Neuromyelitis Optica Spectrum Disorders (NMOSD)

Table of Contents

  1. Disorder
  2. Epidemiology
  3. Risk Factors & Associations
  4. Pathology
  5. Diagnosis
  6. Management
  7. References

Disorder

  • An autoimmune astrocytopathy in which an autoantibody, aquaporin-4, initiates inflammatory lesions in the central nervous system, primarily affecting the spine ("neuromyelitis") and optic nerves ("optica"). The disorder is characterized by relapses of CNS inflammation resulting in accrual of permanent neurologic injury and disability. Symptoms during an inflammatory relapse typically evolve over a period of days and vary based on the area of injury.

  • Prevalence: 0.7 - 10.0 cases per 100,000

  • Median age of onset: 40 years

  • Racial Distribution: Highest rates in African & Afro-Carribean regions, lower rates in white or European regions

  • Sex Distribution:

    • Seropositive (Anti-AQP4 positive): 90% female

    • Seronegative (Anti-AQP4 negative): Equal sex distribution

  • Genetics: Up to 3% of cases are familial

  • Inciting Event: 1/3 of cases are preceded by a viral infection; rarely a vaccination

Risk factors & Associations

Epidemiology

  • 1/2 of seropositive NMOSD have other serum autoantibodies (ex. ANA, thyroperoxidase)

  • 1/3 have an autoimmune disease, such as SLE, Sjogren’s syndrome or thyroiditis

  • ~5% of cases are paraneoplastic. It is advisable to look for malignancy in patients at high risk of malignancy, especially if the condition develops at a late age

Pathophysiology

  • AQP4 is a water channel protein that is integrated into the membrane of many cell types, including muscle, gastrointestinal, kidney, lung, retinal and cells within the central nervous system (CNS). In the CNS, AQP4 is expressed in the astrocyte foot processes, periaquaductal and periventricular regions, cerebellum, optic nerve, and hypothalamus. The job of this protein is to maintain the homeostasis of water in the brain and spine, assisting with transport of water to and from cells.

  • In a genetically susceptible person, an external or internal signal (such as exposure to a viral or bacterial infection, or response to a tumor cell, perhaps) initiates the development of auto-reactive B cells responsible for the development of AQP4-IgG. This can only occur in an environment in which immune tolerance checkpoint defects are present. Subsequently, the blood brain barrier (BBB) is made permeable by an unknown mechanism, allowing AQP4-IgG to enter the CNS and initiate complement activation ultimately facilitating complement mediated astrocyte injury. Cytokines, such as interleukin-6 and activated complement further increase the permeability of the BBB allowing for propagation of the inflammatory process within the CNS, signaling additional inflammatory cells including neutrophils and eosinophils to enter the developing lesion. Without the support of astrocytes, likely, oligodendrocyte apoptosis occurs, leading to demyelination as a secondary consequence during the inflammatory process. Both severe axonal injury and demyelination lead to significant disability with variable recovery.

Diagnostic Criteria

Core Clinical Characteristics:

  1. Optic Neuritis

  2. Acute myelitis

  3. Area postrema syndrome (presenting feature in 10%)

  4. Acute brainstem syndrome

  5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions

  6. Symptomatic cereral syndrome with NMOSD-typical brain lesions

Diagnostic Criteria for NMOSD with AQP4-IgG:

  1. ≥ 1 core clinical characteristic

  2. Positive test for AQP4-IgG (cell-based assay strongly recommended, or best test available)

  3. Alternative Diagnoses excluded

Diagnostic Criteria for NMOSD without AQP4-IgG or unknown AQP4-IgG status

  1. ≥ 2 core clinical characteristics meeting the following requirements

    • ≥ 1 core clinical characteristic must be

      • Optic Neuritis

      • Acute Myelitis with longitudinally extensive transverse myelitis (LETM)

      • Area postrema syndrome

      • Fulfillment of additional MRI requirements, as applicable

    • Dissemination in space (2 or more different core clinical characteristics)

  2. Negative test for AQP4-IgG using best available assay or testing unavailable

  3. Alternative diagnoses excluded

MRI requirements for NMOSD without AQP4-IgG or unknown AQP4-IgG status

  1. Acute Optic Neuritis: requires brain MRI with…

    • Normal findings or nonspecific white matter lesions OR

    • T2-hyperintense lesion or T1-weighted gadolinium-enhancing lesion extending over >1/2 optic nerve length or involving optic chiasm

  2. Acute Myelitis: requires associated intramedullary MRI lesion extending over ≥ 3 contiguous segments (LETM) or ≥ 3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis

  3. Area postrea syndrome: requires associated dorsal medulla/area postrema lesions

  4. Acute brainstem syndrome: requires associated periependymal brainstem lesions

Diagnostic Workup

  • Serum: 
    • Anti-Aquaporin-4 IgG

      • Detected in ~80% of patients

      • Most accurate test is a cell-based flow cytometric assay (Sensitivity 60 - 80%, Specificity >99%)

      • Enzyme-linked Immunosorbent Assay (ELISA) for AQP4 may create diagnostic uncertainty as false positive low-titers may occur

      • Should not be tested directly after plasma exchange or during immunosuppressive therapies as false negative results can occur

  • Cerebrospinal Fluid (not necessary for the diagnosis but may be helpful to distinguish between MS or other similar conditions):
    • Anti-Aquaporin-4 IgG

      • Testing in CSF is relatively insensitive

    • Cell count

      • Pleocytosis (lymphocyte predominate) is commonly seen

    • Oligoclonal bands

      • Not usually present

    • Elevated protein is commonly seen
  • Imaging: 
    • MRI with & without contrast
      • Orbits

        • Predilection for optic chiasm and adjacent posterior optic nerve

        • May involve the full length of the optic nerve or a small segment

      • Brain

        • Area postrema (dorsal medulla) inflammatory lesion (lesion is small and may be difficult to detect on MRI)

        • Diencephalon inflammatory lesion

        • Inflammatory lesions in the cerebrum

      • Spine (Cervical, Thoracic, Lumbar)

        • Longitudinally extensive transverse myelitis (characteristic of NMOSD)

        • Short segment transverse myelitis (as seen in MS) occurs in 15% of sentinel myelitis attacks

Acute Therapy

  1. IV glucocorticoids

    • IV methylprednisolone 1 gram Daily for 3-5 days

    • Studies have shown response to initial therapy is usually suboptimal (~19% remission rate) and requires a 2nd treatment for which PLEX is usually added to IV glucocorticoid administration

  2. Adjunctive Plasma Exchange (PLEX)

    • Often used for patients with severe symptoms or vision loss poorly responsive to glucocorticoids however, it should likely always be used in conjunction with IV steroids for greater chance at remission.

    • Every other day PLEX for 5-7 sessions

*IV Immunoglobulin has not proven to be beneficial in acute NMOSD attacks and so are rarely used in this setting

Preventive Immunotherapy

References

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