Chapter 19 - Autoimmune myelopathies

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Abstract

Autoimmune myelopathies are a heterogeneous group of immune-mediated spinal cord disorders with a broad differential diagnosis. They encompass myelopathies with an immune attack on the spinal cord (e.g., aquaporin-4-IgG (AQP4-IgG) seropositive neuromyelitis optica (NMO) and its spectrum disorders (NMOSD)), myelopathies occurring with systemic autoimmune disorders (which may also be due to coexisting NMO/NMOSD), paraneoplastic autoimmune myelopathies, postinfectious autoimmune myelopathies (e.g., acute disseminated encephalomyelitis), and myelopathies thought to be immune-related (e.g., multiple sclerosis and spinal cord sarcoidosis). Spine magnetic resonance imaging is extremely useful in the evaluation of autoimmune myelopathies as the location of signal change, length of the lesion, gadolinium enhancement pattern, and evolution over time narrow the differential diagnosis considerably. The recent discovery of multiple novel neural-specific autoantibodies accompanying autoimmune myelopathies has improved their classification. These autoantibodies may be pathogenic (e.g., AQP4-IgG) or nonpathogenic and more reflective of a cytotoxic T-cell-mediated autoimmune response (collapsin response mediator protein-5(CRMP5)-IgG). The presence of an autoantibody may help guide cancer search, assist treatment decisions, and predict outcome/relapse. With paraneoplastic myelopathies the initial goal is detection and treatment of the underlying cancer. The aim of immunotherapy in all autoimmune myelopathies is to maximize reversibility, maintain benefits (while preventing relapse), and minimize side effects.

Introduction

Autoimmune myelopathies represent a diverse group of disorders that affect the spinal cord and are unified by their immune-mediated mechanism. Rapid recognition of autoimmune myelopathies is important given the unforgiving nature of spinal cord injury, brisk accumulation of disability in some, and the potential for early appropriate treatment to improve outcomes. However, there are many nonautoimmune causes of myelopathy which present similarly and will also be discussed in this chapter. Idiopathic transverse myelitis is a term that has been used historically to describe acute-subacute inflammatory myelopathies of uncertain cause, but recent discoveries have allowed many of these myelopathies to be categorized into specific etiologies, despite some remaining idiopathic. Autoimmune myelopathies may occur as a primary autoimmune phenomenon (e.g., longitudinally extensive transverse myelitis in neuromyelitis optica (NMO) or its spectrum disorders (NMOSD)), a postinfectious phenomenon (e.g., acute disseminated encephalomyelitis (ADEM)), or as a paraneoplastic autoimmune disorder associated with an underlying cancer (paraneoplastic myelopathy). Other immune-related myelopathies within this umbrella term include spinal cord sarcoidosis and myelopathies from multiple sclerosis (MS). The recent discovery of multiple novel autoantibody markers of autoimmune myelopathies (e.g., aquaporin-4-IgG (AQP-4-IgG) as a biomarker of NMO/NMOSD) improved our understanding of autoimmune myelopathies and allowed more precise classification. Furthermore, it has allowed the development and application of more targeted treatments which have the potential to be more efficacious and less toxic than current treatments.

Section snippets

Diagnostic criteria and categorization of autoimmune myelopathies

Autoimmune myelopathies do not have specific diagnostic criteria, but do encompass a wide variety of spinal cord diseases, some with their own diagnostic criteria, including: MS (Polman et al., 2011), NMO (Wingerchuk et al., 2006), idiopathic transverse myelitis (Transverse Myelitis Consortium Working Group, 2002), paraneoplastic neurologic syndromes (Graus et al., 2004), and neurosarcoidosis (Terushkin et al., 2010).

Demographics

Similar to all autoimmune diseases, autoimmune myelopathies are more common in

Risk factors

A strong personal or family history of autoimmunity is a clue to an autoimmune myelopathy. The presence of concurrent weight loss, deep venous thrombosis, or risk factors for cancer (long history of smoking; known prior cancer) gives a clue to a possible paraneoplastic autoimmune myelopathy, although neoplastic myelopathies or iatrogenic myelopathies (e.g., radiation myelopathy) should also be considered. The presence of recent or intercurrent infection or symptoms supportive of that (fevers,

MRI spine

Magnetic resonance imaging (MRI) of the spine (cervical and/or thoracic) with and without gadolinium is recommended in all patients with myelopathy. The first step is to exclude a compressive cause. The findings on MRI are a very powerful tool in guiding clinicians towards the correct diagnosis.

Differential diagnosis

Idiopathic transverse myelitis is a diagnosis of exclusion and a wide variety of investigations may be necessary to exclude other causes. The presence of recent fever, chills, night sweats, rash, or an immunocompromised state may give a clue to an infectious myelitis and a list of infectious causes is outlined in Table 19.1, Table 19.2. Involvement of the gray matter in the spinal cord may give a clue to West Nile virus and was also seen with an outbreak of enterovirus D68 in the USA in 2015

Serum and cerebrospinal fluid (CSF) evaluation

The diagnostic approach to transverse myelitis is complicated and a diagnostic algorithm is provided in Figure 19.9 (Frohman and Wingerchuk, 2010). Laboratory investigations in autoimmune myelopathies are important both to exclude treatable diseases that mimic autoimmune myelopathies but also to look for markers of systemic or organ-specific autoimmunity (Table 19.4). Given the broad differential diagnosis of myelopathies (Table 19.1, Table 19.2), there is no one diagnostic evaluation that fits

Autoimmune myelopathies in patients with systemic autoimmune disease or markers of systemic autoimmunity

Spinal cord disease has been described in a number of systemic autoimmune diseases, including lupus, Sjögren's syndrome, Behçet’s, and scleroderma. Autoimmune myelopathies have also been described with antiphospholipid antibody syndrome, although some of these may be ischemic from the associated hypercoagulable state (Flanagan et al., 2014c). Certain clinical clues and helpful diagnostic tests are outlined in Table 19.4. Testing for one or more of the following markers of extraneurologic

Spinal cord biopsy and pathology of autoimmune myelopathies

Given its eloquent location and the risk of severe morbidity during surgery, spinal cord biopsy is usually restricted to patients with prominent disability in whom diagnostic uncertainty remains despite extensive investigations. A trial of empiric treatment (usually with corticosteroids) is often recommended prior to pursuing biopsy; however, spinal cord biopsy is appropriate in certain situations, particularly when the biopsy may change management (e.g., by detecting a primary intramedullary

Cancer investigation

The most common cancers associated with paraneoplastic isolated myelopathies are small-cell lung and breast (Flanagan et al., 2011b). In addition to physical examination to look for these cancers, we recommend a mammogram in women and body computed tomography (CT) or positron emission tomography (PET)/CT scan in all to assess for cancer; body PET may improve the sensitivity for the detection of cancer in those at high risk (McKeon et al., 2010). Other sex-specific tests should not be

AQP-4-IgG-seropositive autoimmune myelopathies

AQP-4-IgG is a member of immunoglobulin subclass 1 and is produced mostly by B-cell derivatives (plasma cells and their precursors, plasmablasts). Antibody production depends on T-cell help, often in the form of Th17 cells, which help activate B cells in lymph nodes to differentiate into memory B cells (CD19+, CD27+, CD38), plasmablasts (CD19intermediate, CD27+, CD38+), and plasma cells (CD19, CD27+, CD38+) (Chihara et al., 2011). In this study, AQP4-IgG antibodies were made by plasmablasts

Therapeutic approach

The general approach for using immunotherapy in patients with autoimmune myelopathies is a “three M” approach: (1) maximize reversibility with acute treatments; (2) maintain benefits and prevent relapses; and (3) minimize side effects. The treatment may vary depending on the type of disease, underlying autoantibody, and presence or absence of cancer.

Conclusions and future direction

MRI is a powerful tool in narrowing the differential diagnosis of autoimmune myelopathies and its mimics. A summary of the MRI T2-signal and gadolinium enhancement patterns that help distinguish autoimmune myelopathies and some common mimics are outlined in Fig. 19.11, Fig. 19.12 respectively. In addition to the need for better appreciation of the radiologic features of myelopathy, there is also a need for randomized controlled trials in autoimmune myelopathies to help guide treatments. We

Disclosures

Dr Flanagan has no disclosures to report.

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