Neuromyelitis Optica

Neuromyelitis optica (NMO), also known as Devics disease or Devic's syndrome, is a rare type of autoimmune channelopathy associated with the antigen Aquaporin-4 water channel found in astrocytes which surround and protect the blood brain barrier in central nervous system (CNS). It causes inflammation and demyelination of the optic nerve and spinal cord.

The disease is related to the following processes:  degenerative and has an incidence of about  1 / 100.000.

Overview

Neuromyelitis optica (NMO) is a rare autoimmune disease of the central nervous system (CNS) that presents classically with inflammation and demyelination of the optic nerve (optic neuritis) and spinal cord (transverse myelitis) [1] [2]. It is characterized by loss of vision and disturbed spinal function.

Visual pathway symptoms (Optic neuritis)

  • Decreased or loss of vision in one or both the eyes.
  • Pain in the eye worsening with movement.
  • Loss of color vision or a 'washed out' appearence of the colors.

Spinal cord dysfunction (Longitudinally extensive transverse myelitis (LETM))

  • Weakness in limbs which may further progress to paresis or quadriparesis.
  • Decreased sensation to touch, heat, cold.
  • Painful muscle spasm.
  • Bladder incontinence. 

Due to its striking similarity to multiple sclerosis (MS), NMO was considered to be a variant of multiple sclerosis and often was and is still misdiagnosed. The key features differing NMO from MS are as follows:

  • In the early course of disease NMO does not involve the brain as compared to MS.
  • The attacks seen in NMO are much worse than MS attack.
  • NMO is known to be associated with a anti-aquaporin4 antibodies while MS is a T-cell mediated disease.

NMO is further divided into 2 main types:

  1. Relapsing neuromyelitis optica: This type of NMO is seen more in females than males. The first attack of NMO is followed by frequent attacks that occur over couple of years. Some patients may not recover completely that causes permanent neurological damage and hence causing disability. 
  2. Monophasic neuromyelitis optica: It affects both males and females. The attacks are experienced just over few days or weeks with no relapsing attacks.

Diagnosis

Blood tests can detect anti-aquaporin-4 antibody (NMO-IgG). It is highly specific (>99%) but has a sensitivity of 48-72% depending on the assay used.

Treatment and prevention

For acute management of the disease, IV prednisolone and plasma exchange(PLEX) are considered. To prevent relapses-immusuppresants including mycophenolate mofetil or rituximab are considered along with rehabilitation.

Etiology

It isn't well understood as to why aquaporin-4 in CNS is attacked. NMO is known to being an autoimmune disease but in patients with non-relapsing variant, antibodies to myelin oligodendrocyte glycoprotein were discovered by researchers in the UK and Japan which shows immunological heterogenecity.

Nearly 50% of the patients show strong family history of autoimmunity. Though 95% of the patients have no family history of NMO but 3% of them have reported family history of other neurological condition.

Epidemiology

Though the incidence of NMO per 100,000 population ranges between 0.053 to 0.40, the prevalence per 100,000 population ranges 0.52 to 4.4 [3].

Sex distribution
Age distribution

Pathophysiology

The most characteristic feature of NMO is the autoantibodies produced against aquaporin-4 (AQP4-Ab). The pathogenesis of NMO is based on in vivo and ex vivo experiments that were concluded as follows:

  1. Neuroinflammation: Direct attack on the astrocytes by AQP-4 Ab or activation of the complement system leading to attacking the astrocytes.
  2. Neuromodulation: Internalization of AQP-4Ab resulting in significant changes in astrocytes.

NMO AQP4-Ab possitive belong to a spectrum of autoimmune diseases of the CNS but with the recent discovery of AQP4-Ab autoimmunity; a new spectrum called the 'NMO spectrum disorder', 'aquaporinopathy' or 'autoimmune AQP4 channelopathy' was proposed. Despite of the recent advances, researchers havent been able to identify the pathogenesis behind AQP-4Ab seronegative patients thereby posing a challenge to treat such patients. Studies are also focusing on the T cell involvement in NMO patients. NMO was thought to be a subset of MS for a long time which is proven wrong now hence MS approved treatment modalities are condemned for NMO patients as they cause more harm than good.

According to prospective series and few retrospective studies, several treatment methods have proven effective in preventing an attack and stabilizing NMO patients while relapses were prevented by early intervention wtih immunosuppresants [4].

Prognosis

The prognosis for neuromyelitis optica is not very promising and involves various factors especially number of relapses in initial years of the disease. Complete recovery is unlikely due to frequent relapses. Patients with relapses tend to have slow prognosis ranging from weeks to months. Frequent and severe relapses lead to early disability [5].

Approximately more than 50% of the patients suffering from neuromyelitis optica end up blind in one or both the eyes in just a span of 5 years posing the necessity of ambulatory help. The overall prognosis significantly depends on the severity of the first attach, the number of relapses during the first 2 years of the course of disease and presence of other autoimmune disorders like systemic lupus erythematosus (SLE) [6] [7].

Presentation

The signs and symptoms of NMO are that of optic neuritis or myelitis with anyone presenting initially. 

Symptoms of optic neuritis:

  1. Loss of vision or loss of visual acuity in one eye (unilateral) or both the eyes (bilateral).
  2. Pain in the eye due to inflammation of the optic nerve.
  3. Loss of color vision.
  4. It may or may not precede an upper respiratory infection.

Symptoms of myelitis:

  1. It affects the spinal cord and causes demyelination of the spinal cord affecting bladder and below motor and sensory functions.
  2. Pain in spine or the extremities sometimes accompanied with stiff neck and headaches.
  3. Weakness in the limbs which may be mild or may progress to being as severe as paraplegia or quadriplegia.
  4. Loss of control over bowel and bladder.
  5. Loss of sensation or sensory impairment towards stimuli.
  6. Absent Deep tendon reflexes which may later become exaggerated.

As mentioned earlier MS and NMO are often confused together. Though both present similarly but NMO presents more severely than MS. MRI findings are normal in NMO unlike in MS and spinal tap does not show oligoclonal bands in NMO as compared to MS. NMO patients usually show improvement in vision and paralysis with high dose of corticosteroids with a partial recovery of the sensory and motor functions. Repeated attacks cause permanent damage leading to blindness or impaired mobility.

Workup

Diagnosis of NMO can be done as follows:

  1. MRI of the spine: It shows inflammation of the spinal cord extending more than 3 verterbral segments unlike MS in which only a short segment of spinal cord is affected [8].
  2. MRI of the brain: In NMO brain scans are normal or may show slight changes along with changes in optic nerve unlike MS.
  3. CSF analysis: It shows high number of white blood cells with preponderance of nuetrophils and no oligoclonal banding unlike MS.
  4. Blood test: A new test called as NMO Ig-G test or anti-aquaporin4 antibody test can be carried out. About 70% of patients test positive. This test is negative in MS and thereby marks a significant distinction.

Treatment

Treatment modality revolves around corticosteroids and plasmapheresis.

  1. Corticosteroids: In an acute attack; IV corticosteroids are beneficial.
  2. Plasmapheresis: Patients who did not respond to corticosteroids underwent a randomized, controlled crossover trial where they were treated with seven plamapheresis (1.0 to 1.5 plasma volume per exchange) for a period of 2 weeks and showed results. Another study carried out on 6 patients showed that about 50% of these patients responded to plasmapheresis [9]. Early initiation of plasmapheresis is recommended in cervical myelitis and optic neuritis [12]. Patients suffering from cervical myelitis are at a high risk of developing neurogenic respiratory failure and hence early intervention with plasmapheresis reduces the chances of it [10] [11].

Since MS and NMO were always considered to be one entity, it was believed that the immunomodulatory therapies of MS would help NMO patients. But recent studies have shown that they prove no benefit to the patient and are to be used only in cases of relapse [13].

Prevention

Depending on the AQP4 antibody status, the prevention approach differs.

Postivie AQP4 antibody: Patients who are AQP4 antibody positive and fulfill the NMO criteria and have relapses would need immunosuppressive or immunomodulatory treatment to prevent further relapses.

Negative AQP4 antibody: Patients who have a negative AQP4 antibody and have had a single attack of LETM or ON don't need any preventive measure unless they have relapse. If relapse occurs, immunosuppression is the way to go to avoid further relapses. 

Recurrent relapses increase the chances to keep a patient on immunosuppressive therapy risking long term side effects. Hence the goal in NMO is to achieve faster remission by tapering the dose of corticosteroids in a patient who responds well to them and help curb the side effects.

Patient Information

Neuromyelitis optica (NMO) is a demyelinating disorder that affects the eyes and spinal cord. The underlying etiology is still unknown but its cause is often believed to be due to an autoimmune condition or post infection.

Causes

NMO is considered to be an autoimmune disease and has been associated with an abnormality in channelopathy. The presence of an antibody against the Aquaporin-4 is believed to cause the symptoms seen in NMO.

Symptoms

The symptoms are related to both eyes and the spinal cord.

Symptoms related to eye:

  1. Blurring of vision that could lead to complete loss of vision in one or both the eyes.
  2. Loss of color vision.
  3. Pain in eye movements.

Symptoms related to spinal cord:

  1. Weakness in limbs.
  2. Issues with bladder and bowel control.

Diagnosis

Diagnosis revolves around imaging studies and blood tests.

  1. Imaging studies: MRI of the brain and spinal cord are done to differentiate it from MS since they present in similar fashion.
  2. Visual evoked potential test is also used to diagnose NMO.
  3. Blood Test: AQP4 antibody also called as NMO-IgG is present in patients with NMO. Though in some patients it maybe negative but doesnt rule out NMO. Depending on the constellation of MRI findings and symptoms, a negative NMO-IgG patient can still have a diagnosis of NMO.

Treatment

Unfortunately till date no treatment exists. Various attempts are made to slow the progression of the disease and prevent relapses.

  1. Corticosteroids and immunomodulatory drugs: These have shown positive results and therefore Methylprednisolone and Azathioprine are used. Some studies have shown plasma exchange to be promising in patients refractory to corticosteroids.
  2. Other drugs: Rituximab (an anti–B-cell antibody) has shown to reduce the levels of IgG in the blood thereby reducing the symptom progression and severity.
  3. Drugs to relieve muscle spams: Drugs like Baclofen or tizanidine are used for their anti-spasmodic properties which helo in decreasing muscle spasms.

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References

  1. Jarius S, Ruprecht K, Wildemann B, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients. J Neuroinflammation. 2012; 9:14.
  2.  Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006; 66:1485–89.
  3. Marrie RA, Gryba C. The incidence and prevalence of neuromyelitis optica: a systematic review. Int J MS Care. 2013; 15(3):113-8.
  4. Bernard-Valnet R, Marignier R. Evolution of Devic's neuromyelitis optica spectrum disorders. Presse Med. 2015 Apr; 44(4 Pt 1):401-10.
  5. Kantarci OH, Weinshenker BG. Natural history of multiple sclerosis. Neurol Clin. 2005; 23:17–38.
  6. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology. 2003; 60:848–53.
  7. Erb W. Über das Zusammenkommen von Neuritis optica und Myelitis subacute. Arch Psychiatr Nervenkr. 1879- 1880; 1:146-157.
  8. Filippi M, Rocca MA, Moiola L, et al. MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic's neuromyelitis optica. Neurology. 1999; 53:1705-1710.
  9. Watanabe S, Nakashima I, Misu T, et al. Therapeutic effi cacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler. 2007; 13:128–32.
  10. Wingerchuk DM, Hogancamp WF, et al. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999; 53:1107–14.
  11. Keegan M, Pineda AA, McClelland RL, et al. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 2002; 58: 143–46.
  12. Ruprecht K, Klinker E, Dintelmann T, et al. Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology. 2004; 63:1081–83.
  13. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol. 2005; 7:173–82.

  • A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica - CF Lucchinetti, RN Mandler, D McGavern, W Bruck - Brain, 2002 - Oxford Univ Press
  • Clinical features of children and adolescents with multiple sclerosis - JM Ness, D Chabas, AD Sadovnick, D Pohl, B Banwell - Neurology, 2007 - AAN Enterprises
  • A case of neuromyelitis optica (Devic's syndrome) in systemic lupus erythematosus Clinicopathologic report and review of the literature - RS APRIL, E VANSONNENBERG - Neurology, 1976 - AAN Enterprises
  • A 16-year-old girl with bilateral visual loss and left hemiparesis following an immunization against human papilloma virus - FJ DiMario, M Hajjar, T Ciesielski - Journal of child neurology, 2010 - jcn.sagepub.com


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