Optic neuritis and neuromyelitis optica - clinical and genetic aspects

Forskningsoutput: AvhandlingDoktorsavhandling


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
  • Tienari, Pentti, Handledare
  • Setälä, Kirsi Hannele, Handledare
Tryckta ISBN978-951-51-5367-8
Elektroniska ISBN978-951-51-5368-5
StatusPublicerad - 2019
MoE-publikationstypG5 Doktorsavhandling (artikel)


  • 3125 Öron-, näs- och halssjukdomar, ögonsjukdomar

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