Diagnostic and Therapeutic Approach to Autoimmune Neurologic Disorders

A. Sebastian López-Chiriboga, MD; Eoin P. Flanagan, MD


Semin Neurol. 2018;38(3):392-402. 

In This Article

Cell Surface Antigens Versus Intracellular Antigens

Traditionally neurologic disorders associated with antibodies that recognize intracellular antigens (classic "onconeuronal antibodies") are markers of T-cell–mediated injury and in general less responsive to immunotherapy and more predictive of an underlying paraneoplastic disorder. In contrast, autoantibodies to cell surface antigens are usually associated with a good response to immunotherapy and are less frequently associated with cancer.[59]

Immunotherapy can be divided into acute phase and maintenance phase.

Acute Phase

Typically, high doses of corticosteroids are used as first line. IVIG or PLEX may also be implemented in conjunction; PLEX is particularly effective in autoimmune-demyelinating diseases (e.g., AQP4-IgG) refractory to corticosteroids and some use as first-line treatment for NMOSD.[60] If no response is achieved, transition to second-line therapy with rituximab or cyclophosphamide could be considered. It should be noted that response time can vary depending on the antibody; with LGI-1 antibody encephalitis, complete response can occur within days of corticosteroid treatment, while with NMDA-R encephalitis it can take weeks to months to achieve a response.

IVIG is preferred in children and corticosteroids are avoided if possible in patients with diabetes or GAD 65-associated autoimmunity. We utilize the following non–evidence-based algorithm[1,4] (Figure 2—Flowchart).

Figure 2.


Maintenance Phase

Benefit from acute phase treatment helps support the diagnosis; patients may be subsequently treated with an oral corticosteroid taper or be weaned off of intravenous immunotherapy by increasing the intervals between doses (from weekly to every other week to monthly) and seen in follow-up to determine duration of treatment and implementation of an alternative maintenance immunosuppressant, if needed. To prevent relapses and maximize the response to acute phase therapy, maintenance immunotherapy should be instituted especially if early relapses during steroid taper occur. Commonly used drugs in this phase include oral corticosteroids, IVIG, and steroid sparing agents such as mycophenolate mofetil, azathioprine, and rituximab. There are no guidelines regarding treatment duration; we typically continue maintenance therapy for 3 years after stability is achieved. It is important to remember that the prolonged use of immunosuppressive medications increases the risk of lymphoproliferative disorders, and they have also been associated with progressive multifocal leukoencephalopathy.

Commonly used doses, side effects, and monitoring are summarized in Table 3.


Pneumococcal vaccine(s) and seasonal inactivated influenza vaccine should be administered in all patients prior to initiation of immunotherapy. Live vaccines should be avoided for the duration of the treatment particularly for azathioprine, mycophenolate, and rituximab.[61]

Implications of Pregnancy

A pregnancy test should be obtained prior to the initiation of immunotherapy due to the teratogenic risk; this is particularly important when considering drugs as cyclophosphamide, rituximab, and mycophenolate. Little is known about specific guidelines in pregnant patients with autoimmune neurological disorders, but similar drugs are used in the management of rheumatologic disorders and as such, similar precautions should be taken.[62]

Emerging Therapies

Trials for several new agents are currently ongoing for NMOSD and AIE. Understanding the pathophysiology of these disorders will continue to provide insights for more efficacious, targeted therapies with fewer side effects.

Eculizumab, a humanized monoclonal antibody that neutralizes the complement protein C5, and tocilizumab, a humanized monoclonal antibody against the interleukin-6-receptor (IL-6R), have shown promise in cases of refractory NMOSD[63] and AIE.[64]

Bortezomib, a proteasome inhibitor that may selectively deplete B cells, initially approved for myeloma, has been effective in a small series of patients with NMOSD[65] and AIE.[66]

Reduction in antibody levels with immunoabsorption has been recently reported as a possible treatment approach in AIE patients with antibodies targeting surface membrane proteins.[67]