CHAPTER 53: PARANEOPLASTIC NEUROLOGIC SYNDROMES

Paraneoplastic neurologic disorders (PNDs) are cancer-related syndromes that can affect any part of the nervous system (Table 53-1). 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 53-2). 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 neuromuscular synapses are more responsive to immunotherapy (Table 53-3, and Fig. 53-1). These disorders occur with and without a cancer association, 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.

PARANEOPLASTIC ENCEPHALOMYELITIS AND FOCAL ENCEPHALITIS

The term encephalomyelitis describes an inflammatory process with multifocal involvement of the nervous system, including the 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, and occasionally enhancing with gadolinium); (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 autonomic neuropathy). 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 also been reported. Patients with SCLC and these syndromes usually have anti-Hu antibodies in serum and CSF. Anti-CV₂/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. 53-3); 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 53-2.

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 (glucocorticoids, plasma exchange, IVIg, rituximab, or cyclophosphamide) (Table 53-3).

Encephalitis with antibodies to voltage-gated potassium channels (VGKC)-related proteins (LGI1, Caspr2) predominates in men and frequently presents with memory loss and seizures (limbic encephalopathy) along with hyponatremia and sleep and autonomic dysfunction. Less commonly, patients develop neuromyotonia or a mixed clinical picture (Morvan's syndrome). Approximately 20% of patients with antibodies to VGKC-related proteins have an underlying tumor, usually SCLC or thymoma.

Encephalitis with N-methyl-d-aspartate (NMDA) receptor antibodies (Fig. 53-1) 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. 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 drug abuse or an acute psychosis. The detection of an associated ovarian teratoma is age-dependent; 50% of female patients older than age 18 years have uni- or bilateral ovarian teratomas, while fewer than 9% of girls younger than 14 years have a teratoma. In male patients, the detection of a tumor is rare.

Encephalitis with α-amino-3-hydroxy-5-methylisoxazole-4-propionate (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. The neurologic disorder responds to treatment of the tumor and immunotherapy. Neurologic relapses may occur; these also respond to immunotherapy and are not necessarily associated with tumor recurrence.

Encephalitis with γ-aminobutyric acid type B (GABA_B) receptor antibodies usually presents with limbic encephalitis and seizures; 50% of the patients have SCLC or a neuroendocrine tumor of the lung. Neurologic symptoms often respond to immunotherapy and treatment of the tumor if found. Patients may have additional antibodies to glutamic acid decarboxylase (GAD), of unclear significance. Other antibodies to nonneuronal proteins are often found in these patients as well as in patients with AMPA receptor antibodies, indicating a general tendency to autoimmunity.

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, but more often the clinical features are restricted to the cerebellum. Early in the course, MRI studies are usually normal; later, the MRI typically 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 lymphoma.

Anti-Yo antibodies in patients with breast and gynecologic cancers and anti-Tr antibodies in patients with Hodgkin 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 53-2. A number of single case reports have described neurologic improvement after tumor removal, plasma exchange, IVIg, cyclophosphamide, rituximab, or glucocorticoids. However, large series of patients with antibody-positive paraneoplastic cerebellar degeneration show that this disorder rarely improves with any treatment.

Opsoclonus is a disorder of eye movement characterized by involuntary, chaotic saccades that occur in all directions of gaze; it is frequently associated with myoclonus and ataxia. Opsoclonus–myoclonus may be cancer-related or idiopathic. When the cause is paraneoplastic, the tumors involved are usually cancer of the lung and breast in adults and neuroblastoma in children. The pathologic substrate of opsoclonus–myoclonus is unclear, but studies suggest that disinhibition of the fastigial nucleus of the cerebellum is involved. Most patients do not have detectable antineuronal antibodies. A small subset of patients with ataxia, opsoclonus, and other eye-movement disorders develop anti-Ri antibodies; in rare instances, muscle rigidity, 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 neurologic 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.

Paraneoplastic myelopathy can also produce several syndromes characterized by prominent muscle stiffness and rigidity. The spectrum ranges from focal symptoms in one or several extremities (stiff-limb syndrome or stiff-person syndrome) to a disorder that also affects the brainstem (known as encephalomyelitis with rigidity) and likely has a different pathogenesis. Some patients with encephalomyelitis and rigidity have glycine receptor antibodies.

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. Symptoms improve with sleep and general anesthetics. Electrophysiologic studies demonstrate continuous motor unit activity. Antibodies associated with the stiff-person syndrome target proteins (GAD, amphiphysin) involved in the function of inhibitory synapses utilizing γ-aminobutyric acid (GABA) or glycine as neurotransmitters. Paraneoplastic stiff-person syndrome and amphiphysin antibodies are often related to SCLC and breast cancer. By contrast, antibodies to GAD may occur in some cancer patients but are much more frequently present in the nonparaneoplastic disorder.

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, proliferation of satellite cells, 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, e.g., anti-Hu antibodies and SCLC.

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 in biopsy studies. If demyelinating features predominate, IVIg, plasma exchange, or glucocorticoids may improve symptoms. Occasionally, anti-CV₂/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 the 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 rarely responds 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, or hallucinations, may occur. The electromyogram shows fibrillations; fasciculations; and doublet, triplet, or multiplet single-unit (myokymic) discharges that have a high intraburst frequency. Approximately 20% of patients have serum antibodies to Caspr2-related proteins. 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 adrenergic or cholinergic dysfunction at the pre- or postganglionic levels. Patients can develop several life-threatening complications, such as gastrointestinal paresis with pseudoobstruction, 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-CV₂/CRMP5 antibodies should be sought. Antibodies to ganglionic (α3-type) neuronal acetylcholine receptors are the cause of autoimmune autonomic ganglionopathy, a disorder that frequently occurs without cancer association.

LAMBERT-EATON MYASTHENIC SYNDROME

LEMS is a presynaptic disorder that usually affects the proximal muscles of the lower limbs together with cranial nerve findings in 70% of patients mimicking myasthenia gravis (MG). In contrast to MG, LEMS patients have depressed or absent reflexes and autonomic symptoms such as dry mouth. LEMS is caused by autoantibodies to the P/Q-type calcium channels at the motor nerve terminals.

MYASTHENIA GRAVIS

Muscle weakness and fatigue commonly occur in a characteristic pattern. Diplopia and ptosis are early findings; changes in voice, fatigue on chewing, tongue weakness occur that increases with longer effort and improves with rest. Antibodies to the acetylcholine receptor are etiologic and it is most commonly seen in thymoma.

POLYMYOSITIS-DERMATOMYOSITIS

Cancer can be associated with dermatomyositis, a progressive, symmetric muscle weakness generally affecting proximal muscles that is associated with a rash, usually a flat red rash on the face and upper trunk. The rash may be pruritic. Humoral immune mechanisms are implicated. Muscle enzymes are elevated. Glucocorticoids or other immunosuppressive drugs may produce some improvement at least transiently.

ACUTE NECROTIZING MYOPATHY

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 harbor anti-CV₂/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 53-2). Paraneoplastic retinopathies usually fail to improve with treatment, although rare responses to glucocorticoids, plasma exchange, and IVIg have been reported.