Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section D – Metabolic and Paraneoplastic Syndromes

Chapter 51 – Paraneoplastic Neurologic Syndromes

Josep Dalmau,Myrna Rosenfeld




The paraneoplastic neurologic syndromes include an extensive group of disorders that can affect any part of the central or peripheral nervous system.



Evidence indicates that many of these syndromes have an immunopathogenesis and are mediated by immunologic responses triggered by the presence of a cancer.



Antibodies directly mediate some disorders of the neuromuscular junction and peripheral nervous system, such as myasthenia gravis, the Lambert-Eaton myasthenic syndrome, and neuromyotonia. For these disorders and a few paraneoplastic neurologic syndromes of the central nervous system, immunotherapy may result in neurologic improvement. However, for most paraneoplastic neurologic syndromes of the peripheral and central nervous system the response to any type of therapy is, in general, disappointing. The physician's main concern should be to rule out other diagnostic entities and to uncover the presence of the associated neoplasm.



The treatment approach should be aimed at the tumor, because stabilization and, less often, improvement of neurologic symptoms after tumor treatment have been reported for almost all syndromes. In a few cases, depending on the syndrome and if the patient is in the early stages of the neurologic disease, treatment with immunosuppression may have some effect on the paraneoplastic neurologic syndrome.


Clinically significant paraneoplastic neurologic syndromes occur in fewer than 1% of all cancer patients. Paraneoplastic syndromes may affect any part of the neuraxis. In some, a single cell type, such as the Purkinje cells in paraneoplastic cerebellar degeneration (PCD), is predominantly involved, whereas in others any neuron of the central or peripheral nervous system may be affected, as occurs in paraneoplastic encephalomyelitis (PEM) and sensory neuropathy (PSN). Due to this variable distribution of pathological involvement, patients with these disorders may present with symptoms of unifocal or multifocal involvement of the nervous system.

Most paraneoplastic neurologic syndromes are thought to have an immunopathogenesis. One hypothesis is that the expression of neuronal antigens by the tumor triggers an immune response against the tumor that affects the nervous system. An immune-mediated pathogenesis has been demonstrated for the Lambert-Eaton myasthenic syndrome (LEMS).[1] Patients with LEMS have serum antibodies against voltage-gated calcium channels that are expressed by the tumor, which usually is a small cell lung cancer (SCLC). These antibodies block the entry of calcium necessary for the release of quanta of acetylcholine and result in neuromuscular weakness. Removal of the serum antibodies results in improvement of symptoms. In paraneoplastic myasthenia gravis (MG), a thymoma triggers an immune response against the acetylcholine receptor at the postsynaptic level of the neuromuscular junction, resulting in weakness and fatigability.[2] A similar antibody-mediated mechanism directed against voltage-gated potassium channels has been reported in paraneoplastic neuromyotonia.[3] Antibodies directed to mGluR1 and voltage-gated calcium channels may be pathogenic in a small subgroup of patients with paraneoplastic cerebellar degeneration.[4] Autonomic dysfunction, sometimes associated with cancer, may result from immunity to the nicotonic acetylcholine receptor.[5]

Aside from these syndromes and cancer-associated and melanoma-associated retinopathy (CAR, MAR), the immune origin of other paraneoplastic neurologic disorders has not been proven but is supported by a number of findings[6]:



Patients with these disorders have high titers of antibodies that react with antigens restricted to the nervous system and tumor. [7] [8]



The antibodies are specific markers of characteristic syndromes and tumors and are produced intrathecally. [9] [10]



Similar antibodies are not found in other inflammatory disorders of the central nervous system (CNS) associated with neuronal destruction, or with tumors that do not express the specific antigen.



A pathogenic effect of antibodies has been shown in animals for some of these disorders (anti-Hu and paraneoplastic gut dysmotility and anti-amphyphysin and paraneoplastic stiff-man syndrome). [11] [12]



Recent data indicate that in some paraneoplastic neurologic disorders of the CNS in which the antibodies target cell surface rather than intranuclear antigens, the antibodies may mediate the neurologic dysfunction. [13] [14]

For some paraneoplastic syndromes of the CNS, circumstantial evidence suggests that T-cell-mediated mechanisms play a major pathogenic role. Autopsies of patients with paraneoplastic syndromes of the CNS show intense inflammatory infiltrates of mononuclear cells, including CD4+ and CD8+, which predominate in the areas of the nervous system that are symptomatic. [10] [15] The mechanism whereby CD4+ or CD8+ cytotoxic T-cells recognize antigens expressed in neurons which normally lack expression of the antigen presenting MHC class I and II molecules is unknown.

Identification of the paraneoplastic origin of a patient's symptoms is important because in more than two thirds of patients the neurologic symptoms develop before the cancer is detected. Because similardisorders may occur without cancer, the diagnosis of the paraneoplastic origin of a disorder depends heavily on the index of suspicion. This is based in part on the syndrome, since some syndromes have a paraneoplastic origin more frequently than others. For example, the likelihood that LEMS or subacute cerebellar degeneration in a middle-aged or elderly patient is paraneoplastic is probably more than 50%.[16] In contrast, subacute sensory neuropathy or dermatomyositis probably is paraneoplastic in origin in less than 20% of patients. [17] [18] In most paraneoplastic syndromes, symptoms develop acutely or subacutely and may resemble a viral process. Symptoms evolve over weeks or months and then stabilize, differentiating them from the more chronic and progressive degenerative diseases of middle age and adulthood.

The finding that some paraneoplastic neurologic syndromes of the central or peripheral nervous system are associated with specific antineuronal antibodies has had a major impact on the ability to diagnose and manage these disorders.[19] These antibodies serve as markers of the paraneoplastic origin of neurologic symptoms and as markers for the presence of specific types of tumors ( Table 51-1 ). Criteria have been proposed to facilitate the diagnosis of paraneoplastic disorders that take into consideration the type of neurologic syndrome, the detection of an associated tumor, and the presence or absence of paraneoplastic antibodies[20] ( Box 51-1 and Fig. 51-1 ).

Table 51-1   -- Immune Associations in Paraneoplastic Neurologic Disorders



Most Common Tumor Association(s)






Ovary, breast


Brainstem encephalitis/PCD



Limbic/brainstem encephalitis




Breast, gynecologic



Hodgkin's lymphoma


Stiff-man syndrome

Breast, SCLC


PEM/PCD, peripheral neuropathy, uveitis

SCLC, several




Anti-bipolar cells of retina




Limbic encephalitis, seizures, psychiatric symptoms






Myasthenia gravis



Peripheral nerve hyperexcitability

Thymoma, others

AChR, acetylcholine receptor; CRMP, collapsin response-mediator protein; LEMS, Lambert-Eaton myasthenic syndrome; NMDAR, N-methyl D-aspartate receptor; PCD, paraneoplastic cerebellar degeneration; PEM, paraneoplastic encephalomyelitis; PSN, paraneoplastic sensory neuropathy; SCLC, small-cell lung cancer; VGCC, voltage-gated calcium channel; VGKC, voltage gated potassium channel.



These antibodies may occur with or without a cancer association and therefore are not markers of paraneoplasia.


Box 51-1 


The diagnosis of a paraneoplastic neurologic syndrome is relatively straightforward for patients who develop symptoms of a well-defined syndrome that typically is associated with cancer. The specificity of paraneoplastic antineuronal antibodies for paraneoplastic neurologic syndromes or some types of cancer makes them useful diagnostic tools. Therefore, in the right clinical context, the detection of a paraneoplastic antibody in the serum or cerebrospinal fluid (CSF) helps to establish the diagnosis and focus the search of the neoplasm. If the detected antibody usually does not associate with the patient's neurologic syndrome, other etiologies for the neurologic dysfunction should be considered. Similarly, if the detected cancer is not the histologic type typically found in association with the patient's antibody (e.g., anti-Yo with lung cancer rather than breast or ovarian cancer), the presence of a second neoplasm should be suspected. A search for another neoplasm definitely is indicated if the tumor cells do not express the target antigen of the paraneoplastic antibody. If paraneoplastic antibodies are present but a cancer is not discovered, the patient should be assumed to harbor an occult neoplasm unless proven otherwise. Whole-body positron emission tomographic scans may detect tumors that escape detection by other standard imaging methods. In patients with a history of cancer or who have recently gone into tumor remission, the development of a paraneoplastic neurologic syndrome frequently heralds tumor recurrence.

The diagnosis of paraneoplastic neurologic syndromes 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. In this case and if other non-cancer-associated etiologies have been ruled out, analysis for serologic markers of cancer (e.g., carcinoembryonic antigen, CA-125, CA-15-3, prostate-specific antigen) may provide evidence for the presence of cancer. The CSF may show evidence of inflammation with pleocytosis, elevated protein concentration, intrathecal synthesis of immunoglobulin, and oligoclonal bands. Immunoelectrophoresis may disclose M-proteins in serum or urine, suggesting a plasma cell dyscrasia. A skeletal survey to rule out lytic or osteosclerotic myeloma should be considered for patients with peripheral neuropathy associated with a monoclonal gammopathy. CT of the chest is the study of choice to demonstrate a suspected lung cancer. Due to the common association of breast and gynecologic cancers with paraneoplastic disorders, mammogram and pelvic CT scan or ultrasound should be carried out in all women with a suspected paraneoplastic neurologic syndrome. Symptoms of limbic and brainstem encephalitis should cause men to be examined with testicular ultrasound and young women to be checked for an ovarian teratoma that may appear as a benign cyst. Whole-body PET scans are useful when other tests are negative. The best approach to treating paraneoplastic neurologic syndromes is to discover and treat the tumor promptly and provide supportive care for the neurologic deficits with symptomatic treatment and physical therapy.


Figure 51-1  Approach to the patient with a suspected paraneoplastic neurologic disorder (PND) of the central nervous system (CNS). CSF, cerebrospinal fluid; PET, positron emission tomograhy.




Paraneoplastic Encephalomyelitis

Patients with PEM develop symptoms of multifocal involvement of the nervous system resulting in several syndromes that may occur in isolation or in various combinations. [21] [22] These include limbic encephalitis, cerebellar degeneration, brainstem encephalitis, myelitis, and sensory and autonomic neuropathies.

Paraneoplastic encephalomyelitis has been described in association with many tumors, but in 70% of patients the underlying tumor is an SCLC. Most tumors are diagnosed within 2 years of the first neurologic presentation. Most patients with PEM and SCLC have high titers of anti-Hu antibodies in their serum and CSF, as do some patients with PEM associated with other types of cancer. [8] [23]Antibodies to CV2/CRMP5, with or without anti-Hu antibodies, also occur at a lower frequency and most commonly are associated with thymoma. [21] [24] A subset of patients with PEM and antibodies to CV2/CRMP5 also develop paraneoplastic chorea and uveitis.[25]

The onset of symptoms in PEM is subacute. Sensory neuropathy is the most common initial manifestation, followed by brainstem and limbic encephalopathy. [21] [26] [27] The progression of symptoms usually is relentless, or, less frequently, intermittent, until stabilization. Spontaneous improvement is rare but has been described in patients with limbic encephalitis.[28] For most patients the neurologic deficits are severe and incapacitating. Respiratory or autonomic failure due to neurologic dysfunction is commonly the cause of death.[26]

About one third of patients with PEM develop symptoms of cerebellar and/or brainstem dysfunction. [8] [21] [29] Motor weakness, muscle atrophy, and fasciculations are found in 20% of patients with PEM.[26] When spinal cord involvement predominates, a diagnosis of subacute motor neuron dysfunction or atypical motor neuron disease may be entertained until other areas of the nervous system become involved. [30] [31] Autonomic dysfunction affects about 30% of patients. Symptoms include orthostatic hypotension, gastrointestinal paresis, and pseudoobstruction. [32] [33] Hypothermia, hypoventilation, sleep apnea, and cardiac arrhythmias may be the cause of sudden death in these patients.

About 75% of patients with anti-Hu-associated PEM develop an asymmetric pansensory neuropathy, called paraneoplastic sensory neuronopathy (PSN; see later discussion). [21] [26] Often associated with painful dysesthesias, PSN results from inflammation of the dorsal root ganglia and neuronal degeneration. For patients in whom motor weakness and a sensory neuropathy develop subacutely, the initial diagnosis may be that of acute inflammatory polyneuritis (Guillain-Barré syndrome).[34]

Limbic Encephalitis

Symptoms of paraneoplastic limbic encephalitis may develop alone but more often are found in association with brainstem dysfunction, cerebellar symptoms, or PSN (see Paraneoplastic Encephalomyelitis).[26] The most common underlying tumor is SCLC, followed by testicular cancer. Regardless of the tumor type, the neurologic dysfunction usually precedes the diagnosis of cancer.

The most characteristic finding is short-term memory deficits with relative preservation of other cognitive functions. [35] [36] Memory deficits often become evident after several weeks of depression, personality changes, irritability, and seizures. Partial complex temporal lobe seizures with or without motor involvement of face and extremities are common. Some patients develop signs of diencephalic-hypothalamic dysfunction, including drowsiness, hyperthermia, hyperphagia, and, less frequently, pituitary hormonal deficits. The disorder may resemble a viral encephalitis or a rapidly developing dementia due to a primary neurodegenerative disorder.

Paraneoplastic limbic encephalitis is one of the few paraneoplastic neurologic disorders in which neuroimaging may be useful. Typical MRI findings include unilateral or bilateral mesial temporal lobe abnormalities best seen on T2-weighted and FLAIR images ( Fig. 51-2 ). [28] [37] [38] On T1-weighted sequences, the temporal–limbic regions may be hypointense and sometimes may enhance with contrast injection. Patients with herpes simplex encephalitis may have similar MRI findings in the early stages of the disease. However, these patients usually develop prominent signs of edema and mass effect involving one or both inferomedial temporal lobes, inferior frontal lobes, and cingulate gyrus often associated with gyral enhancement and signs of hemorrhage. [39] [40]


Figure 51-2  MRI abnormalities in a patient with limbic encephalitis. Fluid-attenuated inversion recovery (FLAIR) sequences of two MRI studies of a patient with paraneoplastic limbic encephalitis associated with a papillary thyroid carcinoma that was confined to the thyroid gland. Upper panels, Bilateral hyperintensity of the medial aspect of the temporal lobes (hippocampi) is seen, with the left greater than the right. Lower panels, Another MRI obtained 6 months later shows atrophy of the hippocampi and new signal abnormality in the right posterior insular region. The patient had severe short-term memory loss that did not significantly change between the two MRI studies.



The major pathological findings are from the hippocampus, parahippocampal gyrus, cingular cortex, insular cortex, and diencephalon.[36] Almost all patients have mild abnormalities in other areas of the nervous system in a pattern of distribution resembling PEM, suggesting that paraneoplastic limbic encephalitis should be regarded as PEM with predominant involvement of the limbic structures.

Antineuronal antibodies, when present in serum and cerebrospinal fluid (CSF), facilitate the diagnosis of PLE and often allow for early detection of the associated tumor. In patients with SCLC, the anti-Hu antibody is present in about 50% of cases with predominant or isolated symptoms of limbic encephalitis.[41] A few patients have been reported with limbic encephalitis and anti-CV2 antibodies. In these patients the underlying tumors are SCLC and thymoma.[42] Limbic encephalitis in association with antibodies to voltage-gated potassium channel antibodies is paraneoplastic in about 20% of patients; the most common cancers are thymoma and SCLC.[43]

Anti-Ma2 antibodies may be found in the serum and CSF of patients with limbic and/or brainstem encephalopathy. These patients usually have testicular cancer (either seminomatous or nonseminomatous germ cell tumors), but other tumors have been reported.[10] Patients with anti-Ma2 antibodies often have additional involvement of the hypothalamus and brainstem and are more likely to have abnormal MRI findings than are other patients with paraneoplastic limbic encephalitis.[44]

A paraneoplastic limbic encephalitis recently has been described in young women with ovarian teratoma (in one patient the tumor was a teratoma of the mediastinum). All patients had serum and CSF antibodies to the NR1/NR2 subunits of the NMDA receptor that are highly enriched in hippocampus. These patients often present with acute change in behavior and personality, with delusional thinking, paranoid thoughts, and aggressive behavior, and may be misdiagnosed with acute psychosis, or suspected malingering or drug abuse. Others can have a picture more typical of limbic encephalitis with short-term memory loss and seizures. Most will progress to decreased level of consciousness, with autonomic dysfunction and central hypoventilation, requiring prolonged ventilatory support. [14] [45]

When limbic encephalitis is part of PEM or PSN, it usually responds poorly to treatment. Symptom stabilization or improvement may occur if the tumor is recognized and treated early. [10] [22] [46] A study of patients with SCLC and paraneoplastic limbic encephalitis suggested that the presence of anti-Hu antibodies was associated with a decreased likelihood of improvement.[41] In contrast, about 35% of patients with limbic encephalopathy associated with antibodies to Ma2 improve with immunotherapy and treatment of the tumor (most of these 35% have a testicular germ-cell tumor).[47] The encephalitis of patients with antibodies to NR1/NR2 subunits of the NMDA receptor and teratomas usually responds to removal of the tumor and corticosteroids, intravenous immunoglobulins (IVIg), or plasma exchange.[45]

Paraneoplastic Cerebellar Degeneration

Paraneoplastic cerebellar degeneration (PCD) is characterized by the subacute development of rapidly progressive cerebellar dysfunction, which stabilizes after a few months, leaving the patient severely disabled.[48] Postmortem studies demonstrate near or total loss of Purkinje cells with relative preservation of other cerebellar neurons, and Bergmann astrogliosis ( Fig. 51-3 ). Almost every type of tumor has been reported in association with PCD; the most common neoplasms are gynecologic tumors, breast and lung cancers, and lymphomas. [49] [50] In about 60% of patients the neurologic symptoms precede detection of the tumor.


Figure 51-3  Paraneoplastic cerebellar degeneration. Section of cerebellum from a patient with adenocarcinoma of the ovary and paraneoplastic cerebellar degeneration associated with anti-Yo antibodies. Note the Bergmann gliosis and the absence of Purkinje cells, which normally are located between the granular cell layer (top left) and the molecular cell layer (bottom right).



Presenting symptoms of PCD include dizziness, visual problems, nausea, vomiting, and dysarthria. Within days or even hours the patient develops ataxia of gait and of the extremities, usually accompanied by dysphagia. Some patients with PCD who have gynecologic or breast tumors have serum and CSF antibodies called anti-Yo that react with 34- and 62-kd proteins expressed by Purkinje cells and the underlying tumor.[51] Other patients develop PCD that is not associated with anti-Yo antibodies. Some of these patients have PCD in association with Hodgkin's disease, in which case an antibody called anti-Tr usually is found ( Fig. 51-4 ).[52]


Figure 51-4  Detection of an anticerebellar antibody (anti-Tr) in the serum of a patient with paraneoplastic cerebellar degeneration. A frozen section of rat cerebellum incubated with the serum of the patient shows a characteristic dot-like reactivity with the cytoplasm of Purkinje cells and molecular layer of the cerebellum. This antibody, known as anti-Tr, is a specific marker of paraneoplastic cerebellar degeneration associated with Hodgkin's lymphoma.



For patients with SCLC, PCD may develop in association with LEMS. [49] [53] Because LEMS symptoms often are treatable, suspicion of LEMS should prompt an appropriate investigation with electrophysiologic testing or measurement of antibodies directed against P/Q type voltage gated calcium channels. Recent studies demonstrate that these antibodies also are present in some patients with SCLC and PCD without symptoms of LEMS.[4]

A distinctive clinical syndrome occurring predominantly in women is characterized by the subacute onset of ataxia and opsoclonus.[54] The ataxia predominates in the trunk, causing severe gait difficulty and frequent falls. In half of these patients the neurologic symptoms develop before the tumor is diagnosed. The tumor usually is a breast cancer or, less frequently, gynecologic cancers or SCLC. The serum and CSF of these patients contain an antibody called anti-Ri, which is expressed by neurons and the associated tumor. [54] [55]

In patients with SCLC, the development of PCD may be the presenting symptom of PEM. In such cases, anti-Hu or anti-CV2/CRMP5 antibodies usually are present, and the patients eventually develop signs and symptoms of multifocal neurologic disease. Patients whose symptoms remain restricted to the cerebellum and who do not harbor anti-Hu antibodies may have antibodies to voltage-gated calcium channels.[56]

One subset of patients develop PCD in the setting of brainstem dysfunction. These patients have serum and spinal fluid antibodies against Ma1 and Ma2 proteins expressed in neurons and spermatogenic cells of testis. These patients have a variety of associated cancers, including those of the lung, breast, parotid, colon, and testis.[57]

Most patients with PCD do not improve, although there are isolated reports of improvement with treatment of the tumor, corticosteroids, IVIg, plasma exchange, rituximab, or cyclophosphamide. [58] [59] [60]

Motor Neuron Syndromes

The existence of paraneoplastic motor neuron dysfunction is based on reports of patients with typical amyotrophic lateral sclerosis (ALS) who improved after treatment of the underlying tumor, suggesting more than a coincidental relationship. [61] [62] In patients with cancer and symptoms of motor neuron disease the most common neoplasms are carcinoma of the lung, breast, kidney, and lymphoma. For these patients, the neurologic syndrome and laboratory studies are similar to those seen in typical patients with ALS.

Patients with PEM may develop symptoms resembling motor neuron disease. [26] [30] These patients almost always develop signs of involvement of other areas of the nervous system, which, along with the presence of the anti-Hu antibody, helps to rule out typical ALS.

Patients with Hodgkin's and non-Hodgkin's lymphoma may develop a subacute lower motor neuronopathy.[63] Typically, these patients have a subacute, progressive, painless, and asymmetric involvement of the extremities, with the legs more affected than the arms. In contrast to typical ALS, fasciculations are rare, bulbar muscles usually are spared, and upper motor neuron signs are absent. Examination of the CSF is normal or shows mildly increased proteins, and electrophysiologic studies demonstrate denervation with normal or mild slowing of motor nerve conduction velocities. Neurologic stabilization or spontaneous improvement may occur. Paraneoplastic subacute lower motor neuronopathy must be distinguished from the lower motor neuron dysfunction that patients may develop after radiation therapy of the spinal cord.[64]

Peripheral Nerve Hyperexcitability and Stiff-Man Syndrome

Peripheral nerve hyperexcitability (PNH) is characterized by muscle cramps, stiffness, myokymia, and delayed muscle relaxation (neuromyotonia) due to spontaneous and continuous muscle fiber activity of peripheral nerves. It often is found in association with a sensorimotor polyneuropathy and has been described most often in patients with thymoma and SCLC. [3] [65] An autoimmune etiology for neuromyotonia is supported by the presence of serum antibodies that interfere with the function of voltage-gated potassium channels.[66] Electrophysiologic studies reveal large numbers of bizarre, high-frequency motor unit discharges during voluntary contraction that persist during relaxation, in contrast to patients with stiff-man syndrome (discussed in the following paragraph), who have continuous but relatively normal motor unit activity.[67] Treatment with phenytoin, carbamazepine or plasma exchange may be effective in some patients.

The stiff-man syndrome is an unusual disorder characterized by progressive muscle stiffness, aching, muscle spasms, and rigidity. The stiffness develops over a period of months and is most prominent in the paraspinal muscles and lower limbs. The muscle spasms are painful and are triggered by a variety of stimuli. They are severe enough to produce limb deformities and fractures.[68] There are no other associated neurologic abnormalities; the CSF may show oligoclonal bands, and increased IgG index and neuroradiologic studies are usually normal. The tumors most commonly involved include breast cancer, SCLC, thymoma, and Hodgkin's disease. A subset of patients with paraneoplastic stiff-man syndrome and breast cancer or SCLC have antibodies that react with amphiphysin, a neuronal synaptic protein. [68] [69] [70] When stiff-man syndrome occurs in patients who do not have cancer, the disorder is associated with antibodies against glutamic acid decarboxylase (GAD). [71] [72] [73] These patients usually develop diabetes and other endocrine deficits. Treatment of the tumor and use of corticosteroids may result in improvement. Patients with nonparaneoplastic stiff-man syndrome respond to IVIg, and this approach may be useful for patients with the cancer-associated syndrome. [74] [75] Drugs that enhance GABA-ergic transmission (e.g., diazepam, baclofen, sodium valproate, tiagabine, vigabatrim) improve symptoms of most patients.

A rare disorder seen in patients with cancer is progressive encephalomyelitis with rigidity. [72] [76] In this disorder, most often associated with SCLC, patients usually develop brainstem dysfunction, rigidity, and spinal myoclonus due to widespread dysfunction of the CNS. The cervical portion of the spinal cord is affected most commonly.[77]

Paraneoplastic Opsoclonus-Myoclonus

Opsoclonus is a disorder of ocular motility characterized by the presence of spontaneous, arrhythmic, large-amplitude conjugate saccades occurring in all directions of gaze without a saccadic interval.[78]In patients with cancer, opsoclonus can have a paraneoplastic origin, in which case it often is associated with myoclonus of head, trunk, or extremities (paraneoplastic opsoclonus-myoclonus). The differential diagnosis includes viral, toxic, metabolic, and vascular disorders.

In children, paraneoplastic opsoclonus-myoclonus is a well-known complication of neuroblastoma. [79] [80] In half of the patients, the opsoclonus precedes diagnosis of the neuroblastoma, but it also may develop after tumor diagnosis, during remission, or at recurrence. The onset is subacute, with frequent fluctuations of symptoms; in some patients symptoms may resolve spontaneously. Treatment with corticosteroids, adrenocorticotropic hormone, plasma exchange, IVIg, or rituximab, or treatment of the tumor, results in improvement in one half to two thirds of patients.[81] Despite an initial response, about 60% of patients are left with permanent neurologic deficits, including language and cognitive dysfunction.[82]

Paraneoplastic opsoclonus-myoclonus also has been described in adult patients with cancer. Most have an underlying SCLC, although there are individual case reports associated with other tumors, including carcinoma of the uterus, fallopian tube, breast, bladder, thyroid, thymus, chondrosarcoma, and Hodgkin's disease. [78] [83] [84] [85] A small number of women with breast cancer, anti-Ri antibodies, and opsoclonus have been reported. [54] [86] Patients with anti-Ri antibodies often have other symptoms, suggesting a more diffuse involvement of the brainstem, whereas patients without anti-Ri antibodies tend to have limb or truncal myoclonus and encephalopathy.

Compared to the idiopathic form of opsoclonus-myoclonus, from which patients often recover, paraneoplastic opsoclonus-myoclonus in adults has a more severe clinical course, even when aggressively treated with IVIg or corticosteroids. For those patients who develop an associated encephalopathy, one series noted improved outcomes when the tumor (usually SCLC) was identified and treated promptly.[87] Currently, no immunologic markers have been found that identify most cases of adult or pediatric paraneoplastic opsoclonus-myoclonus. Recent studies have found a high incidence of autoimmune responses to a variety of neuronal autoantigens but did not identify a specific antibody marker. [88] [89]

Paraneoplastic Syndromes of the Visual System

In patients with cancer, visual symptoms and blindness usually are related to metastatic infiltration of the optic nerves by tumor and neurotoxicity from chemo- and radiation therapy. [90] [91] [92] [93]Paraneoplastic visual syndromes can result from retinopathy and optic neuritis. Paraneoplastic optic neuritis is very rare, and while it may develop in isolation, it usually is associated with PEM.[94] The onset is subacute with painless bilateral visual loss. [95] [96]

The paraneoplastic retinopathies are a heterogeneous group of syndromes including CAR and MAR. These two syndromes have specific clinical, electrophysiologic, and pathological characteristics and distinct immunologic associations. Patients with cancer-associated retinopathy develop acute or subacute visual loss due to degeneration of the retinal photoreceptor or ganglion cells. [97] [98] The onset usually is unilateral, but progresses to become bilateral over days or weeks. Initial symptoms include photosensitivity, light-induced glare, color vision deficits, intermittent visual obscurations, and central or ring-like scotomas. For most patients the underlying tumor is SCLC, but a few case reports have been associated with breast or gynecologic cancers. Visual symptoms usually precede diagnosis of the tumor. Visual evoked responses usually are normal, but electroretinograms demonstrate reduced or flat responses to photopic and scotopic stimuli, suggesting dysfunction of cones and rods. Examination of the CSF may reveal a mild pleocytosis; neuroimaging studies are normal.

The serum of some patients with CAR contains antibodies that react with antigens expressed by photoreceptors and ganglion cells. The most common antibody is against recoverin, a 23-kd photoreceptor calcium-binding protein,[99] and the presence of antirecoverin antibodies indicates that the associated tumor almost always is an SCLC.[100] These antibodies cause apoptotic retinal cell death, suggesting a direct pathogenic role.[101] Other antigens that are targets of immune responses in some patients include tubby-like protein 1 and the photoreceptor-specific nuclear receptor (PNR). [102] [103] The role of the latter antibodies in the pathogenesis of the retinopathy is unknown, but it is of interest that mutations of the PNR gene have been identified in a cohort of patients with enhanced S-cone syndrome, a disorder of retinal cell fate that progresses to retinal degeneration. [104] [105] This finding suggests a mechanism whereby antibodies interfere with autoantigen function, resulting in retinal cell death.

Melanoma-associated retinopathy has been described in patients with metastatic cutaneous melanoma. These patients present with acute visual loss, years or months after the diagnosis of the metastatic disease, [106] [107] and have serum antibodies that target unidentified proteins localized in the bipolar cells of the retina. [108] [109] The electroretinogram shows selective loss of the photopic “b” wave with relative preservation of the “a” and “d” wave forms. Intraocular injection of serum from patients with MAR reproduces the retinal abnormalities, demonstrating that the antibodies are pathogenic.[107]

For both CAR and MAR, the visual loss usually is irreversible. Treatment with immunosuppression, plasma exchange, or corticosteroids is mostly ineffective, but in rare cases may result in symptom stabilization. [110] [111]


Paraneoplastic Sensory Neuronopathy

Paraneoplastic sensory neuronopathy (PSN) resulting from dorsal root ganglia dysfunction may develop in isolation but most often is a fragment of PEM.[26] Patients typically develop asymmetric pain and paresthesias that can mimic radiculopathy or multineuropathy.[112] Symptoms usually progress over weeks or months to involve other extremities and, sometimes, the trunk.[26] Cranial nerves may be affected, resulting in loss of taste, facial numbness, and sensorineural deafness. Eventually, there is severe involvement of all modalities of sensation, resulting in pseudo-athetotic movements of the hands, a debilitating sensory gait ataxia, and neuropathic pain that are difficult to control.

In more than 80% of patients with PSN the associated tumor is SCLC. Sensory symptoms usually precede diagnosis of the tumor. Electrophysiologic studies confirm the isolated or predominant involvement of the sensory nerves, but in some patients the motor conduction velocities may be affected.[113] These patients had evidence of both demyelination and axonal degeneration in association with loss of neurons in the dorsal root ganglia, and circulating anti-CV2/CRMP5 antibodies in association with anti-Hu antibodies.

Patients who develop PSN as a component of PEM often have anti-Hu antibodies, and the associated cancer almost always is an SCLC ( Fig. 51-5 ). [21] [26] In patients with PSN without anti-Hu antibodies, associated cancers include SCLC, non-SCLC lung tumors, and breast cancer. Except for the detection of anti-Hu antibodies in patients with SCLC, laboratory studies of patients with PSN are nonrevealing. The CSF may show increased proteins and a mononuclear pleocytosis.


Figure 51-5  Detection of an antineuronal antibody (anti-Hu) in the serum of a patient with paraneoplastic sensory neuronopathy. A frozen section of rat dorsal root ganglion incubated with the serum of the patient shows intense immunolabeling of the neurons, with reactivity predominantly involving the nuclei. This antibody, known as anti-Hu, usually is associated with paraneoplastic sensory neuronopathy (or dorsal-root ganglionitis) and encephalomyelitis. Patients with anti-Hu antibodies usually harbor a small cell lung cancer.



There is no specific treatment for PSN. Studies have suggested that patients with PSN associated with SCLC and anti-Hu antibodies whose tumors responded to therapy were more likely to have stabilization of improvement of the PSN compared with those whose tumors were not treated or did not respond to treatment. [21] [22] Some patients may have partial improvement with corticosteroids. The effects of IVIg, cyclophosphamide, and rituximab are unclear. [60] [114] [115]

Sensorimotor Neuropathies

Many patients with cancer, particularly those with advanced disease and significant weight loss, develop signs and symptoms of peripheral neuropathy. In most patients, an identifiable cause such as a nutritional deficit, hepatic or renal failure, the use of chemotherapeutic agents, or leptomeningeal metastases can be found. Mononeuropathies and plexopathies in patients with cancer most often are secondary to compression of nerves by tumor or hemorrhage and infarction secondary to leukemic infiltration. [116] [117] A paraneoplastic brachial neuritis may occur with increased frequency in patients with Hodgkin's disease. [118] [119] The clinical presentation is similar to that of brachial neuritis observed in patients without cancer, with the initial pain complaints followed by the development of paresthesias and weakness.

A subacute or chronic sensorimotor neuropathy may occur with any malignancy but most commonly is associated with lung cancers. [116] [120] The onset usually follows the cancer diagnosis but may precede it by several months or years. Lower extremities are predominantly involved, with symptoms spreading proximally over the course of the disease with rare involvement of cranial nerves. Weakness occurs late, and most patients have slowly progressive disease.

An acute rapidly progressive sensorimotor polyneuropathy can be seen in association with Hodgkin's lymphoma.[121] The syndrome is clinically indistinguishable from Guillain-Barré syndrome (GBS). A similar syndrome also has been reported in patients with solid tumors. Treatment is the same as for patients with idiopathic GBS and includes plasma exchange and IVIg. There is evidence, however, that cancer-associated GBS has a worse outcome than GBS alone.[122]

Approximately 10% of patients with multiple myeloma will develop a clinically significant neuropathy. The neuropathy, most often sensorimotor, commonly precedes diagnosis of the myeloma and is slowly progressive.[123] Treatment of the myeloma usually does not alter the course of the neuropathy. Other causes of peripheral nerve or nerve root involvement include deposits of amyloid and root compression by spine metastases.

Osteosclerotic myeloma represents about 3% of all cases of myeloma. More than 50% of patients with osteosclerotic myeloma develop a predominantly motor paraneoplastic peripheral neuropathy, which often is the initial presentation of the myeloma.[124] The clinical picture is similar to that of chronic inflammatory demyelinating polyneuropathy.[125] Resection or radiation of the sclerotic lesions, or chemotherapy, often results in neurologic improvement.[123]

Ten percent of patients with Waldenström's macroglobulinemia develop a peripheral neuropathy with predominant sensory involvement. In some, the monoclonal IgM has activity against myelin-associated glycoprotein or gangliosides.[126]

The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinemia, and skin changes) is a rare disorder that can develop in association with all forms of myeloma but is seen predominantly with osteosclerotic myeloma. [125] [127] [128] Patients develop a severe, symmetric, sensorimotor neuropathy that is associated with muscle atrophy.

Castleman's disease is a rare disorder that overlaps with POEMS. Patients commonly develop neuropathies, including a painful sensorimotor neuropathy, a chronic relapsing sensorimotor neuropathy, and a predominantly motor neuropathy.[129] Treatment of the Castleman's disease along with plasma exchange or immunosuppression may result in improvement of the neuropathy.[130]

Vasculitic Neuropathy

Paraneoplastic vasculitis may be systemic or confined to nerve and muscle. When systemic, the small vessels of the skin commonly are affected, and the most commonly associated tumors are lymphomas and leukemias. [131] [132] A paraneoplastic microvasculitis of the muscle and nerve without systemic vasculitis has been reported in older patients with solid tumors, particularly carcinoma of the prostate, kidney, lung, endometrium, and lymphoma.[133] These patients develop symptoms of symmetric or asymmetric painful sensorimotor neuropathy. As a result of the muscle vasculitis, patients can develop proximal muscle weakness. The diagnosis is suggested by the presence of elevated proteins in CSF and an elevated erythrocyte sedimentation rate and is confirmed by biopsy of nerve and muscle. This disorder may respond to corticosteroids and cyclophosphamide or other types of immunosuppression.

Autonomic Neuropathy

Paraneoplastic autonomic neuropathy usually occurs as a component of other disorders, such as LEMS and PEM, but it may occur rarely as the predominant symptom.[26] Patients with paraneoplastic autonomic neuropathy can develop several life-threatening complications, such as gastrointestinal paresis with pseudoobstruction, cardiac dysrhythmias, and postural hypotension. Additional symptoms include dry mouth, erectile dysfunction, anhidrosis, and sphincter dysfunction. Paraneoplastic autonomic neuropathy has been reported in association with several tumors, including SCLC, cancer of the pancreas, cancer of the testis, carcinoid tumors, and lymphoma. When the autonomic dysfunction is a component of PEM, serum anti-Hu and anti-CV2/CRMP5 antibodies may be positive. Serum antibodies to ganglionic acetylcholine receptors have been reported, but they also may occur without a cancer association.[134]


Myasthenia Gravis

Myasthenia gravis (MG) results from an immune response directed against the acetylcholine receptor at the neuromuscular junction. Thymic abnormalities are reported to occur in approximately 75% of patients with MG. Of these, 15% have microscopic or gross evidence of thymoma, and 85% have evidence of thymic hyperplasia. Patients develop weakness of the extremities and the ocular and bulbar muscles; a few patients have pure ocular involvement. [2] [135] The most common presenting signs are ptosis and intermittent diplopia. Proximal muscles tend to be more affected than distal muscles, and muscle atrophy is rare. Deep tendon reflexes are preserved. Pain usually is not reported, although some patients complain of paresthesias. Aspiration secondary to dysphagia and ventilatory paralysis secondary to respiratory muscle involvement may be causes of death.[136]

The initial approach to treatment should be directed at the underlying tumor. Additional therapeutic strategies, including symptomatic treatment (i.e., anticholinesterase drugs), immunomodulation (e.g., plasma exchange, IVIg), and immunosuppression (e.g., corticosteroids, azathioprine) are similar for patients with and without cancer.

Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of the neuromuscular junction in which the presence of autoantibodies against P/Q type voltage-gated calcium channels results in a defect in the presynaptic quantal release of acetylcholine. [137] [138] [139] Approximately 60% of patients with LEMS have an associated SCLC.[16] In most patients (70%), the neurologic symptoms develop before the tumor diagnosis is made; in 25% of patients the symptoms develop at the same time the tumor is diagnosed.[140]

Patients present with lower extremity weakness, increased fatigability, and difficulties walking, rising from a chair, or climbing stairs. Some patients report a brief increase in muscle strength following a period of activity. Nerve conduction studies show a very-low-amplitude compound muscle action potential that increases progressively (>200%) in response to fast rates (20–50Hz) of repetitive stimulation or after a short period of maximum voluntary contraction ( Fig. 51-6 ). Detection of antibodies against the P/Q type voltage gated calcium channel currently is used as a serologic test for LEMS.[138]


Figure 51-6  Electrophysiologic study of a patient with small cell lung cancer and the Lambert-Eaton myasthenic syndrome. A, Facilitation of the compound motor action potential (CMAP) after 10 seconds of maximal voluntary contraction. B, Progressive increase of the CMAP amplitude with high-frequency repetitive stimulation. These are the classic electrophysiologic findings in patients with LEMS.



At least 50% of patients have evidence of autonomic dysfunction, such as dry mouth, impotence, constipation, or impaired sweating. [16] [141] [142] Mild and usually transient cranial nerve dysfunction occurs in most patients.[143] Although rare, respiratory muscle weakness may occur, even to the point of requiring assisted ventilation. In contrast to MG, where the deep tendon reflexes usually are spared, in LEMS they are reduced or absent, especially in the lower extremities. In some patients, LEMS may develop in association with PCD or PEM. [4] [49]

When LEMS is associated with cancer, most patients will have neurologic improvement with combined cancer treatment and therapy directed to LEMS. The latter includes medications that increase the presynaptic release of acetylcholine and immunomodulation. The use of 3,4-diaminopyridine results in moderate to marked neurologic improvement in 80% of patients.[144] If 3,4-diaminopyridine is not available, a combination of pyridostigmine and guanidine may be beneficial.[145] Plasma exchange and IVIg are useful for treating patients with severe weakness.[146] Neurologic improvement occurs within days or weeks but is transient. For patients who are refractory to these treatments, long-term immunosuppression with prednisone or azathioprine may be effective. Patients whose neurologic symptoms relapse should be evaluated for tumor recurrence.



About 9% of patients with polymyositis develop cancer. Since the neoplasm often is diagnosed several years before or after diagnosis of the polymyositis, this may represent a coincidental occurrence and casts doubt on the role of cancer in the pathogenesis of the neurologic disorder.[17] In contrast, 15% of patients with dermatomyositis develop cancer, and in most patients the tumor is diagnosed by the time the myopathic symptoms develop.[17] Cancer of the breast, lung, ovary, and stomach are the most commonly associated tumors.

Clinical symptoms are similar for patients with and without cancer.[147] Patients with dermatomyositis may present with a reddish or purplish skin rash that often precedes the onset of proximal muscle weakness. Serum creatine kinase levels usually, but not always, are elevated. Respiratory muscle weakness may lead to ventilatory failure and contribute to death. Other symptoms include arthralgias and muscle contractures, myocardial inflammation leading to congestive heart failure, and interstitial lung disease.[148] Reflexes and sensory examination usually are normal.

Several autoantibodies have been identified in patients with polymyositis and dermatomyositis. Jo-1 antibodies are identified in a group of patients with either disorder and are associated with interstitial lung disease. [149] [150] Antinuclear antibodies typical of other connective tissue diseases also can be detected.[151] There are no specific markers indicative of the paraneoplastic origin of dermatomyositis. Dermatomyositis and polymyositis usually respond to corticosteroids and other types of immunosuppression (e.g., azathioprine). High-dose IVIg has proved to be effective for dermatomyositis.

Acute Necrotizing Myopathy

Acute necrotizing myopathy has been described in patients with cancer of the lung, bladder, breast, and gastrointestinal tract.[152] Patients present with symmetric weakness of the extremities associated with pain and a marked increase of serum muscle enzymes. Symptoms rapidly progress to involve pharyngeal and respiratory muscles, often resulting in death. The electrophysiologic studies are consistent with myopathy, and pathology studies demonstrate extensive muscle necrosis with little or no inflammatory infiltrates. It has been suggested that acute necrotizing myopathy represents a severe and more rapid form of polymyositis, but this remains unproven.[153]

Treatment and Prognosis

In general, paraneoplastic syndromes of the CNS have a subacute, progressive course that results in severe deficits or death in weeks or months. [26] [51] Spontaneous improvement has been observed in some patients with opsoclonus-myoclonus, mostly children with neuroblastoma,[154] or patients with PCD associated with Hodgkin's disease, [52] [155] subacute motor neuronopathy,[63] and sensorimotor neuropathies, which usually fulfill the criteria of acute or chronic GBS. [121] [156] [157] Progression to severe disability is seen less often in the neuromuscular disorders that develop after the diagnosis of the tumor, such as some sensorimotor neuropathies. A few patients with anti-Hu-associated sensory neuronopathy, and patients with PCD, particularly those without anti-Yo antibodies, may have a mild, indolent clinical course or even stabilize with only moderate neurologic deficits. [49] [158] A classification of the paraneoplastic neurologic disorders by expected treatment response is given in Table 51-2 .

Table 51-2   -- Treatment Response of Paraneoplastic Neurologic Disorders




Myasthenia gravis

Tumor, plasmapheresis, IVIg, immunosuppression

Lambert-Eaton myasthenic syndrome

Tumor, plasmapheresis, IVIg, 3,4-diaminopyridine


Corticosteroids, IVIg, immunosuppression

Opsoclonus/myoclonus (pediatric)

Tumor, corticosteroids, ACTH

Limbic encephalitis with anti-Ma2 antibodies and testicular tumors

Tumor, corticosteroids, IVIg

Encephalitis with anti-NMDAR antibodies and ovarian teratoma

Tumor, corticosteroids, plasmapheresis, IVIg, cyclophosphamide

Carcinoid myopathy

Tumor, cyproheptadine

Neuropathy (osteosclerotic myeloma)

Tumor, radiation


Vasculitis (nerve/muscle)


Opsoclonus/myoclonus (adults)

Tumor, corticosteroids, protein A column, clonazepam, diazepam, baclofen

PCD (Hodgkin's disease)


Opsoclonus/ataxia (anti-Ri associated)

Corticosteroids, plasmapheresis

Guillain-Barré (Hodgkin's disease)

Tumor, plasmapheresis, IVIg

Stiff-man syndrome

Tumor, corticosteroids, diazepam, baclofen, IVIg



ACTH, adrenocorticotropic hormone; IVIg, intravenous immunogbbulin; NMDAR, N-methyl D-aspartate receptor; PCD, paraneoplastic cerebellar degeneration.




Improvement of neurologic symptoms after tumor treatment has been reported for almost all the paraneoplastic syndromes.[159] However, the actual impact of antineoplastic therapy on the paraneoplastic symptoms is difficult to assess. This is due, in part, to the low incidence of neurologic paraneoplastic syndromes and the lack of effective treatment for some neoplasms. The rapid and apparently irreversible neuronal damage that is characteristic of many paraneoplastic symptoms may allow potentially effective treatments to arrest, but not reverse, the neurologic symptoms. Despite these limitations in assessment, some patients with limbic encephalitis have neurologic improvement, which appears to relate to tumor treatment. In particular, limbic encephalitis in young men with anti-Ma2 antibodies and germ cell tumors and young women with anti-NR1/NR2 antibodies and teratomas improves with treatment of the tumor and immunotherapies. [28] [45]

For those paraneoplastic disorders of the peripheral nervous system associated with pathogenic antibodies (e.g., MG, LEMS, neuromyotonia), removal of the antibodies,[160] treatment of the tumor (removing the source of antigen), or immunosuppression often is effective.[161] For other paraneoplastic disorders, the symptoms sometimes evolve independently of the course of the tumor. An exception is osteosclerotic myeloma, in which treatment of the myeloma can result in dramatic improvement of an associated sensorimotor neuropathy. [162] [163] [164] Immunosuppressive treatments including corticosteroids, IVIg, and plasma exchange have been used in paraneoplastic syndromes that appear to result from immune-mediated mechanisms. [159] [165] These include demyelinating sensorimotor neuropathies, vasculitic neuropathy,[166] and dermatomyositis. [167] [168] In these disorders, clinical improvement can be expected after treatment, because the area of the nervous system involved is not irreversibly damaged. Large series examining plasma exchange and IVIg in paraneoplastic disorders of the CNS have not shown any significant benefit. [169] [170] There are, however, individual case reports of improvements. [87] [171] [172] [173]


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