Lund University Hospital Mènière Vad är på gång? Mikael Karlberg MD, PhD Oto-rhino-laryngology, Head & Neck Surgery Lund University Hospital Sweden

New criteria for diagnosing Menière´s disease 2015! Prosper Meniere 1861 New criteria for diagnosing Menière´s disease 2015! Lopez-Escamez JA et al. J Vestib Res 2015;25:1-7 Definite Menière´s disease 2 or more spontaneous episodes of vertigo lasting 20 minutes – 12 hours Documented low-medium frequency sensorineural hearing loss Fluctuating aural symptoms (hearing, tinnitus, fullness) in the affected ear Not better explained by another vestibular diagnosis Probable Menière´s disease 2 or more episodes of vertigo or dizziness lasting 20 minutes – 24 hours

All with definite Meniere´s disease have endolymphatic hydrops!! But all with endolymphatic hydrops do not have Meniere´s disease!!

Prevalence VERY uncommon in children! About 0.5 % (finnish data) Most common between 60-70 years (1,5 %)

Eye doctor? Piece of cake! Can see the organ! Measure pressure!

How do we make a diagnosis of Meniere? History Get a ”typical” audiogram (low-frequency loss) Rule out ”other diseases” = MRI (Vestibular testing: ipsi-lesional vestibular damage)

Diagnostic problems Migraine variants? Meniere without hearing loss? 60% of Meniere mono-symptomatic at start!

Robert Barany 1876-1936 Nobel laureate medicine and physiology 1914

“old faithful” Non-physiologic test Low frequency Slow acceleration

Caloric test and Meniere 60 % of Meniere mono-symptomatic at start! 1 – 20 years latency until next symptom! Recurrent vertigo attacks: 0 audiologic symptoms: Significant canal paresis: probably Meniere in ear with canal paresis

Caloric test and Meniere Recurrent vertigo attacks: 0 audiologic symptoms: Significant directional preponderance: probably Meniere but in what ear?

Caloric test and Meniere Significant canal paresis (>25%) BUT normal video head impulse test (vHIT): Probably Meniere

Normal ampulla Hydrops in ampulla Rizvi 1986

Caloric test Head impulse test

Caloric test and Meniere Recurrent vertigo attacks: 0 audiologic symptoms: Normal caloric test: probably migraine

Animals: experimental endolymphatic hydrops (chronic vasopressin treatment or obstructing the endolymphatic duct) results in hearing loss but no vertigo attacks!

”Multi-factorial”? Many different causes give the same result? Genetics! (no genes found so far) Too much endolymph produced? Disturbed resorption of endolymph? (”stop” in endolymphatic duct) loose otoconias? Disturbed pressure regulation? Stress? Hormones? Inflammation?

I believe that in Meniere´s disease: -there is overpressure in the endolymphatic space (or underpressure in the perilymphatic space!) -when the overpressure suddenly releases there is a Meniere attack -over time there is a permanent lesion of auditory and vestibular hair cells with permanent hearing loss (and no more vertigo attacks) Earlier and more active treatment might save hearing!?

Betaserc / Serc (betahistin) Mechanism of action?? ”increased cochlear blood flow” Är på god väg att godkännas i Sverige (Medical Need) No good studies (one on-going: 24mg x 3 vs 48mg x 3 vs placebo x 3 Academic study, not sponsored) 0 effect??? 24-48 mg x 3 for bilateral Meniere No effect on hearing loss

Possible mechanisms of endolymphatic hydrops perilymph endolymph + 1. Increased endolymphatic volume

Possible mechanisms of endolymphatic hydrops perilymph - endolymph + 2. Decreased perilymphatic pressure

“Typical” case of decreased perilymphatic pressure? Woman 42 years Headache, fluctuating left-sided tinnitus, fullness and hearing loss Attacks of vertigo and nausea > 20 minutes Headache disappears when she lies down = “orthostatic headache” Fluctuating left-sided, low-frequency sensorineural hearing loss

CT brain normal MRI with gadolinium: pachymeningeal enhancement and “sagging brain”

”Idiopathic intracranial hypotension” pachymeningeal contrast enhancement ”Idiopathic intracranial hypotension” Spontaneous spinal CSF leakage

No spontaneous remission After 1 month epidural autologous 20 ml “blood patch” at L2-3, repeated after 3 days 1 day after last blood patch headache disappears Audio-vestibular symptoms gradually disappear during one month MRI and audiometry normal 2 months later

- CSF + 2. Decreased perilymphatic pressure endolymph + 2. Decreased perilymphatic pressure due to decreased CSF pressure / volume

perilymph - endolymph + middle ear 3. Decreased perilymphatic pressure due to low middle ear pressure?

Montandon et al ORL 1988 28 Meniere patients referred for surgery (shunt or VNx) TMD in LA Follow-up at 24-48 months (mean 30 months) 23 patients (82%) total remission or improved 20 (71%) AAO score 0 total remission 1 (4%) AAO score 1-40 much improved 2 (7%) AAO score 41-80 improved 2 (7%) AAO score 81-120 no change 3 (11%) AAO score >120 worse

Latanoprost (Xalatan®) Latanoprost (Xalatan®) used for glaucoma treatment worldwide Prostaglandin F2α analogue Reduces the intraocular pressure by enhancing the drainage of fluid from the eye

Previous study design Randomized Double-blind Cross-over Placebo controlled Active drug or placebo Day: 1, 2 and 3 Study variables monitored Day 1, 5, 15 and 29 Wash out 2 months

Tinnitus loudness

Speech discrimination

Vertigo attacks Placebo Placebo Placebo

A clear trend of improvement Better speech discrimination Less tinnitus

On-going multi-center clinical study ”proof-of-concept” study Lund Kristianstad Karlskrona Linköping Göteborg Stockholm Karlstad Örebro Västerås Uppsala Falun Luleå (Sunderbyn)

Clinical study protocol 1 2 3 Months Placebo: 3 injections 20 patients Latanoprost ester, 0.005%: 3 injections 40 patients Placebo: 1 injection 10 patients Latanoprost ester, 0.005%: 1 injection 30 patients

Clinical study protocol Primary endpoint: Speech discrimination in noise; Change from baseline to day 14 Secondary endpoints: PTA (Pure Tone Average) in lower frequency interval (125, 250 and 500 Hz) PTA in higher frequencey interval (500, 1,000, 2,000 and 3,000 Hz) Subjective Hearing (Likert scale) Subjective Tinnitus (Likert scale) Subjective Dizziness (Likert scale) Number of vertigo attacks > 20 mins Right now? 87 of 100 patients included!

See endolymphatic hydrops on MRI!!! Gadolinium diluted 1:8 with NaCl Injected into middle ear Patient lies 30 min 24 hours later MRI (3T, 3D-FLAIR) Alternatively i.v. gadolinium normal dose - MR 4 hours later

Normal gadolinium enhancement (of perilyphatic space) intratymp. gadolinium Normal gadolinium enhancement (of perilyphatic space) Severe hydrops (black = non-enhanced expanded endolymphatic space)

i.v. gad cochlear hydrops Naganawa S et al 2013 Magn Reson Med Sci 2013 i.v. gad cochlear hydrops

i.v. gad vestibular hydrops

Significant relation between grade of hydrops on MRI and hearing loss! TMV 250, 500, 1000 Hz TMV 500, 1000, 2000, 3000 Hz Significant relation between grade of hydrops on MRI and hearing loss! (no relation between ECoG, VEMP, calorics) Gϋrkow R et al Eur Arch Otorhinolaryngol 2011

Acute unilateral low-frequency hearing loss: 25 patients 23 (92%) endolymphatic hydrops on MRI (40% also on the normal ear!) Shimono M et al Otol Neurotol 2013 Hydrops in a majority of patients with ”vestibular” Meniere and”cochlear” Meniere Kato M et al Acta Otolaryngol 2013 Effect of Betaserc? No decrease in hydrops on MRI after 3-7 months treatment with 16 mg x 3 Gϋrkow R et al Eur Arch Otorhinolaryngol 2013 No effect on hydrops after gentamicin Fiorino F et al Otol Neurotol 2012 A patient with ”typical” Meniere: MR – hydrops Spontaneous remission: MR after 1 år – 0 hydrops Nakashima et al EAONO2014

A 7 T MRI-machine is now in place in Lund! Better resolution of inner ear structures? ”certain” Meniere diagnosis in living patients?