Paraneoplastic Disorders of the Nervous System PDF

Paraneoplastic Disorders of the Nervous System OUTLINE Pathogenesis, 1255 General Diagnostic Approach, 1255 Specific Paraneoplastic Neurological Syndromes and Their Treat- ment, 1257 Paraneoplastic Cerebellar Degeneration, 1257 Paraneoplastic Encephalomyelitis, 1257 Limbic and Brainstem Encephalitis, 1258 Paraneoplastic Opsoclonus-Myoclonus, 1258 Stiff-Person Spectrum Disorders, 1258 Paraneoplastic Sensory Neuronopathy, 1259 PATHOGENESIS Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of disorders that are immune mediated (Table 81.1). It is pos- tulated that the expression of neuronal proteins (called onconeuronal proteins) by a tumor provokes an immune response that is misdirected against the nervous system. This hypothesis is supported by the detec- tion in the serum and cerebrospinal fluid (CSF) of anti-neuronal anti- bodies that react with antigens expressed by the tumor and the nervous system (Dalmau et al., 2008; Darnell et al., 2003). Antibodies that tar- get intracellular antigens (e.g., anti-Hu, Ri, Ma2) are most commonly associated with PNS of the central nervous system (CNS). The detec- tion of one of these antibodies is highly predictive of the presence of a cancer (Table 81.2). The PNSs associated with antibodies to intra- cellular antigens are likely mediated by cytotoxic T-cell responses that produce irreversible neuronal cell death, explaining why many PNSs are not reversible. Since the T cells appear to be directed against the same antigens as the antibodies, the antibodies and the T cells likely play cooperating roles in the pathogenesis of the PNSs that have yet to be defined (Blachere et al., 2014). Other antibodies, in particular those that target antigens on the neuronal cell surface (e.g., acetylcholine receptor [AChR] or γ-aminobutyric acid type B receptor [GABAbR]) occur with specific neurological syndromes regardless of the presence or absence of cancer. These antibodies are pathogenic and act by bind- ing to and altering the function of the target antigens (Dalmau et al., 2018; Ruff et al., 2018). Cytotoxic T-cell mechanisms are not involved and the antibody effects are reversible. Thus these disorders often respond to treatment of the associated cancer (when paraneoplastic) and B-cell or antibody depleting strategies. GENERAL DIAGNOSTIC APPROACH The specificity of paraneoplastic anti-neuronal antibodies for PNSs or some types of cancer makes them useful diagnostic tools (see F ECF FH HE @ @AE C @AE C HE @ D AC FD 1256 PART III Neurological Diseases and TABLE 81.1 Paraneoplastic Neurological Syndromes Syndromes Affecting the Central Nervous System Cerebellar degeneration Encephalomyelitis* Limbic and brainstem encephalitis Opsoclonus-myoclonus Stiff-person spectrum disorders Necrotizing myelopathy† Motor neuron syndromes† (ALS; subacute motor neuronopathy; upper motor neuron dysfunction) Syndromes Affecting the Visual System Retinopathy Optic neuritis Uveitis (usually in association with encephalomyelitis) Bilateral diffuse uveal melanocytic proliferation Syndromes Affecting the Peripheral Nervous System Sensory neuronopathy Vasculitis of the nerve and muscle Subacute and chronic sensorimotor peripheral neuropathy Sensorimotor neuropathies associated with plasma cell dyscrasias and B-cell lymphoma Autonomic neuropathy† Brachial neuritis† Acute polyradiculoneuropathy (Guillain-Barré syndrome) Peripheral nerve hyperexcitability Syndromes Affecting the Neuromuscular Junction and Muscle Lambert-Eaton myasthenic syndrome Myasthenia gravis Dermatomyositis Necrotizing autoimmune myopathy ALS, Amyotrophic lateral sclerosis. *Includes focal cortical encephalitis, cerebellar dysfunction, tis. †Not discussed further in this chapter. Sundermann et al., 2017). Although almost any type of neoplasm can cause PNS, the tumors more frequently involved are small-cell lung cancer (SCLC); cancers of the breast and ovary; thymoma, neuroblas- toma, and plasma cell tumors. The development of PNS frequently heralds tumor recurrence in patients with a history of cancer or those who have recently gone into tumor remission. The diagnosis of PNS is more difficult in patients who develop less characteristic symptoms (e.g., brainstem dysfunction, myelopathy), especially if no antibodies are found in the serum or CSF. Most PNSs have an acute or subacute onset compared with noninflammatory neu- rodegenerative disorders that are chronically progressive. If the patient is known to have cancer, the possibility of metastases and nonmeta- static neurological complications of cancer (side effects of treatment, metabolic encephalopathy, infection, or cerebrovascular disorders resulting from coagulopathy) should be considered before the diag- nosis of PNS. Novel immunotherapeutic treatment strategies such F ECF FH HE @ @AE C @AE C HE @ SPECIFIC PARANEOPLASTIC NEUROLOGICAL SYNDROMES AND THEIR TREATMENT Paraneoplastic Cerebellar Degeneration Paraneoplastic cerebellar degeneration (PCD) is characterized rapid development of severe pancerebellar dysfunction, including truncal and appendicular ataxia, dysarthria, and downbeat Frequently the symptoms of cerebellar dysfunction are preceded by dizziness and vertigo, suggesting peripheral vestibular dysfunction. adults, the subacute onset of PCD differentiates it from chronic erative diseases of the cerebellum. A subset of patients with SCLC develops PCD associated with Lambert-Eaton myasthenic syndrome (LEMS), often before the tumor is diagnosed (Mason et al., some cases LEMS may be overlooked unless it occurs prior to the onset of PCD. The tumors more frequently associated with PCD are SCLC, breast and ovarian tumors, and Hodgkin lymphoma (Shams’ili 2003). Anti-Yo (PCA1) is the most frequent antibody found in PCD and is usually associated with breast or gynecological tumors et al., 1992). Anti-Yo antibodies have been identified in patients with PCD and cancer of the salivary gland, lung, gus. Some patients with predominant truncal ataxia, opsoclonus, and other ocular movement abnormalities may harbor an antibody called anti-Ri. In such cases, the tumor is usually a breast carcinoma frequently, gynecological cancer, bladder cancer, or SCLC (Luque et al., 1991). These patients may also develop dementia, peripheral neuropathy, axial rigidity, myoclonus, brainstem encephalitis, and laryngeal spasms (Pittock et al., 2010). In patients with SCLC the development of PCD may be the pre- senting symptom of paraneoplastic encephalomyelitis (PEM) in which case other areas of the nervous system become involved and anti-Hu or anti-CV2/CRMP5 antibodies are usually identified (Fig. 81.1). Patients with symptoms restricted to cerebellar dysfunction and neg- ative anti-Hu antibodies often harbor voltage-gated calcium channel (VGCC) antibodies (Graus et al., 2002). Patients with PCD associated with Hodgkin disease develop Tr antibodies (Graus et al., 1997); these antibodies are directed against Delta/Notch-like epidermal tor-related receptor (DNER). The neurological disorder may develop before or after the diagnosis of the lymphoma, sometimes heralding tumor recurrence. Sox1 antibodies are found in about 50% of patients with PCD and SCLC but are not found when PCD is associated with other cancers (Sabater et al., 2013). Antibodies reported in isolated cases or small series of patients with acute to subacute onset ataxia and cancer have been shown to target protein kinase Cγ (PKCγ), carbonic anhydrase related protein 8 (CARPVIII), or tripartite motif-containing (TRIM) protein 9 or TRIM protein 67 (Bataller et al., 2004; Do et al., 2019; Hoftberger et al., 2013). These antibodies should be considered in patients for whom there is a strong suspicion of PCD and who do not have any of the more com- mon PNS-associated antibodies. Several single case reports describe patients with PCD who improved after treatment of the tumor, plasma exchange, intravenous immunoglobulin (IVIG), rituximab, or immunosuppression with cyclophosphamide or corticosteroids (Blaes et al., 1999; Shams’ili et al., 2006). However, due to early, irreversible neuronal loss most patients with PCD do not improve with any of these treatments (Vedeler et al., 2006) (see Fig. 81.1). Paraneoplastic Encephalomyelitis Patients with PEM develop features of dysfunction at different levels of the neuraxis (Dalmau et al., 1992; Graus et al., 2001; Sillevis et al., 2002). Many patients will develop a sensory neuronopathy (see para- neoplastic sensory neuronopathy [PSN]) and cerebellar dysfunction: F ECF FH HE @ @AE C @AE C HE @ 1258 PART III Neurological Diseases and Their Limbic and Brainstem Encephalitis Patients with limbic encephalitis have memory deficits with relative preservation of other cognitive functions. The memory deficits may be masked by concurrent confusion, depression, agitation, and anxi- ety. Complex partial seizures are also common. Brainstem encephalitis is characterized by oscillopsia, diplopia, dysarthria, dysphagia, gaze abnormalities, and sometimes subacute hearing loss. Limbic encephalitis is one of the few PNSs in which neuroimaging can suggest the diagnosis. Typical MRI findings include unilateral or bilateral mesial temporal lobe abnormalities best seen on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Gultekin et al., 2000; Ances et al., 2005). The temporal-limbic regions may be hypointense on T1-weighted sequences and rarely enhance with contrast. Limbic and brainstem encephalitis occur in both paraneoplastic and non-paraneoplastic settings. The cancers most commonly asso- ciated are SCLC, testicular germ-cell tumors, teratoma (usually of the ovary), thymoma, and Hodgkin lymphoma (Gultekin et al., 2000). The immune responses in limbic and brainstem encephalitis are classified according to the location of the target antigen; intracellular or on the neuronal cell surface. The main intracellular antigens are Hu, Ma2, and less commonly CV2/CRMP5. In patients with Hu antibod- ies, limbic encephalitis usually develops as part of a more widespread disorder such as PEM (Dalmau et al., 1992). Most of these patients have SCLC (Alamowitch et al., 1997). Men younger than 45 years of age with symptoms of limbic, hypothalamic, and brainstem dysfunction are likely to have antibod- ies against Ma proteins and an underlying germ cell tumor of the testis (Dalmau et al., 1999). Ma antibodies are also encountered in older patients with similar neurological symptoms and other cancers (Dalmau et al., 2004). In contrast to patients with Hu antibodies, in whom the lower brainstem is predominantly affected and symptoms progress in an upward direction, patients with Ma antibodies often present with an upper brainstem syndrome with vertical gaze palsy or hypokinesis, and symptoms progress in a downward direction (Saiz et al., 2009). Limbic or brainstem encephalitis associated with CV2/CRMP5 antibodies usually form part of a syndrome that may include cerebel- lar ataxia, chorea, uveitis, optic neuritis, or sensorimotor neuropathy (Honnorat et al., 1997). CV2/CRMP5 antibodies can co-occur with Hu antibodies, in which case patients almost always have multifocal deficits or PEM. Limbic encephalitis is a frequent manifestation of autoimmune encephalitis syndromes that are associated with antibodies to neuronal cell surface or synaptic proteins such as AMPA or GABAb receptors, LGI1 and Caspr2 proteins. These disorders are discussed further in the chapter on autoimmune encephalopathies with antibodies to cell sur- face antigens. In general, limbic and brainstem encephalitis associated with anti- bodies targeting intracellular antigens show limited response to treat- ment of the tumor or immunotherapy. About one-third of patients with syndromes associated with antibodies against Ma proteins show neurological improvement after treatment of the tumor (usually a testicular germ-cell neoplasm) and immunotherapy (Dalmau et al., 2004). Paraneoplastic Opsoclonus-Myoclonus Opsoclonus-myoclonus consists of spontaneous, arrhythmic, large-amplitude conjugate saccades occurring in all directions of gaze that are associated with myoclonus of the head, trunk, or extremities. In children, paraneoplastic opsoclonus-myoclonus usually has a sub- acute onset with staggering and falling, suggesting the diagnosis of F ECF FH HE @ @AE C @AE C HE @ D AC FD DPPX) (Martinez-Hernandez et al., 2016). Antibodies to GAD are more frequent in patients with SPS or with overlapping syndromes, while antibodies to αGlyR are more often associated with PERM (Carvajal-Gonzalez et al., 2014). The type of antibody and severity of symptoms—but not the syndrome—appear to correlate with out- come; αGlyR antibodies associate with better outcome compared with GAD antibodies or being seronegative, the latter 2 groups having sim- ilar outcomes (Martinez-Hernandez et al., 2016). The majority of SPSDs are not paraneoplastic except for those asso- ciated with amphiphysin antibodies, which usually occur with breast cancer (Pittock et al., 2005); for αGlyR antibodies the frequency of an underlying malignancy is about 10%–20% (Carvajal-Gonzalez et al., 2014). Patients with SPSD or αGlyR antibodies are more responsive to immunotherapy than those who do not harbor antibodies or who have antibodies against GAD or amphiphysin (Martinez-Hernandez et al., 2016). Treatment of the tumor, corticosteroids, and IVIG may improve paraneoplastic SPS; the usefulness of IVIG has been demonstrated in patients with non-paraneoplastic SPS (Dalakas et al., 2001). GABA- enhancing agents, such as benzodiazepines, gabapentin, or baclofen among others, provide symptomatic relief. Paraneoplastic Sensory Neuronopathy PSN is characterized by progressive sensory loss that may involve limbs, trunk, and face, and sometimes sensorineural hearing loss. Painful dysesthesias are common. At onset, symptoms are usually asymmetrical and can be confused with radiculopathy or polyneu- ropathy. All modalities of sensation are eventually affected, and, with progression, the sensory deficits result in sensory ataxia, gait difficulty, and pseudoathetoid movements. In the majority of cases the clinical picture progresses rapidly over a few weeks, although about 10% of cases have a chronic, less severe course (Graus et al., 1994). PSN may develop alone or more commonly in association with PEM (Dalmau et al., 1992; Graus et al., 2001). Neurological dysfunction precedes the cancer diagnosis in two-thirds of patients. Typically, nerve conduction studies show small-amplitude or absent sensory nerve action poten- tials (SNAPs), although motor nerve and F-wave studies are usually normal. These findings are consistent with the pathological involve- ment of the neurons of the dorsal root ganglia, but some patients also have electrophysiological evidence of axonal and demyelinating neu- ropathy (Camdessanche et al., 2002; Oh et al., 2005). The CSF often shows an increased protein level with pleocytosis, oligoclonal bands, and intrathecal synthesis of IgG. For patients with no known cancer, PSN should be suspected when sensory symptoms develop subacutely and asymmetrically, and involve the trunk and cranial nerves, partic- ularly if the patient is a smoker. One study comparing the clinical fea- tures of sensory neuronopathies due to a variety of causes paraneoplastic cases more often had subacute onset, were older (> 60 years) men, and there was early pain and frequent involvement of the arms (Camdessanche et al., 2012). Approximately 80% of patients with PSN have cancer of the lung, usually SCLC, but virtually any type of neoplasm may be found. The anti-Hu antibody is almost always detected in the serum of patients with PSN and SCLC but is rarely present in PSN associated with other tumors (Molinuevo JL et al., 1998; Honnorat et al., 2009). A few patients with PSN have been reported with antibodies to amphiph- ysin or CV2/CRMP5 (Saiz et al., 1999; Antoine et al., 2001). Patients with CV2/CRMP5 antibodies often have motor involvement and evi- dence of axonal and demyelinating features on electrophysiological studies (Antoine et al., 2001); in these patients the symptom presenta- tion can also be asymmetrical and associated with pain (Dubey et al., 2018). F ECF FH HE @ @AE C @AE C HE @ 1260 PART III Neurological Diseases and Their reacts with myelin-associated glycoprotein tend to have sensorimotor axonal loss and demyelination while patients with IgM targeting sul- fatide have sensory axonal loss (Levine et al., 2006). The neuropathy may respond to treatment directed at the Waldenström macroglob- ulinemia including plasma exchange, IVIG, rituximab, chlorambucil, cyclophosphamide, or fludarabine (Latov, 2000; Weide et al., 2000). POEMS syndrome stands for polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. This syndrome may result from sclerotic myeloma or Castleman disease, among others. While not all features must be present for the diagnosis to be made, peripheral neuropathy is one of the mandatory criteria for a POEMS diagnosis (Dispenzieri, 2012). The neuropathy is typically a sub- acute or chronic demyelinating, symmetric, ascending sensorimo- tor neuropathy. This presentation and the fact that there can be CSF albumin-cytologic dissociation often leads to an initial diagnosis of CIDP (Isose et al., 2011). A series comparing patients with POEMS and CIDP showed that patients with POEMS were significantly more likely to have muscle atrophy, distal muscle weakness, and severe leg pain (Nasu et al., 2012). Electrophysiological studies demonstrate that the neuropathy of POEMS has more marked features of axonal loss with greater reductions in compound muscle action potential (CMAP) and SNAP amplitudes, compared to CIDP, among other differentiat- ing features (Mauermann et al., 2012). Treatment of the plasma cell dyscrasia can result in improvement of the neuropathy and includes high-dose alkylator chemotherapy with peripheral blood stem cell transplant or low-dose alkylator chemotherapy with corticosteroids (Dispenzieri, 2014). The use of gabapentin, pregabalin, amitriptyline, and related medications may help if the neuropathy is associated with pain (Dispenzieri, 2012). Castleman disease (also called angiofollicular lymph node hyper- plasia) is a lymphoproliferative disorder that can present with uni- centric or multicentric disease. About one-third of patients with multicentric Castleman disease also fulfill criteria for POEMS syn- drome (Dispenzieri et al., 2012). However, compared with POEMS, the neuropathy in Castleman disease tends to be less severe and mostly sensory (Naddaf et al., 2016). Treatment is aimed at the underlying lymphoproliferative disorder and may include resection or radiation for unicentric disease and immunotherapy with or without cortico- steroids for multicentric disease (Mitsos et al., 2018; van Rhee et al., 2018). An acute to subacute paraneoplastic polyradiculoneuropathy clinically identical to GBS appears to occur at a higher frequency in patients with cancer (Vigliani et al., 2004). The neoplasm most com- monly implicated is Hodgkin lymphoma but other cancers including solid tumors have been reported. In some patients, GBS may be the first manifestation of tumor recurrence. Treatment is the same as for the noncancer-related form and consists of plasma exchange and IVIG. There is some evidence suggesting that patients with cancer-associated GBS have worse neurological outcome compared to patients with GBS without cancer (Vigliani et al., 2004). In a patient with cancer the dif- ferential diagnosis of GBS should include leptomeningeal carcinoma- tosis or neurolymphomatosis. These cases tend to have asymmetric involvement, are often associated with pain, and do not evolve acutely. The use of immune checkpoint inhibitors may also lead to adverse effects resembling GBS. These adverse effects often respond to immu- notherapy and discontinuation of the immune checkpoint inhibitor (Graus and Dalmau, 2019). Lambert-Eaton Myasthenic Syndrome The onset of LEMS symptoms is usually progressive over weeks or months. In most patients the symptoms develop before the tumor diagnosis has been made. Clinical features include fatigue, proximal F ECF FH HE @ @AE C @AE C HE @ D AC FD CHAPTER Myasthenia Gravis Myasthenia gravis (MG) is a postsynaptic disorder of neuromuscu- lar transmission. The main features are weakness and fatigability of skeletal muscles that improves with rest and worsens with activity (Gilhus, 2016). Ptosis and diplopia occur in most patients, and symp- toms remain localized to the extraocular and eyelid muscles in 15% of patients. In the rest, weakness becomes generalized and can impair res- piration to the extent that mechanical ventilation is necessary. Tendon reflexes and sensation are normal. A thymic epithelial tumor (thymoma or thymic carcinoma) is found in 10% of patients with MG, and one-third of patients with thymoma develop MG. In a few instances, MG has been reported in association with other tumors, including thyroid gland tumors, SCLC, breast cancer, and lymphoma. Antibodies to AChR are found in 80%–90% of patients with gen- eralized MG, and in 50% of those with ocular MG. A small percent of AChR-negative patients have antibodies to muscle-specific tyrosine kinase (MusK). Compared to patients with AChR antibodies, those with MusK antibodies have more prominent facial and bulbar involve- ment and more severe muscle weakness (Gilhus, 2016). Antibodies to lipoprotein receptor-related protein 4 (LRP4) are found in 1%–3% of all patients; the presence of these antibodies associates with mild to moderate symptoms. Thymoma-related MG almost invariably asso- ciates with AChR antibodies, but not anti-MusK or LRP4 antibodies. Patients with thymoma often have additional antibodies against skel- etal muscle proteins such as titin and ryanodine (Romi et al., 2005). Treatment strategies for MG include symptomatic treatment (e.g., acetylcholinesterase inhibitors) immunomodulation (e.g., plasma exchange, IVIG), immunosuppression (e.g., steroids, azathioprine, methotrexate, and others) and treatment of the tumor if found (Skeie et al., 2010). Dermatomyositis Dermatomyositis and polymyositis are immune-mediated inflam- matory diseases of muscle. An association exists between cancer and dermatomyositis in adults (Yang et al., 2015), but an association with malignancy is less clear for polymyositis, with cohort studies report- ing conflicting results (Chen et al., 2010; Antiochos et al., 2009). The symptoms of paraneoplastic dermatomyositis are the same as those in patients without cancer. The typical neurological presentation is the subacute onset of proximal muscle weakness. Neck flexors and pharyn- geal and respiratory muscles are commonly involved and may lead to dysphagia and aspiration. Facial weakness and dysarthria can occur but are uncommon. Cutaneous changes include periorbital purplish dis- coloration (heliotrope rash), edema and erythematous lesions over the knuckles (Gottron papules), and an erythematous macular rash on the face, neck and chest, shoulders and upper back. Tendon reflexes and sensation are normal. Serum creatine kinase concentrations are often elevated, although normal levels are occasionally found, even in patients with profound muscle weakness. Electromyography (EMG) shows increased spontaneous activity (fibrillations, positive sharp waves, and complex repetitive discharges), and short-duration, low-amplitude polyphasic motor unit action potentials on voluntary activation. Muscle histology shows inflammatory infiltrates (CD4+ T cells predominate in dermatomyositis and CD8+ T cells in polymyositis) and muscle necro- sis; the presence of perifascicular atrophy is characteristic of dermato- myositis, but is only found in about half of patients (Dalakas, 2002). About 10%–15% of adults with dermatomyositis develop a malig- nancy, usually within 2–3 years of presentation (Yang et al., 2015). Juvenile-onset dermatomyositis is not cancer-associated. Many histo- logical types of cancers have been reported in association with der- matomyositis. The most common are hematological and lymphatic F ECF FH HE @ @AE C @AE C HE @ D AC FD 1262 PART III Neurological Diseases and Their (ERG). Funduscopic examination is frequently normal, or may show nonspecific optic disc pallor and arteriolar narrowing. When one eye is affected, the other becomes symptomatic within days or weeks. Imaging studies and evaluation of the CSF are not revealing. Melanoma-associated retinopathy (MAR) affects patients with metastatic cutaneous melanoma (Boeck et al., 1997). Patients typically present with the acute onset of night blindness and shimmering, flick- ering, or pulsating photopsias. Symptoms often progress to complete visual loss. The ERG typically demonstrates reduction in the b-wave amplitude. Paraneoplastic optic neuritis is very uncommon, and, although it may develop in isolation, it is usually associated with PEM. The onset is subacute with painless, bilateral visual loss. Papilledema may be present. Bilateral diffuse uveal melanocytic proliferation is a rare syndrome that has largely been described in patients with advanced cancers who develop rapid and severe vision loss due to accumulation of uveal tract melanocytes leading to retinal detachment (Gass et al., 2003). Funduscopic examination is often initially normal but eventually shows multiple round or oval pigmented and nonpigmented patches. Fluorescein angiography reveals multifocal hyperfluorescence corre- sponding with these patches. The underlying mechanism of the mela- nocytic proliferation has not been elucidated. F ECF FH HE @ @AE C @AE C HE @ D AC FD Antibodies OUTLINE Specific Syndromes, 1264 Anti-NMDAR Encephalitis, 1264 Anti-GABAB Receptor Encephalitis, 1265 Anti-AMPA Receptor Encephalitis, 1265 Anti-LGI1 Limbic Encephalitis, 1265 Anti-CASPR2 Associated Encephalitis, 1266 Anti-GABAA Receptor Encephalitis, 1266 Autoimmune encephalitis with antibodies to neuronal cell surface/ synaptic antigens (further referred to as autoimmune encephalitis) are a group of neuropsychiatric disorders (Table 82.1) in which the antibodies produce neuronal dysfunction by direct interaction with their target antigen (Dalmau et al., 2017, 2018). These disorders can occur with and without a cancer association and while they affect individuals of all ages, some syndromes preferentially affect young adults and children (Armangue et al., 2012; Wells et al., 2018). The antibody effects are reversible and although the process of recov- ery can be prolonged, patients with autoimmune encephalitis often have full or substantial recovery after immunotherapy. Autoim- mune encephalitis syndromes are therefore different from the clas- sical paraneoplastic encephalitis that are always cancer associated and in which the associated antibodies target intracellular neuro- nal proteins but do not directly mediate the neuronal dysfunction. Rather in the classical paraneoplastic encephalitis, T-cell mecha- nisms appear to play a predominant role and the neuronal effects are often irreversible (Dalmau et al., 2017, 2018). Patients with autoimmune encephalitis develop complex neuro- psychiatric symptoms including memory loss, changes in behavior or cognition, psychosis, seizures, and movement disorders. At pre- sentation one or a few of these symptoms may predominate and can mislead the diagnosis until additional symptoms develop over days or weeks. Patients may initially be diagnosed with idiopathic encephalitis, likely viral but with negative viral studies. Autoimmune encephalitis should be included in the differential diagnosis of any patient, especially if young, with a rapidly progressive encephalopa- thy of unclear origin. For some disorders such as anti-N-methyl-d- aspartate receptor (NMDAR) encephalitis, patients may initially be given a primary psychiatric diagnosis, and the accompanying signs and symptoms such as abnormal movements or fever erroneously ascribed to the use of antipsychotic medication (Kayser et al., 2013; Lejuste et al., 2016). Some patients with autoimmune encephalitis, especially those with NMDAR antibodies, experience a viral-like prodrome including lethargy, headache, upper respiratory symp- toms, nausea, diarrhea, among others (Titulaer et al., 2013). In some F ECF FH HE @ @AE C @AE C HE @ D AC FD 1264 PART III Neurological Diseases and TABLE 82.1 Autoimmune Encephalitis with Antibodies Antigen Target Syndrome NMDA receptor Psychiatric symptoms, seizures, decreased level of consciousness, seizures, and autonomic disturbances GABAB receptor Limbic encephalitis with prominent seizures AMPA receptor Limbic encephalitis with prominent psychiatric symptoms LGI1 Limbic encephalitis. About 60% develop hyponatremia, and less often REM behavior disorder. About 30%–40% patients faciobra- chial dystonic seizures that encephalitis. CASPR2 Morvan syndrome, limbic encephalitis, neuro- pathic pain, peripheral nerve GABAA receptor Rapidly progressive, severe encephalopathy refractory seizures DPPX Agitation, paranoia, hallucinations, tremor, myoclonus, and/or seizures. Less often cerebellar signs, hyperekplexia, syndrome. Symptoms are usually severe diarrhea mGluR5 Encephalitis, no specific syndrome mGluR1 Cerebellar ataxia Dopamine receptor 2 Infrequent cases of basal ganglia encephalitis, Sydenham chorea Neurexin 3α Encephalopathy with seizures IgLON5 Encephalopathy with REM and non-REM parasomnias, obstructive sleep apnea, stridor preceded by or concurrent with gait dysfunc- tion, chorea, and cognitive decline AMPA, Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic protein 6; FLAIR, fluid attenuated inversion recovery; GABAA, decarboxylase; IGLON5, immunoglobulin-like cell adhesion molecule receptor 5; mGluR1, metabotropic glutamate receptor 1; MRI, alomyelitis with rigidity and myoclonus; REM, rapid eye movement. SPECIFIC SYNDROMES Anti-NMDAR Encephalitis Anti-NMDAR encephalitis is the most frequent antibody-associated encephalitis and the second most common cause of immune-medi- ated encephalitis after acute disseminated encephalomyelitis (ADEM) (Granerod et al., 2010). It is most common in young women and children who represent about 80% of patients but can also affect men and older individuals. The syndrome is highly characteristic and usu- ally occurs as a multistage process. Patients develop acute psychiatric symptoms, seizures, memory deficits, decreased level of conscious- ness, and dyskinesias (orofacial, limb, and trunk) (Dalmau et al., 2008; Titulaer et al., 2013). Autonomic instability is common, and, in some patients, it results in central hypoventilation, often requiring weeks of mechanical ventilation. Many adults are initially evaluated by psychi- atry services. Patients or their families should be questioned about a F ECF FH HE @ @AE C @AE C CHAPTER 82 Autoimmune Fig. 82.1 Antibodies to GluN1 subunit of the NMDA receptor with anti-NMDAR encephalitis. Live rat hippocampal neurons with the patient’s CSF are immunolabeled with antibodies against cell surface antigens; subsequent characterization demonstrated that the antigen is the GluN1 subunit of the NMDA receptor. CSF, Cerebrospi- nal fluid; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor. In almost 80% of patients the CSF shows lymphocytic pleocyto- sis and, less commonly, increased proteins and/or oligoclonal bands. About 35% of the patients have increased signal on MRI FLAIR/T2 sequences and less often, faint or transient contrast enhancement of with older patients more likely to have cancer. The presenting features F ECF FH HE @ @AE C @AE C HE @ D AC FD 1266 PART III Neurological Diseases and Their 60% of patients also develop hyponatremia and less often rapid eye movement (REM) sleep behavior disorders, which can be additional clues in formulating the differential diagnoses (Lai et al., 2010). About 30%–40% of patients develop brief tonic or myoclonic-like seizures (also called faciobrachial dystonic seizures) (Irani et al., 2011). In a few cases patients develop additional symptoms of peripheral nerve hyper- excitability (PNH) (Morvan syndrome). The rapidly progressive mem- ory disturbance along with myoclonic-like movements can lead to the suspicion of rapid onset dementia such as Creutzfeldt-Jakob disease. In one study, about 15% of patients presented with rapidly progressive cognitive deficits with no clear evidence of encephalitis (Arino et al., 2016). The disorder is usually not cancer associated, and less than 10% of patients have an underlying neoplasm, usually a thymoma. The MRI often shows findings typical of limbic encephalitis, although seizures can result in similar abnormalities, confounding interpretation. The CSF is usually normal, although mild inflammatory changes or oligo- clonal bands may be present; despite normal routine CSF studies, the antibodies are almost always detectable in both serum and CSF. Patients’ antibodies target LGI1, a secreted neuronal protein that interacts with pre- and postsynaptic epilepsy-related proteins (Fukata et al., 2006). The antibodies cause a decrease of Kv1.1 and AMPAR altering pre- and postsynaptic signaling and resulting in neuronal hyperexcitability (Petit-Pedrol et al., 2018). Mutations in linked to the human disorder, autosomal dominant lateral temporal lobe epilepsy (also called autosomal dominant partial epilepsy with auditory features) (Gu et al., 2002; Kalachikov et al., 2002). About 80% of patients have substantial responses to immuno- therapy although many are left with deficits that prevent them from returning to work. Relapses occur in about 27%–35% of the patients (Arino et al., 2016; van Sonderen et al., 2016b). Anti-CASPR2 Associated Encephalitis Patients with contactin-associated protein-like 2 (CASPR2) antibod- ies often develop symptoms involving both the central nervous system (e.g., encephalopathy, cerebellar dysfunction, hallucinations, seizures, insomnia, autonomic dysfunction) and peripheral nervous system (PNH, neuropathy, allodynia) (Irani et al., 2012; Lancaster et al., 2011a; van Sonderen et al., 2016a). The combination of the indicated CNS symptoms and PNH is called Morvan syndrome. Rare cases of isolated limbic encephalitis or PNH have been reported. Patients may have other coexisting immune-mediated disorders such as myasthe- nia gravis with anti-acetylcholine (AChR) or muscle-specific kinase (MuSK) antibodies (Fleisher et al., 2013). Anti-CASPR2 associated encephalitis is usually not cancer related, and those patients with a tumor (most commonly thymoma) are more likely to have Morvan syndrome as opposed to isolated central or PNH symptoms. In contrast to most of the autoimmune encephalitis (LGI1, DPPX, and IgLON5 are other exceptions), antibodies to CASPR2 are primar- ily of the IgG4 isotype. Studies suggest that patient CASPR2 antibod- ies interfere with the normal clustering of VGKCs at juxtaparanodes, resulting in hyperexcitability of peripheral nerves (Patterson et al., 2018). Anti-GABAA Receptor Encephalitis The median age of patients with this syndrome is 40 years, but it may occur in children and adolescents. Patients develop a progressive, severe encephalopathy that in 90% of cases includes refractory sei- zures with frequent status epilepticus. Other symptoms include cog- nitive impairment, altered behavior, decreased consciousness, and movement disorders (Petit-Pedrol et al., 2014; Spatola et al., 2017). Over half of the patients have CSF abnormalities, including pleocyto- sis, increased proteins, and/or oligoclonal bands. In contrast to other F ECF FH HE @ @AE C @AE C HE @ D AC FD CHAPTER 82 Autoimmune A Fig. 82.2 A, Brain MRI of a patient increased FLAIR signal involving the patients with AMPA or GABAB receptor B, Brain MRI of a patient with GABAA cortical and subcortical regions. These weighted imaging rarely show restricted in an asynchronous manner, are highly patients with other types of antibody-mediated azolepropionic acid; CASPR2, contactin-associated GABAA, gamma-aminobutyric acid A; GABAB, tivated 1; MRI, magnetic resonance imaging. 2011;77(2):179–189 and Spatola et patients, the MRI showed FLAIR abnormalities in limbic or extralimbic regions. There was a tumor association in about half of the cases (most commonly Hodgkin lymphoma, and one patient reported with SCLC). Patients can respond to immunotherapy and tumor treatment when appropriate, but can have relapses. Anti-mGluR1 Cerebellar Dysfunction Cerebellar ataxia in association with antibodies to the mGluR1 receptor was initially described in two patients with a history of Hodgkin dis- ease (Sillevis et al., 2000). Since then a few additional patients have been reported but other than one patient with a T-cell lymphoma, the disorder was not cancer related (Lopez-Chiriboga et al., 2016). All patients devel- oped cerebellar ataxia, and rarely cognitive changes, psychiatric symp- toms, and/or seizures. Some patients responded to early administrat of immunotherapy. Injection of patient antibodies to the subarachnoid space near the cerebellum resulted in progressive ataxia, suggesting a direct pathogenic role of the antibodies in the disorder (Sillevis et al., 2000). Anti-Dopamine Receptor Encephalitis A very rare number of patients, mostly children with basal ganglia encephalitis, Sydenham chorea, or Tourette syndrome have been reported to have antibodies to the dopamine-2 receptor (Dale et al., 2012). There is preliminary evidence that the antibodies have patho- genic effects. These antibodies have also been found in some patients with autoimmune encephalitis, which developed after a herpes simplex viral infection. Most of these patients have concurrent antibodies to NMDAR. Patients can have full recovery with early immunotherapy (Dale et al., 2012). F ECF FH HE @ @AE C @AE C HE @ 1268 PART III Neurological Diseases and Their apnea and stridor. The brain MRI, EEG, CSF studies, and electromy- ography are usually normal. In the patients who were studied, the CSF hypocretin levels were normal. Autopsy studies of six patients showed neuronal loss and gliosis associated with an atypical tauopathy mainly involving the tegmentum of the brainstem and the hypothalamus. There was no glial pathology, grains, or globular glial inclusions that would allow classification of these cases within any of the presently known tauopathies (Gelpi et al., 2016). All patients have antibodies targeting immunoglobulin-like cell adhesion molecule 5 (IgLON5), a member of the IgLON family, which is part of the immunoglobulin superfamily of cell adhesion molecules. The antibodies are predominantly of the IgG4 subclass, and there is a strong association with the HLA-DRB1*10.01 allele (Gaig et al., 2017). The IgLON proteins appear to play a role in neuronal pathfind- ing and synaptic formation although the exact function of IgLON5 is unknown. GENERAL TREATMENT RECOMMENDATIONS The optimal management of these disorders is still being elucidated, and current recommendations are largely derived from the experience with anti-NMDAR encephalitis (Titulaer et al., 2013). Based on data that demonstrate a pathogenic role of the antibodies, treatments are focused F ECF FH HE @ @AE C @AE C HE @ D AC FD 81 Myrna R. Rosenfeld, Josep Dalmau Vasculitis of the Nerve, 1259 Subacute and Chronic Peripheral Neuropathies, 1259 Peripheral Neuropathy Associated with Plasma Cell Dyscrasias and B-Cell Lymphoma, 1259 Lambert-Eaton Myasthenic Syndrome, 1260 Myasthenia Gravis, 1261 Dermatomyositis, 1261 Necrotizing Autoimmune Myopathy, 1261 Paraneoplastic Visual Syndromes, 1261 Table 81.2). In approximately 65% of patients with PNS, the neuro- logical symptoms precede the tumor diagnosis (Giometto et al., 2010). Therefore in the right clinical context the detection of a paraneoplastic antibody in the serum or CSF helps to diagnose the PNS and focus the search for the neoplasm (Graus et al., 2004). Most paraneoplastic neu- ronal antibodies can also be detected, usually at low titers, in the serum of a variable proportion of patients with cancer but without PNS (Monstad et al., 2009). Therefore, if the detected antibody does not correspond with the antibody that usually associates with the neuro- logical syndrome, other causes for the neurological dysfunction should be considered. Similarly, if the detected cancer is not the histological type typically found in association with the antibody (e.g., anti-Yo with lung cancer rather than breast or ovarian cancer), a second neoplasm should be suspected. A search for another neoplasm is required if the tumor cells do not express the target antigen of the paraneoplastic anti- body (Graus et al., 2001). Clinical experience suggests that detection of paraneoplastic antibodies in CSF confirms that the neurological disor- der is paraneoplastic. The diagnosis of PNS can be made to different degrees of certainty by taking into consideration the type of syndrome, detection of a tumor, and presence or absence of paraneoplastic antibodies (Graus et al., 2004). The diagnosis of PNS is relatively straightforward for patients who develop symptoms of a well-defined syndrome that is typically associated with cancer. Patient age is important because symptoms that associate with paraneoplastic mechanisms in adults (e.g., subacute cerebellar dysfunction) are less typical of paraneoplasia in children. Conversely, the development of opsoclonus in children is often para- neoplastic, but in adults is less suggestive of a paraneoplastic cause. In these settings, the detection of an antibody known to be associated with PNS or cancer is practically confirmatory of paraneoplasia. If a cancer is not discovered, the presence of an occult neoplasm is assumed unless proven otherwise. Body [18F]- fluorodeoxyglucose-positron emission tomography (FDG-PET) scans can detect tumors that escape detec- tion by other standard imaging methods (Garcia Vicente et al., 2017; 1255 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Their Treatment TABLE 81.2 Paraneoplastic Anti-neuronal Antibodies, Associated Syndromes, and Cancers* Associated Antibody Syndrome Cancers Anti-Hu (ANNA1) Focal encephalitis, PEM, PCD, SCLC, other PSN, autonomic dysfunction Anti-Yo (PCA1) PCD Gynecological, breast Anti-Ri (ANNA2) PCD, opsoclonus-myoclonus Breast, gynecological, SCLC Anti-Tr PCD Hodgkin lymphoma Anti-CV2/CRMP5 PEM, PCD, peripheral SCLC, other neuropathy chorea, uveitis Anti-Ma proteins† Limbic, diencephalic, Germ cell tumors of brainstem encephalitis, testis, other solid PCD tumors Anti-VGCC‡ LEMS, PCD SCLC Anti-AChR‡ MG Thymoma Anti-amphiphysin Stiff-person syndrome, PEM Breast Anti-recoverin or Retinopathy SCLC against other retinal proteins Anti-bipolar cells Retinopathy Melanoma of the retina *Does not include antibodies against extracellular neuronal antigens, which associate with the autoimmune encephalitis syndromes; these syndromes may occur with or without cancer and are not discussed in this chapter. †Patients with antibodies to Ma2 are usually men with testicular can- cer. Patients with additional antibodies to other Ma proteins are men or women with a variety of solid tumors. ‡These antibodies are markers for the neurological disorder and can occur in patients with or without cancer. These neurological disorders (MG, LEMS) frequently associate with specific cancers and cancer screenings are recommended in all patients with these diagnoses. AChR, Acetylcholine receptor; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; PCD, paraneoplastic cerebellar degeneration; PEM, paraneoplastic encephalomyelitis; PSN, paraneo- plastic sensory neuronopathy; SCLC, small-cell lung cancer; VGCC, volt- age-gated calcium channels. and myeli- as chimeric antigen receptor (CAR) T cells and immune checkpoint inhibitors can produce a wide variety of immune-related neurological complications, including CAR T-cell–related encephalopathy caused by cytokine-release syndrome (Neelapu et al., 2018), or immune-re- lated adverse events caused by immune checkpoint blockade. In fact, there is evidence that immune checkpoint blockade can favor the development of PNS, which may be associated with classic paraneo- plastic neuronal antibodies targeting intracellular antigens or antibod- ies against neuronal cell surface antigens (Graus and Dalmau, 2019). Neuroimaging, in particular magnetic resonance imaging (MRI), helps to exclude some of these complications. Brain FDG-PET in the early stages of some PNS of the CNS may show hypermetabolism in the involved regions even when MRI is normal, and may be indica- tive of early inflammatory changes (Basu and Alavi, 2008; Ances et al., 2005). The CSF profile in patients with PNS of the CNS often suggests an inflammatory process: pleocytosis, increased protein concentration, intrathecal synthesis of immunoglobulin (Ig)G, and oligoclonal bands (Psimaras et al., 2010). D AC FD 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD CHAPTER 81 Paraneoplastic Disorders of the Nervous System 1257 by the nystagmus. In degen- 1997). In A et al., (Peterson a few male and esopha- or, less B Fig. 81.1 A, Extensive loss of Purkinje cells in a patient with a subacute cerebellar syndrome in the context of encephalomyelitis and anti-Hu antibodies. The arrows showing clusters of CD3 T cells in Purkinje cell layer. B, A higher magnification of the Purkinje cell layer shows a neu- ronophagic nodule of T lymphocytes that are probably destroying a Pur- kinje cell. A: (A, ×100, immunostained for CD3 and counterstained with haematoxylin B: × 400 haematoxylin-eosin. (Reprinted with permission growth fac- from Dalmau et al., 2008.) gait ataxia, in particular. Limbic and/or brainstem encephalopathy (see limbic and brainstem encephalitis) occur in up to one-third of patients with PEM. Lower motor neuron involvement secondary to myelitis occurs in approximately 20%; the presence of symptoms affecting other areas of the neuraxis and MRI findings help to rule out pure motor neuron disorders (Flanagan et al., 2011). Approximately one- fourth of patients with PEM develop autonomic nervous system dys- function, including postural hypotension, gastroparesis and intestinal dysmotility, sweating abnormalities, neurogenic bladder, and erectile dysfunction. Cardiac dysrhythmias or respiratory failure are frequent causes of death. PEM, with or without PSN, can be associated with almost any tumor, but in the majority of patients the underlying tumor is lung carcinoma, particularly SCLC (Graus et al., 2001). Patients with PEM/ PSN and SCLC often have anti-Hu antibodies, and at a much lower frequency, anti-CV2/CRMP5 antibodies, or both. CV2/CRMP5 anti- bodies occur more frequently in the context of PEM with chorea, uve- itis, or peripheral neuropathy that is different from PSN (Dubey et al., 2018; Vernino et al., 2002). Anti-CV2/CRMP5 antibodies are also associated with thymoma and other cancers (Benyahia et al., 1999). In general, PEM is poorly responsive to treatment, although there are reports showing symptom stabilization or improvement with prompt treatment of the tumor and immunotherapy (Sillevis et al., 2002; Vernino et al., 2004). D AC FD 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Treatment acute cerebellitis; these symptoms are followed by body jerks, drool- ing, refusal to walk or sit, ataxia, opsoclonus, hypotonia, irritability, and sleep disturbances (Russo et al., 1997; Tate et al., 2005). In adults, symptoms range from opsoclonus with mild truncal ataxia to a more severe syndrome characterized by opsoclonus, myoclonus, ataxia, and encephalopathy that can lead to stupor and death (Bataller et al., 2001). In children, opsoclonus-myoclonus is usually a manifestation of neuroblastoma, although similar neurological symptoms may result from viral infections. The neurological symptoms precede the tumor diagnosis in 50% of patients. Children with neuroblastoma and opso- clonus have a better tumor prognosis than those without opsoclonus (Tate et al., 2005). In adults several underlying tumors have been reported, but the most common are SCLC and cancers of the breast and ovary. Studies have shown the presence of autoimmune responses against a variety of neuronal antigens but no clinically relevant opso- clonus-specific antibodies have been identified (Bataller et al., 2003; Armangue et al., 2016). Patients with breast and gynecological cancers usually harbor anti-Ri (ANNA2) antibodies (Luque et al., 1991). These patients often have additional brainstem and cerebellar dysfunction. Some adult patients, in particular those with SCLC, have anti-Hu or glycine receptor antibodies while 5% of children with neuroblastoma have anti-Hu antibodies (Armangue et al., 2016; Dalmau et al., 1995). In children, the ocular and motor symptoms may resolve spon- taneously or after immunotherapy and treatment of the tumor, if applicable (Bell et al., 2008; Pranzatelli et al., 2018). However, most children are left with cognitive and behavioral abnormalities and lan- guage and psychomotor deficits (Catsman-Berrevoets et al., 2009). Sleep disturbance may respond to trazodone (Pranzatelli et al., 2005). Paraneoplastic opsoclonus-myoclonus in adults may respond to immunosuppression and IVIG; spontaneous remissions rarely occur. Patients whose tumors are treated promptly have a better neurologi- cal outcome than those whose tumors are not treated (Bataller et al., 2001). In the latter group, the disorder often progresses to severe encephalopathy and death. Stiff-Person Spectrum Disorders These disorders share core features of muscle stiffness, spasms, and heightened stimulus sensitivity, but have distinct phenotypes. Stiff- person spectrum disorders (SPSDs) include stiff-person syndrome (SPS), progressive encephalomyelitis with rigidity and myoclonus (PERM), and stiff-limb syndrome (SLS). In some patients SPS or SLS can also overlap with other syndromes such as ataxia, epilepsy, or encephalitis (Malter et al., 2010; Saiz et al., 2008). In a series of 121 patients with SPSD, the median age was 51 years with a female pre- dominance (62% of the cases) (Martinez-Hernandez et al., 2016). SPS is characterized by stiffness and rigidity of the axial muscula- ture with superimposed spasms. Muscle stiffness primarily affects the lower trunk and legs, but it can extend to the arms, shoulders, and neck. Muscle spasms are usually precipitated by emotional upset and auditory or somesthetic stimuli. Electrophysiological studies show continuous activity of motor units innervating the stiffened muscles that improves after treatment with diazepam. The rigidity disappears during sleep and after local or general anesthesia (Espay and Chen, 2006). In SLS one or more limbs are affected with distal rigidity and abnormal posturing of the hands or feet (Saiz et al., 1998) whereas PERM can also associate with cerebellar, brainstem, or autonomic dys- function (Meinck and Thompson, 2002). Multiple auto-antigenic targets have been described. The most common are glutamic acid decarboxylase (GAD) and the α-subunit of the glycine receptor (αGlyR). About one-third of patients are sero- negative or rarely have other antibodies (e.g., amphiphysin, GABAaR, 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD CHAPTER 81 Paraneoplastic Disorders of the Nervous System 1259 Studies of patients with SCLC and anti-Hu-associated PSN and PEM indicate that neurological symptoms in patients whose tumors completely responded to therapy were more likely to stabilize or improve, as compared with those with untreated tumors or tumors that did not respond to therapy (Graus et al., 2001; Sillevis et al., 2002). In some patients, prompt treatment with corticosteroids may partially improve sensory deficits. The effects of IVIG, cyclophosphamide, or rituximab are uncertain although there are case reports of responses (Shams’ili et al., 2006; Giometto et al., 2012). Vasculitis of the Nerve Vasculitis of the nerve usually occurs in older men. It can present as a painful symmetric or asymmetric, subacute, sensorimotor polyneu- ropathy (Oh, 1997). Electrophysiological findings are compatible with multifocal neuropathy or diffuse axonal sensorimotor neuropathy (Zivkovic et al., 2007). The erythrocyte sedimentation rate and the CSF protein concentration are elevated. Nerve and muscle histology shows intramural and perivascular inflammatory infiltrates composed of CD8+ T cells (Vincent et al., 2007). The most common tumor asso- ciation is with SCLC. Less frequently found are lymphoma, cancer of the colon, kidney, bile duct, stomach, and prostate (Oh, 1997). The disorder has no specific serological markers of paraneoplasia, although patients with SCLC may have anti-Hu antibodies. The vasculitis often responds to treatment with steroids, cyclophosphamide, or both (Oh, 1997). Subacute and Chronic Peripheral Neuropathies A mild peripheral neuropathy is common in patients with cancer, especially in the advanced stages of the disease. The cause is multifac- torial and includes metabolic and nutritional deficits and toxicity from chemotherapy. Paraneoplastic sensorimotor neuropathy may develop before or after the diagnosis of cancer. The onset may be subacute or acute, with symmetric, distal paresthesias, occasionally associated with pain. The course is usually progressive. with late development of weakness. A relapsing and remitting course suggests chronic inflam- matory demyelinating polyneuropathy (CIDP) (Antoine et al., 1999). The tumors most commonly associated are lung and breast cancers; anti-neuronal antibodies are usually absent, but some patients with lung cancer or thymoma harbor CV2/CRMP5 antibodies (Antoine et al., 2001). Patients with electrophysiological signs of demyelination may improve with steroids or IVIG (Antoine et al., 1999). The use of immune checkpoint inhibitors may result in several types of immune-related adverse effects, including acute or subacute inflammatory neuropathies, and Guillain-Barré syndrome (GBS); dif- ferentiation from paraneoplastic syndromes can be challenging (Graus and Dalmau, 2019.) found that Peripheral Neuropathy Associated with Plasma Cell Dyscrasias and B-Cell Lymphoma Several malignancies of plasma cells and lymphocytes are associated with neuropathy and include multiple myeloma, Waldenström mac- roglobulinemia, POEMS syndrome, Castleman disease, and B-cell lymphoma. A sensorimotor neuropathy may develop in patients with multiple myeloma that is similar to those seen in other advanced can- cers. If the myeloma is complicated by amyloidosis, the neuropathic symptoms often include autonomic dysfunction and lancinating and burning dysesthesias. In both cases, treatment of the myeloma does not affect the neurological symptoms. Patients with Waldenström macroglobulinemia can develop a sym- metrical, demyelinating, sensorimotor neuropathy predominantly involving large sensory fibers, especially those for vibration sense, often resulting in gait disturbance. Patients whose IgM paraprotein D AC FD 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Treatment muscle weakness, and paresthesias with involvement of the legs as the most common initial symptom (Wirtz et al., 2002). Over time the weakness spreads proximally to distally (Titulaer et al., 2011a). Almost 80% of patients have autonomic dysfunction that includes dry mouth, erectile dysfunction, and blurry vision. Cranial nerve dysfunction may produce diplopia, ptosis, or dysphagia. Neurological examination shows proximal weakness, occurring in the legs more than the arms, and absent or depressed tendon reflexes, which may potentiate after a brief muscle contraction. Strength may improve after brief exercise, but continued exercise increases weakness. The diagnosis is based on electrophysiological studies. Nerve conduction studies show small- amplitude CMAPs. At slow rates of repetitive nerve stimulation (2–5 Hz), a decremental response of greater than 10% is obtained. At fast rates of repetitive nerve stimulation (20 Hz or greater) or after maximal voluntary muscle contraction, facilitation occurs and an incremental response of at least 100% is seen. LEMS can develop in association with other paraneoplastic syndromes such as PCD and PEM (Mason et al., 1997). Recurrence of LEMS after remission often heralds tumor recurrence. Approximately 60% of patients with LEMS have an underlying neoplasm, usually SCLC or rarely other tumors such as lymphoma. The non-paraneoplastic cases often have slower symptom presentation and associate with other autoimmune conditions such as thyroiditis and insulin-dependent diabetes mellitus, among others (Wirtz et al., 2002). The presence of LEMS in a patient with SCLC is associated with improved tumor survival (Maddison et al., 1999). The Dutch-English LEMS Tumor Association Prediction (DELTA-P) score can be used to predict patients with a high risk of an associated SCLC (Titulaer et al., 2011b). Aggressive tumor screening should be carried out as soon as the LEMS diagnosis is confirmed. In one study, 91% of SCLCs were detected within 3 months of LEMS onset and 96% within 1 year (Titulaer et al., 2008). The majority of patients with LEMS have serum antibodies against P/Q type VGCCs (Motomura et al., 1997). The antibodies interfere with the quantal release of acetylcholine at the presynaptic neuro- muscular junction, resulting in failure of neuromuscular transmis- sion. Antibodies to P/Q type VGCCs also occur in a subset of patients with SCLC and paraneoplastic PCD (with or without LEMS). There is a mouse model showing that cisternal injection of these antibodies produces cerebellar dysfunction (Martin-Garcia et al., 2013). When LEMS develops in association with PEM, patients often have anti-Hu antibodies. Detection of Sox1 antibodies in patients with LEMS pre- dicts the presence of SCLC and may be used to follow those LEMS patients with no evidence of cancer at the initial evaluation (Sabater et al., 2008). In about 10% of patients with LEMS no autoantibodies are detected. The clinical phenotype and electrophysiological features of seronegative patients are similar to the seropositive cases except for a lower incidence of SCLC (Nakao et al., 2002). Most patients with cancer improve neurologically with combined treatment of their cancer and therapy for LEMS. The latter includes medication to increase the release of acetylcholine (3,4-diamino- pyridine). and immunomodulation, resulting in improvement of muscle strength and mean resting CMAP amplitude in most patients. The use of 3,4-diaminopyridine results in moderate to marked neuro- logical improvement in 80% of patients (Keogh et al., 2011; McEvoy et al., 1989). Plasma exchange and IVIG are useful for treating severe weakness; strength improves within days or weeks, but the benefits are transient (Bain PG et al., 1996). Long-term immunosuppression with prednisone or azathioprine should be considered if symptoms continue despite the use of 3,4-diaminopyridine. Several reports have demonstrated responses to rituximab in patients who did not respond to other treatments (Maddison et al., 2011). 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD 81 Paraneoplastic Disorders of the Nervous System 1261 cancers (e.g., lymphoma, leukemia, multiple myeloma) followed by breast, lung, ovarian, and gastrointestinal malignancies. Risk factors for malignancy include older age, male gender, necrotic skin ulcer- ations, and rapid onset of symptoms. About 60%–70% of patients have a dermatomyositis-specific anti- body. These include antibodies to Mi-2, melanoma differentiation-as- sociated protein 5 (MDA5), transcriptional intermediary factor 1 (TIF1), and nuclear matrix protein 2 (NXP-2). The presence of anti- bodies to TIF1 or NXP-2, are predictive of an increased risk of malig- nancy (Fiorentino et al., 2013; Trallero-Araguas et al., 2012). In some patients, muscle and dermatological symptoms improve coincidently with treatment of the tumor. No studies are available on the efficacy of immunosuppressants in cancer-associated dermatomy- ositis, but it seems reasonable to use strategies similar to those used in non-paraneoplastic dermatomyositis (corticosteroids, methotrexate, azathioprine, mycophenolate mofetil, IVIG) (McGrath et al., 2018). Rituximab has been considered effective in some patients but its effi- cacy in general remains unclear (Nalotto et al., 2013). Necrotizing Autoimmune Myopathy This disorder is characterized by the acute to subacute onset of severe, progressive, and symmetric proximal muscle weakness (Allenbach et al., 2013). Neck weakness, dysphagia, and dyspnea are common. Serum creatine kinase concentrations are markedly elevated and elec- trophysiological studies demonstrate myopathic findings. Muscle histology shows severe necrotic changes and fiber regeneration with minimal or no inflammatory infiltrates. The disorder can be para- neoplastic and also occurs in association with connective tissue dis- ease, exposure to statin medication, and after treatment with immune checkpoint inhibitors. Antibodies associated with the disorder include anti-3-hy- droxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and anti-signal recognition particle (SRP). Compared to patients with HMGCR antibodies or seronegative cases, patients with SRP anti- bodies have a more severe and refractory disease course. Necrotizing autoimmune myopathy has been reported in association with a vari- ety of solid tumors including carcinomas of the gastrointestinal tract, lung, and ovary (Kassardjian et al., 2015). Cancer occurs more often in patients with HMGCR antibodies and seronegative cases compared with patients with SRP antibodies (Allenbach et al., 2016). No large clinical trials are available to direct treatment strategies. Recent recommendations include the upfront use of corticosteroids and methotrexate (Allenbach et al., 2018). Other agents such as aza- thioprine, mycophenolate, tacrolimus, cyclosporine, or cyclophos- phamide can substitute for methotrexate, with no data supporting increased benefit of one over the other (Kassardjian et al., 2015). Relapses can occur, often when immunotherapy is tapered or dis- continued (Kassardjian et al., 2015). For paraneoplastic cases, tumor treatment is important. Statin-induced necrotizing myopathy may be responsive to IVIG; the efficacy of IVIG in idiopathic or paraneoplastic forms has not been clarified. Paraneoplastic Visual Syndromes Paraneoplastic involvement of the visual system may affect the ret- ina, and less frequently, the uvea and optic nerves (Thirkill, 2005; Ko et al., 2008). Because paraneoplastic visual syndromes are rare, the more important considerations are metastatic infiltration of the optic nerves, toxic effects of chemotherapy or radiation therapy, and severe anemia. The symptoms of cancer-associated retinopathy (CAR) are photosensitivity, progressive loss of visual acuity and color percep- tion, central or ring scotomas, and night blindness. Attenuation of photopic and scotopic responses is recorded on the electroretinogram 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Treatment SCLC is the tumor most commonly associated with CAR. Optic neuritis has been described with SCLC and non-SCLC, as well as with other solid tumors. Bilateral diffuse uveal melanocytic proliferation has most commonly been described with gynecological cancers in women and lung cancers in men. In patients with CAR the antibody most frequently identified is against recoverin, a retinal-specific calcium-binding protein. However, an increasing number of retinal proteins have been found to be antigenic targets in both paraneoplastic and non-paraneoplastic retinopathy, including tubby-like protein 1 (TULP1), α-enolase, the photorecep- tor-specific nuclear receptor, carbonic anhydrase, and arrestin, among others (Adamus et al., 2004). Anti-enolase antibodies predominantly associate with central cone abnormalities and may also occur without a cancer association (Adamus et al., 2004). Patients with MAR typically have antibodies that react with the bipolar cells of the retina. Anti-CV2/ CRMP5 antibodies are reported in some patients with PEM, uveitis, and optic neuritis. Although the paraneoplastic retinopathies rarely improve, responses to tumor treatment, corticosteroids, plasma exchange, IVIG and ritux- imab have been reported (Ferreyra et al., 2009; Or et al., 2013). The complete reference list is available online at https://expertconsult. inkling.com/. 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD 82 Autoimmune Encephalitis with to Cell Surface Antigens Myrna R. Rosenfeld, Josep Dalmau Anti-DPPX Encephalitis, 1266 Anti-mGluR5 Encephalitis, 1266 Anti-mGluR1 Cerebellar Dysfunction, 1267 Anti-Dopamine Receptor Encephalitis, 1267 Anti-neurexin 3α Encephalitis, 1267 Anti-IgLON5 Disease, 1267 General Treatment Recommendations, 1268 but not all cases supporting findings such as inflammatory signs in cerebrospinal fluid (CSF) or the presence of oligoclonal bands can be useful. Abnormalities on magnetic resonance imaging (MRI) flu- id-attenuated inversion recovery (FLAIR) sequences are more com- monly seen in some syndromes than others, as discussed below. Any immunological type of autoimmune encephalitis can have a relapsing course and therefore the diagnosis of these disorders should be con- sidered in a patient with a past history of encephalitis or relapsing encephalopathy. The diagnosis of autoimmune encephalitis is confirmed by the presence of specific neuronal cell surface/synaptic antibodies in serum and CSF. While some laboratories state that evaluation of serum is sufficient, this is incorrect and CSF should always be included in the initial evaluation. A study of patients with anti-NMDAR encephalitis demonstrated that depending on how the testing was performed, up to 13% of CSF positive cases had no antibodies detectable in serum, and thus the diagnosis would have been missed (Gresa-Arribas et al., 2016). Institution of treatment should not be delayed until the results of antibody testing are available as this can negatively affect the out- come. Guidelines for the diagnosis of autoimmune encephalitis based on standard neurological assessment and routinely available labora- tory testing are available (Graus et al., 2016). Based on the level of evi- dence, therapy should be initiated promptly and then adjusted when antibody results become available. The immunological trigger of autoimmune encephalitis is var- ied and, in many cases, is yet to be established. In some patients, the presence of a systemic tumor that expresses the target neuronal/syn- aptic proteins appears to be important. About 25% of patients with herpes simplex viral encephalitis develop autoimmune encephalitis after recovery from the viral infection (Armangue et al., 2018). Specific human leukocyte antigen (HLA) associations have been reported for anti-LGI1 encephalitis, anti-CASPR2 encephalitis, and anti-IgLON5 disease (Sabater et al., 2016; van Sonderen et al., 2017). There are some patients in whom autoimmune encephalitis overlaps with demyelin- ating disorders (Titulaer et al., 2014); whether there is a relationship between the two syndromes is not yet clear. 1263 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Their Treatment to Cell Surface Antigens Other Associations Responses to Immunotherapies memory deficits, Predominantly affects young adults, Almost 80% of cases have full or substantial dyskinesias, teenagers, and children with an recoveries. Improvement occurs slowly and age-related association with ovarian can continue for over 18 months teratoma Median age 62 years. About 50% of the Patients can have full or partial recovery, but patients have an associated cancer this is dependent on tumor control (SCLC or other neuroendocrine tumor). Frequent coexisting autoimmunities Predominantly affects middle-aged About 70% improve with therapy, but neuro- women; about 70% with an associated logical relapses without tumor recurrence cancer (breast, thymus, lung) are frequent and lead to cumulative disability Median age 60 years (men > women). Almost 80% have recovery but are often left Less than 10% have an underlying with residual memory or cognitive deficits tumor (usually thymoma) precede the limbic Frequent coexisting autoimmunities About 70% have full or substantial recovery hyperexcitability with Extensive MRI FLAIR/T2 cortical-subcor- Half of patients have good response to tical abnormalities. Frequent coexisting immunotherapy, but patients may die from autoimmunities (TPO, GAD antibodies) medical complications during status Protracted course with relapses when Partial but meaningful improvement immunotherapy is reduced or PERM-like preceded by Hodgkin lymphoma or no tumor Full recovery No tumor or rarely lymphoma May respond to immunotherapy No tumor association Improvement or full recovery with early immunotherapy No tumor association May partially respond to immunotherapy Usually chronic and slowly progressive, Largely unresponsive to immunotherapy. less often rapidly progressive Patients usually have sudden death during wakefulness acid receptor; CASPR2, contactin-associated protein-like 2; DPPX, dipeptidyl-peptidase-like Gamma-aminobutyric acid-A; GABAB, Gamma-aminobutyric acid-B; GAD, glutamic acid 5; LGI1, leucine-rich glioma-inactivated protein-1; mGluR5, metabotropic glutamate magnetic resonance imaging; NMDA, N-methyl-D-aspartate; PERM, progressive enceph- SCLC, small-cell lung cancer; TPO, thyroid peroxidase. viral-like prodrome that can elevate the suspicion for an autoimmune process. Children are often brought to medical attention due to mood and behavioral change at times with new-onset seizures, movement disorders, insomnia, or reduction of speech. Partial syndromes with predominant psychiatric symptoms or abnormal movements, and less severe phenotypes can occur, although almost all patients eventually develop several elements of the syndrome (Kayser et al., 2013;Titulaer et al., 2013). Atypical symptoms, such as cerebellar ataxia or hemi- paresis, can occur and are more common in children than in adults. Approximately 40% of female patients over 18 years have uni- or bilateral ovarian teratomas compared to less than 9% of girls under 14 years of age. Younger children and men only rarely have tumors. Isolated cases with other tumor types—including teratoma of the mediastinum, small-cell lung cancer (SCLC), Hodgkin lymphoma, neuroblastoma, breast cancer, and germ-cell tumor of the testis—have been reported (Titulaer et al., 2013). HE @ D AC FD 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Encephalitis with Antibodies to Cell Surface Antigens 1265 are almost always those of typical limbic encephalitis with memory loss, confusion, and prominent seizures (Hoftberger et al., 2013; Jeffery et al., 2013). Rare cases presenting with ataxia or opsoclonus-myoclonus have been reported, but in these cases the syndrome progresses to include lim- bic encephalitis (Hoftberger et al., 2013). Most seizures appear to have a temporal-lobe onset with secondary generalization, while some patients have status epilepticus or subclinical seizures demonstrated on EEG. The brain MRI is abnormal is almost two-thirds of the patients, showing unilateral or bilateral medial temporal lobe FLAIR/T2 signal, which is consistent with limbic encephalitis. As in other autoimmune encephalitis, the CSF can show lymphocytic pleocytosis. In addition to the presence of GABABR antibodies, these patients may have other autoantibodies (e.g., TPO, ANA, GAD65) reflecting a tendency to autoimmunity or the presence of an underlying cancer (e.g., Sox1, amphiphysin, and/or Ri antibodies). In contrast to NMDAR antibodies, patient GABABR antibodies act as selective GABABR antag- onists without causing receptor internalization (Dalmau et al., 2017). Patients who receive immunotherapy together with tumor control in a patient often have full or substantial recoveries, including cases where treat- incubated ment is delayed by several months. A previously healthy 3-year-old child developed GABABR and GABAAR antibodies with opsoclonus, limb and trunk ataxia, and seizures; he died as a result of sepsis while receiving intensive care support (Kruer et al., 2014; Petit-Pedrol et al., 2014). Anti-AMPA Receptor Encephalitis Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis predominantly affects middle-aged women (median age 62 years). Just over half the patients present with subacute ( women) who develop memory loss, confusion, and temporal lobe seizures. About 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Treatment autoimmune encephalitis in which the brain MRI is either normal or shows predominant involvement of the limbic system, almost all patients have extensive MRI abnormalities on FLAIR/T2 imaging with multifocal cortical-subcortical involvement without contrast enhance- ment (Fig. 82.2). Almost one-third have an associated tumor (mostly thymoma). More than half of the patients have partial or complete response to immunotherapy despite the severity of the illness and the seizures. Deaths that have been reported were attributed to status epi- lepticus or complications such as sepsis. Most patients also have coexisting autoimmunity including anti- bodies to GAD or thyroid peroxidase (TPO), raising the question of whether some patients with severe seizures attributed to GAD65 antibodies may in fact have other more disease-relevant antibodies such as GABAAR. The findings may also provide an explanation for some encephalitis attributed to TPO antibodies (erroneously consid- ered Hashimoto encephalitis). The disorder can be triggered by viral encephalitis (herpes simplex virus 1 or human herpesvirus 6), and these patients usually have coexisting anti-NMDAR antibodies. Patients’ have antibodies that target the gamma aminobutyric acid A receptor (GABAAR). These antibodies produce a relocation of the receptor from synaptic to extrasynaptic sites, leading to neuronal hyper- excitability and supporting a pathogenic role (Petit-Pedrol et al., 2014). LGI1 are Anti-DPPX Encephalitis Patients with encephalitis associated with antibodies to dipepti- dyl-peptidase-like protein6 (DPPX) develop severe prodromal weight loss or diarrhea followed by the development of prominent neuropsy- chiatric symptoms, CNS hyperexcitability (e.g., agitation, hallucina- tions, myoclonus, tremor, seizures, hyperekplexia), and/or cerebellar or brainstem dysfunction (Boronat et al., 2013; Hara et al., 2017; Tobin et al., 2014).The weight loss and severe diarrhea occur, on average, 4 months before the onset of neurological symptoms and can result in extensive evaluations for a primary gastrointestinal disorder. The triad of weight loss, cognitive dysfunction, and symptoms of CNS hyper- excitability should raise the suspicion for anti-DPPX encephalitis. The encephalitis is chronic and progresses over months (median 8 months to disease peak). The CSF can show pleocytosis or oligoclo- nal bands but can be normal. The MRI is usually nonspecific. Tumor associations are unusual but do occur (mostly B-cell neoplasms). Some patients develop a syndrome resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) or present with hyperekplexia (Balint et al., 2014; Hara et al., 2017). The prodromal gastrointesti- nal symptoms, severe loss of weight, and/or prominent cognitive or mental alterations helps to distinguish DPPX encephalitis from PERM. Patients often respond to immunotherapy with relapses mainly occur- ring in the setting of reduced immunotherapy. All patients have a combination of IgG1 and IgGg4 anti-DPPX antibodies. These antibodies produce a reversible decrease of the den- sity of DPPX receptor clusters as well as the associated Kv4.2 potas- sium channels (Hara et al., 2017). The myenteric plexus is enriched in DPPX receptors and this may explain the prominent gastrointestinal symptoms. Anti-mGluR5 Encephalitis Anti-mGluR5 antibodies were initially described in two patients with limbic encephalitis and Hodgkin lymphoma (Ophelia syndrome) (Lancaster et al., 2011b). An evaluation of additional patients showed that most have a viral-like prodrome followed by the development of a complex neuropsychiatric syndrome with prominent psychiatric and cognitive dysfunction, movement disorders, sleep dysfunction, and/or seizures (Spatola et al., 2018). There is CSF pleocytosis in almost all cases and, less commonly, oligoclonal bands. In approximately half of the 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Encephalitis with Antibodies to Cell Surface Antigens 1267 B with limbic encephalitis and antibodies against LGI1, showing typical medial temporal lobes. Similar findings occur in greater than 50% of antibodies, and less frequently in patients with CASPR2 antibodies. receptor antibodies showing FLAIR abnormalities involving multiple abnormalities occur in 80% of patients with this disorder; diffusion diffusion. These multifocal abnormalities appear and disappear suggestive of GABAA receptor encephalitis, and do not occur in encephalitis. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isox- protein-like 2; FLAIR, fluid-attenuated inversion recovery; gamma-aminobutyric acid B; LGI1, leucine-rich glioma inac- (Reprinted with permission from Lancaster et al., Neurology al., Neurology 2017;88(11):1012–1020.) Anti-neurexin 3α Encephalitis This disorder was initially described in five patients (median age 44 years) who presented with prodromal fever, headache, or gastroin- testinal symptoms followed by the onset of confusion, seizures, and a decreased level of consciousness (Gresa-Arribas et al., 2016). Two of the patients developed facial dyskinesias suggestive of anti-NMDAR encephalitis (anti-NMDAR antibodies were absent). The MRI was nor- mal in four patients, and in one showed medial temporal lobe FLAIR abnormality. Three patients had partial recovery after immunother- apy; however, two patients died—one death was related to refractory seizures and brain edema and the other to sepsis. Studies in cultured neurons showed that the patient antibodies decrease receptor cluster density as well as the number of synapses (Gresa-Arribas et al., 2016). ion Anti-IgLON5 Disease Patients with this disease develop a characteristic sleep disorder before or concurrently with the onset of bulbar symptoms, gait abnormalities, chorea, oculomotor problems and, less commonly, cognitive decline (Sabater et al., 2014). The sleep disorder includes REM and non-REM sleep disturbances characterized by abnormal movements and behaviors that predominate in the early hours of sleep. In some patients the disorder is progressive over years while in other patients the course is rapidly progressive and may result in death within months of symptom onset. The disorder is poorly responsive to treatment. Video polysomnography demonstrates undifferentiated non-REM sleep or poorly structured non-REM stage N2, along with REM para- somnias and sleep breathing dysfunction, including obstructive sleep D AC FD 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD Treatment on antibody depletion and immunosuppression. In tumor-associated cases, the first step in management should be its identification and treatment. Patients with anti-NMDAR or AMPAR encephalitis, whose tumors were not removed, had less frequent recoveries and an increased risk of relapses compared to those whose tumors were treated. While it is not known if this applies to other disorders it strongly supports early tumor treatment when appropriate (Titulaer et al., 2013). Despite the severity of many patients’ symptoms, the majority of patients respond to treatment. Recovery can be slow and some disorders have a tendency to relapse. Corticosteroids and/or intravenous immu- noglobulin (IVIG) or plasma exchange are considered first-line therapies and should be considered in all patients. There are no data to support the use of IVIG over plasma exchange, although the poor medical condi- tion and autonomic instability of some patients may favor the use of IVIG. For patients who do not show early improvement with these ther- apies or who are severely affected, rituximab and/or cyclophosphamide should be considered and are increasingly being used upfront (Nosadini et al., 2015). The use of rituximab appears to reduce the risk of relapses and there is evidence it is effective for IgG4 antibody-mediated diseases (Huijbers et al., 2015), supporting its early or upfront use. The complete reference list is available online at https://expertconsult. inkling.com/. 02.4.(1( 4 ( 1. 4. (0 4). 1) 4 ) 1 HFD

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