# French protocol for diagnosis and management of Cogan's syndrome

Laurent Arnaud, Alexandra Audemard-Verger, Alexandre Belot, Boris Bienvenu, Carole Burillon, François Chasset, Florence Chaudot, Raphael Darbon, Anastasia Delmotte, Mikael Ebbo, et al.

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Laurent Arnaud, Alexandra Audemard-Verger, Alexandre Belot, Boris Bienvenu, Carole Burillon, et al.. French protocol for diagnosis and management of Cogan's syndrome. La Revue de Médecine Interne, 2024, Online ahead of print. 10.1016/j.revmed.2024.09.007. hal-04888049

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## Review article

# French protocol for diagnosis and management of Cogan's syndrome

## Protocole national de diagnostic et de soins – Syndrome de Cogan

<figure><img src="image_2.png" /></figure>

Laurent Arnaud<sup>a</sup>, Alexandra Audemard-Verger<sup>b</sup>, Alexandre Belot<sup>c</sup>, Boris Bienvenu<sup>d</sup>, Carole Burillon<sup>e</sup>, François Chasset<sup>f</sup>, Florence Chaudot<sup>g</sup>, Raphael Darbon<sup>h</sup>, Anastasia Delmotte<sup>g</sup>, Mikael Ebbo<sup>i</sup>, Olivier Espitia<sup>j</sup>, Anne-Laure Fauchais<sup>k</sup>, Alexis F. Guedon<sup>l</sup>, Eric Hachulla<sup>m</sup>, Jérôme Hadjadj<sup>g</sup>, Charlotte Hautefort<sup>n</sup>, Vincent Jachiet<sup>g</sup>, Elisabeth Mamelle<sup>o</sup>, Mickael Martin<sup>p</sup>, Marc Muraine<sup>q</sup>, Thomas Papo<sup>r</sup>, Jacques Pouchot<sup>s</sup>, Grégory Pugnet<sup>t</sup>, Pascal Sève<sup>u</sup>, Thierry Zenone<sup>v</sup>, Arsène Mekinian<sup>g*,s</sup>, and contributors<sup>l</sup>

## INFO ARTICLE

Historique de l'article :
Disponible sur Internet le 24 October 2024

Keywords :
Cogan's syndrome
Diagnosis
Management
Treatment

## ABSTRACT

Cogan's syndrome is a condition of unknown origin, classified as a systemic vasculitis. It is characterised by a predilection for the cornea and the inner ear. It mainly affects Caucasian individuals with a sex-ratio close to one. Ophthalmological and cochleo-vestibular involvement are the most common manifestations of the disease. The most frequent ophthalmological type of involvement is non-syphilitic interstitial keratitis. Cochleo-vestibular manifestations are similar to those of Meniere's syndrome. The disease progresses in ocular and ear-nose-throat (ENT) flares, which may occur simultaneously or in isolation. Association with other autoimmune diseases, particularly other forms of vasculitis such as

<footnote><sup>a</sup> INSERM UMRS-1109, Department of Rheumatology, National Reference Center for Autoimmune diseases (RESO), Strasbourg-Hautepierre University Hospital, Strasbourg, France</footnote>

<footnote><sup>b</sup> Department of Internal Medicine, Tours University Hospital, Tours, France</footnote>

<footnote><sup>c</sup> Department of Paediatric Nephrology, Rheumatology, Dermatology, Reference Centre for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Femme-Mère-Enfant Hospital, Hospices Civils of Lyon, Bron, France</footnote>

<footnote><sup>d</sup> Department of Internal Medicine, Saint-Joseph Hospital, Marseille, France</footnote>

<footnote><sup>e</sup> Department of Ophthalmology, Édouard-Herriot University Hospital, Hospices Civils of Lyon, Lyon, France</footnote>

<footnote><sup>f</sup> Department of Dermatology and Allergology, Tenon Hospital, Faculty of Medicine, Sorbonne University, Paris, France</footnote>

<footnote><sup>g</sup> Service de médecine interne, Hôpital Saint-Antoine, AP-HP, Sorbonne université, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France</footnote>

<footnote><sup>h</sup> French Vasculitis Association, Paris, France</footnote>

<footnote><sup>i</sup> Department of Internal Medicine, Marseille University Hospital, Marseille, France</footnote>

<footnote><sup>j</sup> INSERM UMR1087/CNRS UMR 6291, Team III Vascular & Pulmonary diseases, Department of Internal and Vascular Medicine, institut du thorax, CHU of Nantes, Nantes université, F-44000 Nantes, France</footnote>

<footnote><sup>k</sup> Department of Internal Medicine, Dupuytren University Hospital, Limoges, France</footnote>

<footnote><sup>l</sup> Department of Internal Medicine, Saint-Antoine Hospital, Paris, France</footnote>

<footnote><sup>m</sup> INSERM, Department of Internal Medicine and Clinical Immunology, Reference Centre for Auto-immune Systemic Rare Diseases of North and North-West of France (CeRAINO), Lille University Hospital, Lille University, Lille, France</footnote>

<footnote><sup>n</sup> Department of Ear, Nose, Throat, Lariboisière Hospital, université Paris Cité, Paris, France</footnote>

<footnote><sup>o</sup> Department of Ear, Nose, Throat, Rothschild Hospital, Paris, France</footnote>

<footnote><sup>p</sup> Department of Internal Medicine, Poitiers University Hospital, Poitiers, France</footnote>

<footnote><sup>q</sup> Department of Ophthalmology, Rouen University Hospital, Rouen, France</footnote>

<footnote><sup>r</sup> Department of Internal Medicine, Bichat Hospital, Paris, France</footnote>

<footnote><sup>s</sup> Department of Internal Medicine, Georges-Pompidou European Hospital, Paris, France</footnote>

<footnote><sup>t</sup> Department of Internal Medicine, Toulouse University Hospital, Toulouse, France</footnote>

<footnote><sup>u</sup> Department of Internal Medicine, La Croix-Rousse Hospital, Hospices Civils of Lyon, Lyon, France</footnote>

<footnote><sup>v</sup> Department of Internal Medicine, Valence Hospital Centre, Valence, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>Adresse e-mail : arsene.mekinian@aphp.fr (A. Mekinian).</footnote>

<footnote n="1">¹ Collaborators: Chloé Comarmond, Internal Medicine, Paris; Frédérique Dubrulle, Radiology, Lille; Delphine Family, General Medicine, Paris; Emmanuel Heron, Internal Medicine, Paris; Marc Lambert, Internal Medicine, Lille; Estibaliz Lazaro, Internal Medicine, Bordeaux; Roberta Lorenzon, Internal Medicine, Paris; Isabelle Melki, Paediatric Rheumatology, Robert Degré, Paris; Xavier Puechal, Rheumatology, Paris; Christophe Richez, Rheumatology, Bordeaux; Isabelle Steinl-Stahl, French Vasculitis Association; Benjamin Terrier, Internal Medicine, Paris.</footnote>
polyarteritis nodosa or Takayasu's arteritis, is possible. Ocular involvement, as well as cochleo-vestibular involvement, can be inaugural and initially isolated. Onset is often abrupt. The characteristic involvement is "non-syphilitic" interstitial keratitis. It is usually bilateral from the outset or becomes so during the course of the disease. It presents as a red, painful eye, possibly associated with decreased visual acuity. Cochleo-vestibular involvement is usually bilateral from the outset. It is characterised by the sudden onset of continuous rotational vertigo associated with tinnitus, rapidly progressive sensorineural deafness. Approximately 30-70% of patients present with systemic manifestations. Deterioration in general status with fever may be present. Laboratory evidence of inflammatory syndrome is associated in 75% of cases. Cogan's syndrome is a presumed autoimmune type of vasculitis, although no specific autoantibodies have been identified. Ocular involvement is usually associated with a good prognosis, with total visual acuity recovery in the majority of cases. In contrast, cochleo-vestibular involvement can be severe and irreversible. Therapeutic management of Cogan's syndrome, given its rarity, lacks consensus since no prospective randomised studies have been conducted to date. Corticosteroid therapy is the first-line treatment. Combination with anti-TNF therapy should be promptly discussed.

© 2024 Les Auteurs. Published by Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Keywords :

Mots clés :

Syndrome de Cogan
Diagnostic
Prise en charge
Traitement

Le syndrome de Cogan est une maladie d'origine inconnue, classée parmi les vascularites systémiques. Il se caractérise par une prédilection pour la cornée et l'organe cochléo-vestibulaire. Il touche principalement les individus caucasiens avec un ratio de sexes proche de l'unité. Les atteintes ophtalmologiques et cochléo-vestibulaires sont les manifestations les plus courantes de la maladie. L'atteinte ophtalmologique la plus fréquente est la kératite interstitielle non syphilitique. Les manifestations cochléo-vestibulaires sont similaires à celles du syndrome de Ménière. La maladie évolue par poussées oculaires et oto-rhino-laryngologiques (ORL), qui peuvent survenir simultanément ou isolément. L'association avec d'autres maladies auto-immunes, en particulier d'autres formes de vascularites telles que la périartérite noueuse ou l'artérite de Takayasu, est possible. L'atteinte oculaire, ainsi que l'atteinte cochléo-vestibulaire, peuvent être inaugurales et initialement isolées. Le début est souvent abrupt. L'atteinte caractéristique est la kératite interstitielle « non syphilitique ». Elle est généralement bilatérale dès le début ou le devient au cours de la maladie. Elle se présente sous forme d'un œil rouge, douloureux et larmoyant, potentiellement associé à une diminution de l'acuité visuelle. L'atteinte cochléo-vestibulaire est généralement bilatérale dès le début. Elle se caractérise par l'apparition soudaine d'un vertige rotatoire continu associé à des acouphènes, une surdité neurosensorielle rapidement progressive. Environ 30 à 70% des patients présentent des manifestations systémiques. Une altération de l'état général fébrile peut être présente. Un syndrome inflammatoire biologique est associé dans 75% des cas. Le syndrome de Cogan est une vascularite auto-immune présumée, bien qu'aucun autoanticorps spécifique n'ait été identifié. L'atteinte oculaire est généralement associée à un bon pronostic, avec une récupération totale de l'acuité visuelle dans la majorité des cas. En revanche, l'atteinte cochléo-vestibulaire peut être grave et irréversible. La prise en charge thérapeutique du syndrome de Cogan, compte tenu de sa rareté, manque de consensus puisque aucune étude randomisée prospective n'a été menée à ce jour. Le traitement par corticothérapie est le traitement de première ligne. L'association aux anti-TNF peut être rapidement envisagée.

© 2024 Les Auteurs. Published by Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

## 1. Abbreviations

3D-FLAIR Three-Dimensional Fluid Attenuated Inversion Recovery

ACPA Anti-Citrullinated Peptide Antibodies

ANCA Anti-Neutrophil Cytoplasmic Antibodies

B2GP1 Beta 2 Glycoprotein 1

bFFE Balanced Fast Field Echo

CISS Constructive Interference In Steady State

CRP C-Reactive Protein

CT Computed Tomography

DMARD Disease-Modifying Antirheumatic Drug

DNA Deoxyribonucleic Acid

EBV Epstein-Barr Virus

ELISA Enzyme-Linked Immunosorbent Assay

ENT Ear-Nose-Throat

FDG Fluorodeoxyglucose

FIESTA Fast Imaging Employing Steady State Acquisition

FPDM French Protocol for Diagnosis and Management

HAS French National Authority for Health

HR High Resolution

HTLV1 Human T-Lymphotropic Virus 1

IBD Inflammatory Bowel Disease

IGRA Interferon Gamma Release Assay

MRI Magnetic Resonance Imaging

NS Not Significant

NSAID Non-Steroidal Anti-Inflammatory Drug

OCT Optical Coherence Tomography

PAS Periodic Acid-Schiff

PCR Polymerase Chain Reaction

PET Positron Emission Tomography

TINU Tubulointerstitial Nephritis and Uveitis

TNF Tumour Necrosis Factor

TPE Therapeutic Patient Education

VHIT Video Head Impulse Test

VKH Vogt-Koyanagi-Harada

VZV Varicella Zoster Virus

WHO World Health Organization
## 2. Introduction [1–12]

Cogan's syndrome is a rare form of vasculitis first described in 1945, which may affect vessels of all sizes, characterised by a predilection for the cornea and the cochleo-vestibular system. Its pathophysiology is unknown but presumed to be autoimmune. The two main manifestations of Cogan's syndrome are non-syphilitic interstitial keratitis and cochleo-vestibular deficit. The syndrome is considered typical when these two manifestations appear within a period of less than 2 years. Conversely, it is classified as atypical when there is inflammatory ocular involvement other than interstitial keratitis and/or typical ocular involvement associated with cochleo-vestibular and auditory symptoms not characteristic of Meniere's disease and/or a delay of more than 2 years between the onset of ocular and cochleo-vestibular manifestations. Systemic manifestations (neurological, gastrointestinal, renal, and cutaneous) are present in 30–70% of cases, related to the vascular involvement of the disease. Its exact prevalence is unknown, probably underestimated with approximately 400 cases described in the literature. The disease mainly affects young Caucasian individuals (median age of 25 years), with no gender distinction. Interstitial keratitis, as well as cochleo-vestibular involvement, can be inaugural. Both primary manifestations can progress simultaneously or in isolation. Onset of deafness is often abrupt, sometimes bilateral from the outset. Laboratory evidence of inflammatory syndrome is often present. Ophthalmological examination (slit lamp) as well as ear-nose-throat (ENT) examination (pure-tone audiometry, speech audiometry, Video Head Impulse Test [VHIT], videonystagmography) allow for the identification of interstitial keratitis and cochleo-vestibular deficit. Initial differential diagnosis should include frequent infectious, inflammatory, or autoimmune causes. Angio-computed tomography (angio-CT) and 18-fluorodeoxyglucose (FDG) positron emission tomography (PET-scan) can be helpful to highlight large vessel vasculitis and rule out differential diagnoses. Functional prognosis of Cogan's syndrome is conditioned by cochleo-vestibular involvement leading to sensorineural deafness in 50% of cases. Conversely, interstitial keratitis has a good prognosis and evolves without sequelae after treatment. Therefore, auditory prognosis and vascular complications require early diagnosis of the disease to introduce effective treatment, ideally within the first two weeks after symptom onset. Cogan's syndrome is a rare condition. As a result, no randomised trials have been conducted. Thus, there is no consensus regarding its management, with treatment inspired by the therapeutic regimen of vasculitis. Local ocular treatments with steroids may be added on to systemic treatment. Cogan's syndrome requires regular monitoring of disease progression and to prevent and identify treatment-related adverse effects. In case of relapse or inefficacy of first-line treatment, introduction or modification of immunomodulatory treatment (conventional immunosuppressive agents and/or, biologics) is justified.

## 3. Objectives of the French protocol for diagnosis and management

The objective of this French Protocol for Diagnosis and Management (FPDM) is to clarify for healthcare professionals the optimal diagnostic, management and care pathway of a patient with Cogan's syndrome. It aims to optimise and standardise the management and follow-up of this rare disease across France. It also identifies the medications used for Cogan's syndrome that have not received Marketing Approval as well as the specialties, products, or services necessary for patient care but not usually covered or reimbursed. The FPDM is also a pragmatic tool that general practitioners can refer to for the management of the disease, particularly

when establishing the care pathway jointly with the consulting physician and the patient. However, the FPDM cannot consider all specific cases, comorbidities, therapeutic particularities, hospital care protocols etc. It does not claim to cover all possible management approaches, or replace the individual responsibility of the physician towards his or her patient. The protocol does, however, describe the standard management of patients with Cogan's syndrome. This FPDM has been drafted according to the "Method for drafting a French protocol for diagnosis and management for rare diseases" published by the French National Authority for Health (HAS) in 2012 (methodological guide available on the HAS website: www.has-sante.fr).

## 4. Diagnosis and initial evaluation [1–63]

### 4.1. Objectives

The objectives are as follows:

* to recognise early symptoms suggestive of Cogan's syndrome;

* to confirm the diagnosis and rule out differential diagnoses;

* to identify and anticipate potential complications of Cogan's syndrome.

### 4.2. Professionals involved (and coordination modalities)

The professionals most commonly involved are:

* general practitioner;

* specialist physician with expertise in Cogan's syndrome, typically an internist or rheumatologist;

* ophthalmologist; specialist physician with expertise in Cogan's syndrome, typically an internist or rheumatologist;

* ENT specialist;

* any other specialist according to the site of involvement (vascular physician, rheumatologist, dermatologist, cardiologist, neurologist, hepato-gastroenterologist, vascular surgeon etc.);

* nurse, who provides care, therapeutic education, and potentially coordinates care between hospital and community settings;

* physiotherapist, who plays a central role in vestibular rehabilitation;

* psychologist or psychiatrist in case of significant psychological impact;

* audiologist if hearing aid is needed for deafness;

* social workers to address the social consequences of the disease.

### 4.3. Circumstances of discovery/suspicion of diagnosis

Cogan's syndrome is a systemic condition whose initial symptoms may lead to consultation with various specialists (ophthalmologists, ENT specialists, rheumatologists, internists etc.). In its typical presentation, this syndrome is defined by a characteristic involvement of the cornea in the form of bilateral interstitial keratitis causing redness, photosensitivity, and eye pain. The ENT involvement manifests as vestibular impairment (rotational vertigo, instability, ataxia, nausea, oscillosmia), associated from the outset or subsequently with tinnitus and hearing impairment, which can rapidly progress into permanent deafness. Thus, the association of keratitis with cochleo-vestibular involvement within a span of less than two years should raise suspicion of Cogan syndrome in its typical form. It affects young individuals, typically between 20 and 30 years old, with no gender or ethnic predisposition, although the majority of cases have been described in Caucasians. Systemic involvement such as general symptoms or arthromyalgia is possible (in one-third of patients). Cogan's syn-
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Typical appearance of interstitial keratitis in a female patient with Cogan's syndrome. Left: opacity of the superficial cornea along with intra-corneal neovascularisation. Keratitis is associated with a redness resembling episcleritis. Right: same eye three years later. The inflammation has disappeared along with the intra-corneal neovascularisation. Only a residual whitish corneal opacity remains, sparing the optical axis and allowing for good visual recovery.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Appearance of central retinal vein occlusion in a female patient with Cogan's syndrome. Diffuse retinal haemorrhages on retinography on the left along with their blackened appearance due to masking on angiography on the right. The angiography confirms the absence of vasculitis in this case.</figcaption></figure>

drome is also one of the types of vasculitis that can affect vessels of various types and sizes, with aortitis being the most common involvement (10–15%). Most patients experiencing flares present with laboratory evidence of inflammatory syndrome. Magnetic Resonance Imaging (MRI) of the inner ear may show a labyrinthitis appearance in the acute phase. As this is an extremely rare disease, primarily clinically diagnosed, and in the absence of specific immunological or biological markers, it is important to rule out differential diagnoses, especially infectious causes. Diagnosis is solely clinical. Initial involvement is ocular in 38% of cases, auditory in 46%, and mixed in 15% of cases.

### 4.3.1. Ophthalmological involvement

One of the particularities of Cogan's syndrome is its impact on the eye, especially the cornea. The diagnostic challenge lies in the fact that ocular involvement rarely coincides with ENT involvement, making it difficult to consider the syndrome. The largest French series, published in 2017, included 62 patients and reported that it took an average of 12 months to establish the diagnosis from the onset of symptoms. At this stage, 98% of patients had cochleo-vestibular disorders, 92% had ocular involvement, and 68% had systemic manifestations.

#### 4.3.1.1. Ocular symptoms.
Symptoms can be mild, and ocular involvement may be asymptomatic, hence the necessity of a systematic ophthalmological examination if there is the slightest doubt about the diagnosis to look for incipient peripheral corneal involvement. Ocular symptoms can range from mild irritation to significant photophobia or decreased vision. The disease can affect all layers of the eye, but the most suggestive manifestation is interstitial keratitis (Fig. 1). It presents as a cloudy infiltrate localised in the corneal stroma, visible with a slit lamp, associated with conjunctival redness. An important characteristic is the progression of

neovascularisation from the corneal periphery towards the centre, predominantly invading the stroma, which constitutes 90% of the corneal thickness located between the anterior epithelium and the posterior endothelium. Patients may experience decreased visual acuity due to corneal opacity and eye pain associated with marked photophobia. However, interstitial keratitis described in Cogan's syndrome is not specific, and it is necessary to first rule out more common causes of interstitial keratitis, primarily syphilis, followed by other infectious bacterial (tuberculosis, Lyme's disease, leprosy, brucellosis, leptospirosis, chlamydia, and Whipple's disease), viral (herpes simplex type 1 or 2, Epstein-Barr virus [EBV], Varicella Zoster virus [VZV], rubella, influenza, measles, human T-lymphotropic virus 1 [HTLV1], adenovirus, paramyxovirus), or parasitic (leishmaniasis, African trypanosomiasis, amoebiasis) causes (see Section 5.4).

Furthermore, it is known that Cogan's syndrome belongs to the systemic vasculitis group and, as such, can lead to other inflammatory eye conditions. Thus, conjunctivitis, episcleritis and scleritis, uveitis with or without choroiditis, central retinal vein occlusion (Fig. 2) and retinal vasculitis, optic neuritis, and orbital inflammation have been reported. Ocular involvement may result from a variable combination of these different elements. Uveitis, episcleritis, and scleritis are the most frequent manifestations after interstitial keratitis. Scleritis can persist for several months despite appropriate treatment and can lead to significant scleral thinning, revealing the underlying choroid with its dark blue appearance.

#### 4.3.1.2. Ophthalmological testing.
Urgent assessment by an ophthalmologist is justified in cases of suspected Cogan's syndrome. Visual acuity is measured. Examination with a slit lamp is paramount as it allows for the diagnosis of interstitial keratitis as well as inflammatory ocular surface diseases (conjunctivitis, episcleritis, scleritis) and anterior segment diseases (anterior uveitis). Fundus
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Angiography of a female patient with Cogan's syndrome. Appearance of papillitis (inflammation of the optic nerve head) associated with moderate macular oedema. The angiography confirms the absence of vasculitis in this case.</figcaption></figure>

examination is performed to look for signs of posterior uveitis, vasculitis, retinal vein occlusion, or papillary oedema. It may be complemented by Optical Coherence Tomography (OCT) examination of the retina to identify macular oedema or papillary oedema. Lastly, angiography may be requested to detect even minimal signs of vasculitis or choroiditis (Fig. 3).

### 4.3.2. Cochleo-vestibular involvement

The cochleo-vestibular manifestations of Cogan's syndrome are part of the clinical diagnosis. Although cochleo-vestibular involvement usually appears a few months after ocular involvement, it can sometimes be inaugural (28%). The key elements of the cochleo-vestibular syndrome of Cogan's syndrome are:

* rapidly progressive and bilateral descending sensorineural hearing loss (initially affecting high frequencies);

* acute and prolonged vestibular deficit > 24 hours, initially unilateral then bilateral;

* the steroid-dependent nature of the cochleo-vestibular sensorineural deficit, which can lead to fluctuations upon steroid tapering.

MRI (T1 after contrast injection and ideally three-dimensional fluid attenuated inversion recovery [3D-FLAIR HR] post-gadolinium) quickly confirms the typical appearance of a ruptured blood-labyrinth barrier suggestive of labyrinthitis (see Section 4.4: differential diagnosis with Ménière's disease) (Fig. 4). Vestibular symptoms can manifest in several ways: as rotational vertigo (90%), ataxia (53%), or oscillosmia (25%) directly related to the deterioration in vestibulo-ocular and vestibulo-spinal reflexes. Inaugural vestibular symptoms, often rotational, can last from several hours to several days and progress towards instability. Ataxia is prominent in case of bilateral vestibular involvement from the outset. Vestibular examination of dizzy patients may reveal positional or spontaneous nystagmus (20%), absent when the involvement is bilateral. The clinical head impulse test, performed at the bedside, allows the clinician to identify unilateral or

bilateral vestibulo-ocular reflex deficits confirmed by vestibular tests (caloric tests, V HIT). These abnormalities are present in 93% of cases at the canal level, either unilateral or bilateral (according to the Mayo Clinic team). There is limited literature on vestibular evoked potentials (testing the utricle and saccule), but it is likely that they are also abolished. Cochlear symptoms are revealed by often bilateral sensorineural hearing loss, which can be symmetrical or asymmetrical and rapidly progressive. Deafness is associated with tinnitus in 80% of cases. The specificity of this hearing impairment lies in its fluctuating nature, associated with initial steroid dependence and a tendency for worsening despite immunosuppressive treatments (52% profound deafness). Audiometric assessment (pure-tone and speech audiometry) objectively demonstrates sensorineural hearing loss, typically downward sloping, which may be initially unilateral then bilateral, progressing over a period of 1 to 3 months to total deafness (cophosis) in 60% of cases. The standard imaging modality is MRI of the inner ear with delayed post-gadolinium 3D-FLAIR (+ 4 h), a recently developed sequence, which looks for uni- or bilateral labyrinthitis. MRI shows contrast enhancement of the inner ear affecting the anterior and posterior labyrinth on post-contrast T1 sequences. This contrast enhancement is better detected on delayed post-gadolinium 3D-FLAIR HR sequences, which show overall FLAIR hyperintensity of the inner ear perilymph (cochlea, vestibule, and semicircular canals). This rupture of the blood-labyrinth barrier may only be detected on this sequence, with conventional post-contrast T1 sequences remaining normal. This contrast enhancement of the inner ear may be associated with decreased fluid signal intensity on 3D T2 HR sequences such as fast imaging employing steady state acquisition (FIESTA), constructive interference in steady state (CISS), balanced fast field echo (bFFE). Rare cases of intralabyrinthine haemorrhage (spontaneous T1 hyperintensity) have been described. In advanced Cogan's syndrome, labyrinthine fibrosis appears, manifesting as a hypointense signal on 3D T2 HR sequences. This fibrosis can progress to ossification, also visible on temporal bone CT scans. In initial imaging, there may be, in some cases, contrast enhancement of the meninges of the internal auditory canal or even the posterior
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** MRI findings in Cogan's syndrome. A. Rapidly progressing right-sided cochleo-vestibular syndrome in a 52-year-old patient. Aa. The T1 sequence after injection shows subtle contrast enhancement difficult to visualise in the right inner ear (vestibule arrow). Ab. No decrease in signal of the right intralabyrinthine fluid on the 3D bFFE HR sequence (arrow). Ac. the 3D-FLAIR HR sequence 4 hours after gadolinium injection on a 3Tesla MRI shows overall FLAIR hyperintensity of the perilymph of the right inner ear (arrows) confirming right labyrinthitis. B. 25-year-old patient, rapidly progressing left-sided cochleo-vestibular syndrome with left-sided cophosis and left vestibular areflexia. Ba. Contrast uptake in the left cochlea on T1 sequence after injection (arrow) performed 6 weeks after symptom onset. Decreased fluid signal in the cochlear region on 3D BFFE HR sequence. Bb (arrow). Six months later, no auditory recovery on the left and emergence of right-sided sensorineural hearing loss. 1.5 Tesla MRI shows contrast uptake in the right cochlea (Bc), 3D BFFE HR sequence (Bd) shows bilateral decrease in intralabyrinthine fluid signal predominantly at the cochlear level (arrows), 3D-FLAIR HR sequence performed 10 minutes after injection (Be) shows bilateral FLAIR hyperintensity of the inner ears (arrows). This patient underwent left cochlear implantation 18 months later due to left cophosis with severe right-sided deafness without signs of intralabyrinthine ossification.</figcaption></figure>

fossa, as well as contrast enhancement of the facial nerve (in the fundus of the canal and in the first portion). Cochleo-vestibular involvement in Cogan's syndrome is related to labyrinthitis, the severity, rapid onset, bilateralisation, and steroid sensitivity of which are crucial for considering the diagnosis.

### 4.3.3. Systemic manifestations

#### 4.3.3.1. Cardiovascular involvement.
Cogan's syndrome is classified as a type of vasculitis that can affect vessels of all sizes and types according to the Chapel Hill Consensus Conference nomenclature. The main vascular manifestation is aortitis, most commonly thoracic in location, found in approximately 12% of patients. When it occurs, it appears within a median of 7 months after the diagnosis of the disease, and at least within the first year following the diagnosis for two-thirds of affected patients. It can be associated with thoracic aortic aneurysm and aortic insufficiency, sometimes necessitating valve replacement. When available, histopathological examination may reveal nonspecific aortitis lesions affecting all three vascular layers, predominantly the intima media, with a mixed inflammatory infiltrate composed of neutrophils, mononuclear cells, macrophages, epithelioid cells, and sometimes a few giant cells within necrotic areas of the media. Medium-sized peripheral arteries may also be affected, either asymptomatically or with vascular complications. All branches of the abdominal aorta can be involved, including renal arteries, sometimes revealed by

renal hypertension, as well as mesenteric arteries responsible for mesenteric ischaemia. Involvement of the upper and lower limbs can cause limb claudication or even acute ischaemia with necrosis of the extremities. Lesions of stenosis, thrombosis, and aneurysm of cerebral arteries can result in cerebral infarctions. In addition, involvement of small cutaneous vessels with purpura and histological leukocytoclastic vasculitis lesions may be observed. Regarding the heart, apart from aortic insufficiency secondary to ascending thoracic aortic aneurysms, the mitral valve may be affected, and there are a few cases of pericarditis and ostial coronary stenosis that can lead to myocardial infarction. Pericarditis or myopericarditis has also been reported.

#### 4.3.3.2. Joint involvement.
Arthromyalgia is present in 23 to 57% of cases (Table 1). Joint symptoms include inflammatory arthralgia, myalgia and, to a lesser extent, arthritis. It is difficult to identify a typical clinical presentation of joint involvement in Cogan's syndrome. These manifestations seem to predominantly affect peripheral joints, with frequent involvement of the wrists, ankles, and knees. There is limited available data on the destructive progression of joint involvement in case of arthritis.

#### 4.3.3.3. Cutaneous involvement.
Various cutaneous manifestations have been associated with Cogan's syndrome. Their frequency ranges from 8% to 22% and appears to be higher in atypical
<figure><img src="image_7.png" /><figcaption>**Fig. 4.** (Continued)</figcaption></figure>

forms. Different aspects have been reported, including urticarial lesions, purpura, vesicular lesions, pustules, cutaneous ulcers, subcutaneous nodules, and mucosal erosions or ulcers. Histological evidence of vasculitis has been obtained in less than 10 published

cases on cutaneous biopsies. However, some well-documented clinical cases confirm the presence of small vessel vasculitis as well as necrotising vasculitis of medium-sized arteries compatible with cutaneous polyarteritis nodosa in cases of atypical Cogan's syn-
<table><caption>**Table 1**
Main clinical manifestations described in case series and literature reviews of Cogan's syndrome.</caption><thead><tr><th>Clinical manifestations</th><th>Grasland et al. (n=32) [5]</th><th>Gluth et al. (n=60) [4]</th><th>Durtette et al. (n=52) [2]</th><th>Vavricka et al. (n=22) [60]</th><th>Pagnini et al. (n=23) [11]</th></tr></thead><tbody><tr><td>General symptoms<sup>a</sup>, n (%)</td><td>10 (31)</td><td>—</td><td>17 (43)</td><td>16 (72.7)</td><td>11 (47)</td></tr><tr><td>Fever, n (%)</td><td>—</td><td>16 (27)</td><td>14 (33)</td><td>3 (13.6)</td><td>7 (30.4)</td></tr><tr><td>Arthromyalgia, n (%)</td><td>15 (47)</td><td>—</td><td>24 (57)</td><td>10 (43.5)</td><td>—</td></tr><tr><td>Arthralgia, n (%)</td><td>—</td><td>21 (35)</td><td>—</td><td>10 (45)</td><td>—</td></tr><tr><td>Arthritis, n (%)</td><td>—</td><td>—</td><td>—</td><td>3 (13.6)</td><td>—</td></tr><tr><td>Headache, n (%)</td><td>—</td><td>24 (40)</td><td>—</td><td>15 (68)</td><td>4 (17.4)</td></tr></tbody></table>

drome. A few cases of pyoderma gangrenosum have also been reported.

### 4.3.3.4. Other types of involvement.
Cogan's syndrome affects at least one other organ besides the eyes or ears in nearly 70% of patients. Patients with typical Cogan's syndrome may have systemic clinical manifestations different from those of atypical Cogan's syndrome, with fewer joint manifestations, lymphadenopathy, or splenomegaly, and less neurological involvement (Table 2).

#### 4.3.3.4.1. General signs.
In Cogan's syndrome, general signs (fever, asthenia, weight loss) are reported in one-third to one-half of cases.

#### 4.3.3.4.2. Gastrointestinal manifestations.
Gastrointestinal manifestations are the most frequently reported after visual, cochleo-vestibular, and vascular manifestations. They are nonspecific, presenting as abdominal pain, bowel disorders (mostly diarrhoea), or even gastrointestinal bleeding. A European series reports 22 patients with an association between inflammatory bowel disease (IBD) and Cogan's syndrome, among whom 16 had Crohn's disease and 6 had ulcerative colitis. All patients developed Cogan's syndrome after the diagnosis of IBD. Abnormalities in liver function tests (cytolysis or cholestasis) have been reported. Hepatic vasculitis with hepatic infarction mimicking multiple abscesses has also been described.

#### 4.3.3.4.3. Neurological manifestations.
Headaches are the most common neurological manifestation, present in one-fifth to two-thirds of patients. Various types of peripheral or central neurological involvement have been described: peripheral neuropathies, bilateral facial paralysis, cerebellar syndrome, pyramidal syndrome with hemiplegia, ataxias, meningitis, pachymeningitis, encephalitis with coma. On MRI, nonspecific white matter hyperintensities are observed in 12% of patients in some series.

#### 4.3.3.4.4. Renal involvement.
Renal involvement is rare, secondary to renal artery stenosis or glomerulonephritis. In a review of 78 cases of Cogan's syndrome, 14 had abnormal urine analysis, and 3 had renal failure. Histopathological findings included glomerulonephritis, renal vasculitis, cortical scarring, and renal infarctions.

#### 4.3.3.4.5. Other types of involvement.
Some manifestations reported in isolated case reports or literature series have undetermined significance and are more anecdotal: lymphadenopathy, Raynaud's phenomenon, hepatosplenomegaly, pleurisy, chondritis, testicular pain, pulmonary emphysema, or panniculitis.

#### 4.3.3.4.6. Association with other conditions.
The intertwining with other systemic diseases includes true overlap syndromes with vasculitis or systemic entities (anti-neutrophil associated antibodies [ANCA]-associated vasculitis, renal vasculitis, polyarteritis nodosa, relapsing polychondritis), especially Takayasu's arteritis. Other associations with sarcoidosis, TINU (tubulointerstitial nephritis and uveitis) syndrome, rheumatoid arthritis, or familial Mediterranean fever have been reported.

## 4.4. Confirmation of diagnosis/differential diagnosis

To date, there is no specific diagnostic marker for Cogan's syndrome. Its diagnosis is essentially clinical, based on the combination

of characteristic ophthalmological and cochleo-vestibular signs, separated by a more or less long time interval. Cogan's syndrome will be classified as "typical" or "atypical" according to the criteria defined by Haynes et al. in 1980 [6]. The syndrome is considered "typical" if it meets the following three conditions: (1) ocular involvement with interstitial keratitis; (2) cochleo-vestibular involvement characterised by rotational vertigo, nausea, vomiting, and sudden or subacute tinnitus, associated with sudden or rapidly progressive sensorineural deafness; and (3) interval ≤2 years between the onset of ocular and cochleo-vestibular manifestations. The presence of at least one of the following three characteristics defines "atypical" Cogan's syndrome: (1) inflammatory ocular involvement other than interstitial keratitis; (2) typical ocular involvement but associated with cochleo-vestibular and auditory symptoms not characteristic of Ménière's disease; or (3) interval >2 years between the onset of ocular and cochleo-vestibular manifestations. For a long time, cochleo-vestibular involvement in Cogan's syndrome was incorrectly characterised as Ménière-like syndrome. Current knowledge now allows for rapid exclusion of Ménière's disease clinically: unilateral involvement in >80% of cases, episodic progression with a return to normal between episodes initially, rotational vertigo lasting only a few hours (<12 hours), fluctuating ascending sensorineural deafness (involvement of low frequencies) and associated with fluctuating severe tinnitus. Labyrinthine MRI reveals hydrops (dilatation of endolymphatic spaces) on delayed post-gadolinium 3D-FLAIR sequences (+4 h). Electrophysiologically, VHIT is often normal. Brain MRI, when performed, is usually normal, with a few reported cases of cerebral vasculitis or pachymeningitis. Lumbar puncture, when performed, is usually normal, with a few cases of aseptic lymphocytic meningitis. The reported average time between symptom onset and diagnosis varies from 10 to 12 months in the typical form, but is 35 months for the atypical form, highlighting the diagnostic difficulties in this syndrome, due to its clinical rarity but also the sometimes significant delay between ocular and cochleo-vestibular signs. In practice, the diagnosis should be considered in the presence of compatible ophthalmological and/or cochleo-vestibular involvement, and the main differential diagnoses should be ruled out based on the manifestations present. Cogan's syndrome is therefore primarily a diagnosis of exclusion. Biologically, no specific markers are available in clinical practice, particularly no autoantibodies. Laboratory evidence of inflammatory syndrome is present in approximately three-quarters of patients. By definition, syphilis serology is negative. Depending on the clinical presentation and the presence of extra-ophthalmological/auditory manifestations, an immunological assessment will be performed (anti-nuclear antibodies, ANCA, complement levels). Although classified as a type of systemic vasculitis that can affect vessels of different types (arteries, veins, capillaries) and sizes (large, medium, and small vessels), it is rare to obtain histology which proves vasculitis during the course of Cogan's syndrome, and it is not necessary for diagnosis. In case of potential extra-ophthalmological/extra-auditory involvement, histological sampling will primarily serve to rule out the main potential differential diagnoses (Table 3). In both typical and atypical forms, the diagnostic challenge mainly

<footnote>a Fever, asthenia, weight loss.</footnote>
<table><caption>**Table 2**
Frequency of systemic clinical manifestations associated with typical or atypical forms of Cogan's syndrome according to Grasland et al. [5].</caption><thead><tr><th>Systemic clinical manifestations</th><th>Typical Cogan's syndrome (n = 130)</th><th>Atypical Cogan's syndrome (n = 92)</th><th>P-value</th></tr></thead><tbody><tr><td>Fever, n (%)</td><td>24 (18)</td><td>24 (26)</td><td>NS</td></tr><tr><td>Arthritis/arthralgia, n (%)</td><td>21 (16)</td><td>29 (32)</td><td>0.01</td></tr><tr><td>Skin rash, n (%)</td><td>8 (6)</td><td>10 (11)</td><td>NS</td></tr><tr><td>Lymphadenopathy or splenomegaly, n (%)</td><td>4 (3)</td><td>12 (13)</td><td>0.01</td></tr><tr><td>Peripheral or central neurological involvement, n (%)</td><td>9 (7)</td><td>20 (22)</td><td>0.01</td></tr><tr><td>Associated vasculitis, n (%)</td><td>17 (13)</td><td>20 (22)</td><td>NS</td></tr></tbody></table>

NS: not significant.

<table><caption>**Table 3**
Differential diagnoses of Cogan's syndrome and additional testing useful for diagnosis.</caption><thead><tr><th>Differential diagnosis</th><th>Additional testing (to be performed in case of suggestive clinical context)</th></tr></thead><tbody><tr><td>Syphilis</td><td>Serology</td></tr><tr><td>Tuberculosis</td><td>Chest X-ray, quantiferon (IGRA test)</td></tr><tr><td>Lyme's disease</td><td>ELISA test ± western blot</td></tr><tr><td>Leprosy</td><td>Skin smears, biopsies, M. leprae PCR</td></tr><tr><td>Brucellosis</td><td>Serology</td></tr><tr><td>Leptospirosis</td><td>PCR in the 1st week, serology from the 2nd week</td></tr><tr><td>Chlamydia</td><td>Corneal smears, C. trachomatis PCR, genitourinary samples in case of clinical suspicion</td></tr><tr><td>Whipple's disease</td><td>T. whipplei PCR in stools, saliva ± duodenal biopsies (with PAS staining)</td></tr><tr><td>Herpes simplex type I or II</td><td>Clinical diagnosis, but can be confirmed by PCR on tears or corneal swabs</td></tr><tr><td>EBV</td><td>EBV serology, infectious mononucleosis test</td></tr><tr><td>VZV, rubella, influenza, measles, smallpox, HTLV1, adenovirus</td><td>Corresponding serology and/or PCR depending on the context and the infectious agent involved</td></tr><tr><td>Bilateral acanthamoeba keratitis in a contact lens wearer</td><td>Corneal scraping for culture and PCR</td></tr><tr><td>Sarcoidosis</td><td>Confocal microscopy of the cornea</td></tr><tr><td></td><td>Chest CT scan, histology looking for granuloma oriented for organ involvement</td></tr><tr><td colspan="2"><strong>In case of vestibular syndrome with decreased hearing</strong></td></tr><tr><td>Meniere's disease</td><td>Delayed-enhancement MRI detection of endolymphatic hydrops</td></tr><tr><td>Autoimmune deafness</td><td>Labyrinthitis-like appearance, blood-labyrinth barrier rupture on MRI</td></tr><tr><td colspan="2"><strong>In case of ocular and cochleo-vestibular involvement</strong></td></tr><tr><td>Vogt-Koyanagi-Harada syndrome</td><td>Lumbar puncture (pleiocytosis), OCT, fluorescein retinal angiography and indocyanine green choroidal angiography</td></tr><tr><td>SUSAC syndrome</td><td>Fluorescein angiography, brain MRI</td></tr><tr><td>Polyarteritis nodosa</td><td>Histological search for necrotising vasculitis lesions on biopsies oriented by other organ involvement</td></tr><tr><td>Sarcoidosis</td><td>Chest CT scan, histology looking for granuloma on biopsies oriented by other organ involvement</td></tr><tr><td>Granulomatosis with polyangiitis</td><td>ANCA, histology looking for necrotising and granulomatous vasculitis lesions on biopsies oriented by other organ involvement</td></tr><tr><td>Relapsing polychondritis</td><td>Major (chondritis) and minor clinical criteria</td></tr><tr><td>Behçet's disease</td><td>Brain MRI</td></tr><tr><td>Systemic lupus erythematosus</td><td>Anti-nuclear antibodies ± anti-soluble nuclear antigen antibodies and native DNA, complement assay</td></tr><tr><td>Antiphospholipid syndrome</td><td>Anti-β2GP1 antibodies, anti-cardiolipin antibodies and test for lupus circulating anticoagulant</td></tr><tr><td>Rheumatoid arthritis</td><td>Rheumatoid factor, anti-CCP antibodies, X-rays of the hands and feet</td></tr></tbody></table>

ACPA: anti-citrullinated peptide antibodies; ANCA: anti-neutrophil cytoplasmic antibodies; β2GP1: beta 2 glycoprotein 1; CT: computed tomography; DNA: deoxyribonucleic acid; ELISA: enzyme-linked immunosorbent assay; IGRA: interferon gamma release assay; MRI: magnetic resonance imaging; OCT: optical coherence tomography; PAS: periodic acid-Schiff.

concerns the period between the onset of ocular signs and cochleo-vestibular signs. Thus, in the presence of interstitial keratitis without cochleo-vestibular signs, a bacterial (syphilis, tuberculosis, Lyme's disease, leprosy, brucellosis, leptospirosis, chlamydia, and Whipple's disease), viral (herpes simplex type 1 or 2, EBV, VZV, rubella, influenza, measles, HTLV1, adenovirus, paramyxovirus), or parasitic (leishmaniasis, African trypanosomiasis, amoebiasis) infectious aetiology should be ruled out first according to the epidemiological and clinical context. Local sampling (corneal scraping) with culture (bacteriology/mycobacteriology, parasitology), viral PCR ± amoebic PCR may be performed if any infectious differential diagnosis is suspected. If in doubt, confocal microscopy of the cornea may be performed to rule out amoebic keratitis in contact lens wearers. Conversely, the occurrence of isolated sensorineural deafness associated with vertigo and/or tinnitus should initially raise suspicion of labyrinthitis or Autoimmune Inner Ear Disease.

In case of ocular and cochleo-vestibular involvement, arguments should be sought for other systemic autoimmune or

inflammatory diseases, which should be ruled out before considering the diagnosis of Cogan's syndrome (Table 3):

* Susac's syndrome: in this case, fluorescein angiography may observe multiple occlusions of the branches of the central retinal artery, characteristic of this disease but asymptomatic in 50% of cases. The presence of persistent, unusual headaches and/or neuropsychiatric manifestations will justify a brain MRI to search for multifocal supratentorial ischaemic lesions, notably of the corpus callosum, and leptomeningitis;

* Vogt-Koyanagi-Harada syndrome (VKH): cochleo-vestibular involvement is very inconsistent in VKH. This syndrome combines flu-like syndrome with headaches, meningeal signs, and pleocytosis of the cerebrospinal fluid, characteristic ocular involvement (diffuse choroiditis with bilateral serous retinal detachments), vertigo, tinnitus, sensorineural deafness, vitiligo, alopecia, and poliosis;

* Behçet's disease (see [64]): a pseudo-Ménière's syndrome may be the mode of presentation of neuro-Behçet's disease. Other
suggestive elements to be sought include: recurrent oral and/or genital aphthae; uveitis with retinal vasculitis; suggestive cutaneous involvement (erythema nodosum, pseudofolliculitis, papulopustules, acneiform nodules); central nervous system involvement on MRI; positive pathergy test;

* sarcoidosis: although rare in sarcoidosis, cochleo-vestibular involvement may be inaugural, resulting from involvement of the cochleo-vestibular nerve and manifesting as progressive, mainly bilateral, moderate to severe sensorineural deafness associated with vertigo and vestibular ataxia. The search for extra-ENT involvement, especially thoracic (bilateral and symmetrical non-compressive hilar and mediastinal lymphadenopathy, suggestive pulmonary interstitial involvement...), and the demonstration of non-necrotising granulomas on biopsies guided by clinical and complementary assessment will be key elements of the differential diagnosis;

* relapsing polychondritis (see [65]): hearing loss is observed in 25-50% of patients with relapsing polychondritis. Sensorineural deafness, the most common, usually presents as sudden unilateral or bilateral deafness. It is related to cochlear involvement and usually predominates at high frequencies. A vestibular syndrome may be associated with cochleo-vestibular involvement or occur in isolation. Cochleo-vestibular involvement is part of the minor diagnostic criteria of the disease. Major criteria (auricular, nasal, tracheal chondritis) and other minor criteria such as ocular inflammation (episcleritis, scleritis, less frequently uveitis, keratitis, or conjunctivitis) and seronegative polyarthritis should be sought;

* systemic lupus erythematosus and antiphospholipid syndrome (see systemic lupus erythematosus FPDM [https://www.has-sante.fr/jcms/c.2751894/fr/lupus-systemique] and [66]): deafness is mainly sensorineural, bilateral, and moderate to severe. It may also be associated with vertigo and tinnitus. No association has been observed with a specific antiphospholipid or anti-nuclear antibody type. Cases of sudden deafness and significant hearing loss compared to healthy subjects have also been reported in patients with primary antiphospholipid syndrome;

* rheumatoid arthritis: sensorineural hearing loss is possible and various types of ocular involvement are possible (kerato-conjunctivitis sicca, peripheral or central ulcerative keratitis, episcleritis, scleritis, retinal vasculitis). These usually occur after many years of progression and hearing loss is less rapid and less severe than in Cogan's syndrome. The presence of isolated positive rheumatoid factor is not specific to rheumatoid arthritis, anti-citrullinated peptide antibodies may be requested in case of clinical signs of joint involvement;

* granulomatosis with polyangiitis (see [67]): sensorineural deafness may be found in nearly a quarter of patients. It may be due to vasculitis in cochlear vessels, immune complex deposits in the cochlea, or inflammatory involvement of the central nervous system or meninges. Involvement may be progressive or present as acute vertigo with sudden deafness, most often bilateral. The main ophthalmological manifestations are episcleritis, scleritis, peripheral ulcerative keratitis, and orbital inflammation syndromes. ANCA testing, typically negative in Cogan's syndrome, will be a valuable diagnostic aid, as will the presence of granulomatous necrotising vasculitis on histology based on biopsy of one or more affected organs;

* polyarteritis nodosa (see [67]): in addition to inflammatory ocular involvement, cases of sensorineural deafness are also reported. The presence of other suggestive signs (marked constitutional symptoms, livedo, testicular sensitivity, myalgia, mono-or polyneuropathy, hypertension, renal failure, arterial aneurysms) will suggest the diagnosis, which may be confirmed in case of vasculitis lesions with polymorphonuclear cells in the arterial wall;

### 4.5. Severity assessment/extent of disease/potential comorbidities/prognosis assessment

Auditory involvement with bilateral, total, and irreversible sensorineural deafness in over half of patients makes it one of the most severe manifestations of Cogan's syndrome, a primary cause of disability. Conversely, ocular involvement usually has a good prognosis. The rare cases of permanent loss of visual acuity occur in atypical Cogan's syndrome, with inflammatory involvement of the posterior segment, retinal vasculitis, or optic neuritis. Aortitis can complicate into aortic insufficiency, coronary artery involvement, and sometimes aneurysms and dissections that worsen the prognosis. Aortitis may manifest during follow-up in patients who are paucisymptomatic and in remission from other manifestations. Its detection may require a CTA or 18-FDG PET-scan. Assessing the extent of the disease primarily relies on clinical examination data, supplemented by paraclinical testing and specialist consultations. Cogan's syndrome is associated with autoimmune diseases in about 10% of patients, notably vasculitis such as Takayasu's arteritis, polyarteritis nodosa, GPA, as well as relapsing polychondritis, sarcoidosis, rheumatoid arthritis, and chronic IBD. Cogan's aortitis, similar to Takayasu's, is likely to be distinguished from other associations: a) aortitis serves as a prognostic factor, b) the possibility of asymptomatic Takayasu-like aortitis in typical Cogan's, c) in atypical Cogan's, it is difficult to determine whether polyarteritis nodosa, ANCA-associated vasculitis, relapsing polychondritis, and sarcoidosis are actually responsible for ocular inflammation and ENT involvement (Cogan-like). Looking for and managing cardiovascular risk factors such as hypertension, smoking, obesity, diabetes, and dyslipidaemia is recommended, even in the absence of systemic vasculitis, in patients exposed to chronic and/or recurrent steroids. Since Cogan's syndrome can lead to disability, often auditory, systematic investigation into social or professional marginalisation is recommended. Disease progression is marked by ocular or cochleo-vestibular relapses that can worsen severity and prognosis with each relapse. Relapses occur in 50% of patients. Risk factors for relapse are not well defined. However, weight loss, abdominal and cardiovascular manifestations, and persistent abnormalities in laboratory findings (increased C-reactive protein [CRP], anaemia, leucocytosis, thrombocytosis) seem to be significantly associated with a poor prognosis.

### 4.6. Diagnosis disclosure and patient information

Once diagnosed, if possible, the diagnosis should be explained to the patient during a dedicated time, addressing the consequences and general principles of therapeutic management, as well as the potential adverse effects of therapies. The patient should be informed about the main symptoms and signs of relapses and what to do when they occur. It is essential to emphasise that Cogan's syndrome is not a contagious or hereditary disease and is therefore not transmissible to relatives or descendants. Psychological support can be offered if necessary.

## 5. Therapeutic management
[1-4,6-10,12,14,19,20,28,29,31,39,53,59,63,68-78]

### 5.1. General principles

Cogan's syndrome is a type of vasculitis that progresses in unpredictable relapses of variable severity and duration. Therefore, disease management includes:

* treatment of relapses: it depends on the type of involvement and its severity. It may be purely symptomatic (non-steroidal anti-
inflammatory drugs [NSAIDs] and analgesics) or more commonly involve steroid therapy and conventional immunosuppressants, alone or in combination with biological treatments;

* maintenance therapy is indicated in some patients to reduce the frequency and severity of relapses, prevent sequelae, and/or reduce exposure to steroids (steroid-sparing). It is discussed on a case-by-case basis depending on clinical phenotype, progression, sequelae, and prognosis of the disease.

The main treatment goals are:

* to control symptoms;

* to prevent auditory and ophthalmologic functional sequelae primarily, as well as cardiovascular complications;

* to maintain optimal quality of life;

* to prevent adverse effects of medications.

The effectiveness of these drugs is difficult to assess because the natural history of Cogan's syndrome varies greatly from one patient to another. Thus, due to the lack of therapeutic trials and prospective cohorts of sufficient size, treatment guidelines rely primarily on the accumulated experience of experts, retrospective case series, often of limited size, and isolated observations.

## 5.2. Professionals involved

Like diagnosis, the therapeutic management of the patient relies on concerted multidisciplinary collaboration between the ophthalmologist, ENT specialist, internist or rheumatologist, and the patient's general practitioner. Practitioners from other medical specialties may be involved in patient care on a case-by-case basis: cardiologists, vascular physicians etc. Other healthcare professionals, whose involvement is essential for supportive and rehabilitation care, are required: audiologists, sign language interpreters, dieticians, psychologists, physiotherapists.

## 5.3. Pharmacological treatment

The medications used include:

* NSAIDs;

* glucocorticoids (prednisone, intravenous methylprednisolone) are often necessary. Steroid therapy, in its various administration modalities and dosages, remains a major medication in this disease due to its rapid effectiveness and manageability. However, steroid dependence is common, justifying the use of sparing agents (immunosuppressants and/or biologics);

* conventional immunosuppressants: methotrexate (weekly), azathioprine, mycophenolate mofetil (or mycophenolic acid), intravenous cyclophosphamide;

* targeted therapies: several targeted therapies approved for inflammatory rheumatic diseases have been tried with inconsistent and sometimes transient efficacy, particularly infliximab and tocilizumab;

* the potential of other targeted therapies remains to be evaluated.

In the French series, 61 patients received glucocorticoids alone or in combination with conventional immunosuppressants or targeted biologic therapy (infliximab, n = 10). Oral steroid therapy remains the most commonly used first-line treatment at a dosage of 1 mg/kg/day (not exceeding 60 mg/day unless in exceptional circumstances), sometimes preceded by intravenous methylprednisolone boluses (15 mg/kg/day for 3 days not exceeding 1 g per bolus). No study has investigated the optimal duration of steroid therapy in Cogan's syndrome, which is why treatment regimens

(dosage and duration) are based on those used in systemic vasculitis. Prolonged steroid therapy should not be prescribed long-term at more than 5 to 7.5 mg/day of prednisone without considering steroid-sparing therapy. Maintenance therapy with an immunosuppressant/biologic therapy is justified in case of frequent steroid use, steroid dependence, or significant adverse effects. Conventional immunosuppressants (including methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide) and/or targeted therapy (preferably infliximab, especially in case of cochlear vestibular involvement) may be used. It is worthy to note that the response rate to various treatments does not differ between patients with typical and atypical Cogan's syndrome.

## 5.4. Indications

The indications for different medications are empirical, taking into account clinical common sense, pathophysiological and pharmacological considerations, accumulated experience, and expert opinions. No prospective therapeutic trials are available in this disease.

### 5.4.1. Cochleo-vestibular manifestations

The treatment goal should be to prevent irreversible sensorineural hearing loss. Unlike ocular involvement, cochleo-vestibular involvement has a poor prognosis and justifies the rapid introduction of immunosuppressive treatment or biologic therapy. In mild to moderate forms, systemic steroid therapy alone may be offered. However, even in these forms, discussions about steroid-sparing should occur early on. Intratympanic steroid injections may be offered as adjunctive therapy to systemic treatment. In moderate to severe forms or in case of failure or inadequate response, immunosuppressants are recommended (methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide) according to their use in vasculitis (see [67]). More recently, anti-TNFα agents, particularly infliximab, have been offered in addition to steroid therapy, either alone or in combination with disease-modifying antirheumatic drugs (DMARDs). Data on other biologic therapies is even more limited; five isolated cases report the efficacy of tocilizumab, and two cases of rituximab. In the French series, the response of cochleo-vestibular involvement was significantly higher in patients treated with infliximab compared to those treated with conventional immunosuppressants and/or steroid therapy alone (80% vs. 39% and 35%, respectively). Audiovestibular management includes conventional hearing rehabilitation, speech therapy, and vestibular rehabilitation. Due to the risk of progression from labyrinthitis to cochlear fibrosis and ossification, cochlear implant rehabilitation should be promptly discussed with a specialist ENT team as soon as severe to profound hearing loss occurs to achieve satisfactory auditory performance over time. Indeed, progressing intracochlear lesions (fibrosis, ossification) may render implantation impossible if management is delayed.

### 5.4.2. Ophthalmological manifestations

Although the ophthalmological prognosis is considered good, untreated ocular involvement can lead to permanent visual sequelae (significant corneal opacity). Anterior segment eye involvement (keratitis, conjunctivitis, episcleritis, scleritis, and anterior uveitis) generally benefits from topical steroid therapy only, while more posterior involvement usually requires systemic steroid therapy. The most commonly used molecule is dexamethasone, with dosages ranging from 1 drop three times daily for moderate forms to 1 drop every hour for severe forms for 2 to 3 weeks. In some cases, the ophthalmologist may perform subconjunctival or peribulbar steroid injections. Other locally used molecules include prednisolone (eye drops), fluorometholone (eye drops), hydrocortisone (eye drops), betamethasone (subconjunctival injection), and triamcinol
lone (subconjunctival injection). Initiating such treatment requires regular monitoring of intraocular pressure due to the risk of steroid-induced glaucoma, sometimes severe, which can occur as early as 3 weeks into treatment. The patient should also be informed of the delayed risk of secondary cataracts when local treatment is prescribed at significant doses for more than 6 to 12 months. In all cases where ENT or systemic involvement is present, local treatment is combined with systemic steroid or immunosuppressant therapy under the supervision of the internist. However, in the French series, the ophthalmological response was not better in patients who received infliximab compared to those treated with conventional immunosuppressants and/or steroid therapy alone. The ophthalmological manifestations of Cogan's syndrome respond favourably to steroid therapy alone in 84% of cases and to immunomodulatory treatments in 90 to 100% of cases. The prognosis remains good in the end, with only 3% of patients experiencing long-term disabling ocular complications.

### 5.4.3. Other manifestations

The treatment goal should be to prevent systemic complications due to vasculitis. The treatment of other manifestations (constitutional symptoms, central nervous system involvement, cardiovascular involvement) is not codified. In severe forms, treatment may primarily rely on high-dose steroid therapy (prednisone 1 mg/kg/day), preceded by methylprednisolone boluses (1 g/day for 3 days), and associated with an immunosuppressant and/or targeted therapy. The development of ascending aortic aneurysm or aortic or mitral valve disease may require surgical intervention. In the case of a surgical decision, efforts should be made to intervene in a planned manner in a patient controlled for systemic inflammation, on 20 mg/day or less of prednisone. There is a risk of wound dehiscence in case of surgery on an actively inflamed aorta. Infective endocarditis should systematically be sought in case of ascending aortic involvement or aortic insufficiency.

### 5.5. Supportive measures

Supportive measures are those of any systemic steroid therapy. Patients should be vaccinated as soon as possible against pneumococcus, COVID-19, and flu in addition to the regular vaccination schedule. Complications of steroid therapy must be systematically prevented, and patients educated about the risks associated with these medications, as well as with immunosuppressants and targeted therapies. Prevention of steroid-induced osteoporosis should be carried out in accordance with current guidelines. Particular attention should be paid to controlling cardiovascular risk. The patient and their general practitioner should be informed about the risks of progression in this disease and the situations that should prompt urgent consultation. The patient can obtain a personal emergency card from their specialist physician at reference and expert centres. Bilateral cochlear implants have been one of the most significant advances in the management of hearing loss, which is common in this condition.

### 5.6. Therapeutic patient education (TPE)

TPE is an integral part of managing a chronic disease. TPE is a key element of the overall patient care. This multidisciplinary approach has been defined by the World Health Organization (WHO):

TPE aims to help patients acquire or maintain the skills they need to manage their living with a chronic illness more effectively. It is an integral and permanent part of patient care. It includes organised activities, psychosocial support, designed to make patients aware and informed about their illness, care, organisation and hospital procedures, and health and illness-

related behaviours. This is intended to help them (and their families) understand their illness and treatment, collaborate, and take responsibility for their own care in order to help them maintain and improve their quality of life. Oral or written information, prevention advice, can be provided by a healthcare professional on various occasions, but they do not equate to TPE. The educational approach is participatory and person-centred, not just the transmission of knowledge or skills.

It is a partnership between the patient, their family, and the healthcare team aimed at helping the sick person take care of themselves.

Thus, TPE gives patients the opportunity to be at the centre of an individualised and controlled healthcare journey between a therapeutic norm offered by the healthcare team and that of the patient based on their representations and plans. Various means are available to healthcare professionals to assist them in their therapeutic education projects. Reference and expert centres as well as rare disease healthcare networks have a duty to inform. Patient advocacy groups and websites can provide useful information. Currently, there is no validated TPE programme dedicated to Cogan's syndrome in France. However, patients with Cogan's syndrome can be enrolled in programmes intended for patients with chronic diseases treated with long-term steroid therapy and/or biologic therapy. It seems necessary in this population to offer an appointment with a dietitian at the time of diagnosis of Cogan's syndrome and the initiation of steroid therapy to adjust the diet as necessary. Healthcare providers caring for these patients should inform them and their caregivers about the importance of regular adherence to steroid therapy, the risk of sudden discontinuation of therapy, and signs suggestive of relapse or complication of Cogan's syndrome.

### 5.7. Use of patient advocacy groups

All patients, their relatives, and professionals should be informed about the existence of patient advocacy groups by their doctors, reference and expert centres, institutional websites, and Orphanet. These organisations contribute to better overall management of the disease by promoting cooperation between patients, healthcare providers, medical-social and administrative institutions. They enable patients to become stakeholders in their care. Association France Vascularites, founded in 2006, is a non-profit association recognised as promoting the public interest. It consists of patients with vasculitis, their relatives, and benefactor members. It aims to create links between patients to break social isolation and share experiences and information. It can contribute to improving the patient's healthcare journey by relying on recognised care networks. The organisation disseminates validated information to physicians through its scientific council. It also contributes to promoting medical research and holds charity events to support research. Several actions are undertaken to help patients live with the disease on a daily basis:

* listening, support, guidance:

* telephone hotline,

* messaging service: association.vascularites@gmail.com or contact@association-vascularites.org,

* virtual informal meetings held every Thursday,

* social media monitoring,

* discussion forums;

* training/education:

* conducting TPE workshops dedicated to vasculitis and promoting these workshops nationwide,

* immunity/autoimmunity training to help patients and their relatives understand the biological mechanism of vasculitis,
simplify medical vocabulary used by doctors, interpret blood test results etc.,

* supplementary workshops to TPE,

* simplification of medical terms,

* specific documentation;

* meetings:

* setting up meetings between patients,

* information meetings with the assistance of specialists,

* webinars,

* replay/DVDs of conferences,

* France Vascularites YouTube Channel,

* participation in research efforts,

* institutional partnerships within rare disease networks,

* the association France Vascularites is accredited to represent healthcare system users in various hospital or institutional committees;

* improving daily life:

* well-being, invisible disabilities, caregivers, transition, education, professional integration etc.,

* raising awareness among the medical community about vasculitis and its implications on daily life and to limit diagnostic delays and dead ends.

# 6. Follow-up

[1-4,6-12,14,19,20,29-31,34,44,46,47,49-51,54-59,62,63]

## 6.1. Objectives

The follow-up objectives are as follows:

* to specify the activity and severity of the disease;

* to screen for potential visceral involvement;

* to evaluate the acceptability, efficacy, and tolerability of treatments;

* to search for potential comorbidities, assess vascular risk and risk of infection related to therapeutic management.

## 6.2. Professionals involved and coordination modalities

Like other chronic conditions, Cogan's syndrome requires specialist management in collaboration with the attending physician.

Monitoring involves, depending on the initial assessment and progression:

* involvement of reference or expert centres;

* specialist consultations (internists, ENT specialists, rheumatologists, ophthalmologists...);

* consultations with the attending physician;

* other specialist physicians, usually upon request from the aforementioned doctors, as well as paramedical specialties (physiotherapists, psychologists...).

## 6.3. Frequency and content of consultations

Outpatient management may not always be possible, and hospitalisation may be considered when necessary. The frequency of follow-up will be adjusted to the patient's clinical condition, severity, and disease progression profile, type of visceral involvement and/or occurrence of intercurrent events, treatments used, and specific situations (pregnancy, non-adherence).

### 6.3.1. Interview and clinical examination

The follow-up medical interview and clinical examination are identical to those conducted during the initial evaluation. Special attention should be paid to verify the patient's understanding of

their disease and treatment, as well as their adherence to management. Evaluation of adverse effects, particularly of steroid therapy, should be performed.

### 6.3.2. Additional testing

Additional investigations aim to monitor the disease and detect specific, sometimes asymptomatic, types of involvement (especially cardiac, aortic), to monitor cochleo-vestibular and ocular involvement, and to detect treatment complications.

Laboratory-based monitoring includes, notably:

* monitoring of potential inflammatory syndrome, with the absence of inflammatory syndrome not excluding the potential progression of Cogan's syndrome;

* depending on prescribed treatments: complete blood count, creatinine level, liver enzymes (transaminases, gamma-glutamyl transferase), and alkaline phosphatases.

In case of ophthalmological or cochleo-vestibular involvement, joint follow-up with an ophthalmologist and ENT specialist will be applied.

# 7. Paediatric forms [70,73,79-81]

Cogan's syndrome is a complex condition primarily affecting the auditory system and the eyes and has been very rarely described in children, with around fifty reported cases. The median age of onset of Cogan's syndrome in children is 12 years with a male predominance (sex-ratio: 2:3). Sudden deafness (95%), more common than in adults, and ocular symptoms (92%) are the most commonly found manifestations in children. Ocular involvement is intermittent and more commonly of the interstitial keratitis type (44%), uveitis type (28%), and less commonly conjunctivitis type (18%). Cutaneous involvement occurs less frequently. Involvement of large vessels manifests as aortitis, observed in nearly 20% of cases, requiring surgical intervention in 44% of cases.

Differential diagnoses include those of adult forms:

* infectious: congenital syphilis, tuberculosis, chlamydia...;

* sarcoidosis;

* VKH syndrome;

* systemic vasculitis.

There is usually an inflammatory syndrome during flares (elevated CRP or erythrocyte sedimentation rate).

Treatment relies on steroid therapy and immunosuppressants, with a preference for mycophenolate mofetil or azathioprine over cyclophosphamide in case of systemic involvement due to their tolerability profile. Infliximab is the only reported biologic agent in children with good tolerability, but the therapeutic approach is generally guided by the experience of adult physicians.

# 8. Transition [82,83]

The transition of patients from paediatrics to adult medicine has been the subject of recent guidelines in the field of rare autoimmune and autoinflammatory diseases. Tools such as a transition checklist have also been described by a group of European experts, addressing topics such as the disease, complications, treatments, as well as issues related to sexuality, fertility, pregnancy, alcohol consumption and smoking, and risky behaviours. The aim of transition is to support adolescents with chronic illness in their medical, psychosocial, and educational needs with adapted and expert teams. Transition should be anticipated and begin around the ages of 12-14 years: a preparation stage, continuing towards
the ages of 16-18 years into the transfer stage, and concluding with the engagement stage in young adulthood. A transition protocol must be written, and a medical and paramedical duo (paediatrician/physician and nurse) must be identified, which is essential. The objectives of transition are to understand the autoinflammatory disease, its complications, and its treatments, allowing the adolescent to acquire skills specific to their condition. Thus, the adolescent gradually becomes independent, becoming an stakeholder in their health. TPE can help facilitate the transition process. The goal of transition is to avoid a disruption to medical care, leading to a loss of follow-up. The risk of poorly controlled or uncontrolled disease, of complications of inflammatory disease, is real during this pivotal period in the lives of adolescents with chronic diseases starting in childhood. The progressive preparation of the transitioning adolescent, the chosen time for transfer (stable disease), the availability, and coordination of teams are key to a successful transition. Transition and follow-up into adulthood should be organised collectively in advance with all multidisciplinary teams (ENT, ophthalmologist, rheumatologist/internist) for continuity of care.

## 9. Pregnancy

There is usually no particular interaction of pregnancy on Cogan's syndrome or of Cogan's syndrome on pregnancy, but the available data is extremely limited. Pregnancy should be planned and anticipated, especially when it comes to treatments and vaccinations to be administered beforehand. Given the typically young age of patients, particular attention should be paid to the teratogenic risk and conditions of use of immunosuppressants/biologic therapies that may be required in the treatment of the disease.

## Disclosure of interest

All participants in the development of the FPDM completed a declaration of interest. The declarations of interest are online and available on the FAI²R website.

## Funding

This study was not supported by research funding but FAI²R is funded by "le ministère des Solidarités et de la Santé" (French Ministry of Solidarity and Health).

## Authors' contributions

All authors wrote the first draft and participated in drafting the manuscript. All authors participated in editing the manuscript, as well as reading and approving the final version of the manuscript.

## Acknowledgements

We would like to thank the Rare Autoimmune and Autoinflammatory Diseases Network (FAI²R) for its technical assistance and help with editing (Hélène Maillard and Charlotte Lejeune).

The French version is available free of charge on the HAS website.

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