H Bodet

A Löfberg

C Pirovano

M C Steil

E Bordes-Richard

R N Vannier

Effect of a current polarisation on BIMEVOX membranes for oxidation of propane in a Catalytic Dense Membrane Reactor

Keywords: Catalytic Dense Membrane Reactor, oxidation, BIMEVOX, electrocatalysis

A BICOVOX dense membrane covered with BICOVOX/Au cermet was investigated at 700°C in the partial oxidation of propane under OCV and under electrical bias. The propane conversion remained constantly equal to 12% whatever the conditions of polarisation. Hydrogen was the main product with a selectivity of 60%.

At OCV, no product of oxidation was detected except water which could not be quantified. Under anodic polarisation, traces of CO were observed as well as a small increase of propylene content which can be explained by partial oxidation and oxidative dehydrogenation of propane, respectively. An anodic polarisation led to a decrease of hydrogen due to its oxidation into water. In contrast, an increase of the hydrogen content was observed under cathodic polarisation. However one cannot exclude some thermal cracking of propane, and the role of the BIMEVOX membrane in the catalytic process remains to be clarified.

Introduction

BIMEVOX materials derive from the parent compound Bi 4 V 2 O 11 and are known for their high oxide ion conduction properties at intermediate temperatures, 400-700°C [1]. In the past decade, they were tentatively developed as membranes for the electrically driven separation of oxygen from air. Current density up to 2 A/cm 2 with 100% efficiency (1A/cm 2 corresponds to an oxygen flow of 3.5 cm 3 /min) could be applied without the need of any electrode material. The membrane was simply made up of a dense BIMEVOX electrolyte sandwiched between two gold grids, which were stuck on the surface by means of a porous layer of BIMEVOX [2,3]. Under Open Circuit Voltage (OCV), 18 O/ 16 O isotope exchange combined with Secondary Ion Mass Spectroscopy revealed that the rate of exchange of molecular oxygen at the membrane surface is very low [4]. In contrast, the kinetics of oxygen transfer was considerably increased when an electrical bias was applied to the membrane [5]. By in-situ X-ray diffraction under electrical bias, the transfer at the surface was confirmed to be due to the partial reduction of vanadium (V) into vanadium (IV) under current polarisation [6].

Because bismuth and vanadium are a priori active cations for the catalytic oxidation of hydrocarbons, BIMEVOX were investigated as dense membranes in the Catalytic Dense Membrane Reactor (CDMR) for the oxidation of hydrocarbons. The principle of a CDMR is based on a Mixed Ionic Electronic Conductive dense ceramic membrane.

The latter separates two compartments, one containing air or oxygen (High Oxygen partial Pressure; HOP), the other containing the (diluted) hydrocarbon (Low Oxygen partial Pressure; LOP). Because of the difference between the oxygen chemical potentials in HOP and in LOP, the oxide ions O 2-migrate from HOP to LOP and may react with hydrocarbons in LOP to yield oxidised products.

The BICOVOX.10 composition (Bi 2 V 0.9 Co 0.1 O 5.35+δ ) has been chosen to study the oxidation of propane at OCV and under an electrical polarisation. In previous studies, the oxidation of propylene and propane has been investigated on BIMEVOX membranes with low surface roughness [7][8][9][10]. Because of a low oxygen transfer coefficient at the surface, BIMEVOX membranes exhibit very low semi-permeability to oxygen [11]. Therefore, a BICOVOX/gold cermet has been deposited on both faces of the membrane to enhance the surface exchange and to allow the possibility of application of an electrical bias.

Experimental Membrane preparation

Bi 2 V 0.9 Co 0.1 O 5-δ powders were prepared by solid state route as described in [12,13]. The powder was then shaped into a disk pressed in a 20 mm diameter die at 750 bars with an isostatic press. The membrane was then pre-sintered at 650°C for 30 minutes with heating and cooling rates of 5°C/min. The cermets were prepared by mixing an attrited powder with a gold paste (90 wt% gold) in ethanol and 1% of cellulose using an ultrasonic bath, before evaporation of the ethanol at 40°C. Two compositions were prepared, one containing 65/35 vol/vol of BICOVOX/gold, the other 30/70 vol/vol BICOVOX/ gold. An ink for serigraphy was then prepared by mixing 75% of cermet with 25% of EC3 binder (mixture of terpenic alcohols and ethylcellulose terpineol, content > 83%). A layer of each cermet composition was deposited on both membrane faces as shown in Figure 1, an intermediate drying step being carried out at 60°C between each deposition. The pre-sintered membrane/cermet was finally annealed at the sintering temperature of BICOVOX, following a protocole defined in a previous study [13]. Successive heating steps (up to 140°C at 1°C/min, up to 440°C at 0.25°C/min, and up to 750°C at 5°C/min heating rate) were applied, and followed by cooling down to room temperature at 5°C/min after a dwell at 750°C for 1 hour. After sintering, the diameter and thickness of the membrane were 16 mm and 1.5 mm, respectively. A cross section of the membrane/cermet obtained by SEM is shown on Figure 2 and reveals that the two porous cermet layers were 20 µm thick each.

The Catalytic Dense Membrane Reactor

The membrane was placed in the reactor between two mullite tubes and sealed by means of pyrex glass o-rings (see details in [7]). The study was carried out at 700°C. The gas phase composition in the two compartments was monitored using a mass spectrometer (Omnistar Pfeiffer). Propane (1% in He, F = 50 cm 3 min -1 , contact time, t = 2.4 s) was flowed in LOP and air was flowed in HOP at the same flowrate (P = 1 atm). Two gold wires were connected to the cermet on both surfaces. The catalytic behaviour of the membrane in the oxidation of propane was first studied at OCV. The surface polarisation was in situ determined by measuring the difference of electric potential between the two gold electrodes. In a second step, the electrodes were connected to an external circuit and electric potentials between -100 and +300 mV and current up to 100 mA were applied.

Results and Discussion

Catalytic behaviour under propane at OCV

At OCV, a stationary regime was rapidly obtained, and the conversion of propane was X = 12 mol%. With air in HOP (p O2 = 0.21.10 -5 Pa), and assuming that the equivalent oxygen content in diluted propane in LOP is less than 3 ppm, a potential difference ∆E th = -233 mV was expected between the two faces of the membrane from Nernst equation. As the measured value is ∆E exp = -27 mV only, it means that the LOP face of the membrane is strongly polarised. The same behaviour was formerly observed in the case of propylene oxidation [7]. This strong polarisation is in good agreement with the low kinetics of exchange of oxygen molecules at the surface of the membrane. All proceeds as if the oxide ions (O 2-) were blocked close to the membrane surface and act as an oxygen reservoir available for oxidation of hydrocarbon molecules. However, as shown in Figure 3, only hydrogen, methane, propylene and ethylene were observed with selectivity of 60, 17, 17 and 9 %, respectively.

No CO, neither CO 2 were detected. No coke was visually evidenced on the membrane after the reactor was opened. However, the amount of methane, propylene and ethylene only cannot account for the high selectivity of hydrogen and carbon deposition is likely to occur.

Catalytic behaviour under propane under polarisation

With the aim to increase the amount of oxidation products, a polarisation was applied on the membrane. Whatever the polarisation, the conversion was maintained at 12% and there was no electrochemical promotion of catalysis. A cathodic polarisation of -100 mV was first applied, followed by an anodic polarisation of +300 mV. As Figure 4 shows and compared with Figure 3, the distribution of products is only slightly affected by the applied polarisation. The partial pressure of hydrogen increases under a cathodic polarisation and decreases under an anodic polarisation. However, traces of CO were observed under + 300 mV.

A second experiment was performed on galvanostatic mode with an anodic polarisation. The current was increased by step of +20 mA, up to +100 mA. An increase of the oxygen content in the gas phase with the current density was observed, the partial pressure of oxygen being 50 Pa at 100 mA. The propane conversion remained almost constant during the whole experiment, X ~ 12%. Figure 4 shows the evolution of the selectivity to products with the current polarisation. It confirms that hydrogen decreases and CO increases as the current bias increases. A small increase of selectivity to propylene and ethylene is also to be noticed.

The formation of CO and the increase of propylene can be accounted for by partial oxidation (C 3 H 8 + 3/2O ). The decrease of hydrogen content is easily explained by its oxidation into water.

The exact role of the membrane is not clear. Does the oxidation of hydrogen, partial oxidation of propane and ODH occurs in the gas phase or on the surface membrane? The question remains open at that stage.

Figures

Conclusions

A BICOVOX membrane with BICOVOX/Au cermet on surface was investigated for the partial oxidation of propane under OCV and under an electrical bias at 700°C. The propane conversion remained constant equal to 12% whatever the conditions of polarisation. Hydrogen was the main product with a selectivity of 60%. At OCV, no product of oxidation was detected except water which could not be quantified. Traces of CO were observed under an anodic polarisation and a small increase of propylene content which can be explained by partial oxidation and oxidative dehydrogenation of propane. An anodic polarisation led to a decrease of the hydrogen content in the gas phase due to its oxidation into water. In contrast, an increase of the hydrogen content was observed under cathodic polarisation. However one can not exclude some thermal cracking and the role of the BIMEVOX membrane in the catalytic process remains to be clarified. Further experiments will be performed at lower temperature and the possibility of deposition of a catalyst on the membrane surface will be considered. Effects are modest, but show the possibility that such a system offers for modifying the catalytic properties of membrane materials in a CDMR.

Figure 1 :

 1 Figure 1: A schematic of the BICOVOX membrane with 2 layers of cermet on both faces

Figure 2 :

 2 Figure 2: A SEM image of BICOVOX/cermet membrane cross section after sintering

Figure 3 :

 3 Figure 3: Selectivity to products vs. time using a BICOVOX membrane covered with BICOVOX/Au cermet at OCV (700°C, 1% C 3 H 8 /He in LOP, air in HOP).

Figure 4 :

 4 Figure 4: Distribution of products vs. time using a BICOVOX membrane with BICOVOX/Au cermet under OCV, and with cathodic (-100 mV) and anodic (+300 mV) polarisation (700°C, 1% C 3 H 8 /He in LOP, air in HOP).

  2 → 3 CO + H 2 O) and by the oxidative dehydrogenation of propane (C 3 H 8 + O 2 → C 3 H 6 + H 2 O), respectively. However the CO amount and the C 3 H 6 increase are very small and one cannot exclude thermal cracking (C 3 H 8 → C 3 H 6 + H 2 , C 3 H 8 → C 2 H 4 + CH 4

Acknowledgments

Hervé Bodet is grateful to the CNRS and the Région Nord Pas-de-Calais for the funding of his PhD grant.


Yorck Mohr

Marc Renom-Carrasco

Clément Demarcy

] Elsje

Alessandra Quadrelli

Clément Camp

Florian M Wisser

Eric Clot

Chloé Thieuleux

Jérôme Canivet

Regiospecificity in Ligand-Free Pd-Catalyzed C-H Arylation of Indoles: LiHMDS as Base and Transient Directing Group

Keywords: cross-coupling, indole, C-H arylation, palladium, LiHMDS

A highly efficient catalyst-base pair for the C-H arylation of free (NH)-indoles in the C-3 position is reported. Ligandfree palladium acetate coupled with lithium hexamethyldisilazide (LiHMDS) catalyzed the regiospecific, i.e. 100% regioselective, C-3 arylation of indoles with high turnover numbers. This catalytic system has been successfully applied to a wide range of substrates including various functional aryl halides and indolic cores. The unique role of LiHMDS as both a base and unexpected transient directing group has been revealed experimentally and elucidated computationally, in line with a Heck-type insertion-elimination mechanism.

Heterobiaryls and in particular those containing indolic cores are ubiquitous motifs in active pharmaceutical ingredients (API) of marketed drugs. [START_REF] Taylor | Rings in Drugs[END_REF][START_REF] Sravanthi | Indoles -A Promising Scaffold for Drug Development[END_REF][START_REF] Kaushik | Biomedical Importance of Indoles[END_REF] Their synthesis often involves at least one catalytic step based on carbon-carbon coupling reactions such as the Pd-catalyzed aryl boronate/aryl halide Suzuki-Miyaura cross-coupling reaction. [START_REF] King | Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals[END_REF] Only in the last decade, the formidable challenge of activating aromatic C-H bonds has led to reduced synthetic steps and improved atom economy. [START_REF] Jia | Efficient Activation of Aromatic C-H Bonds for Addition to C-C Multiple Bonds[END_REF][START_REF] Daugulis | Anilide Ortho-Arylation by Using C-H Activation Methodology[END_REF][START_REF] Yu | III)-Catalyzed C-H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation[END_REF][START_REF] De Sarkar | Weakly Coordinating Directing Groups for Ruthenium(II)-Catalyzed C-H Activation[END_REF][START_REF] Schranck | Functionalization of Remote C-H Bonds: Expanding the Frontier[END_REF][START_REF] Segawa | Synthesis of Extended π-Systems through C-H Activation[END_REF] Heteroarene C-H arylation is reported to proceed following three main pathways, often supported by DFT calculations: electrophilic aromatic substitution, [START_REF] Kurokhtina | Mechanistic Study of Direct Arylation of Indole Using Differential Selectivity Measurements: Shedding Light on the Active Species and Revealing the Key Role of Electrophilic Substitution in the Catalytic Cycle[END_REF] concerted metalationdeprotonation [START_REF] Gorelsky | Analysis of the Concerted Metalation-Deprotonation Mechanism in Palladium-Catalyzed Direct Arylation across a Broad Range of Aromatic Substrates[END_REF][START_REF] Guihaumé | Importance of Palladium-Carbon Bond Energies in Direct Arylation of Polyfluorinated Benzenes[END_REF][START_REF] García-Melchor | Mechanistic Analysis of Iridium(III) Catalyzed Direct C-H Arylations: A DFT Study[END_REF][START_REF] Gorelsky | Analysis of the Palladium-Catalyzed (Aromatic)C-H Bond Metalation-Deprotonation Mechanism Spanning the Entire Spectrum of Arenes[END_REF][START_REF] Santoro | Mechanism and Selectivity of Rhodium-Catalyzed C-H Bond Arylation of Indoles[END_REF] or Heck-type carbo-metalation. [START_REF] Steinmetz | Mechanistic Studies on the Pd-Catalyzed Direct C-H Arylation of 2-Substituted Thiophene Derivatives with Arylpalladium Bipyridyl Complexes[END_REF][START_REF] Colletto | Room-Temperature Direct β-Arylation of Thiophenes and Benzo[END_REF] The reaction's regioselectivity is often a key to discriminate mechanisms for a given catalytic system and is mostly explained on the basis of the substrate's electronic or steric properties, the directing effect of a ligand on the catalyst or the presence of permanent or transient directing groups. [START_REF] Colletto | Room-Temperature Direct β-Arylation of Thiophenes and Benzo[END_REF][START_REF] Tang | Mechanistic Origin of Ligand-Controlled Regioselectivity in Pd-Catalyzed C-H Activation/Arylation of Thiophenes[END_REF][START_REF] Yamamoto | σ-π Continuum in Indole-Palladium(II) Complexes[END_REF][START_REF] Liégault | Modulating Reactivity and Diverting Selectivity in Palladium-Catalyzed Heteroaromatic Direct Arylation through the Use of a Chloride Activating/Blocking Group[END_REF][START_REF] Gensch | Mild Metal-Catalyzed C-H Activation: Examples and Concepts[END_REF][START_REF] Sambiagio | A Comprehensive Overview of Directing Groups Applied in Metal-Catalysed C-H Functionalisation Chemistry[END_REF][START_REF] Gandeepan | Transient Directing Groups for Transformative C-H Activation by Synergistic Metal Catalysis[END_REF] Regarding free (NH)-indoles, their C-H arylation at the C-3 position combined with regiospecificity and high activity has never been accomplished so far. The few reported systems which show high selectivities for the C-3 arylated products display only moderate TON values up to 81 (the catalysts in these cases are mostly Pd-or Ir-based systems). [START_REF] Lane | Direct Palladium-Catalyzed C-2 and C-3 Arylation of Indoles: A Mechanistic Rationale for Regioselectivity[END_REF][START_REF] Zhang | Direct Palladium-Catalyzed C-3 Arylation of Indoles[END_REF][START_REF] Bellina | Direct Palladium-Catalyzed C-3 Arylation of Free (NH)-Indoles with Aryl Bromides under Ligandless Conditions[END_REF][START_REF] Cusati | First Heterogeneously Palladium-Catalysed Fully Selective C3-Arylation of Free NH-Indoles[END_REF][START_REF] Join | Iridium Catalysis for C-H Bond Arylation of Heteroarenes with Iodoarenes[END_REF][START_REF] Perato | Pyridylmethylamine-Palladium Catalytic Systems: A Selective Alternative in the C-H Arylation of Indole[END_REF][START_REF] Yamaguchi | Palladium-Catalyzed Direct C3-Selective Arylation of n-Unsubstituted Indoles with Aryl Chlorides and Triflates[END_REF][START_REF] Vaidya | A Micellar Catalysis Strategy Applied to the Pd-Catalyzed C-H Arylation of Indoles in Water[END_REF] Yields of up to 76% for the C-3 arylated product (after 35 hours) were obtained via a transition metal-free system developed by Chen and Wu using four equivalents of potassium tert-butoxide and an excess of indole. [START_REF] Chen | Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides[END_REF] However, this system led to mixtures of regioisomers. Another metal-free system for the arylation of indoles was described by Ackermann et al. using substituted diaryliodonium salts as reagents without any catalyst. [START_REF] Ackermann | Metal-Free Direct Arylations of Indoles and Pyrroles with Diaryliodonium Salts[END_REF] This procedure gave rise to almost exclusively C-3 arylation albeit in moderate yields. Despite these synthetic limitations, C-3 arylated indoles are considered to be promising API, for instance, as antimicrobial agents, enzyme inhibitors and anticancer drugs (Scheme 1). [START_REF] Dekker | Structure-Activity Relations of Some Antifungal Indoles[END_REF][START_REF] Wu | Structure and Synthesis of Murrapanine, a Novel Skeletal Indole-Naphthoquinone Alkaloid and Cytotoxic Principal from Murraya Paniculata Var. Omphalocarpa[END_REF][START_REF] Pedras | Synthesis, and Evaluation of Potential Inhibitors of Brassinin Glucosyltransferase, a Phytoalexin Detoxifying Enzyme from Sclerotinia Sclerotiorum[END_REF][START_REF] Leboho | The Synthesis of 2-and 3-Aryl Indoles and 1,3,4,5-Tetrahydropyrano[4,3-b]Indoles and Their Antibacterial and Antifungal Activity[END_REF][START_REF] Richardson | Novel 3-Aryl Indoles as Progesterone Receptor Antagonists for Uterine Fibroids[END_REF][START_REF] Patel | Indole-Based Allosteric Inhibitors of HIV-1 Integrase[END_REF][START_REF] Browne | A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification[END_REF] Scheme 1. API based on C-3 arylated free (NH)-indoles and their biological activity. [START_REF] Dekker | Structure-Activity Relations of Some Antifungal Indoles[END_REF][START_REF] Wu | Structure and Synthesis of Murrapanine, a Novel Skeletal Indole-Naphthoquinone Alkaloid and Cytotoxic Principal from Murraya Paniculata Var. Omphalocarpa[END_REF][START_REF] Pedras | Synthesis, and Evaluation of Potential Inhibitors of Brassinin Glucosyltransferase, a Phytoalexin Detoxifying Enzyme from Sclerotinia Sclerotiorum[END_REF][START_REF] Leboho | The Synthesis of 2-and 3-Aryl Indoles and 1,3,4,5-Tetrahydropyrano[4,3-b]Indoles and Their Antibacterial and Antifungal Activity[END_REF] In this context, we report here the ligand-free palladium-catalyzed regiospecific, i.e. 100% regioselective, C-3 arylation of free (NH)-indole derivatives. Catalyzed by a standard palladium salt, the reaction mechanism is driven by a specific lithiated base whose dual role is crucial as demonstrated experimentally and elucidated by DFT calculations.

After extensively screening reaction parameters (Scheme 2 and SI), we determined that palladium acetate, with a loading as low as 0.05 mol%, efficiently catalyzed the phenylation of 1H-indole with 100% selectivity for the C-3 position using lithium hexamethyldisilazide (LiHMDS) as base and bromobenzene as the arylating agent, in toluene at 120°C. After 16 hours, the product was isolated with a yield of 90%, corresponding to a TON of 1800 moles of isolated 3-phenyl-1H-indole per mole of palladium. In toluene, classical inorganic bases such as carbonates or acetates with lithium, potassium and caesium as counter-cations, gave very poor yields. Organic bases such as triethylamine (TEA), diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) were found to be inefficient. Lithium and potassium tert-butoxide did not allow the arylation to proceed in toluene, in contrast to the activity reported by Chen and Wu in dimethylsulfoxide (DMSO). [START_REF] Chen | Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides[END_REF] Scheme 2. The Pd(OAc)2/LiHMDS catalytic system for efficient C-3 arylation of 1H-indole and overview of screened parameters. Scheme 3. Scope of aryl halides. TON are calculated from isolated yields if not otherwise stated. [a] 3 equivalents of 1-bromo-4-chlorobenzene were used. [b] 0.5 mol% of Pd(OAc)2 used. [c] TON calculated from GC-FID yield.

Using LiHMDS, solvents other than toluene and mesitylene, such as tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethylacetamide (DMAc) and DMSO, gave essentially N-arylation or no reaction at all (see SI, Table S7). In contrast to the work of Chen and Wu who noticed a change in selectivity towards N-arylation in the presence of oxygen, [START_REF] Chen | Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides[END_REF] here the standard reaction with bromobenzene and a metal loading as low as 0.05 mol% did not require an anhydrous or deoxygenated solvent but could be performed in technical grade toluene without affecting neither yield nor regiospecificity (Table S7).

To demonstrate the versatility of the present catalytic system, different aryl electrophiles were evaluated (Scheme 3). The C-3 indole arylation was found to proceed efficiently using either iodo-(TON = 1900), bromo-(TON = 1800) or chlorobenzene (TON = 380) with the Pd(OAc)2/LiHMDS catalytic system. High activity was also achieved using p-iodoanisole (TON = 1840) and p-bromodimethylaniline (TON = 1220). When N,Nbis(trimethylsilyl)-protected 4-bromo-aniline was used as substrate, the coupling at the C-3 position also proceeded efficiently (TON = 800). Using three equivalents of 1-bromo-4chlorobenzene as arylating agent gave rise to 3-(4-chlorophenyl)-1H-indole with a TON of 700. Here the superior reactivity of the bromide compared to the chloride moiety allowed reaching 100% chemoselectivity. Further aromatic systems, like naphthalene, benzothiophene and ferrocene could be used efficiently as electrophiles with average to high activity and full regioselectivity. Noteworthy, the Pd(OAc)2/LiHMDS system allowed preparing 3-(o-tolyl)indole, which cannot be obtained using the previously reported transition metal-free system, since the latter operates via a benzyne intermediate. [START_REF] Chen | Transition-Metal-Free C3 Arylation of Indoles with Aryl Halides[END_REF] The scope of applicable functionalized indoles is presented in Scheme 4. The C-3 arylation efficiently proceeded with both phenyl iodide and bromide in most cases. Scheme 4. Scope of functionalized indoles. TON are calculated from isolated yields if not otherwise stated. [a] 0.5 mol% of Pd(OAc)2 used. [b] TON calculated from GC-FID yield. [c] 2.0 mol% of Pd(OAc)2 used.

Indoles functionalized either at the C-5 or C-7 positions can be efficiently arylated leading to a 100% regioselectivity in all but one case. Only for 5-methyl-1H-indole, traces of a presumably N-or C-2 arylated product were detected with, nonetheless, a selectivity of 99% for the C-3 arylated product (Figure S3). 2-Methyl-1H-indole can also be C-3 arylated with, however, a TON one order of magnitude lower than other functionalized indoles. This lower activity is probably due to steric hindrance resulting from the presence of the methyl group. Similarly, the use of 2-phenylindole as substrate leads to no reaction.

Overall, the Pd(OAc)2/LiHMDS catalytic system is tolerant to various halide, methoxy, substituted amino, and boronate substituents (Scheme 3 & 4), offering the possibility for further functionalization of the 3-phenyl-1H-indole moiety. Unfortunately, compounds bearing nitro or trifluoromethyl groups, either at the electrophile or the indolic core, decompose under the reaction conditions. Aryl halides based on pyridine or with protic functional groups (-OH, -NH2) did not react with 1H-indole (see SI, Scheme S1).

Following the concept of "homeopathic" catalysis introduced by Beletskaya and Cheprakov [START_REF] Beletskaya | Reaction as a Sharpening Stone of Palladium Catalysis[END_REF] and demonstrated by de Vries and co-workers for ligand-free Pd-catalyzed C-C coupling reactions, [START_REF] De Vries | Homeopathic Ligand-Free Palladium as a Catalyst in the Heck Reaction. A Comparison with a Palladacycle[END_REF][START_REF] Alimardanov | Use of "Homeopathic" Ligand-Free Palladium as Catalyst for Aryl-Aryl Coupling Reactions[END_REF] we tested the Pd(OAc)2/LiHMDS catalytic system at Pd loadings as low as 5 ppm with respect to the quantity of indole (i.e. 0.0005 mol%) and a TON of ca. 16000 was reached without affecting the selectivity for the C-3 arylated product (Table 1, entry 8). However, the yield decreased significantly at such a low palladium loading. Table 1. Effect of lowering the palladium loading down to the ppm level. [a] Entry Pd loading (mol%) [a] Reaction conditions: 1H-indole (0.5 mmol), bromobenzene (0.6 mmol), palladium acetate and LiHMDS (1.1 mmol) in toluene (4 mL) at 120°C. [b] GC-FID yields with dodecane as internal standard. [c] Turnover number defined as (moles of 3-phenylindole)/(moles of palladium) (n.d.: not determined). [d] Reaction performed under microwave irradiation (300 W).

Time (h) Temperature (°C) C-3 yield (%) [b] TON [c]
We also investigated the use of microwave irradiation as heating protocol. [START_REF] Larhed | Microwave-Accelerated Homogeneous Catalysis in Organic Chemistry[END_REF][START_REF] Gawande | Microwave-Assisted Chemistry: Synthetic Applications for Rapid Assembly of Nanomaterials and Organics[END_REF][START_REF] Kokel | Application of Microwave-Assisted Heterogeneous Catalysis in Sustainable Synthesis Design[END_REF] In the presence of 0.05 mol% of palladium and under microwave irradiation, a TON of 1200 was reached at 120°C after two hours and a TON of 1600 was obtained at 150°C after only one hour of reaction (Table 1, entries 3 and 4, respectively). In the latter case, the turnover frequency (TOF), defined as moles of 3-phenyl-1H-indole per mole of palladium per hour, reaches a value of 1600 h -1 , which represents one of the highest TOF for metal-catalyzed C-H arylation reactions reported so far. [START_REF] Roger | Ligand-Free Palladium-Catalyzed Direct Arylation of Thiazoles at Low Catalyst Loadings[END_REF][START_REF] Gensch | Increasing Catalyst Efficiency in C-H Activation Catalysis[END_REF] Furthermore, using only 20 ppm of palladium acetate, the 3-phenyl-1H-indole was obtained with full regioselectivity and a TON of 11400 (Table 1, entry 7). In the absence of palladium, under microwave heating, only the formation of traces of N-arylated indole were observed after 16 hours (Table 1, entry 10 and SI).

From a mechanistic point of view, since the use of LiHMDS was key for both activity and selectivity, a series of experiments was carried out to gain more insight into the role of the lithiated base (Table 2). Under optimized conditions, we found that reducing the amount of LiHMDS from 2.2 equiv. to 1.5 or 1.0 equiv. drastically lowered the yield of the reaction from 90% to 38% and 0.6%, respectively (Table 2, entries 1-3), thus suggesting that two equivalents of LiHMDS are mandatory. When using NaHMDS, KHMDS or Mg(HMDS)2 instead of LiHMDS, very low arylation yields were observed (0.05 mol% Pd, Table 2, entries 4-6). When 5 mol% Pd were used, Mg(HMDS)2 was found to be capable to drive the reaction with however a lower regioselectivity (33% yield, 96% selectivity, Table S1 andS2), whereas KHMDS was not. It is noteworthy that Sames and coworkers also reported in 2005 the use of Mg(HMDS)2 as base for this reaction, among a series of Mg salts, albeit with the formation of both C-2 and C-3 arylated products and the nature of the magnesium salt of indole as well as its role in the reaction mechanism not being elucidated. [START_REF] Lane | Direct Palladium-Catalyzed C-2 and C-3 Arylation of Indoles: A Mechanistic Rationale for Regioselectivity[END_REF] The use of alternative lithiated bases such as lithium diisopropylamide (LDA, pKa ~ 36), which is a stronger lithiated base than LiHMDS (pKa ~ 26), or n-butyl lithium (BuLi, pKa ~ 50) gave rise to only 0.3% yield (Table 2, entry 7) or no arylated product (Table 2, entry 8), respectively. Table 2. Evaluation of the effect of different lithiated and different silazide bases on the catalytic performance. [a] Entry Base (equiv.) 1.3 26 [a] Reaction conditions: 1H-indole (0.5 mmol), bromobenzene (0.6 mmol), palladium acetate (0.25 µmol) and base in toluene (4 mL) at 120°C for 16 h. [b] GC-FID yields with dodecane as internal standard. [c] Turnover number defined as (moles of 3-phenylindole)/(moles of palladium) (n.d.: not determined). [d] Indole and the two bases were stirred in toluene for 15 min prior to the addition of bromobenzene and Pd(OAc)2.

C-3 yield (%) [b] TON [c]
To further elucidate the role of both the lithium cation and the hexamethyldisilazide anion (HMDS -) in the reaction, different base combinations were evaluated. A mixture of BuLi and LiHMDS gave comparable results to those found under standard conditions (Table 2, entry 9). In contrast, when one equivalent of Li was removed from the reaction mixture by using either BuLi/NaHMDS or LiHMDS/NaHMDS, almost all the activity was suppressed (Table 2, entries 10 and 11) similar to when one equivalent of LiHMDS was employed (Table 2 entry 3). Thus, the palladium-based catalytic system requires two equivalents of base, at least one being HMDS -, and two equivalents of Li + with respect to the substrate.

Further, the product of mixing 1H-indole with two equivalents of LiHMDS was isolated as a white powder and characterized by liquid and solid-state NMR spectroscopy as well as ICP-OES and elemental analysis (see SI). 1 H and [START_REF] Guihaumé | Importance of Palladium-Carbon Bond Energies in Direct Arylation of Polyfluorinated Benzenes[END_REF] C liquid state NMR spectra of the isolated precipitate recorded at 105°C in toluene-d8 show the presence of indolide and HMDS -in a 1:1 ratio (Figure S55 andS56). In addition, well-resolved [START_REF] Guihaumé | Importance of Palladium-Carbon Bond Energies in Direct Arylation of Polyfluorinated Benzenes[END_REF] C Cross-Polarization (CP) Magic Angle Spinning (MAS) solidstate NMR spectra were obtained with chemical shifts in good agreement to those obtained from liquid state [START_REF] Guihaumé | Importance of Palladium-Carbon Bond Energies in Direct Arylation of Polyfluorinated Benzenes[END_REF] C NMR (Figure S56 and S59) spectroscopy. ICP-OES and elemental analysis evidence the presence of two Li cations, which appear as a single signal in both the liquid-state and the MAS solid-state [START_REF] Yu | III)-Catalyzed C-H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation[END_REF] Li NMR spectra at -1.5 ppm and -2.5 ppm, respectively (Figure S57 andS60). In contrast, the [START_REF] Yu | III)-Catalyzed C-H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation[END_REF] Li NMR signal of LiHMDS in toluene-d8 at 105°C is found at +1.4 ppm (Figure S63), confirming a different chemical environment of Li in the two compounds. Furthermore, 1 H-1 H NOESY experiments display a correlation between the methyl groups of the HMDS -moiety and several indole protons at 105°C in toluene-d8 (Figure S58).

These data strongly suggest that, as it is known for lithium bis(silyl)amides, [START_REF] Wannagat | The Chemistry of Silicon-Nitrogen Compounds[END_REF][START_REF] Popenova | Density Functional Study of Lithium Hexamethyldisilazide (LiHMDS) Complexes: Effects of Solvation and Aggregation[END_REF][START_REF] Neufeld | Introducing a Hydrogen-Bond Donor into a Weakly Nucleophilic Brønsted Base: Alkali Metal Hexamethyldisilazides (MHMDS, M=Li, Na, K, Rb and Cs) with Ammonia[END_REF][START_REF] Nicholas | Structural Characterization of Lithium and Sodium Bulky Bis(Silyl)Amide Complexes[END_REF] the lithiated compound is present predominantly as a bis-lithium indolide hexamethyldisilazide species with the general formula [indolide•Li2•HMDS] (Scheme 5), the presence of larger aggregates being however not excluded. [START_REF] Reich | Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms[END_REF] Scheme 5. Postulated reactivity of 1H-indole with two equivalents of LiHMDS leading to [indolide•Li2•HMDS] as a key intermediate.

When the deprotonation of indole is carried out in the presence of two equivalents of Li + and one equivalent of HMDS -at room temperature, [indolide•Li2•HMDS] precipitates in toluene but then dissolves back upon heating above 100°C. In contrast, the use of other lithiated bases gave precipitates that were not soluble even at 120°C in toluene (Figure S52). This unique solubility of [indolide•Li2•HMDS] was confirmed by in-situ liquid state NMR spectroscopy. Hexamethyldisilazane was the sole product observed in the 1 H spectrum of a 1:2 mixture of 1Hindole and LiHMDS in toluene-d8 at room temperature. Furthermore, no soluble Li species were detected, i.e. no signal in the [START_REF] Yu | III)-Catalyzed C-H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation[END_REF] Li NMR spectrum. This evidences that at room temperature all indole and Li species are insoluble. Upon heating to 105°C the signals belonging to the [indolide•Li2•HMDS] species become visible in both 1 H and [START_REF] Yu | III)-Catalyzed C-H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation[END_REF] Li NMR spectra (Figure S53 andS54).

A catalytic test was carried out with the isolated precipitate [indolide•Li2•HMDS] without adding any additional base under standard conditions (see SI), giving 3-phenyl-1H-indole in 85% yield. In light of these observations, only the combination of indole with two equivalents of Li + and one equivalent of HMDS -gives rise to a soluble reaction intermediate [indolide•Li2•HMDS] which can be readily arylated by the palladium catalyst.

To get deeper insight into the possible reaction mechanism, deuterium-labelling experiments were performed. When (2-2 H)-1H-indole was used as a substrate, the final product was obtained with complete retention leading to 3-phenyl-(2-2 H)-1H-indole, which excludes any C-H activation at the C-2 position. This is further supported by the fact that 2-methyl-1H-indole could be C-3 arylated (Scheme 4 and section 4 of SI). As a blank experiment, we performed the reaction using 3-methyl-1H-indole as substrate and the starting reagents were quantitatively recovered showing that neither C-2 nor N-arylation occurred as side reactions (Scheme S1). Using 1-methyl-1H-indole, also no reaction was observed, highlighting the importance of this position in the reaction mechanism (Scheme S1).

When the reaction was carried out using (3-2 H)-1H-indole and 1H-indole as substrates in parallel reactions or in a 1:1 mixture for an intermolecular competition experiment, no kinetic isotopic effect (KIE) was observed, kH/kD = 1 (Figure S64-S66). Thus, the C-H cleavage at the C-3 position is not the rate-determining step. [START_REF] Simmons | On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes[END_REF] The absence of any KIE makes a CMD mechanism very unlikely, and thus is not considered any further. [START_REF] Colletto | Room-Temperature Direct β-Arylation of Thiophenes and Benzo[END_REF][START_REF] Lapointe | Overview of the Mechanistic Work on the Concerted Metallation-Deprotonation Pathway[END_REF] Calculations performed at the DFT level allow to draw the energy profile of the reaction between phenyl bromide and indole catalyzed by Pd(II) in the presence of two equivalents of LiHMDS (Figure 1). The calculations clearly show that a mechanism based on the insertion of a Pd-aryl into the indole C-2=C-3 bond (carbo-palladation) followed by a base-assisted elimination in a Heck-type mechanism is much more favored than an electrophilic aromatic substitution pathway (SEAr) (Figure S72, see SI for detailed calculations). The Heck-type mechanism represents here a new pathway since previously proposed pathways for catalytic indole C-H arylation reactions were of SEAr type. [START_REF] Kurokhtina | Mechanistic Study of Direct Arylation of Indole Using Differential Selectivity Measurements: Shedding Light on the Active Species and Revealing the Key Role of Electrophilic Substitution in the Catalytic Cycle[END_REF][START_REF] Lane | Direct Palladium-Catalyzed C-2 and C-3 Arylation of Indoles: A Mechanistic Rationale for Regioselectivity[END_REF] Noteworthy, the selectivity of the SEAr reaction in the Mg(HMDS)2 catalyzed indole arylation was explained so far only by steric effects. The use of a bulky counter ion such as HMDS -was supposed to hinder the required C-3 to C-2 migration of palladium, thus increasing the amount of C-3 arylated indole.

Here, in the Heck-type insertion-elimination mechanism, the overall energy barriers are very similar for both the C-2 and C-3 arylation pathways. However, two key intermediates, both implying the second LiHMDS molecule, favorably drive the arylation to the C-3 position, namely D3 and D3' (Figure 1). First, in the insertion step, the D3 species is stabilized by 19.3 kcal/mol compared to the analogous D2 species due to the interaction between one lithium atom and the bromide of the palladium complex.

This stabilizing effect of LiHMDS is already present in the coordination of Pd to C-2=C-3 as illustrated by the larger stability of C3 compared to C2. The energy barrier to achieve the base-assisted elimination at C-3 is composed of two individual events: decoordination of LiHMDS from D3 to reach a configuration (D3') prone to effectively deprotonate the C-3 position, and actual base-assisted elimination through TS-D3. Even though the transition state from D3 to D3' could not be located, the first step has an energy barrier of approximately 18.8 kcal/mol, whereas the second one has an energy barrier of 15.5 kcal/mol. In comparison, base-assisted elimination in the C-2 pathway shows a direct transition from D2 to reach the corresponding TS-D2 having a much higher energy barrier of 33.9 kcal/mol.

The calculations highlight that the transition between D3 and D3' with the highest energy barrier (approximately 18.8 kcal/mol) should be the rate-determining step. This supports the absence of a KIE observed experimentally, in line with the "no KIE" scenario reported by Simmons and Hartwig. [START_REF] Simmons | On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes[END_REF] Here the rate-determining step has to occur before the cleavage of the C-H bond, e.g. the formation of a complex undergoing subsequent deprotonation at the functionalized carbon.

Moreover, the computed structures confirm the experimental evidence that the [indolide•Li2•HMDS], denoted B in Figure 1, is the most stable species in a system of one molecule of 1Hindole and two molecules of LiHMDS.

Based on experimental and computational findings, we demonstrate herein for the first time the direct C-3 arylation of indoles proceeding via a Heck-type mechanism. In this insertion-elimination pathway LiHMDS acts not only as a base but also as a unique transient directing group driving the regiospecificity of the reaction towards the C-3 position. In summary, we have uncovered a catalytic system able to achieve the arylation of free (NH)-indoles with 100% selectivity for the C-3 arylated product and remarkable turnover numbers at the same time. Experimental findings combined with DFT calculations highlight the key relevance of a bis-lithium indolide hexamethyldisilazide [indolide•Li2•HMDS] species as activated indole substrate. For the first time in indole C-H arylation, the observed selectivity is explained by a Heck-type mechanism in which LiHMDS uniquely plays the role of both a base and transient directing group. In light of these results, the use of LiHMDS opens new perspectives for the transition metal catalyzed regiospecific C-H arylation of heteroarenes.

Figure 1 .

 1 Figure 1. Schematic relative free energy profile for the reported reaction calculated at the DFT (PBE0-D3) level. Pathways towards C-2 or C-3 arylated indole are shown in red and blue, respectively. Structures of calculated intermediates and transition states are represented.

ACKNOWLEDGMENT

This work has been carried out within the H-CCAT project that has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 720996. F.M.W. gratefully acknowledges financial support from the Deutsche Forschungsgemeinschaft (DFG, Postdoctoral Research Fellowship, grant number WI 4721/1-1) and from CNRS through Momentum 2018 excellence grant. The authors are very grateful to P. Mascunan for ICP-OES analysis, and to C. Lorentz for solidstate NMR spectroscopy.

AUTHOR INFORMATION

Corresponding Author *jerome.canivet@ircelyon.univ-lyon1.fr *thieuleux@cpe.fr

Author Contributions

All authors have given approval to the final version of the manuscript.

ASSOCIATED CONTENT

Supporting Information

Experimental procedures, characterization data and computational details. This material is available free of charge via the Internet at http://pubs.acs.org.

Insert Table of Contents artwork here


A Nérot

X Wang

H Pillet

W Skalli

Estimation of hip joint center from the external body shape: a preliminary study

Keywords: hip joint, biplanar X-rays, external predictors

Introduction

Human external shape model is becoming easily available using scanning technology, stereophotogrammetry, or Microsoft Kinect systems. However locating the internal skeleton from the external shape remains a challenging issue. Using low dose biplanar radiographs of the whole body, subject-specific 3D reconstructions of the bones and the surface envelope have been developed, providing data of both external body shape and internal skeleton [START_REF] Dubousset | Eos: a new imaging system with low dose radiation in standing position for spine and bone & joint disorders[END_REF]. The basic idea of this research project was to explore the relationships between characteristics of internal skeleton and those of external body shape.

Hip joint center (HJC) prediction was considered in this preliminary study. Subject-specific HJC prediction is currently performed either using functional methods based on the relative motion of the femur and pelvis, or predictive methods relying on empirical regression equations using palpable femoral and pelvic landmarks as predictors. Yet functional methods may be ineffective when hip motion is limited. Different regressions between HJC and predictive landmarks were established based on direct measurements on pelvic and femoral bone specimen surface, using cadavers, medical imaging or 3D CT-scans [START_REF] Peng | Methods for determining hip and lumbosacral joint centers in a seated position from external anatomical landmarks[END_REF]. However, in most applications when medical imaging is not available, manual palpation over the skin of the bony predictors might increase the prediction error on HJC compared to cases where bone information is available directly [START_REF] Sholukha | Femur shape prediction by multiple regression based on quadric surface fitting[END_REF][START_REF] Sangeux | Which method of hip joint centre localisation should be used in gait analysis?[END_REF].

In this paper, new predictors from external body shape were explored for HJC prediction.

Methods

A database of biplanar X-ray acquisitions (EOS Imaging, Paris, France) of the whole body of 40 volunteers (20 males, 20 females, average age: 33 ± 14 years), equally split into three BMI groups BMI < 21, 21 < BMI < 25 and BMI > 25Kg/m², was analyzed. From these two radiographs, 3D reconstruction of the pelvis, lower limbs and external envelope was performed.

HJC was identified as the centre of the femoral head by least square sphere fitting. Three sets of external parameters were considered in this exploratory approach: (1) Morphological parameters using the major, minor axes and centroid of ellipses fitted in a least square sense over the contour of body segments (Figure 1); (2) Barycentremetric parameters including the centers of mass (COM) of body segments which were calculated assuming homogeneous segment densities [START_REF] Dempster | Space requirements of the seated operator[END_REF][START_REF] Amabile | Prediction of the rib cage volume from anthropometric data[END_REF]; (3) Distances between anatomical landmarks on the skin surface. Anatomical bony landmarks were identified from the bone reconstructions and the closest point on the envelope was considered as the corresponding palpated landmark. Different statistical methods were implemented in order to find the best compromise between number of predictors and standard errors of estimate (multilinear regression, partial least square regressions, principal component regression). Leave-one-out cross validation (LOOCV) was used to test how each regression equation would perform on new input data. The existing data (n = 40) were iteratively split into a training set of n-1data points and a validation set with one value. Using the regression equations established from the training sets, the HJC coordinates were predicted (Yestimated) and compared to the HJC coordinates of the validation set (Ytrue). The procedure was then repeated n times with each data point used once as the validation data.

95% confidence intervals (95% CI) around the true HJC location was calculated using 2 standard deviations (2SD) over the n residuals (Yestimated-Ytrue) obtained from the LOOCV. Results were compared to those obtained using the regression equation in [START_REF] Bell | Prediction of hip joint centre location from external landmarks[END_REF], widely used in descriptors and barycentremetric parameters might provide more reproducible regressors compared to manually palpated landmarks. With that in mind, work is in progress to set the estimation that could provide the best compromise.

Conclusions

We proposed a method for HJC estimation using a combination of morphological and barycentremetric parameters. This method was evaluated on a large panel of subjects with variable morphotypes and BMIs, and provided improved estimation with regard to existing ones. clinical gait analysis. HJC coordinates were estimated from the pelvis width, defined as the distance between the two antero-superior iliac spines (ASIS), first using ASIS palpated on the skin surface (RASIS_skin, LASIS_skin), then using the ASIS identified on the pelvic bone (RASIS_bone, LASIS_bone) (Figure 1).

Results and discussion

Combining morphological and barycentremetric predictors helped improving the regression equations. As an example, one multiple regression is provided in Table 1 using the predictors defined in Figure 1. The regression allowed locating HJC with a 95% CI of 11.8 mm, which is similar to Bell's estimation when bone information is available directly (11.5 mm), while it was lower compared to Bell's estimation from external palpated landmarks (22.7 mm). This showed that soft tissue interposition around the pelvis might have affected Bell's prediction accuracy which relies on the identification of predictors from the direct bone surface, while building regression based on external body shape predictors as in the proposed regression method enabled to improve the estimate.

The best estimation method should be accurate (small 95% CI), reliable (with robust describing predictors) and include easily available predictors. As an example ellipse Figure 1. morphological predictors used in the example regression: d1, d2: major and minor axes of ellipses fitted in a least square sense at the height of anterior superior iliac spines (asis), d3: distance between the top of the head and the centroid of the ellipse at the asis level. d4: distance between the centroid of the ellipse at the asis level and the centroid of the ellipse at the height of the femoral epicondyles. Barycentremetric predictors: C1: Com of the lower limbs. C2: Com of the upper body. the local coordinate system is defined by the minor axis (x) and major axis (y) of the asis ellipse, with the z vertical gravitational axis and origin at the intersection of the ellipse's axes.

Table 1. example of a regression equation obtained by combining morphological and barycentremetric predictors, and associated 95% Ci of the distances around true hJC position (in three axes and 3d) using a looCV method. results are compared to an existing regression using landmarks on the envelope surface (rasis_skin, lasis_skin), and landmarks on the pelvic surface (rasis_bone, lasis_bone)* as predictors to calculate pelvic width.


J.-Y Lazennec

H D'astorg

M.-A Rousseau

Cervical spine surgery in ankylosing spondylitis: Review and current concept

Keywords:

a b s t r a c t Ankylosing spondylitis of the cervical spine is associated with stiff kyphosis and increased risk of transversal unstable fracture. A spine surgeon may be involved mainly in the management of trauma cases, but in some situations, corrective surgery of a kyphotic cervical deformity is needed. Both types of cases carry specific aspects and rely on principles that differ from those associated with more common cervical surgery. This paper is a review of the literature regarding cervical surgery in cases of ankylosing spondylitis. It addresses practical technical questions.

Introduction

Ankylosing spondylitis (AS) is an inflammatory rheumatism that may induce structural damage in the cervical spine. Microscopic changes include bone fragility [START_REF] Feldtkeller | Prevalence and annual incidence of vertebral fractures in patients with ankylosing spondylitis[END_REF] arising from decreased bone density, which has been shown to be related to persistent systemic inflammation and hypervascularisation of the bone. In the severest forms, macroscopic changes result in spontaneous intervertebral fusion and kyphosis [START_REF] Etame | Surgical management of symptomatic cervical or cervicothoracic kyphosis due to ankylosing spondylitis[END_REF] of the entire spine (the so-called "bamboo spine"). The ossification concerns the disc space anteriorly and the facet joints posteriorly. While the normal cervical spine provides mobility and allows upright posture of the head, the AS spine is excessively stiff and the flexed posture of the neck is mostly debilitating. In addition to other possible AS locations (hips, sacroiliac joint, and lumbar spine), the cervical effects lead to a significant impairment of quality of life and an increased risk of cervical spine fracture.

Cervical spine surgery is associated with AS in two main situations: management of trauma [START_REF] Cornefjord | Posterior fixation of subaxial cervical spine fractures in patients with ankylosing spondylitis[END_REF][START_REF] El Masry | Combined anterior and posterior stabilisation for treating an unstable cervical spine fracture in a patient with long standing ankylosing spondylitis[END_REF][START_REF] Mountney | Lessons learned from cervical pseudoarthrosis in ankylosing spondylitis[END_REF][START_REF] Payer | Surgical management of cervical fractures in ankylosing spondylitis using a combined posterior-anterior approach[END_REF][START_REF] Shen | Surgical management of lower cervical spine fracture in ankylosing spondylitis[END_REF][START_REF] Taggard | Management of cervical spinal fractures in ankylosing spondylitis with posterior fixation[END_REF] and correction of sagittal "chin-to-chest" deformity [START_REF] Etame | Surgical management of symptomatic cervical or cervicothoracic kyphosis due to ankylosing spondylitis[END_REF][START_REF] Belanger | Cervicothoracic extension osteotomy for chin-on-chest deformity in ankylosing spondylitis[END_REF][START_REF] Chin | Controlled cervical extension osteotomy for ankylosing spondylitis utilizing the Jackson operating table: technical note[END_REF][START_REF] Hoh | Management of cervical deformity in ankylosing spondylitis[END_REF][START_REF] Khoueir | Use of hinged rods for controlled osteoclastic correction of a fixed cervical kyphotic deformity in ankylosing spondylitis[END_REF][START_REF] Langeloo | Cervical osteotomy in ankylosing spondylitis: evaluation of new developments[END_REF][START_REF] Pavlov | Correction and stabilisation in ankylosing spondylitis of the cervicothoracic spine[END_REF][START_REF] Tokala | C7 decancellisation closing wedge osteotomy for the correction of fixed cervicothoracic kyphosis[END_REF][START_REF] Willems | Spinal osteotomy in patients with ankylosing spondylitis: complications during first postoperative year[END_REF]. Both remain strategically and technically challenging.

As with cervical spine fractures in the general population, traumatic fracture/dislocation in the patient with AS usually occurs in the lower cervical spine (C5 to T1). However, AS-related fractures are frequently more severe, with specific features compared to cervical fractures in the healthy population [START_REF] Feldtkeller | Prevalence and annual incidence of vertebral fractures in patients with ankylosing spondylitis[END_REF]. AS fractures are, for example, highly unstable because the anterior and the posterior elements are involved in a transverse or short oblique pattern that does not follow the classical three-column criteria for stability as seen in normal spines [START_REF] Argenson | Traumatic rotatory displacement of the lower cervical spine[END_REF]. Moreover, the broken "bamboo spine" behaves somewhat like a long bone with diaphyseal fracture: the long lever arms are extremely unstable with an associated higher risk of neurological deterioration [START_REF] Foo | Cervical spinal cord injury complicating ankylosing spondylitis[END_REF][START_REF] Grisolia | Fractures and dislocations of the spine complicating ankylosing spondylitis. A report of six cases[END_REF][START_REF] Podolsky | Neurologic complications following immobilization of cervical spine fracture in a patient with ankylosing spondylitis[END_REF]. In addition, the kyphotic deformation does not provide the most appropriate sagittal balance for primary stability, and the hemorrhagic trend produces a supplementary risk of neurological complication through an increased possibility of compressive epidural hematoma [START_REF] Payer | Surgical management of cervical fractures in ankylosing spondylitis using a combined posterior-anterior approach[END_REF]. In spite of all of these considerations, there is a good propensity of the AS bone to fuse.

For these reasons, the surgical treatment of AS spinal fractures is totally different from that for a usual cervical spine fracture. Cases are rare, which means that guidelines and references are sparse. Based on the literature and our experience, we discuss here some relevant issues in the management of AS fractures. Is there room for orthopaedic treatment? What should the fixation be posterior, anterior, or circumferential? What would be the optimal reduction, the former kyphosis or the "more ideal" lordosis? And finally, what is the healing potential of the anterior gap at the site of the fracture?

Outside of the traumatic context, the procedure of posterior cervical subtraction has been described several times [START_REF] Chin | Controlled cervical extension osteotomy for ankylosing spondylitis utilizing the Jackson operating table: technical note[END_REF][START_REF] Hoh | Management of cervical deformity in ankylosing spondylitis[END_REF][START_REF] Khoueir | Use of hinged rods for controlled osteoclastic correction of a fixed cervical kyphotic deformity in ankylosing spondylitis[END_REF][START_REF] Tokala | C7 decancellisation closing wedge osteotomy for the correction of fixed cervicothoracic kyphosis[END_REF], and a few series have reported the surgical treatment of kyphotic deformation [START_REF] Etame | Surgical management of symptomatic cervical or cervicothoracic kyphosis due to ankylosing spondylitis[END_REF][START_REF] Belanger | Cervicothoracic extension osteotomy for chin-on-chest deformity in ankylosing spondylitis[END_REF][START_REF] Langeloo | Cervical osteotomy in ankylosing spondylitis: evaluation of new developments[END_REF][START_REF] Tokala | C7 decancellisation closing wedge osteotomy for the correction of fixed cervicothoracic kyphosis[END_REF][START_REF] Willems | Spinal osteotomy in patients with ankylosing spondylitis: complications during first postoperative year[END_REF]. However, the surgical strategy regarding which level of osteotomy to choose (i.e. cervical or lumbar) has barely been discussed.

Management of trauma cases

The occurrence of traumatic cervical spine injury in the case of AS is significantly greater than the incidence in the normal population because of the global imbalance among the spine, hip, and knees and because of bone fragility [START_REF] Weinstein | Spinal cord injury, spinal fracture, and spinal stenosis in ankylosing spondylitis[END_REF]. These patients should be advised to use aids for ambulation and to avoid chiropractic manipulations. Fractures may occur even from low-energy trauma. Hyperextension is classically considered to be the most frequent mechanism of injury; however, the circumstances are not always clear. Sometimes, the patient does not describe any trauma at all and the lesion appears to have occurred spontaneously. In addition, the diagnosis might sometimes be delayed [START_REF] Smith | Minor neck trauma in chronic ankylosing spondylitis: a potentially fatal combination[END_REF]. In AS patients, a recent increase in neck pain or an acute change in neurological status, even if no trauma has occurred, is an indication for a full imaging study of the vertebral column. For example, we encountered one case in which confusion syndrome was the only symptom, similar to what has been described with fractures of the odontoid.

Proper initial treatment of the patient with AS and acute cervical trauma is crucial to avoid iatrogenic complications. Because the fractured ankylotic spine resembles a long-bone fracture, in the absence of bone and ligament stability, the only means of spinal stabilisation left for these patients is the cervical musculature. In addition, the cervical musculature might be atrophied, as is common with a history of ankylosis. Ambulance and emergency staff should be educated that the routinely recommended neutral position can be disastrous in these patients, who should remain in their usual degree of flexion. Related mistakes could be avoided if the diagnosis of AS is suspected in any case in which patients voluntarily hold the head in flexion.

Imaging of the cervical spine may be difficult in the context of AS because of the bone remodelling, kyphosis, and intervertebral fusion [START_REF] Harrop | Failure of standard imaging to detect a cervical fracture in a patient with ankylosing spondylitis[END_REF]. Visualisation may be especially difficult at the cervicothoracic area, leading to a risk of failed diagnosis and neurological complications. Some authors have advocated MRI for detecting traumatic lesions, specifically at the cervicothoracic junction, which is radiologically poorly documented [START_REF] Wang | Imaging manifestations of spinal fractures in ankylosing spondylitis[END_REF]. At the very least, a CT scan is necessary. The CT scan can show the fracture line, which usually is transverse or shortly oblique and complete from the anterior to the posterior side, similar to the classical Chance fracture at the thoracolumbar spine.

Traction and halo braces

Once a cervical fracture is confirmed, patients with AS can be managed with axial traction. However, the traction direction must be placed in a superior and anterior direction so that the patient is realigned to the pre-existing kyphosis, and minimal weight should be used (Fig. 1). Placing the neck in an extended position may induce neurological complications. Even with properly positioned axial traction, the possibility of further neurological deterioration exists, as this means of immobilisation still allows for rotational movement. Monitoring of the traction must be quite precise: repeated clinical evaluations must focus on the detection of potential neurological worsening including consciousness alterations. Axial traction is an emergency stabilisation procedure that can be used as a transitory stabilisation before surgery. It can be converted to a halo brace if non-operative treatment is ultimately the management choice.

Controversy exists as to whether patients with a fracture/dislocation should be treated with external immobilisation alone or with surgical fusion followed by external immobilisation. The halo brace alone has been advocated as a "classical" mode of treatment, but it is not without complications [START_REF] Surin | Fractures of the cervical spine in patients with ankylosing spondylitis[END_REF]. While the majority of patients placed in a halo brace achieve spinal fusion without difficulty, failures of union or increased neurological deficit have been encountered. Some details regarding the installation of the halo brace require emphasis: because of the cervical kyphosis, a standard halo vest is usually inappropriate, and the device must be custom fitted. The connectors between the halo and the vest must be positioned so as to resist the tendency for anterior flexion. Therefore, the lateral connectors should not be placed at the projection of the shoulders because this placement may induce a side effect tendency for hyperextension, excessive traction on the pins, and risk of pulling out from the skull. Other significant side effects include dramatic translation and overdistraction at the site of the fracture. The anterior turnbuckles have to be placed on the anterior valve of the vest because of the kyphosis. An additional posterior turnbuckle can be used posteriorly. In cases of extreme kyphosis or if a progressive correction is planned using the halo vest, another anterior turnbuckle can be used anteriorly (Fig. 2). Our experience is that in the first few days, the specific tools have to be easily available in case of an urgent need to remove the halo vest (e.g., neurological medullar decompensation with neurogenic cardiovascular or respiratory acute complication). Among the complications of non-operative treatment, the disruption of both the anterior and posterior supporting vertebral structures may lead to instability of such a degree that halo fixation is not successful with translation and rotational displacements. This risky situation is not easily detected on x-rays, mainly at the lower cervical levels. In some cases, CT scan is the only solution in severely kyphotic patients. The same problems can arise in the assessment of bone fusion at the end of the theoretical 3 months of immobilisation. Another issue is pressure ulcerations, which are more prone to develop beneath the halo vest in the case of the AS spine because of the extensive thoracic kyphosis. This process might occur especially when patient care is difficult, as may be the case in those patients in a suboptimal general condition and who are potentially poorly compliant for verticalisation and for accepting such an uncomfortable brace. This complication can be avoided by scrupulous padding or the use of custom-fitted vests. Cranial fixation may also induce severe complications, such as septic intolerance or mobilisation of the pins. Providing that the halo is placed properly without any skin contact and sufficiently below the ears to reduce pull-out risk, and providing that the pins are precisely monitored, the halo vest remains a therapeutic option.

Surgical treatment

Surgical treatment is indicated in case of neurological deficit, when it can clearly be related to evidence of cord or nerve root compression on imaging (Table 1). Then, a procedure of decompressive laminectomy and fusion is performed. In some cases, the cord compression is not obvious because local instability can be the actual cause of a neurological worsening. We have also observed this situation in some cases initially treated with a halo brace in which clinical monitoring identified some neurological worsening resulting from a lack of stabilisation. The main potential advantage of surgical fixation is the possibility of immediate mobilisation of the patient and improvement for nursing care. However, technical difficulties may carry some important limitations because of the kyphosis and instability, including problems with tracheal intubation, installation in the prone position, and the surgery itself (Fig. 3). Most of the time, a postoperative immobilisation is mandatory because of the specificities of those patients (residual kyphosis and sagittal imbalance, poor bone quality, highly unstable lesions). A custom-made cervical collar can be sufficient.

Because the cervical spine is fully stiff or even completely fused in some cases, the usual classification for cervical fractures is not completely appropriate for defining the surgical strategy and technical aspects. Based on therapeutic considerations, one would propose here classification of cervical lesions in the case of AS according to the position of the disruption line: within the former disc space or within the cancellous bone of the vertebral body, namely transdiscal and transosseous lesions (Fig. 4). Transdiscal lesions are located between the former endplates, which are reinforced structures. We consider that this type of lesion preserves the bone stock of the anterior column, with fair contact between the fragments after reduction. While a case of corpectomy at the site of a C6C7 transdiscal fracture has been reported without complication [START_REF] El Masry | Combined anterior and posterior stabilisation for treating an unstable cervical spine fracture in a patient with long standing ankylosing spondylitis[END_REF], for most authors, posterior fixation alone seems stable enough, providing that the number of fixations is sufficient with at least two above and two below [START_REF] Cornefjord | Posterior fixation of subaxial cervical spine fractures in patients with ankylosing spondylitis[END_REF][START_REF] Shen | Surgical management of lower cervical spine fracture in ankylosing spondylitis[END_REF][START_REF] Taggard | Management of cervical spinal fractures in ankylosing spondylitis with posterior fixation[END_REF]. Cervical pedicle screws are reported to be the most reliable but the most challenging fixation [START_REF] Cornefjord | Posterior fixation of subaxial cervical spine fractures in patients with ankylosing spondylitis[END_REF]; however, screws in the lateral mass fixations show satisfactory outcomes [START_REF] Shen | Surgical management of lower cervical spine fracture in ankylosing spondylitis[END_REF][START_REF] Taggard | Management of cervical spinal fractures in ankylosing spondylitis with posterior fixation[END_REF]. Of note is the fact that posterior montages should not end at the cervicothoracic junction and must be extended to the thoracic spine if necessary. No authors have proposed laminar hook fixation, which we also do not recommend because of the risk of spinal hematoma in the context of AS. Only few authors have suggested anterior fixation alone as an option because of the lack of fixation [START_REF] Payer | Surgical management of cervical fractures in ankylosing spondylitis using a combined posterior-anterior approach[END_REF], even if Kouyoumdjian et al. [START_REF] Kouyoumdjian | Fracture of the lower cervical spine in patients with ankylosing spondylitis: Retrospective study of 19 cases[END_REF] suggested anterior plate fixation to provide sufficient stability if the hardware is long enough to avoid significant moment arms such as long bone fractures.

Furthermore, Einsiedel et al. [START_REF] Einsiedel | Injuries of the cervical spine in patients with ankylosing spondylitis: experience at two trauma centers[END_REF] reported about historic series that early implant failures occurred exclusively after single-session anterior stabilization (50%). That's why they now perform circumferential approach in one or two stage.

Combined anterior and posterior instrumentation may be necessary when the structural integrity of the vertebral body has been significantly compromised, and kyphotic deformity at the site of the fracture is present. Some authors [START_REF] El Masry | Combined anterior and posterior stabilisation for treating an unstable cervical spine fracture in a patient with long standing ankylosing spondylitis[END_REF][START_REF] Einsiedel | Injuries of the cervical spine in patients with ankylosing spondylitis: experience at two trauma centers[END_REF] believe that the circumferential fusion should be the suitable method on these reasons:

• inelastic nature of all spinal structures, a fracture in ankylosing spondylitis always extends across all anterior and posterior elements; • poor bone quality; • difficulty in localising anatomical land marks.

A purely posterior fixation/fusion seems indicated if the anterior weight-bearing column is well aligned and without fracture gaps [START_REF] El Masry | Combined anterior and posterior stabilisation for treating an unstable cervical spine fracture in a patient with long standing ankylosing spondylitis[END_REF][START_REF] Payer | Surgical management of cervical fractures in ankylosing spondylitis using a combined posterior-anterior approach[END_REF][START_REF] Taggard | Management of cervical spinal fractures in ankylosing spondylitis with posterior fixation[END_REF].

Transosseous lesions tend to collapse the cancellous bone of the vertebral body, resulting in a lack of bony contact in extension and a potential increase in instability for flexion, translation, and rotation. This problem raises the question of whether or not to perform an additional anterior approach for filling the gap with a cage or bone graft. Major gaps are to be grafted [START_REF] Mountney | Lessons learned from cervical pseudoarthrosis in ankylosing spondylitis[END_REF] for stability and fusion, specifically at the cervicothoracic junction. However, in our experience and for other authors [START_REF] Chang | Posterior correction and fixation without anterior fusion for pseudoarthrosis with kyphotic deformity in ankylosing spondylitis[END_REF], minor bony gaps at the anterior column are likely to fuse with posterior fixation alone. This idea is supported by the good rate of fusion reported in the literature regarding anterior opening osteotomies at the cervical and lumbar levels [START_REF] Etame | Surgical management of symptomatic cervical or cervicothoracic kyphosis due to ankylosing spondylitis[END_REF][START_REF] Belanger | Cervicothoracic extension osteotomy for chin-on-chest deformity in ankylosing spondylitis[END_REF]. While the indication limit is not clear cut, we would like to emphasise that the anterior approach is not systematic to us even for transosseous lesions. In addition, such an anterior approach may be problematic because of the kyphosis deformity and the depth of the grafting site. In some cases, the kyphosis necessitates a partial sternotomy for anterior access to the lower cervical spine. Fig. 5 shows a proposed algorithm for summarising the management of acute cervical lesions. Lesions of the upper cervical spine require a specific strategy: in our experience, the cases are not frequent and are mainly located at C2. Facing these potentially unstable lesions and poor bone quality, an extensive occipitocervical fixation is the safest option despite the limited mobility at follow-up. This stabilisation procedure generally requires a posterior autogenous bone graft to fuse the skull to the C2 or C3 levels. Postoperatively, an additional cervical collar is mandatory, and in some highly unstable lesions, a postoperative halo vest is initially preferred.

Chronic spinal lesions with non-union constitute another type of patient. Most of the cases correspond to failed or delayed diagnoses. Their management includes an initial stage of cervical traction to assess the possibility of reduction. In our experience, if no correction can be obtained and if the neurological status is normal, a posterior fixation without laminectomy can be proposed. Then, the aim is to stabilise to the point that the sagittal balance is considered acceptable. If some correction can be obtained, the management of the lesions is the same as for acute lesions. We have found that posterior fixation alone is sufficient to obtain fusion provided that the fixation is long enough and that postoperative immobilisation is adequate. The indication for additional anterior surgery is rare and is mainly associated with a severe anterior bone defect or highly significant imbalance. As for anterior approaches in acute cases, the kyphosis is a significant technical difficulty. In some cases, the imbalance is unacceptable in a stiff spine without any significant improvement after the traction stage; in these extreme situations, a correction using a wedge osteotomy can be considered despite the risks of the procedure. Fig. 6 provides a proposed algorithm summarising the management of chronic cervical lesions.

Spinal epidural hematoma is a severe potential complication, with a risk rate that is higher than in the non-AS population. AS affects the cancellous bone in such a way that, with a fracture, there is persistent bleeding that may predispose to formation of an epidural hematoma in the rigid cervical canal. This potential complication raises the question of whether or not to perform laminectomy in cases of posterior fixation. Should this choice be considered standard? The potential advantage is that it would create a passageway for the postoperative bleeding. The disadvantage is the related increase in local instability after the removal of the spinous processes, and a reduction of the key zone for avivement and grafting. Septic complications constitute a significant issue because of the specific anatomical features of the skin and deep soft tissues (e.g., postoperative bleeding, fatty involution of the muscles). In addition, the general status of these patients is frequently debilitated. The septic risk is significantly increased in patients initially treated with a halo brace and then operated as a secondary measure because of local displacement or neurological worsening. Severe respiratory complications may also be observed as the lungs are frequently fibrotic and the ribs ankylosed, thus fixing the rib cage. These complications may necessitate making difficult decisions regarding postoperative immobilisation to avoid chest compressions and significantly interfere with the surgical strategy.

Correction of sagittal deformity

Because the cervical spine is kyphotic, the occurrence of the fracture could be an opportunity to increase lordosis at the site of the fracture. Such a case has been reported in a patient whose surgery was delayed from the time of the fracture [START_REF] Payer | Surgical management of cervical fractures in ankylosing spondylitis using a combined posterior-anterior approach[END_REF], but most published series aim only at restoring the former kyphosis. In our experience, another option can be the progressive correction of kyphosis in patients treated with a halo vest. Progressive anterior distraction can be applied on the anterior turnbuckles (Fig. 2) to gradually increase the chin-to-chest distance. The rhythm and amount of correction must be adapted to the patient's tolerance and to the radiological evolution. This procedure is demanding and necessitates daily monitoring of the patient. It is clear that the risk of translation and overdistraction is major during the lordosis manoeuvres because of the instability. The anterior opening must be limited, specifically above C6, for avoiding the additional cerebral risk of stretching the vertebral arteries. The risk of posterior impingement of the medulla in extension would require associated laminectomy, such as for a correction osteotomy (see below). As for deformation surgery at the medullar levels, electrophysiological monitoring of the spinal tracks is relevant [START_REF] Langeloo | Cervical osteotomy in ankylosing spondylitis: evaluation of new developments[END_REF].

Outside the context of trauma, the loss of horizontal gaze and onset of breathing and eating difficulties arising from stiff kyphosis are the main indications for cervical extension osteotomy. The site of osteotomy is C7 for all studies, with the following technique initially described by Simmons, inspired by the Smith Petersen procedure at the lumbar spine. C7 is the best choice for several reasons: the vertebral arteries are not involved, the spinal canal is sufficiently wide, and the lever arm for extension is maximised.

Technically, the removal of the articular joint at C7/T1 is performed to avoid impingement of the T1 roots. A partial decancellation of the vertebral body has been proposed for avoiding the uncontrolled anterior opening, which is quite a dangerous step [START_REF] Tokala | C7 decancellisation closing wedge osteotomy for the correction of fixed cervicothoracic kyphosis[END_REF]. Neuromonitoring (or the wake-up test) is helpful in preserving the medulla from irreversible lesions [START_REF] Langeloo | Cervical osteotomy in ankylosing spondylitis: evaluation of new developments[END_REF]. The gain in lordosis may reach 30 • to 40 • . The results in the literature yield a contrast with two clear-cut types of outcomes: a pretty satisfied patient with good outcomes, no complications, and good fusion, and rare but major neurological complications or even death.

The measurement of the kyphotic deformity is usually done using the chin-brow angle (CBA). The 0 • value indicates the normal and horizontal gaze. However, the CBA integrates the sagittal balance of the whole spine. We emphasise here that one needs to analyse the kyphosis separately at the cervicothoracic spine, the thoracolumbar spine, and even the hip joints. The chin-on-chest (CC) distance is the portion of the deformation that is related only to the cervical spine. A normal CC distance categorises the indications into two types: local kyphosis of the upper spine, based on CC distance, which may require cervical extension osteotomy, and global kyphosis that could be treated at the lumbar level (Fig. 7).

Discussion and conclusion

This review is a level IV of evidence combining experts' opinion and series of cases reported in the literature. The analysis is limited by the number of references in the literature regarding cervical surgery in the context of AS. Most series are retrospective, concern a limited number of patients, and are not fully documented. The large period of inclusion of the published series accounts for the low frequency of cases and introduces some heterogeneity into the reported studies. In elderly patients and those with a severe cord lesion, the presence of AS leads to an especially poor prognosis with a high mortality rate despite appropriate management of trauma cases [START_REF] Foo | Cervical spinal cord injury complicating ankylosing spondylitis[END_REF][START_REF] Weinstein | Spinal cord injury, spinal fracture, and spinal stenosis in ankylosing spondylitis[END_REF][START_REF] Hunter | Spinal fractures complicating ankylosing spondylitis. A longterm follow-up study[END_REF][START_REF] Kiwerski | Fractures of the cervical spine in ankylosing spondylitis[END_REF]. Based on the literature and our experience with AS at the cervical level in our department, we cannot address all the questions that remain. However, our main point is that these cervical lesions are specific. Further points to emphasise are as follows: emergency management should respect the kyphotic posture. While limited, non-operative treatment using a halo vest remains a therapeutic option, as long as its use is rigorously monitored. Classifying the fractures according to the anterior bony gap could be a way of selecting the most appropriate techniques for the surgical procedure. In the case of surgical treatment, fixations have to be long but not systematically circumferential. Regarding kyphosis correction surgery, the technical aspects and the neurological complications have been reported previously. To us, the strategy is always to consider the lumbar osteotomy first when possible, with a clear distinction of the CC distance from the CBA.

Fig. 1 .

 1 Fig. 1. Axial traction: in the case of ankylosing spondylitis, the direction of the traction has to be considered in the context of the cervical kyphosis.

Fig. 2 .

 2 Fig. 2. AP and lateral radiographs of a patient non-operatively treated using a halo vest. Note that the anterior turnbuckles have to rely on the chest because of the kyphosis.

Fig. 3 .

 3 Fig. 3. Kyphosis-related technical difficulties: endotracheal intubation, installation, and the surgical approach are demanding.

Fig. 4 .

 4 Fig. 4. Imaging classification of the cervical fractures: (A) transdiscal, and (B) transcorporeal. Transcorporeal lesions correspond to the collapse of the cancellous bone and induce a gap after reduction that may require an anterior approach. Transdiscal lesions show no bone defect, and a posterior fixation alone is sufficient.

Fig. 5 .

 5 Fig. 5. Algorithm for the management of acute cervical lesions in the case of ankylosing spondylitis.

Fig. 6 .

 6 Fig. 6. Algorithm for the management of chronic cervical lesions in the case of ankylosing spondylitis.

Fig. 7 .

 7 Fig. 7. Different types for the impairment of the chin-brow angle in ankylosing spondylitis. A. Upper kyphosis indicating cervical osteotomy. B. Lower kyphosis indicating lumbar osteotomy.

Table 1

 1 Surgical management of AS cases at the cervical level: bibliography table.

	Author	Year	Journal	n	Age	Neurological	Level	Management	Results	Complications
						status
	Taggard and	2000	Spine	7	60 y.o. (49-83)	3 tetraplegia	3 C5C6	Posterior approach	100% fusion at	1 deep venous
	Traynelis						4 C6C7	± cervical traction	3/4 month	thrombosis
	[8]							preop rib		1 upper
								harvesting		gastrointestinal
										hemorrhage
										2 pneumoniae
										2 deceased
	El Masry et al.	2004	Injury	1	82 y.o.	Sensory C7	C6C7	Circumferential	Anatomical	None
	[4]					deficit		single session	reduction and
									fusion 4 years
	Cornefjord	2005	Eur Spine J	19	60 y.o. (32-78)	2 paraplegia	5 C5C6	Posterior fixation	No reoperated for	1 deep wound
	et al. [3]					2 motor	5 C6C7		loosening of the	infection
						weakness			instrument or	2 extensive
						4 sensory			healing pb	peroperative
						deficit				bleeding
	Mountney	2005	Eur Spine J	1	36 y.o.	Hyperflexia	C7	Traction first	Good results at	None
	et al. [5]							And anterior	18 months
								approach
								And posterior
								fixation 15 days
								after
	Payer [6]	2006	J Clin	4	77 y.o.	C7 motor	C6C7	Posterior approach	Partially recover	None
			Neurosci		70 y.o.	weakness	C6C7	Anterior approach	redislocation	Reopearted
					66 y.o.	Tetraplegia	C6C7	Circumferential	Stable fixation,	circumferential
					52 y.o.	Normal	C6C7	two-session	12 months	None
						Tetraplegia		Circumferential	Stable fixation, no	None
								single session	neurological
									recovery
	Shen and	2006	J Trauma	2	79 y.o. (77-81)	1 tetraplegia	2 C6C7	Posterior approach	Fusion and intact	1 pneumoniae with
	Samartzis								instrumentation at	death at 3 months
	[7]								1 year and 3 month
	Einsiedel	2006	J Neurosurg	37	65 y.o. (36-82)	9 Frankel A	19 C6C7	10 anterior	5 early implant	3 deceased (RDS
	et al. [26]				Two	11 Frankel B	6 two-	approaches	failure with	and cerebral
					institutions	6 Frankel C	segments	11 circumferential	anterior approach	ischemia)
						10 Frankel D		single session		3 infections
								13 circumferential		1 deep venous
								two-session		thrombosis
								3 posterior
								approaches
	Kouyoumdjian	2012	OTSR	19	61 y.o. (33-64)	10 medular	9 C5C6	13 anterior	Good for bone	5 deceased
	et al. [27]					deficit	10 C6C7	approaches	healing	1 haematoma
						7 radicular pain		3 conservative		drained
								treatment		2 cases of screw
								2 circumferential		brached out
								1 posterior		1 pressure sore on
										minerva

Y.O.: year old; pre-op: preoperative.

Funding

None.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.