Introduction
In recent years the field of neuroimmunology has grown as diagnostic assays for the detection of pathogenic autoantibodies have been developed and refined. Improved diagnostic assays have improved our understanding of the clinical and radiographic spectrum of some of these conditions. Yet, despite increased recognition, there remains a need for further biomarker development and standardization of management that could in turn support appropriate and timely initiation of treatment. The etiologic classifications of neuroimmunologic conditions are diverse: autoantibody mediated, paraneoplastic, inflammatory, para- or postinfectious, idiopathic, or iatrogenic ( Table 10.1 ). An understanding of the pathophysiology of a given neuroimmunologic presentation can be helpful in determining the diagnosis, anticipating associated conditions, and determining appropriate treatment.
| T-Cell Mediated | Autoantibody Mediated |
|
| Iatrogenic |
|---|---|---|---|---|---|
| Disorders | Multiple sclerosis | SLE | Sarcoidosis | Behçet disease | Checkpoint inhibitors |
| ADEM | Demyelinating disorders associated with anti-AQP4 (NMOSD) and anti-MOG antibodies | GCA | Monogenic periodic fever syndromes | CAR-T | |
| PACNS (PCNSV) | Miller Fisher syndrome (anti-GQ1b antibodies) | Granulomatosis with polyangiitis (Wegener granulomatosis) | |||
| Aβ-related angiitis | Bickerstaff encephalitis (anti-GQ1b antibodies) | ||||
| Antibodies against intracellular antigens: ANNA-1 (Hu), ANNA-2 (Ri), ANNA-3, Ma1/Ma2, CV2/CRMP5, PCA1 (Yo), PCA-2, GFAP, amphiphysin, GAD65 | Antibodies against cell-surface synaptic receptors and ion channels causing encephalitis (NMDA, AMPA, LGI1, CASPR2, GABA-A GABA-B, glycine receptor, mGluR1, mGluR5, DR2, DPPX), LEMS (VGCC), MG (AChR) | ||||
| Sjögren syndrome | |||||
| IgG4-RD | |||||
| CLIPPERS |
a Autoantibodies to the intracellular synaptic antigen GAD65 may not be pathogenic.
Pathogenesis
Autoantibody-Mediated Neuroimmunologic Disease
Autoantibody-mediated neuroimmunologic conditions are thought to reflect a maladaptive loss of self-tolerance. Such conditions include demyelinating central nervous system (CNS) disorders, such as myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis and myasthenia gravis (MG), among others (see Table 10.1 ). Pathogenic autoantibodies may cause cellular dysfunction or injury through several different mechanisms, including receptor agonist or antagonist effect, antigen/receptor internalization, activation of the complement system, and antibody-dependent cell–mediated cytotoxicity. Broadly, pathogenic autoantibodies are classified as those that target surface antigens versus those that target intracellular antigens. Distinguishing the targeted antigen location helps to tailor treatment approach (e.g., anti-CD20 immunosuppressive therapies, such as rituximab, are more commonly used for autoantibody conditions targeting cell-surface antigens, whereas cytotoxic therapies, such as cyclophosphamide, are used to treat autoantibody conditions targeting intracellular antigens). It is recognized that the location of the targeted antigen type may correlate with prognosis. Receptor agonist and antagonist effect, including receptor internalization, are generally reversible. Thus neuroimmunologic conditions secondary to pathogenic cell-surface antigens may more favorably respond to treatment. Whereas, neuroimmunologic conditions mediated by pathogenic antigens that are intracellular, may cause damage that is less likely to be reversible. This is observed in practice when we examine the overall treatment responsivity of limbic encephalitis secondary to a cell-surface autoantibody to that of an intracellular autoantibody-mediated cerebellar degenerative syndrome.
It is important to note that not all detectable autoantibodies are pathologic. In some cases, detected autoantibodies may be a nonspecific marker of autoimmunity, or a bystander autoantibody. Knowledge of the expected clinical syndrome and titer ranges of positivity that yield clinical significance are important to mind.
Paraneoplastic Autoantibody–Mediated Disease
As clinical awareness of various autoantibody-mediated neuroimmunologic syndromes evolves, we are better able to define the expected features of certain “classic syndromes” ( Table 10.2 ). This improved recognition can help clinicians to then order appropriate diagnostic studies and ideally become more apt to initiate empiric treatment while still remaining in the investigative stage of assessment. Paraneoplastic neuroimmunologic conditions can occur in an individual with a known, preceding cancer diagnosis; however, it may also be that the development of a neuroimmunologic syndrome is what leads to the diagnosis of or precedes the development of an associated malignancy. Conditions such as autoimmune encephalitis, autoimmune cerebellar degenerative disease, and NMOSD are among neuroimmunologic conditions in which the etiologic driver is a present, prior, or a yet-to-be-detected malignancy. Similarly, the identification of a neuroimmunologic syndrome with a risk of associated malignancy should prompt cancer screening. As an example, a patient presently with a progressive cerebellar syndrome, found to test positive for anti–PCA1 (anti-Yo) autoantibodies, should then have a detailed evaluation for malignancy as ~90% of patients with anti–PCA1 cerebellar degeneration have an associated cancer. In such paraneoplastic conditions, the resultant immune dysregulation is believed to be triggered by the atypical expression of neuronal antigens by the associated malignancy leading to inappropriate self-attack (e.g., limbic encephalitis caused by expression of the ANNA-1 [anti-Hu] antigen by small cell lung cancer).
| Classic Syndromes | Etiologies |
|---|---|
| Limbic encephalitis | Paraneoplastic or primary autoimmune (several autoantibodies), HSV, HHV6, syphilis |
| with faciobrachial dystonic seizures, hyponatremia | Anti-LGI1 antibodies |
| with abnormal behavior (psychiatric manifestations), movement disorder (dyskinesias), dysautonomia | Anti–NMDAR antibodies |
| Cerebellar ataxia (subacute cerebellar degeneration) | Paraneoplastic (anti-PCA1 [Yo]), autoimmune (mGluR1, GAD65), parainfectious and infectious (VZV, EBV, CJD), toxic/metabolic (ethanol, phenytoin, lithium, chemotherapy [cytarabine], vitamin E deficiency, gluten sensitivity), genetic (spinocerebellar ataxias) |
| Opsoclonus-myoclonus(-ataxia) | Anti–ANNA-2 (Ri), anti–ANNA-1 (Hu) antibodies, anti–GAD65 antibodies |
| Neuromyelitis optica | Anti-AQP4, anti-MOG disease |
| Cerebral cortical encephalitisMiller Fisher syndrome | Anti-MOG diseaseAnti-GQ1b antibodies |
| Stiff person syndrome | Anti–GAD65, antiamphiphysin, antiglycine receptor antibodies |
| Morvan syndrome (myokymia or neuromyotonia, dysautonomia, sleep disturbance, encephalopathy with visual hallucinations) | Anti-CASPR2 antibodies |
| Sensory ganglionopathy (neuronopathy) | Paraneoplastic (anti–ANNA-1 [Hu] antibodies), Sjögren syndrome, pyridoxine intoxication, platinum-based chemotherapy |
| Myasthenia gravis | Anti-AChR, anti-MuSK, anti-LRP4 antibodies |
| Lambert-Eaton myasthenic syndrome | Anti-VGCC antibodies |
Para- and Postinfectious Neuroimmunologic Conditions
In para- or post-infectious conditions, immune dysregulation is incited by an adaptive immune response to a foreign antigen that results in inappropriate targeting of similar appearing self-antigen. This is the proposed pathophysiologic mechanism of postinfectious Guillain-Barré Syndrome [GBS], classically following Campylobacter jejuni infection. Infectious processes may also heighten an inflammatory state leading to immune dysregulation as is thought to occur in parainfectious myopathies and postinfectious acute disseminated encephalomyelitis (ADEM). Infections may also play an inciting causative role in the development. of a subsequent, secondary neuroimmunologic disease as has been described for post–herpes simplex virus (HSV) N -methyl- d -aspartate receptor (NMDAR) limbic encephalitis. Clinical history and supportive evidence of CNS inflammation provide diagnostic support for these conditions. There may not be a present autoantibody, or other biomarker, to further diagnostic certainty of these para- or post-infectious entities.
Neuroinflammatory Conditions
Broadly, neuroinflammatory conditions are mediated by pro-inflammatory cytokines, no defined autoantibody is implicated. A prominent example of such a condition is neurosarcoidosis.. In neurosarcoidosis, TNF-alpha and other pro-inflammatory factors are thought to culminate in chronic inflammation and the pathologic formation of non-caseating granulomas. The clinical and radiographic manifestations of neurosarcoidosis are in turn quite variable given its heterogeneity as to where the disease may be present within the nervous system. A diagnostic search for neurosarcoidosis includes an evaluation of any systemic burden of disease, excluding alternative etiologies, and importantly evaluating for lymphadenopathy, which if biopsied may provide pathologic evidence of non-caseating granulomas, improving diagnostic certainty. The standard approach to treatment of neurosarcoidosis is administration of glucocorticosteroids. The exact dosing, duration, and when to escalate treatment and/or whether to start a steroid-sparing agent initially, are areas of active research.
Other prominent neuroinflammatory granulomatous diseases include those with underlying vasculitis, rheumatologic disease. Giant cell arteritis (GCA), also referred to as temporal arteritis, is among this group. Suspicion for GCA should be prompted by the development of a headache, vision change/loss, jaw claudication, with or without proximal joint pains in an individual older than 50 years of age, with elevated inflammatory markers (i.e., ESR, CRP). Glucocorticosteroids are again mainstay of treatment (see Table 10.1 ).
Lastly, autoinflammatory disorders, which are disorders of a dysregulated innate immune system, are within this category. These tend to be less common, but generally steroid responsive. Examples of such diagnoses include idiopathic hypertrophic pachymeningitis and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). In some cases, steroid-sparing agents may be required for adequate treatment response. At, but often require steroid-sparing agents for disease control. At present, the management of these conditions is driven by retrospective series and anecdotal experience.
Iatrogenic Neuroimmunologic Complications and Neurotoxicities
Oncologic therapies and disease-modifying antirheumatic drugs (DMARDs) are iatrogenic exposures with risks of neuroimmunologic complications and toxicities. Chemotherapies may cause neurologic side effects such as peripheral neuropathy, headache, encephalopathy, seizures, and posterior reversible encephalopathy syndrome; direct toxicities, that is, leukoencephalopathies, are also possible from chemotherapy. Lastly, a risk of severe infection due to immunosuppression should be considered (e.g., progressive multifocal leukoencephalopathy (PML)). For these reasons, attention to and appropriate evaluation of new neurologic deficits/symptoms in patients receiving chemotherapies are pertinent.
Novel oncologic-directed immunotherapies, for example, immune checkpoint inhibitors (ICI) and genetically altered chimeric antigen receptor T cells (CAR-T cells), are among agents with potential to cause iatrogenic neurotoxicities. ICIs are a novel class of therapeutics designed to target the inhibitory pathways in the immune system that maintain self-tolerance and modulate the immune response. The checkpoint inhibitors ipilimumab (human antibody to CTLA-4) and pembrolizumab and nivolumab (PD-1 antagonists) all function to block pathways that normally suppress the activation and expansion of T cells, harnessing the host’s native immune response against cancer. However, they have also unmasked a broad spectrum of immune-related neurologic adverse events ( Table 10.3 ), the incidence of which may be as high as 1%. The array of potential peripheral and central neuroimmunologic complications from ICI exposure is vast. Expert consensus guidelines have been published to guide an understanding of diagnostic approach and severity grading of these neurotoxicities, referred to as immune-related adverse effects (iRAEs). Assessing the severity grading of a recognized iRAE guides management, as lesser grade iRAEs warrant watchful observation whereas higher grades iRAEs warrant treatment with corticosteroids and potentially second-line disease-directed therapies while withholding further ICI exposure as per the American Society of Clinical Oncology guidelines.
| Treatment Class | Medication | Clinical Syndrome |
|---|---|---|
| Anti–TNF-α |
| Demyelinating disorders (CNS [including optic neuritis]PNS) |
| Anti–IL-6R | Tocilizumab |
|
| Anti–PD-1/L1 |
|
|
| Anti–CTLA-4 |
|
|
CAR-T cells are genetically modified T cells that have a fabricated antigen receptor from multiple sources engineered to a specific target cell antigen. A patient’s own cells are isolated, genetically modified, cloned, and reinfused to redirect T-cell specificity to a specific tumor-associated antigen. Cytokine release syndrome (CRS) is a potential systemic side effect encountered with CAR-T-cell therapy, which results from T-cell activation, proliferation, and production of endogenous cytokines. Neurologic CRS manifestations may range from headache and confusion/delirium to seizures, cerebral edema, and coma. A standardized approach to assessment, as developed by the American Society for Transplantation and Cellular Therapy, guides appropriate triage and management of patients with immune effector cell-associated neurotoxicity syndrome (ICANS). Generally, prompt recognition and management of iatrogenic immunotherapy-related neurotoxicities, particularly iRAEs and ICANS, can lessen morbidity and mortality. However, despite improved recognition, we continue to lack reliable biomarkers to predict and prognostic toxicity risk and outcome. Thus a greater understanding of the pathogenesis of CNS-related adverse effects and how to evade development of these toxicities remains an active need.
DMARDs also carry risk of neuroimmunologic complications, such as the induction or exacerbation of demyelinating syndromes or the development of neurosarcoidosis-like presentations (see Table 10.3 ). Presently, expert consensus and anecdotal clinical experience guide current practice that emphasizes avoidance of the inciting agent and appropriate management based on the consequential phenotype developed.
Epidemiology
Age, race, or sex in which a neuroimmunologic condition may be more likely to occur is dependent upon the condition. Conditions that may be present in children include ADEM, Rasmussen encephalitis, MOG-AD, pediatric multiple sclerosis, particular autoimmune/paraneoplastic encephalitides such as anti–NMDAR encephalitis, and genetic conditions such as Aicardi-Goutières syndrome and hemophagocytic lymphohistiocytosis. In contrast, certain disorders, such as GCA and IgG4-related disease (IgG4-RD), occur almost exclusively in older populations. Some conditions, such as opsoclonus/myoclonus/ataxia, have both pediatric and adult forms. Similarly, MG has a bimodal age distribution of incidence, with peaks in age in late adolescence/early adulthood and in the elderly. Regarding associations with an individual’s race, neurosarcoidosis is prevalent among individuals with African descent, whereas multiple sclerosis is more common in Caucasians. Autoimmunity, in general, is more prevalent in females than males; however, Behçet is the exception to this rule. Among neuroimmunologic conditions, NMOSD, multiple sclerosis, Susac, anti–NMDAR encephalitis, and GCA are female predominant. Whereas GBS, chronic inflammatory demyelinating polyneuropathy, ADEM, IgG4-RD, and MG in older patients are all slightly more common in males. No sex predilection exists in sarcoidosis or primary angiitis of the CNS.
Evaluation
Patient History
Accurate and detailed assessment of a patient’s presenting history is key for refining your differential diagnosis. Attention to the rate at which a condition occurred, and/or progressed is critical as this time course informs both the differential diagnosis and general approach to management. In general, demyelinating events tend to be either discrete occurrences (either monophasic or relapsing) or gradually progressive. Autoimmune encephalitides are commonly subacute in onset and progressive in the absence of appropriate treatment. Post- or parainfectious conditions tend to occur either concurrently or subacutely in the days to weeks following an infection. Iatrogenic neurotoxicities tend to develop subacutely, but acute toxicity is possible. Lastly, the great masquerader, neurosarcoidosis, may present acutely, subacutely, or gradually, with various stages severity at symptom onset.
In addition to attention to duration of onset and progression, identifying the clinical sympotomatology (i.e., how the condition is clinically and/or radiographically manifests), is the next step in localizing the pathology and categorizing its underlying etiology. Localization of neurologic signs and symptoms at the onset of an evaluation, with clinical course trajectory in mind, will help to inform which diagnostic studies are warranted. Lastly, demographic details and associated nonneurologic signs or symptoms will help to further refine the differential and management. It remains important to exclude potential mimickers, inclusive of toxic, metabolic, infectious, genetic, and iatrogenic etiologies, as well as to consider nonneuroimmunologic conditions when appropriate. There are several well-defined syndromes for which a thorough clinical history can lead to a plausible diagnosis (see Table 10.2 ); however, more frequently, clinical findings can be nonspecific and will require appropriate diagnostic studies for support.
Diagnostic Investigations
Serologic Tests
Similar to the need for a thorough yet focused history and physical examination, serum studies to exclude toxic, metabolic, and infectious causes are an essential component of the diagnostic approach to neuroimmunologic disease. Commonly, we consider excluding nutritional deficiencies, syphilis infection, toxins, among other studies, while also seeking to assess for any associated systemic conditions such as rheumatologic disease or malignancies ( Table 10.4 ).
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