tessier showing the careful anticipation and

Fig. 2 :Fig. 3 :

 23 Fig. 2: Examples of post-noma defects using Montandon classification. Type I (upper left)

Fig. 4 :

 4 Fig. 4: Case B, lateral defect (type IV), lips reconstructed with masseter flap, inner cheek

Fig. 5 :

 5 Fig. 5: Orbital floor reconstruction using a temporal flap associated with a nasofrontal flap

Fig. 6 :

 6 Fig.6: Barron-Tessier platysma myocutaneous island flap. Illustration(Tessier et al., 2011)

Fig. 7 :

 7 Fig. 7: Translation of Fig. 1 (to be made available online).

Acknowledgement

The authors would like to express their sincere gratitude to the Association Française des Chirurgiens de la Face (AFCF) for granting access to the documents and photos of the Tessier Collection (Centre Hospitalo-Universitaire d'Amiens, Université de Picardie).


MD Cécile Delorme
email: delorme.cec@gmail.com

MD Fleur Cohen
email: fleur.cohen@psl.aphp.fr

MD Cécile Hubsch
email: cecile.hubsch@psl.aphp.fr

MD Emmanuel Roze
email: emmanuel.flamand-roze@psl.aphp.fr

Chorea as the presenting manifestation of primary Sjögren's syndrome in a child

Keywords: Chorea, Sjögren's syndrome, anti-SSA, autoimmune diseases Study sponsorships: None

come

2 Disclosures

 2 Cécile Delorme received a research grant from ARS, and received travel funding from JNLF and Movement Disorders Society. Dr. Roze is the recipient of a grant "poste d'accueil" AP-HP/CNRS. He received research support from INSERM (COSSEC), AP-HP (DRC-PHRC), Fondation pour la Recherche sur le Cerveau (FRC), the Dystonia Coalition (Pilot project), Ipsen, and Merz-Pharma, Novartis, Teva, Lundbeck, Orkyn; served on scientific advisory boards for Orkyn, Ipsen, and Merz-pharma; received speech honorarium from Novartis, Teva and Orkyn, received travel funding from Teva, Novartis, the Dystonia Coalition, the Movement Disorders Society, the World Federation of Neurology Association of Parkinsonism and Related Disorders, International Federation of Clinical Neurophysiology. Dr. Cohen and Dr. Hubsch report no disclosures.

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Delorme 3

Visual diagnosis

A 12-year-old boy presented with subacute chorea (Video). He had no personal or familial medical history.

Chorea occurred without any history of fever or infection, and rapidly worsened over 3 weeks. Examination was otherwise normal. Brain Magnetic resonance imaging (MRI) and cerebrospinal fluid examination were normal.

Diagnosis of chorea associated with a primary Sjögren's syndrome was made according to American-European Consensus Group (AECG) criteria [START_REF] Vitali | Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group[END_REF], because of the association of xerophthalmia (Schirmer test < 5mm in 5 minutes), positive antinuclear antibodies (1:320) with anti-SSA specificity, and focal lymphocytic infiltration on salivary gland histology (2 infiltrates containing at least 50 lymphocytes in a 4mm 2 glandular section, focus score =2). Screening for other causes of chorea was negative, in particular anticardiolipin and antistreptococcal biology. There was no other clinical manifestation of Sjögren's syndrome. The patient was treated symptomatically with Tetrabenazine and Valproic acid. Chorea gradually improved within 6 months, until the patient became asymptomatic without any treatment.

The association of chorea and primary Sjögren's syndrome has never been reported in children and is rare in adults. Various central nervous system (CNS) disorders have been linked to Sjögren's syndrome, including movement disorders such as parkinsonism and dystonia [START_REF] Alexander | Sjögren syndrome: central nervous system manifestations[END_REF]. Diagnosis can be very challenging, as these symptoms are non-specific and may precede the onset of systemic features of Sjögren's syndrome. The causal association between Sjögren's syndrome and CNS involvement is a subject of debate. In our patient, the association of a remitting subacute chorea with unequivocal Sjögren's syndrome features, and the absence of another cause of chorea support a direct causality. Two mechanisms may account for CNS injury in Sjögren's syndrome: an indirect mechanism involving a vasculitis, and a direct pathogenicity of anti-SSA antibodies. Two adult patients with chorea and Sjögren's syndrome have been previously reported and both improved under steroid regimen [START_REF] Venegas Fanchke | Primary Sjögren's syndrome presenting as a generalized Chorea[END_REF][START_REF] Min | Bilateral basal ganglia lesions of primary Sjogren syndrome presenting with generalized chorea[END_REF]. In our child patient, we decided to postpone steroid therapy, taking into account i) the normality of brain MRI, which was not in favor of vasculitis ii) the potential deleterious effect of this treatment on growth, iii) the possibility of a spontaneous remission in autoimmune choreas. Childhood-onset primary Sjögren's syndrome itself is very rare and usually revealed by an isolated parotid swelling. Recognition and follow-up of this condition is crucial as it may precede the onset of severe autoimmune diseases such as systemic lupus erythematosus or juvenile arthritis. Subacute chorea can be the initial manifestation of autoimmune diseases. Sjögren's syndrome should be considered in this setting, even in children, and immunosuppressive drugs should be used only in case of symptomatic treatment failure.


archive ouverte pluridisciplinaire HAL, est destinée au dépôt

Neurohistiocytose : de la classification clinique à la thérapie ciblée

Ahmed Idbaih AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de neurologie 2-Mazarin, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France Inserm, U 1127, ICM, Paris, F-75013 Paris, France CNRS, UMR 7225, ICM, Paris, F-75013 Paris, France ICM, Paris, 75013 France Les histiocytoses regroupent des maladies multisystémiques hétérogènes caractérisées par la prolifération de cellules du lignage monocytes-macrophages-cellules dendritiques. Trois grands groupes d'histiocytoses, eux-mêmes subdividés en plus entités, sont individualisés: (i) dendritiques, (ii) macrophagiques, et (iii) malignes. Les histiocytoses dendritiques sont dominées par l'histiocytose langerhansienne, autrefois appelée histiocytose « X » résultant de la fusion de plusieurs entités (i.e. le granulome éosinophile, la maladie de Hand-Schüller-Christian, et la maladie de Abt-Letterer-Siwe). Les histiocytoses dendritiques non langerhansiennes regroupent notamment le xanthogranulome juvénile et la maladie d'Erdheim-Chester. La lymphohistiocytose hémophagocytique primitive et la maladie de Rosai-Dorfman font, quant à elles, partie des histiocytoses macrophagiques. Enfin, les histiocytoses malignes regroupent certaines leucémies et certains sarcomes.

Les histiocytoses touchent le système nerveux central avec deux principaux types de lésions: (i) pseudotumorale et (ii) pseudodégénérative. Ces lésions s'opposent en tous points. En effet, l'épidémiologie, les manifestations cliniques, l'aspect neuroradiologique, les caractéristiques histologiques et le pronostic de ces types de lésions observées dans les histiocytoses sont radicalement différents. Ces dernières années ont été marquées par la découverte de mutations activatrices récurrentes du gène BRAF dans les histiocytoses. Des thérapies moléculaires ciblées contre le produit de ces anomalies génétiques ont été développées. Elles ont révolutionné le pronostic des lésions pseudotumorales systémiques et neurologiques des histiocytoses avec des régressions lésionnelles importantes. La classification diagnostique des histiocytoses et de leurs atteintes neurologiques ont été raffinées grâce notamment à la microscopie électronique, à la biologie moléculaire et à l'imagerie. Cette meilleure caractérisation multimodale des histiocytoses a également ouvert la voie à des stratégies thérapeutiques innovantes.

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