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Paraneoplastic Neurologic Syndromes
Summary of Key Points
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The paraneoplastic neurologic syndromes include an extensive group of immune-mediated disorders that can affect any part of the central or peripheral nervous system.
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Patients with paraneoplastic neurologic syndromes may have serum and cerebrospinal fluid antibodies that are highly specific for the presence of a cancer. The detection of these antibodies serves as a marker of paraneoplasia. Other antibodies are associated with specific neurologic syndromes that occur with or without cancer. In these cases, the antibodies serve as markers for the neurologic syndrome but do not distinguish between a paraneoplastic or nonparaneoplastic etiology.
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Antibodies directly mediate some disorders such as the Lambert-Eaton myasthenic syndrome, myasthenia gravis, neuromyotonia, and anti– N -methyl- d -aspartate receptor encephalitis and likely mediate other disorders such as anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and anti-γ-aminobutyric acid type B (GABA B ) receptor encephalitis, among others. In these disorders the antibodies target neuronal cell surface proteins (e.g., receptors and ion channels), and immunotherapy along with tumor treatment often results in substantial neurologic improvement.
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For paraneoplastic neurologic syndromes in which T-cell mechanisms are predominant, the associated antibodies target intracellular neuronal proteins. In this group of disorders, the response to 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. For these syndromes 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 whether the patient is in the early stages of the neurologic disease, treatment with immunosuppression may have some effect on the paraneoplastic neurologic syndrome.
Paraneoplastic syndromes may affect any part of the neuraxis. In some syndromes, a single cell type, such as the Purkinje cells in paraneoplastic cerebellar degeneration (PCD), is predominantly involved, whereas in other syndromes any neuron of the central or peripheral nervous system may be affected, as occurs in paraneoplastic encephalomyelitis (PEM) and paraneoplastic sensory neuronopathy (PSN). Because of this variable distribution of pathologic involvement, patients with these disorders may have symptoms of unifocal or multifocal involvement of the nervous system.
Identification of the paraneoplastic origin of a patient's symptoms is important because the neurologic symptoms often develop before the cancer diagnosis is known. Because similar disorders may occur without cancer, the diagnosis of the paraneoplastic origin of a disorder depends on the index of suspicion, which is based in part on the syndrome, because some syndromes have a paraneoplastic origin more frequently than do others. For example, the likelihood that Lambert-Eaton myasthenic syndrome (LEMS) or subacute cerebellar degeneration in a middle-aged or elderly patient is paraneoplastic is probably greater than 50%. In contrast, subacute sensory neuropathy or dermatomyositis is probably paraneoplastic in less than 25% of patients. In most paraneoplastic syndromes, symptoms develop acutely or subacutely and may resemble a viral process. Symptoms evolve over weeks or months and then stabilize or, depending on the syndrome and treatment response, improve, differentiating them from the chronic and progressive degenerative diseases of middle age and adulthood. Criteria and guidelines have been proposed to facilitate the diagnosis of paraneoplastic neurologic disorders based on the type of neurologic syndrome, the detection of an associated tumor, and the presence or absence of specific serum and/or cerebrospinal fluid (CSF) antibodies ( Box 44.1 ).
Box 44.1
Diagnostic Strategies
The diagnosis of a paraneoplastic neurologic syndrome is relatively straightforward for patients who experience symptoms of a well-defined syndrome that typically is associated with cancer. The specificity of some paraneoplastic antineuronal antibodies for paraneoplastic neurologic syndromes or some types of cancer makes them useful diagnostic tools. In the right clinical context, the detection of a paraneoplastic antibody in the serum or cerebrospinal fluid (CSF) helps establish the diagnosis and focus the search of the neoplasm. If the detected antibody usually is not associated with the patient's neurologic syndrome, other causes 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. If paraneoplastic antibodies are present but a cancer is not discovered, the patient should be assumed to harbor an occult neoplasm. Whole-body positron emission tomography (PET) scans may be used to 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.
In addition to the paraneoplastic antibodies that invariably are associated with cancer, there is a group of antibodies that are associated with specific neurologic syndromes in the presence and absence of cancer. These disorders include the antibody-mediated disorders of the neuromuscular junction and antibody-associated autoimmune encephalitis. The need for an oncologic evaluation when one of these antibodies is found is based on the syndrome and antibody and in some cases can be focused to particular cancer types.
The diagnosis of a paraneoplastic neurologic syndrome is more difficult in patients who exhibit less characteristic symptoms (e.g., brainstem dysfunction and myelopathy), especially if no antibodies are found in the serum or CSF. Examination of the CSF can support a paraneoplastic etiology by showing evidence of inflammation (pleocytosis, elevated protein concentration, intrathecal synthesis of immunoglobulin, and/or oligoclonal bands), although normal CSF studies do not rule out paraneoplasia. Cancer screening can be approached by focusing on the tumors more commonly associated with the neurologic syndrome and then expanding based on clinical history and presence of cancer risk factors. Because of the common association of breast and gynecologic cancers with paraneoplastic disorders, a mammogram and pelvic computed tomography scan or ultrasound examination 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 test results are negative. The best approach to treating paraneoplastic neurologic syndromes is to discover and treat the tumor promptly, start immunotherapy early when symptoms are still progressing, and provide supportive care for the neurologic deficits with symptomatic treatment and physical therapy.
The antibodies that are associated with paraneoplasia can be divided into two groups. In one group are antibodies that are highly specific for the paraneoplastic origin of the neurologic symptoms and are not found (or are rarely found and at low titers) in patients with similar neurologic disorders without cancer. These antibodies serve as markers of the paraneoplastic origin of neurologic symptoms and for the presence of specific tumor types ( Table 44.1 ). In general, these antibodies are directed against intracellular neuronal antigens and are not directly responsible for the neurologic dysfunction. Rather, pathogenicity appears to be mediated by cytotoxic T cells, with the antibodies playing a role in inducing or enhancing the autoimmune response. Autopsies of patients with these antibodies often demonstrate intense inflammatory infiltrates of mononuclear cells, including CD4+ and CD8+, which predominate in symptomatic areas. Because of the neuronal destruction caused by the cytotoxic T cells, these disorders tend to be refractory or minimally responsive to treatment.
Table 44.1
Immune Associations in Paraneoplastic Neurologic Disorders
| Antibody | Syndrome | Most Common Tumor Association |
|---|---|---|
| Anti-Hu | PEM/PSN | SCLC |
| Anti-Yo | PCD | Ovary, breast |
| Anti-Ma proteins | Limbic/brainstem encephalitis (Ma2); less commonly PCD (Ma1 and Ma2) | Testicular germ cell tumors, other solid tumors |
| Anti-Ri | Opsoclonus-ataxia | Breast, gynecologic |
| Anti-Tr/DNER | PCD | Hodgkin lymphoma |
| Anti-amphiphysin | Stiff man syndrome | Breast, SCLC |
| Anti-CV2/CRMP5 | PEM/PCD, peripheral neuropathy, uveitis | SCLC, several |
| Anti-recoverin | Retinopathy | SCLC |
| Anti-bipolar cells of retina | Retinopathy | Melanoma |
| Anti-NMDAR a | Limbic encephalitis, seizures, psychiatric symptoms | Teratoma |
| Anti-VGCC a | LEMS, PCD | SCLC |
| Anti-AChR a (muscle) | Myasthenia gravis | Thymoma |
| Anti-AChR a (neuronal) | Autonomic neuropathy | SCLC |
| Anti-Caspr2 a | Peripheral nerve hyperexcitability (with or without CNS involvement) | Thymoma, others |
| Anti-LGI1 a | Limbic encephalitis | Thymoma, SCLC |
| Anti-AMPAR a | Limbic encephalitis with tendency to relapse | SCLC, thymoma, breast |
| Anti-GABA B a | Limbic encephalitis with prominent seizures | SCLC |
| Anti-GABA A a | Rapidly progressive encephalitis with refractory seizures | thymoma |
| Anti-mGluR5 | Limbic encephalitis | Hodgkin lymphoma |
AChR, Acetylcholine receptor; AMPAR, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; Caspr2, contactin-associated protein 2; CNS, central nervous system; CRMP, collapsin response-mediator protein; DNER, Delta/Notch-like epidermal growth factor-related receptor; LGI1, leucine-rich glioma inactivated 1; GABA B , γ-aminobutyric acid type B; GABA A , γ-aminobutyric acid type A; LEMS, Lambert-Eaton myasthenic syndrome; mGluR5, metabotropic glutamate receptor-5; NMDAR, N -methyl- d -aspartate receptor; PCD, paraneoplastic cerebellar degeneration; PEM, paraneoplastic encephalomyelitis; PSN, paraneoplastic sensory neuronopathy; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel.
a This antibody may occur with or without a cancer association and is therefore not a marker of paraneoplasia.
In contrast, in the other group are antibodies that are known to be pathogenic or for which there is evidence supporting their pathogenicity. The target antigens of these antibodies are neuronal cell surface receptors, ion channels, or synaptic proteins. Patients with these antibodies often respond to antibody-depleting immunotherapies in addition to treatment of the underlying tumor. For example, patients with LEMS have serum antibodies against voltage-gated calcium channels. These antibodies block the entry of calcium necessary for the release of quanta of acetylcholine and result in neuromuscular weakness. In myasthenia gravis, most patients develop antibodies against the acetylcholine receptor at the postsynaptic level of the neuromuscular junction that result in weakness and fatigability. In patients with encephalitis and anti– N -methyl- d -aspartate (NMDA) receptor antibodies, the antibodies produce progressive decrease of the density of synaptic NMDA receptor clusters and a reduction of NMDA receptor–mediated currents, resulting in a clinical phenotype resembling the syndrome seen in patients taking NMDA receptor antagonists. All of these disorders occur with or without cancer, and the antibodies are markers of the neurologic syndromes. Although the presence of these antibodies does not distinguish between a paraneoplastic or nonparaneoplastic etiology, some antibodies tend to be associated with one or a few cancer types when the disorder is paraneoplastic (e.g., small cell lung cancer [SCLC], LEMS, and voltage-gated calcium channel antibodies; thymoma, myasthenia gravis, and anti–acetylcholine receptor antibodies; teratoma, autoimmune encephalitis, and anti-NMDA receptor antibodies).
Paraneoplastic Syndromes of the Central Nervous System
Paraneoplastic Encephalomyelitis
Patients with PEM experience symptoms of multifocal involvement of the nervous system, resulting in several syndromes that may occur in isolation or in various combinations. Syndromes include limbic encephalitis, cerebellar degeneration, brainstem encephalitis, myelitis, and sensory and autonomic neuropathies.
PEM has been described in association with many tumors, but in 70% of patients the underlying tumor is a SCLC. Most tumors are diagnosed within 2 years of 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 that is associated with other types of cancer. Antibodies to CV2/CRMP5, with or without anti-Hu antibodies, occur at a lower frequency and most commonly are associated with thymoma. A subset of patients with PEM and antibodies to CV2/CRMP5 also experience paraneoplastic chorea and uveitis.
The onset of symptoms in PEM is usually subacute. Sensory neuropathy is the most common initial manifestation, followed by brainstem and limbic encephalopathy. Symptom progression is usually relentless, or, less frequently, intermittent, until stabilization. Spontaneous improvement is rare but has been described in patients with limbic encephalitis. For most patients the neurologic deficits are severe and incapacitating. Responses (mostly stabilization) are more often reported in patients treated with immunotherapy early in the PEM course when disability is still moderate. Respiratory or autonomic failure due to neurologic dysfunction is commonly the cause of death.
About one-third of patients with PEM will experience symptoms of cerebellar and/or brainstem dysfunction. Motor weakness, muscle atrophy, and fasciculations are found in 20% of patients with PEM. 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. Autonomic dysfunction affects about 30% of patients. Symptoms include orthostatic hypotension, gastrointestinal paresis, and pseudoobstruction. 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 experience an asymmetric pansensory neuropathy called paraneoplastic sensory neuronopathy (PSN; see later discussion). PSN is often associated with painful dysesthesias that result 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 [GBS]).
Limbic Encephalitis
Symptoms of paraneoplastic limbic encephalitis (PLE) may develop alone but more often are found in association with brainstem dysfunction, cerebellar symptoms, or PSN (see Paraneoplastic Encephalomyelitis ). 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. 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 the face and extremities are common. Some patients show signs of diencephalic-hypothalamic dysfunction, including drowsiness, hyperthermia, hyperphagia, and, less frequently, pituitary hormonal deficits. The disorder may resemble viral encephalitis or a rapidly developing dementia due to a primary neurodegenerative disorder.
PLE is one of the few paraneoplastic neurologic disorders in which neuroimaging may be useful. Typical magnetic resonance imaging (MRI) findings include unilateral or bilateral mesial temporal lobe abnormalities best seen on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images ( Fig. 44.1 ). On T1-weighted sequences, the temporal-limbic regions may be hypointense and may enhance with contrast. Patients with herpes simplex encephalitis can have similar MRI findings in the early stages of the disease. However, these patients usually exhibit prominent signs of edema and mass effect involving one or both inferomedial temporal lobes, inferior frontal lobes, and the cingulate gyrus, which often is associated with gyral enhancement and signs of hemorrhage. Fluorodeoxyglucose–positron emission tomography (FDG-PET) studies of patients with limbic encephalitis may show hypermetabolism in the temporal lobes, even when MRI findings are normal.
The major pathologic findings are seen in the hippocampus, parahippocampal gyrus, cingular cortex, insular cortex, and diencephalon. Almost all patients have mild abnormalities in other areas of the nervous system in a pattern of distribution resembling PEM, suggesting that PLE should be regarded as PEM with predominant involvement of the limbic structures.
A variety of immune responses associate with limbic encephalitis. In patients with SCLC the anti-Hu antibody is present in about 50% of cases with predominant or isolated symptoms of limbic encephalitis. Fewer patients have been reported with anti-CV2/CRMP5 antibodies. In these patients the underlying tumors are SCLC and thymoma. 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. 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 PLE.
Limbic encephalitis may be associated with antibodies to leucine-rich glioma-inactivated–1 protein (LGI1), an epilepsy-related protein. In addition to seizures, 60% of patients experience hyponatremia, and some develop rapid eye movement sleep disturbances. The disorder is paraneoplastic in about 10% of cases, with thymoma being the most commonly associated tumor. Until recently this disorder was incorrectly attributed to antibodies to voltage-gated potassium channels.
Acute limbic dysfunction, sometimes with psychiatric features in association with antibodies to the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor has been reported and appears to more commonly affect middle-aged women. Approximately 70% of cases are paraneoplastic, with lung, breast, or thymic tumors being the most common.
Limbic encephalitis has also been reported with antibodies to the γ-aminobutyric acid type B (GABA B ) receptor. Patients with this condition usually have seizures, and in about 50% of cases, patients have SCLC or a neuroendocrine tumor of the lung. Some patients have ataxia or opsoclonus-myoclonus at presentation, but symptoms progress to include limbic encephalitis. Additional antibodies to glutamic acid decarboxylase and antibodies to nonneuronal proteins of unclear significance are frequently present, suggesting a tendency toward autoimmunity. MRI studies show unilateral or bilateral medial temporal lobe FLAIR/T2 abnormalities in almost two-thirds of cases.
Patients with antibodies to contactin-associated protein 2 (Caspr2) frequently develop limbic encephalitis, peripheral nerve hyperexcitability (neuromyotonia), or Morvan syndrome. Morvan syndrome is the combination of neuromyotonia, neuropathic pain, encephalopathy with hallucinations, and a characteristic sleep disorder called agrypnia excitata. In about a third of cases the progression of symptoms can evolve over many months in contrast to most paraneoplastic and autoimmune encephalitis that have acute or subacute onset. This can lead to delay in diagnosis and confusion with other entities. The disorder is often responsive to immunotherapy and tumor treatment, when a tumor is present.
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. A study of patients with SCLC and PLE suggested that the presence of anti-Hu antibodies was associated with a decreased likelihood of improvement. In contrast, about 35% of patients with limbic encephalopathy associated with antibodies to Ma2 improve with immunotherapy and treatment of the tumor (of these, most have a testicular germ cell tumor).
The syndromes associated with LGI1, AMPA receptor, GABA B receptor, and Caspr2 antibodies often respond to treatment of the tumor, when present, and immunotherapy, but patients are often left with residual deficits. Overall, outcomes appear worse for patients with LGI1 antibodies, with only 35% of patients returning to baseline cognitive function. Patients with AMPA receptor antibodies have a tendency to have relapses that can be successfully treated with reinstitution of immunotherapy. Relapses have been reported in 25% to 37% of patients with Caspr2 antibodies, although because of the low number of reported cases, response of relapses to treatment is unclear.
Anti– N -Methyl-d-Aspartate Receptor Encephalitis
Anti-NMDA receptor encephalitis is the most common of the autoimmune encephalitis syndromes associated with antibodies to neuronal cell surface and synaptic proteins. The disorder usually occurs in young women and children of both sexes, although older men and boys may be affected. Patients have an acute change in behavior and personality and memory loss, and may be diagnosed with a psychiatric disorder or be suspected of malingering or drug abuse. Symptoms progress within days or weeks to include seizures, decreased level of consciousness, abnormal movements (e.g., orofacial and limb dyskinesias and dystonia), and autonomic instability with frequent hypoventilation.
Despite the severity of the disease, less than half of patients have MRI findings, usually increased signal in cortical or subcortical brain or cerebellar regions on MRI FLAIR/T2 sequences and, less often, mild contrast enhancement. The CSF shows lymphocytic pleocytosis in almost 80% of cases, at times with increased proteins and/or oligoclonal bands. Almost 90% of patients have EEG abnormalities including generalized slow or disorganized activity without epileptic discharges that may overlap with electrographic seizures. A unique electroencephalographic pattern called extreme delta brush is found in a subset of cases.
Patients have IgG antibodies directed against the GluN1 subunit of the NMDA receptor ( Fig. 44.2 ). Studies in vitro and in vivo have shown that the binding of the antibodies to the receptors alter the number and function of the receptors in a reversible manner, and intracerebroventricular infusion of patients' antibodies in mice reproduced the behavioral symptoms of the disorder. Titers of antibodies are higher in CSF than in serum, and CSF titers may remain elevated even when serum is negative. Initial antibody testing should always include CSF because a recent study demonstrated that with some testing methods up to 13% of CSF-positive cases were serum negative.
About half of girls older than 12 years and women have unilateral or bilateral ovarian teratomas (either benign or malignant) that may be mistaken for benign ovarian cysts on imaging, whereas only 8% of girls younger than 12 years have an associated tumor. Tumors occur in only 5% of male patients (usually a testicular germ cell tumor). There are isolated reports of other tumors including SCLC, germ cell tumor of the testis, Hodgkin lymphoma, neuroblastoma, and breast cancer. About 20% of patients with herpes simplex encephalitis develop autoimmune relapses that are due to the development of antibodies to the NMDA and other receptors; these patients do not have associated tumors.
The course of the disorder may be prolonged even with aggressive treatment. Early institution of therapy improves outcome, but even patients with prolonged courses often have substantial if not complete recovery with continued care. Treatment should focus on identification and removal of a tumor, if present, and immunotherapy. Many patients are initially given corticosteroids, intravenous immunoglobulins (IVIGs), or plasma exchange, with just over half responding within a few weeks. Patients who do not respond will often respond to additional therapy with cyclophosphamide and/or rituximab. Increasingly, these two agents are being used up-front because data suggest they improve outcome and reduce relapses.
Anti-γ-Aminobutyric Acid Type A Receptor Encephalitis
Patients with anti-GABA A receptor encephalitis develop rapidly progressive encephalitis characterized by refractory seizures, status epilepticus, or epilepsia partialis continua that may require pharmacologically induced coma for control. All patients have additional symptoms, which can include cognitive impairment, altered level of consciousness, change in behavior, and movement disorders including dyskinesias. The latter can initially lead to a diagnosis of anti-NMDA receptor encephalitis. Patients of all ages are affected, and almost half of the patients are teenagers or children. The CSF is normal or may show a moderate lymphocytic pleocytosis. MRI is especially useful; findings are abnormal in almost 90% of patients, and images show multifocal cortical and FLAIR/T2 signal abnormalities predominantly but not limited to the temporal and frontal lobes. About 40% of cases are paraneoplastic, mostly thymoma. Children are less likely than adults to have a tumor. Patients often respond to immunotherapy, but deaths have been reported as consequences of status epilepticus and sepsis during the acute illness.
Paraneoplastic Cerebellar Degeneration
PCD is characterized by the subacute development of rapidly progressive cerebellar dysfunction that stabilizes after a few months, leaving the patient severely disabled. Postmortem studies demonstrate near or total loss of Purkinje cells with relative preservation of other cerebellar neurons and Bergmann astrogliosis ( Fig. 44.3 ). Many types of tumors have been reported in association with PCD; the most common neoplasms are gynecologic tumors, breast and lung cancers, and lymphomas. Neurologic symptoms precede detection of the tumor in about 60% of patients.
Manifesting symptoms of PCD include dizziness, visual problems, nausea, vomiting, and dysarthria. Within days or even hours, ataxia of gait and of the extremities develops, usually accompanied by dysphagia. Some patients with PCD who have gynecologic or breast tumors have serum and CSF antibodies called anti-Yo (also called PCA-1 ) that react with proteins expressed by Purkinje cells and the underlying tumor. Other patients may have PCD in association with Hodgkin disease, in which case an antibody called anti-Tr usually is found ( Fig. 44.4 ). Anti-Tr antibodies are directed against Delta/Notch-like epidermal growth factor-related receptor (DNER).
For patients with SCLC, PCD may develop in association with LEMS. 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. These antibodies may also be present in some patients with SCLC and PCD without symptoms of LEMS.
A distinctive clinical syndrome occurring predominantly in women is characterized by subacute onset of ataxia and opsoclonus. 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, a gynecologic cancer or SCLC. The serum and CSF of these patients contain an antibody called anti-Ri (also called ANNA-2 ), which is expressed by neurons and the associated tumor.
In patients with SCLC, the development of PCD may be the manifesting symptom of PEM. In such cases, anti-Hu or anti-CV2/CRMP5 antibodies usually are present, and 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.
In one subset of patients, PCD develops in the setting of brainstem dysfunction. These patients have serum and CSF antibodies against Ma1 and Ma2 proteins expressed in neurons and spermatogenic cells of the testis. These patients have a variety of associated cancers, including those of the lung, breast, parotid, colon, and testis.
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.
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. Although the co-occurrence of ALS and cancer is likely coincidental in most patients, there are several situations that are supportive of a paraneoplastic etiology.
Patients with Hodgkin and non-Hodgkin lymphoma may experience a subacute lower motor neuronopathy. Typically, these patients have subacute, progressive, painless, and asymmetric involvement of the extremities, with legs affected more than the arms. In contrast to typical ALS, fasciculations are rare, bulbar muscles are usually 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, suggesting that the underlying pathophysiologic mechanism does not result in neuronal degeneration. Paraneoplastic subacute lower motor neuronopathy must be distinguished from the lower motor neuron dysfunction that may develop after radiation therapy of the spinal cord and was likely the cause of motor neuron symptoms in some of the early cases reports.
Patients with PEM may experience symptoms resembling motor neuron disease. These patients almost always exhibit signs of involvement of other areas of the nervous system that, along with the presence of the anti-Hu antibody, help to rule out ALS.
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