Neuromyelitis optica

Neuromyelitis optica (NMO), also known as Devic’s disease is a single phase inflammatory demyelinating CNS disease which causes lesions of optic nerve (ON – optic neuritis) and spinal cord (LETM – longitudinal extensive transverse myelitis).

Asians and women are affected more frequently.

Pathophysiology

Aquaporine 4 (AQP4) is a protein which maintains influx and efflux of water into CNS cells. AQP4 is expressed on the membranes of astrocytes in CNS and optic nerves. Hypothalamus, periventricular area around 3 and 4th ventricles, hippocampus and cerebellum has the densest expression of AQP4 through the CNS.

There are regions of CNS with better permeability of blood-brain barrier because of not so tight interaction of astrocytes and endothelial cells. It is proven with immunohistochemical stains that the optic nerve is the most vulnerable area of the CNS because of its high permeability of the blood-brain barrier. Patients suffering from NMO may have simultaneously ON and LETM but it’s typical for NMO to cause ON in the early stage of disease and LETM latter, when dissemination happens. Usually, LETM evolve after 2 weeks – months after ON.

Diagnostic Criteria

Optical neuritis and myelitis + 2/3:

  • AQP4 antibodies +
  • Longitudinal transverse myelitis (at least 3 vertebras long)
  • Brain lesions on MRI not consistent with MS criteria

Neuromyelitis optica spectrum disorders

  1. Limited form of NMO – idiopathic recurrent longitudinal transverse myelitis at least 3 vertebras long or recurrent ON with positive AQP4 antibodies
  2. Asian-type opticospinal MS variant
  3. ON or LEMT associated with systemic autoimmune disease
  4. ON or myelitis associated with characteristic to NMO brain lesions (hypothalamus, periventricular area, brainstem)

Diagnosis

It’s necessary to have MRI, neuroophthalmologist consultation and laboratory tests to diagnose NMO.

Non specific lesions not consistent with MS criteria or no lesions at all are seen in the early stages of NMO. Typically, lesions are localized in AQP4 abundant regions like hypothalamus, periventricular area of 3 and 4th ventricle. The exception is a brainstem lesion which can be isolated or like the extension of cervical myelitis. Spinal cord lesion should be at least 3 cervical vertebras long.

Ophthalmoscopic examination shows atrophy of optic nerve.

Laboratorie data: Blood AQP4 a/b (Sensistivity 70-75%, specificity 85-99%). The diagnostic value of antibodies titer uncertain and it is still the object of clinical trials. Liquor tests show pleocytosis  and positive oligoclonal antibodies in 30%.

Therapy

I Acute stage

1)      Steroids (for first episode or relapse)

  • Methylprednisolon 1g i/v 3-5 days long, continuing with oral prednisolon tapering the dose slowly;
  • Before starting plasmapheresis repeated high dose prednisolon course should be considered;

2)      Plasmapheresis – if there is no improvement with steroid therapy.

  • 7x procedures should be taken with day by day intervals. The therapeutic regimen is adapted from MS treatment plan, there is no any trials testing it on NMO.

3)      Intravenous immunoglobuline (IVIG)

  • There are no any trials tested IVIG for treatment of ON/LETM relapses of NMO/NMO spectrum disorders;
  • Rarely is used in case of disease refractory to steroid;

II Relapse prophylaxis

First line drugs:

  • Azathioprine 2.5-3 mg/kg/d p/o + Prednisolon 1mg/kg/d p/o dose of Prednisolon should be tapered slowly after Azathioprine gains therapeutic effect (after 2-3 months)
  • Rituximab

a)      i/v 375mg/m2 every week, 1 month (Lymphoma protocol)

b)      1000mg i/v 2x with 2 week break between infusions (Rheumatoid arthritis protocol)

c)       A and B: repeated infusions after 6-12 months. Optimal length of therapeutic course is unknown.

Second line drugs:

  • Cyclophosphamide 7-25 mg/kg i/v every month, 6 months long; specifically for NMO associated with SLE/SS;
  • Mitoxantrone 12 mg/m2 i/v every month, 6 months long, then 12mg/m2 every 3 month for 9 months;
  • Mycophenolate mofetil 1-3 g p/o every day;
  • IVIG, methotrexate
  • Intermitent plasmapheresis