Neuromyelitis optica - harvinaissairaus, joka on tärkeä erottaa MS-taudista

Vertaisarvioitu. Teema : neuroimmunologia.Neuromyelitis optica on autoimmuunisairaus, joka alkuperäisen määritelmänsä mukaan kohdistuu pääasiassa näköhermoratoihin ja selkäytimeen. Viime vuosina taudin diagnostiset kriteerit ja oirekirjo ovat kuitenkin laajentuneet ja nimeksi on muotoutunut neuromyelitis optica -kirjon sairaudet (neuromyelitis optica spectrum disorder, NMOSD). Sairaus muistuttaa aaltomaista MS-tautia, josta se on kuitenkin tärkeää erottaa. Taudit eroavat toisistaan immunologisesti, ja osa MS-taudin lääkkeistä voi jopa pahentaa NMOSD:tä. Näköhermo- ja selkäydintulehdus ovat yleensä vaikeampia kuin MS-taudissa. Taudin oirekirjon ja magneettikuvauslöydösten täsmentyminen sekä akvaporiini-4 (AQP4)- ja myeliinioligodendrosyyttiglykoproteiini (myelin oligodendrocyte glycoprotein, MOG) -vasta-aineiden löytyminen ovat selkeyttäneet diagnostiikkaa. Hoitoperiaatteetkin alkavat vähitellen selkiytyä viimeaikaisten havainnoivien ja kaksoissokkotutkimusten ansiosta.Peer reviewe

Incidence and Mimickers of Acute Idiopathic Optic Neuritis : Analysis of 291 Consecutive Patients from Southern Finland

Purpose: To estimate the population-based incidence of acute idiopathic optic neuritis (ON) and analyse its differential diagnosis in patients referred with symptoms suggestive of ON. Methods: Patients with suspected ON referred to the Helsinki University Hospital, serving a population of 1.5 million in Southern Finland, were reviewed between 1st May 2008 and 14th April 2012. Brain and optic nerve magnetic resonance imaging (MRI) was performed within 24 hours in 83% of patients. Results: Of 291 referred patients, 184 (63%; 95% confidence interval [CI], 57-69%) were diagnosed with ON whereas 107 (37%) had another condition. The estimated crude incidence of ON in Southern Finland was 3.0 (95% CI 2.8-3.3) per 100,000 (females, 4.6 and males, 1.4). Mean age was 34years (range 15-61), 76% were female. Two (1%) were diagnosed with neuromyelitis optica. ON as the first demyelinative episode was diagnosed in 108 (59%) patients, and MRI showed demyelinating lesions (MRI+) in 82% (95% CI, 75-89) of them. MRI+ predicted the development of multiple sclerosis (MS): 54% of MRI+vs. 5% MRI-patients were diagnosed as MS during a mean follow-up of 7.7years. The most common differential diagnosis was non-arteritic anterior ischemic optic neuropathy (12%). Six (2%) intracranial compressive lesions were found upon MRI scan. Conclusions: More than a third of patients with symptoms suggestive of ON had another condition. Demyelinative lesions on MRI indicated higher risk of developing MS. We recommend the use of MRI to improve the differential diagnostic accuracy of ON and to identify patients with high risk of MS.Peer reviewe

Optic Neuritis and Neuromyelitis Optica : Clinical and Genetic aspects

Optic neuritis (ON) is caused by immune-mediated demyelination of the optic nerve. In ON the visual acuity of the patient usually decreases in one eye. Common additional symptoms include impaired colour vision, pain with eye movements, and pupillary dysfunction. While ON may present as a single episode, in about 20% of patients it is the first symptom of multiple sclerosis (MS). Approximately half of patients with MS are affected by ON at some stage of the disease. MS typically causes demyelination in the optic tract, cerebrum, brainstem, and spinal cord; MS symptoms are therefore extensive. With the revised diagnostic criteria of MS, the diagnosis of MS may sometimes be confirmed already after the first episode of ON. In addition to MS, another demyelinating disease associated with ON is neuromyelitis optica (NMO), also known as Devic disease. As the diagnostic criteria for this disease have recently evolved the most common term is neuromyelitis optica spectrum disorders (NMOSD). NMOSD is characterized by demyelinating changes in the spinal cord and an increased aquaporin-4 (AQP4) antibody index. There are currently no treatments that improve the prognosis of ON. However, high-dose corticosteroids may reduce the duration of symptoms and some medications may reduce the risk of MS development among patients with ON. The diagnosis of ON is demanding as the diagnosis is based on exclusion of other causes. Little is known about the factors that affect the natural course of ON. Severe visual impairment may result after multiple recurrences. We analysed the natural course of ON and its differential diagnosis, clinical findings, incidence, and connection to MS in Southern Finland during the period from 2008 to 2012. In addition, we studied the prevalence of NMO associated with ON in southern Finland and the development of NMO diagnostics. We also analysed genetic mutations by exome sequencing in NMO patients in Southern Finland. We observed that the incidence of ON in Finland has increased. This may be due to improved diagnostic methods and because diagnostic delay is briefer as patients nowadays actively seek medical attention with even minor symptoms. The seasonal variation in the number of ON diagnoses was also confirmed. The challenges in diagnosing ON were notable, as over one third of patients with suspected ON at onset were later diagnosed with a disease other than ON. Our study confirmed that ON occurs more frequently in women (F:M ratio 3:1) and most cases is related to MS. Both bilateral ON (1.6%) and NMO (1%) are rare in Finland. The natural course of ON showed good recovery; approximately 70% of patients achieved visual acuity >0.8 (average follow-up time of 38 days). When analysing the factors that affect prognosis for patient visual impairment, our data suggest that in addition to baseline visual acuity, optic disc swelling and lesions in the optic nerve on magnetic resonance imaging (MRI) are associated with poorer prognosis. Nearly one-third (30%) of patients were already diagnosed with MS before diagnosis of ON. Among patients with their first ON, 82% were diagnosed with demyelinating changes in brain MRI. Demyelinating changes in brain MRI were a significant risk factor for MS; 54% of ON patients with early-stage demyelination in brain MRI developed MS (average follow-up time of 7 years). Only 5% of those without demyelinating changes in brain MRI developed MS. The practice of performing MRI before any medical treatment was also supported by our finding of six intracranial compressive lesions (2%) as mimickers of ON. We investigated the sensitivity and specificity of the AQP4 antibody assay in the diagnosis of NMO in our ON patient cohort. The number of patients with NMO was very low (n=2). The AQP4 antibody test sensitivity was only 1/2 and had a positive predictive value of 1/3. The exome sequencing study of patients with NMO (n=5) was the first published study of this kind in this disease. No genetic variants common to all patients were found. Four of the mutations were shared by two patients with NMO (C3ORF20, PDZD2, C5ORF47, and ZNF606). Another PDZD2 variant was also found in a third patient. Additionally, two rare, probably functional variants in the non-coding region of DNA were found in two patients. The significance of these findings cannot yet be evaluated. However, as extensive research in this field is ongoing we assume that the role of these variants will be revealed in the future.Optikusneuriitti eli näköhermotulehdus aiheutuu näköhermon immuunivälitteisestä demyelinaatiosta. Optikusneuriitissa potilaan näöntarkkuus useimmiten heikkenee toisessa silmässä. Tavanomaisia optikusneuriitin lisäoireita ovat värinäön ongelmat, silmien liikuttelukipu sekä mustuaisen toimintahäiriöt. Optikusneuriitti voi olla yksittäinen episodi, mutta jopa 40–50 % potilaista se on multippelinskleroosin eli MS-taudin ensioire. MS-potilaista noin puolet sairastuu jossakin vaiheessa optikusneuriitin. MS-tauti tyypillisesti aiheuttaa demyelinaatiota näköradan lisäksi muualla isoaivoissa, aivorungossa ja selkäytimessä ja oirekirjo on tämän myötä laaja. MS-taudin lisäksi toinen optikusneuriittiin liittyvä demyelinisoiva sairaus on neuromyelitis optica eli NMO, joka tunnetaan myös nimellä Devicin tauti. NMO:lle tyypillistä ovat erityisesti selkäytimen demyelinoivat muutokset sekä akvaporiini-4 vasta-ainepitoisuuden kohoaminen. Optikusneuriitin ennusteeseen vaikuttavaa hoitoa ei tunneta, mutta suuriannoksisella kortisonihoidolla oireiden kestoa voidaan usein lyhentää. Optikusneuriitin diagnostiikka on vaativaa, koska diagnoosi perustuu keskeisesti muiden syiden poissuljentaan. Optikusneuriitin ennusteeseen vaikuttavista tekijöistä on vasta vähän tietoa. Useita kertoja toistuessaan siihen liittyy herkästi näkövammaisuutta. Tutkimme optikusneuriitin luonnollista kulkua sekä sen erotusdiagnostiikkaa, kliinistä kuvaa, ilmaantuvuutta ja yhteyttä MS-tautiin. Lisäksi selvitimme optikusneuriittiin liittyvän NMO:n yleisyyttä Etelä-Suomessa sekä sen diagnostiikan kehittämistä. Analysoimme myös NMO potilaiden geneettisiä muutoksia eteläsuomalaisissa potilaissa eksomisekvensoinnilla. Optikusneuriitin esiintyvyys Suomessa on tutkimuksemme mukaan lisääntynyt, mikä voi johtua diagnostisten menetelmien parantumisesta ja väestön herkemmästä hakeutumisesta sairaanhoitopalvelujen pariin. Optikusneuriitissa aikaisemmissakin tutkimuksissa todettu vuodenaikavaihtelu diagnoosikuukauden suhteen vahvistui myös HUS-piirin aineistossamme. Optikusneuriitin diagnosoimisen vaikeus oli hyvin havaittavissa, sillä yli kolmasosalla potilaista, joiden silmäoireiden aiheuttajana alkuvaiheessa epäiltiin optikusneuriittia, todettiinkin tarkemmissa tutkimuksissa jokin muu silmäsairaus, jonka oirekuva alkuvaiheessa muistutti optikusneuriittia. Tutkimuksemme vahvisti, että näköhermontulehdus esiintyy useammin naisilla (suhde 3:1). Molempien silmien (bilateraali) näköhermontulehdus (1,6 %) sekä NMO (1 %) ovat harvinaisia suomalaisilla. Näkökyvyn paraneminen seurannassa oli hyvää tasoa, noin 70% potilaista saavutti näöntarkkuuden 0.8 tai enemmän (keskimääräinen seuranta-aika 38 päivää). Arvioidessamme potilaiden näkökyvyn paranemiseen vaikuttavia tekijöitä havaitsimme, että alkuvaiheen näöntarkkuuden lisäksi näköhermon pään turvotuksella ja magneettikuvauksessa havaituilla näköhermon demyelinaatiomuutoksilla oli tähän merkittävä ennustetta heikentävä vaikutus. Lähes kolmasosa (30 %) tutkimuksen potilaista sairasti MS-tautia jo ennen optikusneuriitti diagnoosia. Ensimmäisen optikusneuriitin yhteydessä todettiin 82 % potilaista demyelinoivia aivojen magneettikuvausmuutoksia. Demyelinoivat muutokset todettiin merkittäväksi MS-taudin riskiä kohottavaksi tekijäksi: 54%:lle optikusneuriittipotilaista, joilla alkuvaiheessa havaittiin demyelinaatiomuutoksia, kehittyi keskimäärin seitsemän vuoden seurannassa MS-tauti, kun vastaavasti vain 5%:lle niistä, joiden aivojen magneettikuvauksessa ei todettu demyelinoivia muutoksia kehittyi MS-tauti. Aivojen ja orbitoiden magneettikuvauksen tärkeyttä optikusneuriittipotilailla tukee myös havaintomme kuudesta (2 %) mahdollisesti henkeä uhanneesta näköhermoa painavasta kallonsisäisestä muutoksesta. Selvitimme käytössämme olevan akvaporiini-4 vasta-aineen sensitiviteettiä ja spesifiteettiä NMO:n diagnostiikassa etelä-suomalaisessa optikusneuriitti populaatiossa. NMO potilaiden määrä osoittautui hyvin vähäiseksi (n=2). Akvaporiini-4 vasta-aine laboratoriotutkimuksen sensitiviteetti oli vain ½ ja positiivinen ennuste arvo 1/3. Eteläsuomalaisten NMO potilaiden (n=5) eksomisekvensointitutkimuksemme oli laatuaan ensimmäinen julkaistu tutkimus tässä sairaudessa. Yhtään kaikille potilaille yhteistä geneettistä varianttia ei löydetty. Kahta NMO-potilasta yhdistäviä pistemutaatiota todettiin neljä kappaletta: C3ORF20, PDZD2, C5ORF47 ja ZNF606. Toinen PDZD2-variantti löytyi myös kolmannelta potilaalta. Tämän lisäksi kahdella potilaalla todettiin kaksi samaa DNA:n ei-koodaavan alueen todennäköisesti funktionaalista harvinaista mutaatiota. Löytämiemme varianttien merkitystä ei vielä voida arvioida, mutta koska alan tutkimusta on laajalti meneillään, oletamme että löytämiemme varianttien rooli paljastunee lähitulevaisuudessa

The clinical spectrum and prognosis of idiopathic acute optic neuritis: A longitudinal study in Southern Finland

Background: To analyse in a population-based setting the clinical features, prognostic factors, and seasonality of patients diagnosed with acute idiopathic optic neuritis (ON). Methods: Retrospective analysis of ophthalmological records, laboratory parameters, and magnetic resonance imaging (MRI) of patients with symptoms suggestive of ON referred to the Helsinki University Hospital (serving a population of 1.53 million in Southern Finland) were analysed between May 1, 2008 and April 14, 2012. Results: Of the 291 patients with suspected ON, 184 (63%) were diagnosed with ON (mean age 34 years, 76% females). Intravenous methylprednisolone treatment was administered in 131 (71%) patients. First ON was diagnosed in 123 patients (67%), 55 (30%) had a previous diagnosis of multiple sclerosis (MS) and two patients with their first ON were diagnosed with neuromyelitis optica. Evolution of best corrected visual acuity (BCVA) was analysed in 132 (72%) patients, who were reviewed median of 38 days after onset. Median and mean BCVAs in these reviewed patients were 0.4 and 0.2 at the time of diagnosis and 1.0 and 0.5 at the time of the review. Recovery was relatively good in the majority of patients; 82% (n = 108) had reached BCVA of >= 0.5 and 70% (n = 92) and BCVA of >= 0.8 at the time of the review, while thirteen (10%) had poor prognosis, BCVA Conclusions: Our data suggest that besides baseline visual acuity, optic disc swelling and lesions in the optic nerve on MRI are associated with poorer prognosis. As in previous studies, we observed that diagnostics of ON is difficult, accessory clinical findings such as pain and RAPD are not always present. Although the diagnosis of ON is clinical, the role of MRI should be considered in differential diagnostics and in defining potential prognostic markers.Peer reviewe

Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients

Background: Optic neuritis (ON) can occur as an isolated episode or will develop to multiple sclerosis (MS) a chronic autoimmune disease. What predicts ON progression to MS remains poorly understood. Methods: We characterised the antibody epitope repertoire in three independent clinical cohorts (discovery (n = 62), validation (n = 20) and external cohort (n = 421)) using mimotope variation analysis (MVA), a next generation phage display technology to identify epitopes that associate with prognosis of ON. Findings: We observed distinct epitope profiles for ON, MS and the controls, whereas epitope repertoires of sera and CSF were highly similar. Two unique and highly immunogenic epitopes A and B were detected in subjects with ON progressing to MS. These epitopes A and B were strongly associated with herpesviral antigens (VCA p18 of Epstein-Barr virus (EBV); gB of Cytomegalovirus (CMV)). ROC addressed 75% of MS subjects with ON onset correctly (at 75% sensitivity and 74.22% specificity) based on the two-epitope biomarker analysis. Interpretation: This is the first report on epitope diagnostics for MS employing the unbiased strategy of MVA for identification of novel immunological features of disease. (C) 2021 The Authors. Published by Elsevier B.V.Peer reviewe

Incidence and Mimickers of Acute Idiopathic Optic Neuritis: Analysis of 291 Consecutive Patients from Southern Finland

<p><i><b>Purpose</b></i>: To estimate the population-based incidence of acute idiopathic optic neuritis (ON) and analyse its differential diagnosis in patients referred with symptoms suggestive of ON.</p> <p><i><b>Methods</b></i>: Patients with suspected ON referred to the Helsinki University Hospital, serving a population of 1.5 million in Southern Finland, were reviewed between 1st May 2008 and 14th April 2012. Brain and optic nerve magnetic resonance imaging (MRI) was performed within 24 hours in 83% of patients.</p> <p><i><b>Results</b></i>: Of 291 referred patients, 184 (63%; 95% confidence interval [CI], 57–69%) were diagnosed with ON whereas 107 (37%) had another condition. The estimated crude incidence of ON in Southern Finland was 3.0 (95% CI 2.8–3.3) per 100,000 (females, 4.6 and males, 1.4). Mean age was 34 years (range 15–61), 76% were female. Two (1%) were diagnosed with neuromyelitis optica. ON as the first demyelinative episode was diagnosed in 108 (59%) patients, and MRI showed demyelinating lesions (MRI+) in 82% (95% CI, 75–89) of them. MRI+ predicted the development of multiple sclerosis (MS): 54% of MRI+ vs. 5% MRI− patients were diagnosed as MS during a mean follow-up of 7.7 years. The most common differential diagnosis was non-arteritic anterior ischemic optic neuropathy (12%). Six (2%) intracranial compressive lesions were found upon MRI scan.</p> <p><i><b>Conclusions</b></i>: More than a third of patients with symptoms suggestive of ON had another condition. Demyelinative lesions on MRI indicated higher risk of developing MS. We recommend the use of MRI to improve the differential diagnostic accuracy of ON and to identify patients with high risk of MS.</p