28 - 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis

99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis

Josep Dalmau, Francesc Graus

Paraneoplastic Neurologic

Syndromes and

Autoimmune Encephalitis Paraneoplastic neurologic disorders (PNDs) are cancer-related syn­ dromes that can affect any part of the nervous system (Table 99-1). Initially defined as syndromes of unknown cause, currently most PNDs are considered to have an autoimmune pathogenesis triggered by the underlying cancer. In 60% of patients, the neurologic symptoms pre­ cede the cancer diagnosis. Clinically disabling PNDs occur in 0.5–1% of all cancer patients, but they affect 2–3% of patients with neuroblas­ toma or small-cell lung cancer (SCLC) and 30–50% of patients with thymoma. PATHOGENESIS Most PNDs are mediated by immune responses triggered by neuro­ nal proteins ectopically expressed by tumors (e.g., SCLC and other cancers) or as a result of altered immunologic responses caused by some types of tumors such as thymomas or lymphomas. In PNDs of the central nervous system (CNS), many antibody-associated immune responses have been identified. These antibodies react with neurons and the patient’s tumor, and their detection in serum or cerebrospinal fluid (CSF) variably predicts the presence of cancer. According to the frequency of an underlying tumor, these antibodies are classified as high risk (>70% probability of an underlying tumor; Table 99-2); inter­ mediate risk (30–70% probability of an underlying tumor; Table 99-3), and low risk (<30% probability of an underlying tumor; Table 99-4). All the target antigens of high-risk antibodies are intracellular proteins except for Tr (DNER [delta/notch-like epidermal growth factor-related receptor]), which is expressed on the cell surface. By contrast, all target antigens of intermediate- and low-risk antibodies are cell-surface pro­ teins or receptors except for GAD65 and glial fibrillary acidic protein (GFAP), which are intracellular. When the antigens are intracellular, most neurologic syndromes are associated with extensive infiltrates of CD4+ and CD8+ T cells, microglial activation, gliosis, and variable neuronal loss. The infiltrating T cells are often in close contact with neurons undergoing degeneration, suggesting a primary pathogenic role. T-cell–mediated cytotoxicity may contribute directly to cell death TABLE 99-1  Paraneoplastic Syndromes of the Nervous System CLASSIC SYNDROMES: HIGH RISK OF ASSOCIATED CANCERa NONCLASSIC SYNDROMES: MODERATE OR LOW RISK OF ASSOCIATED CANCER Encephalomyelitis Limbic encephalitis Cerebellar degeneration (adults) Opsoclonus-myoclonus Sensory neuronopathy Gastrointestinal pseudoobstruction (enteric neuropathy) Dermatomyositis (adults) Lambert-Eaton myasthenic syndrome Cancer- or melanoma-associated retinopathy Brainstem encephalitis Stiff-person syndrome Progressive encephalomyelitis with rigidity and myoclonus Necrotizing myelopathy Motor neuron disease Subacute axonal sensory-motor neuropathies Paraproteinemic neuropathies Pure autonomic neuropathy Acute necrotizing myopathy Polymyositis Optic neuropathy BDUMP Peripheral nerve hyperexcitability (neuromyotonia) Myasthenia gravis aThese syndromes frequently associate with cancer. Abbreviation: BDUMP, bilateral diffuse uveal melanocytic proliferation.

TABLE 99-2  High-Risk Antibodies (>70% Probability of an Underlying Cancer), Syndromes, and Associated Tumors ANTIBODYa ASSOCIATED NEUROLOGIC SYNDROME(S) TUMORS Anti-Hu (ANNA1) Encephalomyelitis, sensory neuronopathy SCLC Anti-Yo (PCA1) Rapidly progressive cerebellar syndrome Ovary, breast Anti-Ri (ANNA2) Cerebellar degeneration, opsoclonus, brainstem encephalitis Breast, gynecologic, SCLC Anti-CRMP5 (CV2) Encephalomyelitis, chorea, optic neuritis, uveitis, peripheral neuropathy SCLC, thymoma, other Anti-Tr (DNER) Rapidly progressive cerebellar syndrome Hodgkin’s lymphoma Anti-Ma proteins Limbic, hypothalamic, brainstem encephalitis Testicular (Ma2), other (Ma) Anti-PCA2 (MAP1B) Sensorimotor neuropathy, rapidly SCLC, non-SCLC, breast cancer progressive cerebellar syndrome, and encephalomyelitis Anti-Kelch-like protein 11 Brainstem encephalitis, ataxia, sensorineural hearing loss Seminoma, germ cell tumor, teratoma, CHAPTER 99 Anti-amphiphysinb Stiff-person syndrome, encephalomyelitis Breast, SCLC Anti-SOX1 LEMS, rapidly progressive cerebellar syndrome with and without LEMS SCLC Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
aAll the antibodies of this table are against intracellular antigens, except for Tr (DNER), which is a cell-surface protein. bAmphiphysin is likely exposed to the cell surface during synaptic vesicle endocytosis. Abbreviations: CRMP, collapsin response-mediator protein; DNER, delta/notch-like epidermal growth factor-related receptor; LEMS, Lambert-Eaton myasthenic syndrome; MAP1B, microtubule associated protein 1B; PCA, Purkinje cell antigen; SCLC, small-cell lung cancer. in these PNDs and probably underlies the resistance of many of these conditions to therapy. In contrast to the predominant role of cytotoxic T-cell mechanisms in PNDs associated with antibodies against intracellular antigens, those asso­ ciated with antibodies to antigens expressed on the neuronal cell surface of the CNS or at the neuromuscular junction are mediated by direct antibody effects on the target antigens and are more responsive to immunotherapy (Tables 99-3 and 99-4, Fig. 99-1). These disorders occur with and without a cancer association and may affect children and young adults. Some disorders are triggered by viral encephalitis such as herpes simplex virus encephalitis or Japanese encephalitis leading to autoimmune encephalitis. TABLE 99-3  Intermediate-Risk Antibodies (30–70% Probability of an Underlying Cancer), Syndromes, and Associated Tumors TUMOR TYPE WHEN ASSOCIATED ANTIBODYa NEUROLOGIC SYNDROME Anti-NMDARb Anti-NMDAR encephalitis Teratoma in young women (children and men rarely have tumors) Anti-AMPARb Limbic encephalitis with relapses SCLC, thymoma, breast Anti-GABABRc Limbic encephalitis with early and prominent seizures SCLC Anti-Caspr2b Morvan syndrome Thymoma Anti-mGluR5b Autoimmune encephalitis without distinctive features Hodgkin lymphoma Anti-VGCCb LEMS, cerebellar degeneration SCLC aAll the antibodies of this table are against neuronal cell-surface proteins. bA direct pathogenic role of these antibodies has been demonstrated in cultured neurons or animal models. cThese antibodies are strongly suspected to be pathogenic. Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Caspr2, contactin-associated protein-like 2; GABABR, γ-aminobutyric acid B receptor; LEMS, Lambert-Eaton myasthenic syndrome; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-d-aspartate receptor; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channel.

TABLE 99-4  Low-Risk Antibodies (<30% Probability of an Underlying Cancer), Syndromes, and Associated Tumors TUMOR TYPE WHEN ASSOCIATED ANTIBODYa NEUROLOGIC SYNDROME Anti-LGI1b Limbic encephalitis, hyponatremia, faciobrachial dystonic seizures Rarely thymoma Anti-GABAARb Encephalitis with prominent seizures and status epilepticus Thymoma in ~20% of the patients Anti-DPPXb Agitation, myoclonus, tremor, seizures, hyperekplexia, encephalomyelitis with rigidity No cancer, but frequent diarrhea or cachexia suggesting paraneoplasia Anti-glycine receptorb PERM, stiff-person syndrome Rarely, thymoma, lung, Hodgkin’s lymphoma Anti-IgLON5b NREM and REM sleep disorder, brainstem dysfunction, movement disorder, obstructive sleep apnea, stridor No tumor association Anti-GAD65 Stiff-person, cerebellar syndrome, encephalitis with seizures, limbic encephalitis Infrequent tumor association (thymoma, lung, and breast cancer) Anti-mGluR1b Cerebellar syndrome Hodgkin’s lymphoma in <10% of patients PART 4 Oncology and Hematology Anti-GFAP Meningoencephalitis and myelitis No cancer association Anti-aquaporin 4b Neuromyelitis optica spectrum Lung and breast adenocarcinomas in a few patients disorders Anti-MOG ADEM, optic neuritis, myelitis, cortical encephalitis No cancer association Anti-AChR (muscle)b Myasthenia gravis Thymoma Anti-AChR (neuronal)b Autonomic ganglionopathy SCLC aAll the antibodies of this table are against cell-surface proteins except for

GAD65 and GFAP which are intracellular proteins. Rare antibodies reported in

<30 patients are not included. bA direct pathogenic role of these antibodies has been demonstrated in cultured neurons or animal models. Abbreviations: AChR, acetylcholine receptor; ADEM, acute disseminated encephalomyelitis; DPPX, dipeptidyl-peptidase-like protein-6; GABAAR, γ-aminobutyric acid A receptor; GAD, glutamic acid decarboxylase; GFAP, glial fibrillary acidic protein; LGI1, leucine-rich glioma-inactivated 1; mGluR, metabotropic glutamate receptor; MOG, myelin oligodendrocyte glycoprotein; NREM, non–rapid eye movement; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement; SCLC, small-cell lung cancer. In patients with cancer, the use of immune checkpoint inhibitors is associated in <3% of cases with neurologic immune-related adverse events that may be accompanied by neuronal antibodies, in which case the associated syndromes are indistinguishable from PNDs. Other PNDs are likely immune-mediated, although their antigens are unknown. The best example is opsoclonus-myoclonus syndrome associated with neuroblastoma or SCLC. For still other PNDs, the cause remains quite obscure. These include, among others, several neuropathies that occur in the terminal stages of cancer and a number of neuropathies associated with plasma cell dyscrasias or lymphoma without evidence of tumor infiltration or deposits of immunoglobulin, cryoglobulin, or amyloid. APPROACH TO THE PATIENT Paraneoplastic Neurologic Disorders Three key concepts are important for the diagnosis and manage­ ment of PNDs. First, it is common for symptoms to appear before the presence of a tumor is known; second, the neurologic syndrome usually develops rapidly, producing severe deficits in a short period of time; and third, there is evidence that prompt tumor control improves the neurologic outcome. Therefore, the major concern of

the physician is to recognize a disorder as paraneoplastic as early as possible and to identify and treat the tumor. PND OF THE CENTRAL NERVOUS SYSTEM AND DORSAL ROOT GANGLIA When symptoms involve brain, spinal cord, or dorsal root ganglia, the suspicion of PND is usually based on a combination of clinical, radiologic, and CSF findings. Presence of antineuronal antibodies (Tables 99-2, 99-3, and 99-4) may help in the diagnosis, but only 60–70% of PNDs of the CNS and <20% of those involving the peripheral nervous system have neuronal or neuromuscular junc­ tion antibodies that can be used as diagnostic tests. Magnetic resonance imaging (MRI) and CSF studies are impor­ tant to rule out neurologic complications due to the direct spread of cancer, particularly metastatic and leptomeningeal disease. In most PNDs, the MRI findings are nonspecific. Paraneoplastic limbic encephalitis is usually associated with characteristic MRI abnormalities in the mesial temporal lobes (see below), but similar findings can occur with other disorders (e.g., nonparaneoplastic autoimmune limbic encephalitis and human herpesvirus type 6 [HHV-6] encephalitis) (Fig. 99-2A). The CSF profile of patients with PND of the CNS or dorsal root ganglia typically consists of mild to moderate pleocytosis (<200 mononuclear cells, predomi­ nantly lymphocytes), an increase in the protein concentration, and a variable presence of oligoclonal bands. There are no specific electrophysiologic tests that are diagnostic of PND of the CNS. Moreover, a biopsy of the affected tissue is often difficult to obtain, and although useful to rule out other disorders (e.g., metastasis), the pathologic findings are not specific for PND. PND OF NERVE AND MUSCLE If symptoms involve peripheral nerve, neuromuscular junction, or muscle, the diagnosis of a specific PND is usually established on clinical, electrophysiologic, and pathologic grounds. The clinical history, accompanying symptoms (e.g., anorexia, weight loss), and type of syndrome dictate the studies and degree of effort needed to demonstrate a neoplasm. For example, the frequent association of Lambert-Eaton myasthenic syndrome (LEMS) with SCLC should lead to a chest and abdomen computed tomography (CT) or body positron emission tomography (PET) scan and, if negative, periodic tumor screening for at least 3 years after the neurologic diagnosis. In contrast, the weak association of polymyositis with cancer calls into question the need for repeated cancer screenings in this situation. Serum and urine immunofixation studies should be considered in patients with peripheral neuropathy of unknown cause; detection of a monoclonal gammopathy suggests the need for additional studies to uncover a B-cell or plasma-cell malignancy. In paraneoplastic neuropathies, diagnostically useful neuronal antibodies are limited to CRMP5 (CV2) and Hu (ANNA1). For any type of PND, if neuronal antibodies are negative, the diagnosis relies on the demonstration of cancer and the exclusion of other cancer-related or independent neurologic disorders. Com­ bined CT and PET scans often uncover tumors undetected by other tests. For germ cell tumors of the testis and teratomas of the ovary, ultrasound (testicular, transvaginal, or pelvic) and MRI or CT of the abdomen and pelvis may reveal tumors undetectable by PET. SPECIFIC PARANEOPLASTIC NEUROLOGIC SYNDROMES ■ ■PARANEOPLASTIC ENCEPHALOMYELITIS AND FOCAL ENCEPHALITIS WITH HIGH-RISK ANTIBODIES FOR AN UNDERLYING CANCER The term encephalomyelitis describes an inflammatory process with multifocal involvement of the nervous system, including brain, brain­ stem, cerebellum, and spinal cord. It is often associated with dorsal root ganglia and autonomic dysfunction. For any given patient, the clinical

A B C D E F G H I J FIGURE 99-1  Antibody reactivity and pathologic findings in patients with antibodies against intracellular antigens compared with those of patients with antibodies against neuronal surface antigens. In encephalitis associated with antibodies against intracellular antigens, the antibodies cannot reach the intracellular epitopes and cytotoxic T-cell mechanisms are predominantly involved (A), whereas in encephalitis with antibodies against surface antigens, the antibodies have access to the epitopes and can potentially alter the structure and function of the antigen (B). The Hu antibodies (C, E) are shown here to exemplify the group of antibodies against intracellular antigens, and the NMDAR antibodies (D, F) are shown to exemplify the group of antibodies against cell-surface antigens. In rodent brain immunofluorescence with tissue permeabilized to allow entry of antibodies, the Hu antibodies produce a discrete pattern of cellular immunolabeling (C), whereas the NMDAR antibodies produce a pattern of neuropil-like immunolabeling (D). In contrast, with live cultured neurons, only the NMDAR antibodies have access to the target antigen showing intense immunolabeling (F), whereas the Hu antibodies cannot reach the intracellular antigen showing no immunolabeling (E). In autopsy studies, patients with encephalitis associated with antibodies to intracellular antigens (Hu or other) have extensive neuronal loss and inflammatory infiltrates (not shown); the T cells show direct contact with neurons (arrows in G) likely contributing to neuronal degeneration via perforin and granzyme mechanisms (arrow in H). In contrast, patients with antibodies against cell-surface antigens (NMDAR shown here, and probably applicable to other antigens) have moderate brain inflammatory infiltrates along with plasma cells (brown cells in I), deposits of IgG (diffuse brown staining in J), and microglial proliferation (inset in J), without evidence of predominant T-cell–mediated neuronal loss (not shown). All human tissue sections (G-J) were obtained from hippocampus. (From J Dalmau: Antibody mediated encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.)

CHAPTER 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis

A B PART 4 Oncology and Hematology C D FIGURE 99-2  Brain MRI findings in paraneoplastic and autoimmune encephalitis. Representative MRI studies of patients with several types of autoimmune encephalitides. A. Limbic encephalitis (LE) may result from several different immune responses (Hu, Ma2, AMPAR, GABABR, LGI1, Caspr2) and typically manifests with unilateral or bilateral medial temporal lobe increased FLAIR signal. B. AntiNMDAR encephalitis often occurs with normal MRI findings or mild FLAIR signal abnormalities. C. In contrast, anti-GABAAR encephalitis usually occurs with multiple cortical-subcortical increased FLAIR signal changes. D. Cortical encephalitis can occur in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies, as shown in this T2-weighted MRI image from a 3-year-old boy who presented with extensive cortical abnormalities with mild enhancement (not shown here) suggesting cortical necrosis. (Panels A-C from J Dalmau: Antibody mediated encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission. Panel D from T Armangue: Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: A multicentre observational study. Lancet Neurol 19:234, 2020.) manifestations are determined by the areas predominantly involved, but pathologic studies almost always reveal abnormalities beyond the symptomatic regions. Several clinicopathologic syndromes may occur alone or in combination: (1) cortical encephalitis, which may present as “epilepsia partialis continua”; (2) limbic encephalitis, characterized by confusion, depression, agitation, anxiety, severe deficit forming new memories (“short-term memory deficit”), and temporal lobe or gen­ eralized seizures (the MRI usually shows unilateral or bilateral medial temporal lobe abnormalities, best seen with T2 and fluid-attenuated inversion recovery [FLAIR] sequences); (3) brainstem encephalitis, resulting in eye movement disorders (nystagmus, opsoclonus, supra­ nuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia, unsteady gait, and central autonomic dysfunction; (4) cerebellar gait and limb ataxia; (5) myelitis, which may cause lower or upper motor neuron symptoms, myoclonus, muscle rigidity, spasms, fasciculations, sensory deficits, and sphincter dysfunction; and (6) autonomic dys­ function as a result of involvement of the neuraxis at multiple levels, including hypothalamus, brainstem, and autonomic nerves (see “Paraneoplastic Peripheral Neuropathies,” below). Cardiac arrhythmias, postural hypotension, and central hypoventilation can be the cause of death in patients with encephalomyelitis.

Paraneoplastic encephalomyelitis and focal encephalitis are usually associated with SCLC, but many other cancers have been implicated. Patients with SCLC and these syndromes usually have Hu antibodies in serum and CSF. CRMP5 antibodies occur less frequently; some of these patients may develop chorea, uveitis, or optic neuritis. Antibodies to Ma proteins are associated with limbic, hypothalamic, and brainstem encephalitis and occasionally with cerebellar symptoms; some patients develop hypersomnia, cataplexy, and severe hypokinesia. MRI abnor­ malities are frequent, including those described with limbic encepha­ litis and variable involvement of the hypothalamus, basal ganglia, or upper brainstem. Kelch-like protein 11 antibodies are predominantly associated with brainstem encephalitis, vertigo, sensorineural hearing loss, and seminomas, germ cell tumors, and teratomas. Amphiphysin antibodies usually are associated with paraneoplastic stiff-person syndrome, but in some patients, they can occur with paraneoplastic encephalomyelitis or isolated myelitis. The oncologic associations of these antibodies are shown in Table 99-2. Most types of paraneoplastic encephalitis and encephalomyelitis in which the antigens are intracellular respond poorly to treatment. Sta­ bilization of symptoms or partial neurologic improvement may occur, particularly if there is a satisfactory response of the tumor to treatment. Controlled trials of therapy are lacking, but many reports and the opin­ ion of experts suggest that therapies aimed to remove the antibodies against intracellular antigens, such as intravenous immunoglobulin (IVIg) or plasma exchange, usually fail. The main concern should be to treat the tumor and consider immunotherapies aimed at cytotoxic T-cell responses. Approximately 30% of patients with anti-Ma2-associ­ ated encephalitis respond to treatment of the tumor (usually a germ cell neoplasm of the testis) and immunotherapy. Cortical encephalitis can occur with antibodies against myelin oligodendrocyte glycoprotein (MOG) (Chap. 456), and encephalomy­ elitis can occur with antibodies against GFAP (Chap. 456). These two disorders rarely associate with cancer and respond better to immu­ notherapy than the indicated paraneoplastic syndromes. Encephalitis with seizures, limbic encephalitis, stiff-person syndrome, or cerebellar ataxia can occur with GAD65 antibodies; this type of autoimmunity rarely associates with cancer but responds less frequently to immu­ notherapy than similar syndromes associated with antibodies against neuronal surface proteins. ■ ■ENCEPHALITIDES WITH INTERMEDIATE- OR LOW-RISK ANTIBODIES FOR AN UNDERLYING CANCER These disorders are important for four reasons: (1) they can occur with and without tumor association; less frequently, they develop after a viral encephalitis (herpes simplex or Japanese encephalitis); (2) some syndromes predominate in young individuals and children; (3) despite the severity of the symptoms, patients usually respond to treatment of the tumor, if found, and immunotherapy (e.g., glucocorticoids, IVIg, plasma exchange, rituximab, or cyclophosphamide); and (4) for many of these disorders, the antibody pathogenicity has been demonstrated in models using cultures of neurons or passive transfer of patients’ antibodies to animals (Fig. 99-3). Encephalitis with N-methyl-d-aspartate receptor (NMDAR) antibod­ ies usually occurs in young women and children, but men and older patients of both sexes can be affected. The disorder has a character­ istic pattern of symptom progression that often includes a prodrome resembling a viral process, followed in a few days by the onset of severe psychiatric symptoms, sleep dysfunction (usually insomnia), reduced verbal output, memory loss, seizures, decreased level of consciousness, abnormal movements (orofacial, limb, and trunk dyskinesias, dystonic postures), autonomic instability, and frequent hypoventilation. Mono­ symptomatic episodes, such as pure psychosis, occur in about 5% of patients. Clinical relapses occur in 12–24% of patients (12% during the first 2 years after initial presentation). Most patients have intrathe­ cal synthesis of antibodies, likely by infiltrating plasma cells in brain and meninges (Fig. 99-1I). In about 65% of patients, the brain MRI is normal; in the other 35%, it shows FLAIR abnormalities that can affect cortical and subcortical regions, usually mild and transient, and rarely

A B D E F FIGURE 99-3  Proposed mechanisms of disease and functional interactions of autoantibodies with neuronal surface proteins. The graph shows a multistep process that results in antibody-mediated neuronal dysfunction; some of the steps have been demonstrated in reported studies, whereas others are based on proposed hypotheses. Two well-known triggers of autoimmune encephalitides are represented: herpes simplex encephalitis (A) and systemic tumors (B); the genetic susceptibility of some autoimmune encephalitides and unknown immunologic triggers are not depicted. It is postulated that antigens released by viral-induced neuronal destruction or apoptotic tumor cells are loaded into antigen-presenting cells (APCs; dendritic cells) and transported to regional lymph nodes. In the lymph nodes, naïve B cells exposed to the processed antigens, with cooperation of CD4+ T cells, become antigen-experienced and differentiate into antibody-producing plasma cells. After entering the brain, memory B cells undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-producing plasma cells (C). The contribution of systemically produced antibodies to the pool of antibodies present in the brain is unclear and may depend on systemic antibody titers and integrity of the blood-brain barrier. Based on experimental models with cultured neurons, the presence of antibodies in the brain may lead to neuronal dysfunction by different mechanisms, including functional blocking of the target antigen (GABABR antibodies; D), receptor crosslinking and internalization (NMDAR antibodies; E), and disruption of protein-protein interaction, leading to downstream effects on receptors (LGI1 leading to a decrease of Kv1 potassium channels and AMPAR; F). These mechanisms are influenced by the type of antibodies; for example, whereas IgG1 antibodies frequently crosslink and internalize the target antigen, IgG4 antibodies are less effective at crosslinking the target and more often alter protein-protein interactions. (Panels D-F from J Dalmau: Antibody mediated encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.) the presence of contrast enhancement (Fig. 99-2B). The syndrome may be misdiagnosed as a viral or idiopathic encephalitis, neuroleptic malignant syndrome, or encephalitis lethargica, and some patients are initially evaluated by psychiatrists with the suspicion of acute psychosis as the presentation of a primary psychiatric disease. The detection of an associated teratoma is dependent on age and gender: 46% of female patients 12 years or older have uni- or bilateral ovarian teratomas, whereas <7% of girls younger than 12 have a teratoma (Fig. 99-4A). In young male patients, the detection of a tumor is rare. Patients older than 45 years are more frequently male; about 20% of these patients have tumors (e.g., cancer of the breast, ovary, or lung). Prompt diag­ nosis and treatment with immunotherapy (and tumor removal when it applies) improve outcome. Treatment usually includes first-line immunotherapy (steroids, IVIg, or plasma exchange), and if there is no response, second-line immunotherapy (rituximab and cyclophospha­ mide). Rituximab is highly effective and is increasingly used as part of first-line treatments. The response to treatment can take several weeks, and the improvement is usually slow. Overall, about 85–90% of patients have substantial neurologic improvement or full recovery. Deficits of

C CHAPTER 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
attention, memory, and executive functions may recover slowly over many months. During the process of recovery, patients often develop transient hypersomnia and, less frequently, hyperphagia, hypersexual­ ity, apathy, and irritability, resembling a Kleine-Levin syndrome. Approximately 25% of patients with herpes simplex encephalitis develop a form of autoimmune encephalitis that usually is associ­ ated with abnormal movements (choreoathetosis after herpes simplex encephalitis) in children and with cognitive and psychiatric symptoms in adults. This disorder develops a few weeks after the viral infection has resolved, is associated with new synthesis of antibodies against the NMDAR and other neuronal cell surface proteins, and is usually less responsive to immunotherapy than anti-NMDAR encephalitis (idio­ pathic or teratoma-associated). Encephalitis with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibodies affects middle-aged women, who develop acute limbic dysfunction or, less frequently, prominent psychi­ atric symptoms; 70% of patients have an underlying tumor in the lung, breast, or thymus (Fig. 99-4B). In about 50% of cases, the brain MRI shows typical features of limbic encephalitis (similar to Fig. 99-2A).

A B FIGURE 99-4  Immunopathological studies in tumors of patients with autoimmune encephalitis. A. Neurons and neuronal processes (brown cells; stained with MAP2) in the teratoma of a patient with anti-NMDA receptor encephalitis; these neurons express NMDAR (not shown). B. Lung cancer from a patient with anti–α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis showing expression of AMPA receptors by the neoplastic cells (brown cells). (Panel B from M Lai et al: AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 65:424, 2009.) PART 4 Oncology and Hematology Neurologic relapses may occur; these also respond to immunotherapy and are not necessarily associated with tumor recurrence. Encephalitis with GluK2 antibodies can affect children and adults and is associated with rapidly progressive encephalopathy with cer­ ebellar ataxia or cerebellitis. Symptoms of encephalopathy may include impairment of memory and level of consciousness and motor altera­ tions such as dyskinesias, choreoathetosis, bradykinesia, and spastic paraparesis. Some patients develop intracranial hypertension. In one patient, the symptoms were associated with teratoma. Encephalitis with γ-aminobutyric acid type A (GABAA) receptor anti­ bodies may affect children and adults and is associated with prominent seizures and status epilepticus often requiring a pharmacologically induced coma. In approximately 80% of patients, the brain MRI shows multifocal, asynchronous, cortical-subcortical T2/FLAIR abnormali­ ties predominantly involving temporal and frontal lobes, but also basal ganglia and other regions (Fig. 99-2C). Most patients do not have an underlying tumor, but some may have thymoma. Encephalitis with GABAB receptor antibodies is usually associated with limbic encephalitis and seizures. In >50% of cases, the MRI shows increased medial temporal lobe FLAIR changes characteristic of limbic encephalitis (similar to Fig. 99-2A). In rare instances, patients develop cerebellar symptoms and opsoclonus. Fifty percent of patients have SCLC or a neuroendocrine tumor of the lung. The outcome is substan­ tially better in patients without cancer. Encephalitis with glycine receptor (GlyR) antibodies usually manifests with a syndrome characterized by progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person spectrum of symptoms. The disease usually occurs in adults and rarely in children. About 20% of adult patients have a concurrent underlying tumor (thymoma, B-cell lymphoma, or breast or lung cancer) or past history of cancer (thymoma, breast cancer, Hodgkin’s lymphoma, or melanoma). Encephalitis with metabotropic glutamate receptor 5 (mGluR5) anti­ bodies is characterized by nonspecific clinical features of encephalitis (confusion, agitation, memory loss, delusions, paranoid ideation, hallucinations, psychosis, or seizures) without distinctive MRI changes and frequent association with Hodgkin’s lymphoma. The encephalitis is highly responsive to immunotherapy and treatment of the tumor. Encephalitis with antibodies against dopamine-2 receptor has been reported in children with basal ganglia encephalitis manifesting with abnormal movements (coarse tremor, parkinsonism, chorea, ocu­ logyric crises) along with psychiatric features, lethargy, drowsiness,

brainstem dysfunction, or ataxia. The disorder is extremely rare and is not associated with cancer. Encephalitis with leucine-rich glioma-inactivated 1 (LGI1) antibod­ ies predominates in patients older than 50 years (65% male) and frequently presents with short-term memory loss and seizures (limbic encephalopathy), along with hyponatremia and sleep dysfunction. The MRI often shows increased FLAIR signal in one or both medial temporal lobes. In about 40% of patients, these symptoms are preceded by faciobrachial dystonic seizures, which consist of sudden, shortlasting, mainly distal muscle contractions involving the arm, face, or leg. These are unilateral but can independently affect both sides and occur multiple times during the day or night. About 15% of patients present with rapidly progressive cognitive decline, resembling a rap­ idly progressive dementia. Less than 5% of patients have thymoma. An association with the human leukocyte antigen (HLA) haplotypes DRB1∗07:01, DQB1∗02:02, DQA1∗02:01, and DRB4 has been identi­ fied. All symptoms, including faciobrachial dystonic seizures, respond to immunotherapy, although about two-thirds of patients are left with memory or cognitive deficits. Despite the improvement with initial immunotherapy, video-polysomnography or prolonged electroen­ cephalogram studies frequently uncover persistent alterations (facio­ brachial dystonic seizures, other seizures, rapid eye movement [REM] sleep behavior disorder) only detectable during sleep. These altera­ tions, which might contribute to residual memory or cognitive deficits, respond to additional or prolonged immunotherapy. Encephalitis with contactin-associated protein-like 2 (Caspr2) anti­ bodies predominates in patients older than 50 years and is associated with a form of encephalitis with three or more of the following core symptoms: encephalopathy (which can be similar to limbic encephali­ tis), cerebellar symptoms, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, and weight loss. Patients with Morvan syndrome, which includes clinical features of encephalitis (confusion, hallucinations, prominent sleep dysfunction, or “agrypnia excitata”), autonomic alterations, and peripheral nerve hyperexcitabil­ ity or neuromyotonia, usually have Caspr2 antibodies. About 20% of patients with Caspr2 antibody–associated syndromes have thymoma; this percentage is higher (~50%) in patients with Morvan syndrome. An association of Caspr2 antibody–associated syndromes with HLA DRB1∗11.01 has been reported. Encephalitis with dipeptidyl-peptidase-like protein-6 (DPPX) anti­ bodies is usually preceded or develops concurrently with diarrhea, other gastrointestinal symptoms, and substantial loss of weight that

often suggest the presence of a gastrointestinal disease. Neurologic symptoms include agitation, hallucinations, paranoid delusions, and features of CNS hyperexcitability such as hyperekplexia, tremor, myoc­ lonus, nystagmus, or seizures. Some patients develop a clinical picture similar to progressive encephalomyelitis with rigidity and myoclonus. The few patients reported with an associated tumor usually had B-cell neoplasms. Encephalitis with antibodies against neurexin 3 alpha does not have distinctive clinical features; the experience is limited, and the disorder does not appear to be associated with cancer. Anti-IgLON5 disease is a chronic or subacute encephalopathy that characteristically is associated with REM and non-REM (NREM) parasomnia along with obstructive sleep apnea that may be preceded or accompanied by bulbar symptoms (mainly dysphagia and stridor due to vocal cord palsy), unsteadiness, movement disorders (chorea, craniofacial dyskinesias), oculomotor dysfunction, and, in less than half of cases, cognitive decline. The median age of the patients is in the early 60s, and men and women are equally affected. The sleep disorder is characterized by abnormal sleep initiation with undifferentiated NREM sleep associated with frequent vocalizations and quasi-purposeful movements. Brain MRI is unrevealing or demonstrates minor changes of unclear clinical relevance; the CSF is usually normal or may show transient lymphocytic pleocytosis. It is not associated with cancer but shows a strong association with the HLA-DRB1∗10:01 and HLADQB1∗05 haplotypes, which are present in 60% of patients. The response to immunotherapy is poor. In some patients, neuropathologic studies show a neuronal tauopathy predominantly involving the hypo­ thalamus and tegmentum of the brainstem; however, not all autopsy studies show deposits of hyperphosphorylated tau, and in some patients, mild inflammatory infiltrates have been identified. With the exception of patients with anti-IgLON5 disease, who rarely respond to treatment, most patients with autoimmune or paraneoplas­ tic encephalopathies associated with antibodies against cell-surface or synaptic proteins respond to immunotherapy and treatment of the tumor (if appropriate). Although there are no specific standardized treatment protocols, the most frequent approach is similar to that indi­ cated for anti-NMDAR encephalitis and consists of progressive escala­ tion of immunotherapy using first a combination of glucocorticoids, IVIg, and plasma exchange, and then, if there is no response, rituximab or cyclophosphamide. Encephalitis with MOG antibodies can present with a clinical picture suggestive of autoimmune encephalitis related to neuronal antibodies. Most patients with MOG antibody–associated syndromes are children and young adults who present with optic neuritis, myelitis, brainstem (mainly pons) and cerebellar symptoms, or acute disseminated enceph­ alomyelitis (ADEM). About 85% of patients with these syndromes respond to immunotherapy, although relapses occur in about 30% of cases. Besides these syndromes, there is a small group of adults and children who present with unilateral or bilateral cortical encephalitis, and their response to treatment is variable. In children, two pheno­ types of poor prognosis include ADEM-like relapses progressing to leukodystrophy-like features and extensive cortical encephalitis evolv­ ing to atrophy (Fig. 99-2D). In general, MOG antibody syndromes are not associated with tumors. ■ ■PARANEOPLASTIC CEREBELLAR DEGENERATION This disorder is often preceded by a prodrome that may include dizzi­ ness, oscillopsia, blurry or double vision, nausea, and vomiting. A few days or weeks later, patients develop dysarthria, gait and limb ataxia, and variable dysphagia. The examination usually shows downbeating nystagmus and, rarely, opsoclonus. Brainstem dysfunction or upgoing toes may occur. Early in the course, MRI studies are usually normal; later, the MRI reveals cerebellar atrophy. The disorder results from extensive degeneration of Purkinje cells, with variable involvement of other cerebellar cortical neurons, deep cerebellar nuclei, and spinocer­ ebellar tracts. The tumors more frequently involved are SCLC, cancer of the breast and ovary, and Hodgkin’s lymphoma. Anti-Yo (PCA1) antibodies in patients with breast or gynecologic cancers typically are associated with prominent or pure cerebellar

degeneration. A variable degree of cerebellar dysfunction can be asso­ ciated with virtually any of the antibodies and PND of the CNS shown in Table 99-2. A number of single case reports have described neuro­ logic improvement after tumor removal, plasma exchange, IVIg, cyclo­ phosphamide, rituximab, or glucocorticoids. However, most patients with paraneoplastic cerebellar degeneration and any of the antibodies shown in Table 99-2 do not improve with treatment; an exception are the cerebellar syndromes associated with antibodies against surface antigens (e.g., Tr antibodies and Hodgkin’s lymphoma, VGCC antibod­ ies and SCLC), which are more responsive to immunotherapy.

Antibody-associated cerebellar symptoms can also occur without cancer association. The most common is cerebellar ataxia with anti­ bodies against GAD65 (an intracellular synaptic protein). The median age at diagnosis is 60 years and 75% of cases are women. Concurrent organ-specific autoimmune diseases, mainly type 1 diabetes, are pres­ ent in 80% of patients. The clinical course is chronic, but in 40% of patients, the presentation is subacute (<6 months). Response to immu­ notherapy is poor. Subacute onset of symptoms and prompt initiation of immunotherapy are associated with a better chance for improve­ ment. By contrast, the cerebellar syndrome associated with mGluR1 antibodies is more responsive to immunotherapy, and a substantial improvement occurs in almost half of the patients. Immunotherapy is also effective in patients with GluK2 antibodies, who can present with cerebellitis and posterior fossa edema with compression of the fourth ventricle, and in those with septin-5 antibodies. Although septin-5 is an intracellular antigen, it is likely exposed to the cell surface during the process of endo- and exocytosis at synaptic terminals. CHAPTER 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
■ ■PARANEOPLASTIC OPSOCLONUS-MYOCLONUS SYNDROME Opsoclonus is a disorder of eye movement characterized by involuntary, chaotic saccades that occur in all directions of gaze; it is frequently associated with myoclonus and ataxia. Opsoclonus-myoclonus may be cancer-related or idiopathic. When the cause is paraneoplastic, the tumors involved are usually cancer of the lung and breast in adults and neuroblastoma in children. The pathologic substrate of opsoclonusmyoclonus is unclear, but studies suggest that disinhibition of the fas­ tigial nucleus of the cerebellum is involved. Most patients do not have neuronal antibodies. A small subset of patients with ataxia, opsoclonus, and other eye-movement disorders have Ri antibodies; these patients may also develop muscle rigidity, laryngeal spasms, and autonomic dysfunction. The tumors most frequently involved in anti-Ri-associated syndromes are breast, ovarian, and lung cancers. If the tumor is not successfully treated, the syndrome in adults often progresses to encephalopathy, coma, and death. In addition to treating the tumor, symptoms may respond to immunotherapy (glucocorticoids, plasma exchange, and/or IVIg). At least 50% of children with opsoclonus-myoclonus have an underlying neuroblastoma. Hypotonia, ataxia, behavioral changes, and irritability are frequent accompanying symptoms. Neurologic symp­ toms often improve with treatment of the tumor and glucocorticoids, adrenocorticotropic hormone (ACTH), plasma exchange, IVIg, ritux­ imab, or cyclophosphamide. Many patients are left with psychomotor retardation and behavioral and sleep problems. ■ ■PARANEOPLASTIC SYNDROMES OF THE SPINAL CORD The number of reports of paraneoplastic spinal cord syndromes, such as subacute motor neuronopathy and acute necrotizing myelopathy, has decreased over the years. This may represent a true decrease in incidence, due to improved and prompt oncologic interventions, or the identification of nonparaneoplastic etiologies. Some patients with cancer or lymphoma develop upper or lower motor neuron dysfunction or both, resembling amyotrophic lateral sclerosis. It is unclear whether these disorders have a paraneoplastic etiology or simply coincide with the presence of cancer. Paraneoplastic myelitis may present with upper or lower motor neu­ ron symptoms, segmental myoclonus, sensory deficits, sphincter dys­ function, and neurogenic pruritus and can be the first manifestation of

encephalomyelitis. The spine MRI usually shows longitudinally exten­ sive, symmetric tract or gray matter abnormalities in the spinal cord. It is mainly associated with breast and lung carcinomas and with CRMP5 or amphiphysin antibodies. The prognosis is poor. Neuromyelitis optica (NMO) with aquaporin 4 antibodies may occur in rare instances as a paraneoplastic manifestation of a cancer. NMO is discussed in detail in Chap. 456.

■ ■PARANEOPLASTIC STIFF-PERSON SYNDROME This disorder is characterized by progressive muscle rigidity, stiff­ ness, and painful spasms triggered by auditory, sensory, or emotional stimuli. Rigidity mainly involves the lower trunk and legs, but it can affect the upper extremities and neck. Sometimes, only one extremity is affected (stiff-limb syndrome). Symptoms improve with sleep and general anesthetics. Electrophysiologic studies demonstrate continuous motor unit activity. The associated antibodies target proteins (GAD65, amphiphysin) involved in the function of inhibitory synapses that use γ-aminobutyric acid (GABA) or glycine as neurotransmitters. The presence of amphiphysin antibodies usually indicates a paraneoplastic etiology related to SCLC and breast cancer. By contrast, GAD antibod­ ies may occur in some cancer patients but are much more frequently present in the nonparaneoplastic disorder. GlyR antibodies may occur in some patients with stiff-person syndrome; these antibodies are more frequently detectable in patients with PERM (Fig. 99-5). PART 4 Oncology and Hematology Optimal treatment of stiff-person syndrome requires therapy of the underlying tumor, glucocorticoids, and symptomatic use of drugs that enhance GABA-ergic transmission (diazepam, baclofen, sodium valproate, tiagabine, vigabatrin). IVIg and plasma exchange are tran­ siently effective in some patients, and there are reports of responses FIGURE 99-5  Schematic representation of an inhibitory synapse showing the main autoimmune targets (GAD, amphiphysin, GABA receptor, and glycine receptor) and the corresponding neurologic disorders. GAD antibodies predominantly occur in stiff-person syndrome (SPS), cerebellar ataxia, and epilepsy, sometimes in the setting of encephalitis. Amphiphysin antibodies are markers of paraneoplastic SPS and breast cancer, GlyR antibodies often associate with progressive encephalomyelitis with rigidity and myoclonus (PERM), and GABAA receptor antibodies occur in a form of autoimmune encephalitis that is frequently associated with refractory seizures and status epilepticus. (Modified from F Graus et al: Nat Rev Neurol 16:353, 2020.)

to rituximab and CD19 CAR T-cell therapy in patients who did not respond to other treatments. ■ ■PARANEOPLASTIC SENSORY NEURONOPATHY OR DORSAL ROOT GANGLIONOPATHY This syndrome is characterized by sensory deficits that may be symmetric or asymmetric, painful dysesthesias, radicular pain, and decreased or absent reflexes. All modalities of sensation and any part of the body including face and trunk can be involved. Special senses such as taste and hearing can also be affected. Electrophysiologic stud­ ies show decreased or absent sensory nerve potentials with normal or near-normal motor conduction velocities. Symptoms result from an immune-mediated process that targets the dorsal root ganglia, causing neuronal loss and secondary degeneration of the posterior columns of the spinal cord. The dorsal and, less frequently, the anterior nerve roots and peripheral nerves may also be involved. This disorder often precedes or is associated with encephalomyelitis and autonomic dys­ function and has the same immunologic and oncologic associations (Hu antibodies, SCLC). As with anti-Hu-associated encephalomyelitis, the therapeutic approach focuses on prompt treatment of the tumor and cytotoxic T-cell–mediated mechanisms. Glucocorticoids occasionally produce clinical stabilization or improvement. The benefit of IVIg and plasma exchange is not proven. ■ ■PARANEOPLASTIC PERIPHERAL NEUROPATHIES These disorders may develop any time during the course of the neo­ plastic disease. Neuropathies occurring at late stages of cancer or lymphoma usually cause mild to moderate sensorimotor deficits due

to axonal degeneration of unclear etiology. These neuropathies are often masked by concurrent neurotoxicity from chemotherapy and other cancer therapies. In contrast, the neuropathies that develop in the early stages of cancer frequently show a rapid progression, sometimes with a relapsing and remitting course, and evidence of inflammatory infiltrates and axonal loss or demyelination. Besides the subacute onset, an asymmetric distribution of symptoms, presence of neuropathic pain and dysautonomia, clinical or neuroimaging evidence of involvement of the spinal cord or nerve roots, and detection of an axonal pattern in the electrophysiological studies are features that suggest the possibility of a paraneoplastic etiology. The response to treatment is usually poor, but if demyelinating features predominate (Chaps. 457 and 458), IVIg, plasma exchange, or glucocorticoids may improve symptoms. Occa­ sionally, CRMP5 antibodies are present; detection of Hu antibodies suggests concurrent dorsal root ganglionitis. Guillain-Barré syndrome (Chap. 458) and brachial plexitis (Chap. 457) have occasionally been reported in patients with Hodgkin’s lymphoma, but there is no clear evidence of a paraneoplastic association. Diseases associated with paraproteinemia such as multiple myeloma, osteosclerotic myeloma, cryoglobulinemia, amyloidosis, Waldenström’s macroglobulinemia, or POEMS (polyneuropathy, organomegaly, endo­ crinopathy, M-protein spike, and skin manifestations) syndrome, among others, may cause neuropathy by a variety of mechanisms, including compression of roots and plexuses by metastasis to verte­ bral bodies and pelvis, by deposits of amyloid in peripheral nerves, or through a direct interaction of the abnormal immunoglobulin with peripheral nerve antigens. In other patients, the mechanisms under­ lying the neuropathy remain unknown and paraneoplastic immunemediated mechanisms have not been ruled out. Neuropathies more often occur with IgM paraproteinemia followed by IgG and IgA. The phenotype of the neuropathy and likelihood of improvement with suc­ cessful treatment of the paraproteinemia are dependent on the under­ lying hematologic disorder (Chap. 458). Vasculitis of the nerve and muscle causes a painful symmetric or asymmetric distal axonal sensorimotor neuropathy with variable proximal weakness. It predominantly affects elderly men and is associ­ ated with an elevated erythrocyte sedimentation rate and increased CSF protein concentration. SCLC and lymphoma are the primary tumors involved. Glucocorticoids and cyclophosphamide often result in neurologic improvement. Peripheral nerve hyperexcitability (neuromyotonia, or Isaacs’ syn­ drome) is characterized by spontaneous and continuous muscle fiber activity of peripheral nerve origin. Clinical features include cramps, muscle twitching (fasciculations or myokymia), stiffness, delayed muscle relaxation (pseudomyotonia), and spontaneous or evoked carpal or pedal spasms. The involved muscles may be hypertrophic, and some patients develop paresthesias and hyperhidrosis. The elec­ tromyogram (EMG) shows fibrillations; fasciculations; and doublet, triplet, or multiplet single-unit (myokymic) discharges that have a high intraburst frequency. Some patients have Caspr2 antibodies usually in the context of Morvan syndrome, but most patients with isolated neu­ romyotonia are antibody negative. The disorder often occurs without cancer; if paraneoplastic, benign and malignant thymomas and SCLC are the usual tumors. Phenytoin, carbamazepine, and plasma exchange improve symptoms. Paraneoplastic autonomic neuropathy usually develops as a compo­ nent of other disorders, such as LEMS and encephalomyelitis. It may rarely occur as a pure or predominantly autonomic neuropathy with cholinergic or adrenergic dysfunction at the pre- or postganglionic levels. Patients can develop several life-threatening complications, such as gastrointestinal paresis with pseudo-obstruction, cardiac dys­ rhythmias, and postural hypotension. Other clinical features include abnormal pupillary responses, dry mouth, anhidrosis, erectile dys­ function, and problems with sphincter control. The disorder occurs in association with several tumors, including SCLC, cancer of the pancreas or testis, carcinoid tumors, and lymphoma. Because auto­ nomic symptoms can be the presenting feature of encephalomyelitis, serum Hu and CRMP5 antibodies should be sought. Antibodies to ganglionic (α3-type) neuronal acetylcholine receptors are the cause

of autoimmune autonomic ganglionopathy, a disorder that frequently occurs without cancer association (Chap. 451).

■ ■LAMBERT-EATON MYASTHENIC SYNDROME LEMS is discussed in Chap. 459. ■ ■MYASTHENIA GRAVIS Myasthenia gravis is discussed in Chap. 459. ■ ■POLYMYOSITIS-DERMATOMYOSITIS Polymyositis and dermatomyositis are discussed in detail in Chap. 377. ■ ■IMMUNE-MEDIATED NECROTIZING MYOPATHY Patients with this syndrome develop myalgias and rapid progression of weakness involving the extremities, neck, pharyngeal, respiratory, and sometimes cardiac muscles. Serum muscle enzymes are elevated, and muscle biopsy shows extensive necrosis with minimal or absent inflammation and sometimes deposits of complement. The disorder may occur without cancer association (sometimes as a result of statin exposure, connective tissue disease, or HIV) or with cancer asso­ ciation. Patients with antibodies against 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) and seronegative patients are more likely to have an underlying cancer than those with antibodies against signal recognition particle. No specific type of cancer has been found to be predominant. Successful treatment of the tumor and aggressive immunotherapy (steroids, IVIg, and steroid-sparing immunosuppres­ sants) may lead to complete or substantial recovery. Immune-mediated necrotizing myopathy is discussed in Chap. 377. CHAPTER 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
■ ■PARANEOPLASTIC VISUAL SYNDROMES This group of disorders involves the retina and, less frequently, the uvea and optic nerves. The term cancer-associated retinopathy is used to describe paraneoplastic cone and rod dysfunction characterized by photosensitivity, progressive loss of vision and color perception, central or ring scotomas, night blindness, and attenuation of photopic and scotopic responses in the electroretinogram (ERG). The most com­ monly associated tumor is SCLC. Melanoma-associated retinopathy affects patients with metastatic cutaneous melanoma. Patients develop acute onset of night blindness and shimmering, flickering, or pulsating photopsias that often progress to visual loss. The ERG shows reduced b-waves with normal dark adapted a-waves. Paraneoplastic optic neu­ ritis and uveitis can develop in association with encephalomyelitis. Patients with paraneoplastic uveitis and optic neuritis may harbor CRMP5 antibodies. Some paraneoplastic retinopathies are associated with serum anti­ bodies that specifically react with the subset of retinal cells undergoing degeneration, supporting an immune-mediated pathogenesis. The best-characterized retinal antibodies are against recoverin and have been described in patients with SCLC and cancer-associated retinopa­ thy. However, the specificity of this and other retinal antibodies is low as they have also been reported in nonparaneoplastic autoimmune and nonautoimmune retinopathies. Paraneoplastic retinopathies rarely show substantial improvement after treatment of the tumor and immu­ notherapy; however, stabilization of symptoms and partial responses to a variety of immunotherapies (glucocorticoids, plasma exchange, IVIg, rituximab, or alemtuzumab) have been reported. ■ ■FURTHER READING Armangue T et al: Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: A multicentre observational study. Lancet Neurol 19:234, 2020. Armangue T et al: Neurological complications in herpes simplex encephalitis: Clinical, immunological and genetic studies. Brain 146:4306, 2023. Cellucci T et al: Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuro­ inflamm 7:e663, 2020. Dalmau J, Graus F: Autoimmune Encephalitis and Related Disorders of the Nervous System. Cambridge, Cambridge University Press, 2022.