Chapter 55: Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis

Paraneoplastic neurologic disorders (PNDs) are cancer-related syndromes that can affect any part of the nervous system (Table 55-1). They are caused by mechanisms other than metastasis or by any of the complications of cancer such as coagulopathy, stroke, metabolic and nutritional conditions, infections, and side effects of cancer therapy. In 60% of patients, the neurologic symptoms precede the cancer diagnosis. Clinically disabling PNDs occur in 0.5–1% of all cancer patients, but they affect 2–3% of patients with neuroblastoma or small-cell lung cancer (SCLC) and 30–50% of patients with thymoma or sclerotic myeloma.

Most PNDs are mediated by immune responses triggered by neuronal proteins (onconeuronal antigens) expressed by tumors. In PNDs of the central nervous system (CNS), many antibody-associated immune responses have been identified (Table 55-2). These antibodies react with the patient’s tumor, and their detection in serum or cerebrospinal fluid (CSF) usually predicts the presence of cancer. When the antigens are intracellular, most 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 in these PNDs. Thus both humoral and cellular immune mechanisms participate in the pathogenesis of many PNDs. This complex immunopathogenesis may underlie the resistance of many of these conditions to therapy.

In contrast to the disorders associated with immune responses against intracellular antigens, those associated with antibodies to antigens expressed on the neuronal cell surface of the CNS or at the neuromuscular junction are more responsive to immunotherapy (Table 55-3, Fig. 55-1). These disorders occur with and without a cancer association and may affect children and young adults, and there is increasing evidence that they are mediated by the antibodies.

Other PNDs are likely immune-mediated, although their antigens are unknown. These include several syndromes of inflammatory neuropathies and myopathies. In addition, many patients with typical PND syndromes are antibody-negative.

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 inflammatory infiltrates or deposits of immunoglobulin, cryoglobulin, or amyloid.

APPROACH TO PATIENT

PARANEOPLASTIC ENCEPHALOMYELITIS AND FOCAL ENCEPHALITIS

The term encephalomyelitis describes an inflammatory process with multifocal involvement of the nervous system, including brain, brainstem, cerebellum, and spinal cord. It is often associated with dorsal root ganglia and autonomic dysfunction. For any given patient, the clinical 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 short-term memory deficits, partial complex seizures, and sometimes dementia (the MRI usually shows unilateral or bilateral medial temporal lobe abnormalities, best seen with T2 and fluid-attenuated inversion recovery sequences); (3) brainstem encephalitis, resulting in eye movement disorders (nystagmus, opsoclonus, supranuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia, and central autonomic dysfunction; (4) cerebellar gait and limb ataxia; (5) myelitis, which may cause lower or upper motor neuron symptoms, myoclonus, muscle rigidity, and spasms; and (6) autonomic dysfunction 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 are frequent causes 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 anti-Hu antibodies in serum and CSF. Anti-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 (Fig. 55-3); some patients develop hypersomnia, cataplexy, and severe hypokinesia. MRI abnormalities are frequent, including those described with limbic encephalitis and variable involvement of the hypothalamus, basal ganglia, or upper brainstem. The oncologic associations of these antibodies are shown in Table 55-2.

TREATMENT

ENCEPHALITIDES WITH ANTIBODIES TO CELL-SURFACE OR SYNAPTIC PROTEINS

These disorders are important for three reasons: (1) they can occur with and without tumor association, (2) some syndromes predominate in young individuals and children, and (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) (Table 55-3).

Encephalitis with N-methyl-d-aspartate (NMDA) receptor antibodies (Fig. 55-1) usually occurs in young women and children, but men and older patients of both sexes can be affected. The disorder has a characteristic pattern of symptom progression that includes a prodrome resembling a viral process, followed in a few days by the onset of severe psychiatric symptoms, memory loss, seizures, decreased level of consciousness, abnormal movements (orofacial, limb, and trunk dyskinesias, dystonic postures), autonomic instability, and frequent hypoventilation. Monosymptomatic episodes, such as pure psychosis, occur in 4% of the patients. Clinical relapses occur in 12–24% of patients (12% during the first 2 years after initial presentation). Most patients have intrathecal synthesis of antibodies, likely by infiltrating plasma cells in brain and meninges (Fig. 55-4A). The syndrome is often misdiagnosed as a viral or idiopathic encephalitis, neuroleptic malignant syndrome, or encephalitis lethargica, and many patients are initially evaluated by psychiatrists with the suspicion of acute psychosis. 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 less than 7% of girls younger than 12 have a teratoma (Fig. 55-4B). In 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).

Encephalitis with leucine-rich glioma-inactivated 1 (LGI1) antibodies predominates in patients older than 50 years (65% male) and frequently presents with memory loss and seizures (limbic encephalopathy), along with hyponatremia and sleep dysfunction. In a small number of patients, the encephalitis is preceded by or occurs with myoclonic-like movements called faciobrachial dystonic or tonic seizures. Less than 10% of patients have thymoma.

Encephalitis with contactin-associated protein-like 2 (Caspr2) antibodies predominates in patients older than 50 years and is associated with Morvan’s syndrome (encephalitis, insomnia, confusion, hallucinations, autonomic dysfunction, and neuromyotonia) and, less frequently, with limbic encephalitis, neuromyotonia, and neuropathic pain. About 30–40% of patients have thymoma.

Encephalitis with γ-aminobutyric acid type B (GABA_B) receptor antibodies is usually associated with limbic encephalitis and seizures. In rare instances, patients develop cerebellar symptoms and opsoclonus. Fifty percent of patients have SCLC or a neuroendocrine tumor of the lung. Patients may have additional antibodies to glutamic acid decarboxylase (GAD), which are of unclear significance. Other antibodies to nonneuronal proteins are often found in these patients as well as in patients with α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antibodies, indicating a general tendency to autoimmunity.

Encephalitis with GABAA receptor antibodies may affect children and adults. When antibodies are present at high titer in serum and CSF, the disorder associates with prominent seizures and status epilepticus, often requiring pharmacologically induced coma. Low titer antibodies in serum are often associated with other autoimmune conditions, and the spectrum of symptoms is wider, including encephalitis, seizures, opsoclonus, or stiff-person syndrome. Most patients do not have an underlying tumor, but some may have thymoma.

Encephalitis with AMPA receptor antibodies affects middle-aged women, who develop acute limbic dysfunction or, less frequently, prominent psychiatric symptoms; 70% of the patients have an underlying tumor in the lung, breast, or thymus. Neurologic relapses may occur; these also respond to immunotherapy and are not necessarily associated with tumor recurrence.

Encephalitis with glycine receptor (GlyR) antibodies has been described in adults with progressive encephalomyelitis with rigidity and myoclonus (PERM) and stiff-person spectrum of symptoms (with or without GAD antibodies). The disorder usually occurs without tumor association, although some patients have lung cancer, thymoma, or Hodgkin’s lymphoma.

Encephalitis with dipeptidyl-peptidase-like protein-6 (or DPPX) antibodies results in symptoms of CNS hyperexcitability including agitation, hallucinations, paranoid delusions, tremor, myoclonus, nystagmus, seizures, and sometimes hyperekplexia. Some patients develop progressive encephalomyelitis with rigidity and myoclonus. Diarrhea, other gastrointestinal symptoms, and substantial loss of weight often suggest the presence of an underlying tumor, but no tumor association has been identified. The disorder responds to immunotherapy.

PARANEOPLASTIC CEREBELLAR DEGENERATION

This disorder is often preceded by a prodrome that may include dizziness, 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, upgoing toes, or a mild neuropathy 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 spinocerebellar tracts. The tumors more frequently involved are SCLC, cancer of the breast and ovary, and Hodgkin’s lymphoma.

Anti-Yo antibodies in patients with breast and gynecologic cancers and anti-Tr antibodies in patients with Hodgkin’s lymphoma are the two immune responses typically associated with prominent or pure cerebellar degeneration. Antibodies to P/Q-type voltage-gated calcium channels (VGCC) occur in some patients with SCLC and cerebellar dysfunction; only some of these patients develop LEMS. A variable degree of cerebellar dysfunction can be associated with virtually any of the antibodies and PND of the CNS shown in Table 55-2.

A number of single case reports have described neurologic improvement after tumor removal, plasma exchange, IVIg, cyclophosphamide, rituximab, or glucocorticoids. However, most patients with paraneoplastic cerebellar degeneration do not improve with treatment.

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, neuroblastoma in children, and ovarian teratoma in adolescents and young women. The pathologic substrate of opsoclonus-myoclonus is unclear, but studies suggest that disinhibition of the fastigial nucleus of the cerebellum is involved. Most patients do not have antineuronal antibodies. A small subset of patients with ataxia, opsoclonus, and other eye-movement disorders develop anti-Ri antibodies; in rare instances, muscle rigidity, laryngeal spasms, autonomic dysfunction, and dementia also occur. The tumors most frequently involved in anti-Ri-associated syndromes are breast and ovarian cancer. 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 symptoms often improve with treatment of the tumor and glucocorticoids, adrenocorticotropic hormone (ACTH), plasma exchange, IVIg, and rituximab. 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 in recent 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 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. There are isolated case reports of cancer patients with motor neuron dysfunction who had neurologic improvement after tumor treatment. A search for lymphoma should be undertaken in patients with a rapidly progressive motor neuron syndrome and a monoclonal protein in serum or CSF.

Paraneoplastic myelitis may present with upper or lower motor neuron symptoms, segmental myoclonus, and rigidity, and can be the first manifestation of encephalomyelitis. Neuromyelitis optica (NMO) with aquaporin 4 antibodies may occur in rare instances as a paraneoplastic manifestation of a cancer.

PARANEOPLASTIC STIFF-PERSON SYNDROME

This disorder is characterized by progressive muscle rigidity, stiffness, 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 (GAD, amphiphysin) involved in the function of inhibitory synapses using 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 antibodies 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 also detectable in patients with PERM.

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 transiently effective in some patients.

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. Specialized sensations such as taste and hearing can also be affected. Electrophysiologic studies show decreased or absent sensory nerve potentials with normal or near-normal motor conduction velocities. Symptoms result from an inflammatory, likely 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 dysfunction 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. 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 neoplastic 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. If demyelinating features predominate, IVIg, plasma exchange, or glucocorticoids may improve symptoms. Occasionally anti-CRMP5 antibodies are present; detection of anti-Hu suggests concurrent dorsal root ganglionitis.

Guillain-Barré syndrome and brachial plexitis have occasionally been reported in patients with lymphoma, but there is no clear evidence of a paraneoplastic association.

Malignant monoclonal gammopathies include: (1) multiple myeloma and sclerotic myeloma associated with IgG or IgA monoclonal proteins; and (2) Waldenström’s macroglobulinemia, B cell lymphoma, and chronic B cell lymphocytic leukemia associated with IgM monoclonal proteins. These disorders may cause neuropathy by a variety of mechanisms, including compression of roots and plexuses by metastasis to vertebral bodies and pelvis, deposits of amyloid in peripheral nerves, and paraneoplastic mechanisms. The paraneoplastic variety has several distinctive features. Approximately half of patients with sclerotic myeloma develop a sensorimotor neuropathy with predominantly motor deficits, resembling a chronic inflammatory demyelinating neuropathy; some patients develop elements of the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes). Treatment of the plasmacytoma or sclerotic lesions usually improves the neuropathy. In contrast, the sensorimotor or sensory neuropathy associated with multiple myeloma is more refractory to treatment. Between 5 and 10% of patients with Waldenström’s macroglobulinemia develop a distal symmetric sensorimotor neuropathy with predominant involvement of large sensory fibers. These patients may have IgM antibodies in their serum against myelin-associated glycoprotein and various gangliosides. In addition to treating the Waldenström’s macroglobulinemia, other therapies may improve the neuropathy, including plasma exchange, IVIg, chlorambucil, cyclophosphamide, fludarabine, or rituximab.

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 associated 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’ syndrome) 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. CNS dysfunction, including mood changes, sleep disorder, hallucinations, and autonomic symptoms may occur. The electromyogram (EMG) shows fibrillations; fasciculations; and doublet, triplet, or multiplet single-unit (myokymic) discharges that have a high intraburst frequency. Some patients have Caspr2 antibodies in the context of Morvan’s syndrome, but most cases of isolated neuromyotonia 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 component 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 dysrhythmias, and postural hypotension. Other clinical features include abnormal pupillary responses, dry mouth, anhidrosis, erectile dysfunction, and problems in sphincter control. The disorder occurs in association with several tumors, including SCLC, cancer of the pancreas or testis, carcinoid tumors, and lymphoma. Because autonomic symptoms can be the presenting feature of encephalomyelitis, serum anti-Hu and anti-CRMP5 antibodies should be sought. Antibodies to ganglionic (alpha3-type) neuronal acetylcholine receptors are the cause of autoimmune autonomic ganglionopathy, a disorder that frequently occurs without cancer association.

Patients with this syndrome develop myalgias and rapid progression of weakness involving the extremities and the pharyngeal and respiratory muscles, often resulting in death. Serum muscle enzymes are elevated, and muscle biopsy shows extensive necrosis with minimal or absent inflammation and sometimes deposits of complement. The disorder occurs as a paraneoplastic manifestation of a variety of cancers including SCLC and cancer of the gastrointestinal tract, breast, kidney, and prostate, among others. Glucocorticoids and treatment of the underlying tumor rarely control the disorder.

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 commonly 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 neuritis and uveitis are very uncommon and can develop in association with encephalomyelitis. Some patients with paraneoplastic uveitis and optic neuritis have anti-CRMP5 antibodies.

Some paraneoplastic retinopathies are associated with serum antibodies that specifically react with the subset of retinal cells undergoing degeneration, supporting an immune-mediated pathogenesis (Table 55-2). Paraneoplastic retinopathies usually fail to improve with treatment, although rare responses to glucocorticoids, plasma exchange, and IVIg have been reported.