1. Immune responses are traditionally classified as adaptive (acquired or specific) and innate (nonspecific). The adaptive immune system targets specific antigens. Its key players are antibodies, B lymphocytes (B cells), T lymphocytes (T cells), antigen-presenting cells, complement system, and cytokines mediating signaling. Adaptive immune responses can be further divided into antibody-mediated and cell-mediated responses.
2. Autoimmune diseases are defined as diseases in which the immune system erroneously targets self (autologous or autoantigens) resulting in tissue damage. The inappropriate, misdirected adaptive immune response results from a loss of self-tolerance.
3. Autoimmune disorders likely have multistep pathogenesis and contributing factors include infections, tumors, environmental exposures, and genetic predispositions.
4. Some autoimmune neurological disorders exclusively affect the nervous system (such as multiple sclerosis) or occur in the context of broader multisystemic disease (such as sarcoidosis).
5. Conditions such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis can be autoimmune (without an associated neoplasm or a preceding infection), paraneoplastic (related to ovarian teratoma), or postinfectious (post-herpes simplex virus [HSV] encephalitis). There are numerous individually named autoimmune diseases that are phenotypically diverse and difficult to study because of their low incidence. The management of these disorders often requires a multidisciplinary approach by neurologists, rheumatologists, oncologists, and other specialists.
6. The organization of these disorders based on the pathophysiology of the underlying immune dysfunction delineated in this chapter allows expedited and more targeted interventions.
1. Autoimmune disorders of the nervous system can be diagnosed throughout the life span of individuals ranging from pediatric to older adults.
2. Individual disorders may have specific sex differences such as neuromyelitis optica (NMO; 5-10:1 favoring females) that do not hold true more broadly for other autoimmune disorders.
3. There are racial and regional variations in epidemiology of autoimmune disorders such as sarcoidosis (African American) and Behçet disease (Mediterranean region).
1. Autoimmunity is caused by loss of immunologic tolerance to self. Several mechanisms are responsible including loss of “central tolerance” (originating in dysfunction of germinal nodes in the thymus), failure of peripheral regulation (in lymph nodes and tissues), presentation of an autoantigen (through molecular mimicry, release of sequestered autoantigens), or by costimulation of T and B cells by antigen-presenting cells.
2. Distinct immune mechanisms are implicated in particular autoimmune disorders of the nervous system. In many instances, multiple pathways may be active:
a. T-cell-mediated pathology
b. B-cell-mediated pathology
c. Granulomatous pathology
d. Autoinflammatory pathology
e. Complement activation
f. Unclear/not otherwise specified (NOS)
3. Disorders mediated by autoantibodies (such as anti-NMDAR encephalitis and anti-GAD65 ataxia) often have more robust treatment response to antibody sequestration therapies compared to cell-mediated disorders such as paraneoplastic cerebellar degeneration.
4. Not all autoantibodies detected in panel testing are likely pathogenic. In clinical practice, matching known syndromes with detected autoantibodies is an important part of diagnosis. Lack of clear correlation can lead to misdiagnoses.
1. Clinical symptoms in autoimmune neurological disorders tend to be subacute in onset progressing over the space of days to weeks rather than over hours or over years. The pace of onset has major diagnostic value.
2. For possible autoimmune encephalitis, criteria include subacute onset of neuropsychiatric symptoms over less than 3 months and demonstration of one of the following: focal neurological deficits, seizures, CSF pleocytosis, or MRI features consistent with encephalitis.
3. Autoimmune myelitis generally requires clinical evidence of myelopathy plus demonstration of inflammation either by CSF examination or compatible MRI changes.
4. Diagnosis of autoimmune disorders is accompanied by exclusion of infectious, vascular, neoplastic, or toxic/metabolic mimics.
5. Identifying specific clinical syndromes, the examples of which are listed in Table 11-1, can be helpful to have a narrower list of diagnoses.
Table 11-1 Well-Defined Autoimmune Syndromes of the Central Nervous System | ||||||||||||||||
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1. Autoimmune neurological disorders can occur without visible lesions on MRI or without CSF pleocytosis. These markers are not sufficiently sensitive individually to exclude autoimmune neurological disorders.
2. For central nervous system disorders, diagnostic testing typically includes neuroimaging, blood serologic testing, and CSF testing.
3. Antibodies that appear in blood but not in CSF should prompt consideration of whether the syndrome matches what is known with the antibody-associated disorder (eg, cerebellar syndrome with anti-Yo antibody).
4. Laboratory tests are used to demonstrate alternative, noninflammatory conditions or provide evidence of ongoing inflammatory/autoimmune dysfunction. Systemic inflammatory markers such as ESR or CRP are frequently normal in autoimmune neurological disorders but when elevated suggest that the disease is more systemic.
5. Neuroimaging is of great value in patients with suspected autoimmune disorders of the nervous system. Contrast-enhanced magnetic resonance imaging (MRI) of the brain and spine has become the cornerstone of advanced neurologic evaluation for these disorders. The diagnostic yield from cranial computed tomography (CT) is poor but sometimes the only imaging available. Patterns of T2/fluid-attenuated inversion recovery (FLAIR) abnormalities, diffusion restriction, contrast enhancement, and perfusion may be specific for certain autoimmune, infectious, parainfectious, toxic, metabolic (including mitochondrial), and neoplastic autoimmune conditions (Table 11-2).
6. Advanced imaging, including spectroscopy and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (FDG-PET/CT) of the brain, might be indicated to narrow the differential diagnosis.
7. Analysis of the cerebrospinal fluid (CSF) is as valuable as neuroimaging. Table 11-3 lists CSF studies that may be requested in patients with suspected inflammatory disorders. CSF inflammation is most frequently identified by the presence of one or more of the following: pleocytosis (>5 white blood cells), elevated protein (>50 mg/dL), oligoclonal bands (>1), and an elevated IgG index (>0.66). Hypoglycorrhachia is more typically seen in infectious (bacterial, fungal) and neoplastic conditions (leptomeningeal carcinomatosis) but can be observed in some inflammatory disorders such as neurosarcoidosis. It is important to recognize that autoantibodies or oligoclonal bands may be present in CSF without CSF inflammation. The most frequent example of this configuration is MS, but oligoclonal bands in CSF are not unique to this disease and may be present in other autoimmune disorders.
Presence of oligoclonal bands or elevation of IgG index may represent activation of CNS-targeted humoral response (Table 11-4).
a. The sensitivity of oligoclonal bands is laboratory-specific. Isoelectric focusing on agarose gels followed by some form of immunodetection (immunoblotting or immunofixation) is now the accepted gold standard for detecting the presence of oligoclonal immunoglobulin bands (OCBs). There must be a parallel investigation of serum with a report on the relative band patterns in the CSF and serum.
b. Quantitative IgG analysis (ie, IgG index) is an informative complementary test but is not considered a substitute for qualitative IgG assessment (oligoclonal immunoglobulin bands), which has the highest sensitivity and specificity. Elevated levels of kappa free light chain (either as concentration in CSF or as an index) also indicate intrathecal immunoglobulin production.
8. Electroencephalography (EEG) is usually nonspecific for autoimmune CNS diseases but is very informative in evaluating and guiding treatment of the patients with altered level of consciousness. Occasionally, certain findings may be suggestive of specific disease processes (see Table 11-5 for details).
9. Additional investigations may be required to narrow the differential diagnosis, establish a definitive diagnosis, or determine the extent of a systemic disease (Table 11-6). For example, whole-body PET/CT can be used to determine appropriate sites for diagnostic biopsy in patients with multisystem involvement.
10. In patients with neurologic disease of unknown etiology, the value of brain biopsy is sufficiently high and the morbidity sufficiently low to justify its use. Usually, the highest yield is achieved when specific and enhancing lesions are targeted. When random biopsy is considered, it is important to obtain a larger sample that includes white matter, gray matter with overlying leptomeninges, vessels, and dura. Demonstration of characteristic histopathologic findings is the method of choice for making definitive diagnosis of vasculitis, sarcoidosis, IgG4-related disease, as well as neoplasms.
11. Antibody testing is an important step in diagnoses of autoimmune neurological disorders and should be sent from both serum and CSF. Antibody testing should generally be sent in panels instead of individually and tailored to a specific clinical syndrome (eg, sending for autoimmune encephalopathy panel rather than ‘paraneoplastic antibodies.’) Most major testing centers now organize antibodies in the context of syndrome-associated panels.
Table 11-2 Magnetic Resonance Imaging Findings and Patterns of Contrast Enhancement | |||||||||||||||||||||||||||
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