Neurologic Paraneoplastic Syndromes Producing Weakness Or Sensory Loss

Christopher G. Potter, M.D. and Kevin B. Boylan, M.D.
Christopher G. Potter, M.D. and Kevin B. Boylan, M.D.
are with the Neurology Department at Mayo Clinic Jacksonville.

Weakness, sensory loss, and paresthesias are common, nonspecific symptoms, but can be important indicators of neurologic disorders associated with malignancy, referred to as paraneoplastic disorders. Paraneoplastic syndromes are the remote effects of a cancer unrelated to metastasis. Loosely defined, these may include nonspecific systemic effects such as fever, infections, metabolic abnormalities, and so forth. Additionally, several specific neurological disorders are recognized as the remote effects of a neoplasm.^1,2 Many have associated paraneoplastic serological autoantibody markers or monoclonal proteins. The most common and best described syndromes are subacute cerebellar degeneration, encephalomyelitis, and neuromuscular diseases. The latter include peripheral neuropathies associated with monoclonal gammopathy, other peripheral neuropathies (especially subacute sensory neuronopathy and sensorimotor peripheral neuropathies), Lambert-Eaton myasthenic syndrome, and some cases of myasthenia gravis, polymyositis, or dermatomyositis. These diseases also occur in the absence of cancer, often as dysimmune phenomena. In the context of malignancy they are usually significantly disabling.

Recognition of these conditions is important because they may be the presenting feature of an occult malignancy. Neurologic paraneoplastic disorders may occur years before a malignancy is detected, for example up to 8 years in the study by Lucchinetti, et al.³ Sometimes a neoplasm is strongly suspected but not found; e.g., patients having neurologic symptoms and signs suggestive of a paraneoplastic disorder and positive for autoantibody markers. Alternatively, some patients may have cancer and a recognized neurological paraneoplastic syndrome without currently identifiable autoantibody markers.

In most cases, the neurological paraneoplastic syndromes are believed to result from immune-mediated mechanisms with antigenic cross-reactivity between neural and tumor epitopes, although this is usually not clearly established.¹ For example, Lambert-Eaton syndrome is likely caused by autoantibodies directed against neuronal voltage-gated calcium channels which are also expressed in small cell lung cancer cells.

In general, the management of these conditions consists of discovery and treatment of any unrecognized malignancy. Small cell lung, breast, and gynecologic cancers, and lymphomas are the malignancies most commonly associated with neurologic paraneoplastic syndromes but a variety of neoplasms have been implicated. In a majority of cases a cancer has not been diagnosed at the time of presentation.^3,4 These neurological disorders may, but usually do not, respond to cancer treatment. Those that respond best to cancer treatment are Lambert-Eaton syndrome, neuromyotonia, dermatomyositis, and neuropathies associated with myeloma.⁴ Additionally, thymoma is associated with myasthenia gravis and improvement often follows thymectomy.⁵

Diagnostic testing may include, but is not limited to, complete blood count, chemistry panel, serum and urine protein and immunoelectrophoresis to detect monoclonal protein, a serological paraneoplastic autoantibody panel, nerve conduction studies/electromyography, mammography, chest x-ray, and CT or MR imaging of the chest, abdomen, and pelvis. In cases where occult malignancy is strongly suspected, serial testing may be necessary.

Any portion of the peripheral nervous system may be involved by a paraneoplastic disorder: motor neurons of the anterior horn, sensory neurons of the dorsal root ganglia, their axons or nerve terminals, the neuromuscular junction, muscle, or the autonomic nervous system. Spinal inhibitory interneurons are affected in stiffman syndrome. These disorders are listed in Table 1. This review will focus on the paraneoplastic disorders that produce weakness or sensory loss. These diseases are relatively rare but need to be included in the differential diagnosis of patients presenting with sensory loss or weakness, particularly those with risk factors for malignancy. Further in the article the more commonly encountered paraneoplastic serologic markers are listed with a discussion of their associated malignancies and neuromuscular diseases; this information is summarized in Table 2.

Patients present with subacute (weeks to months) numbness, paresthesias, dysesthesias, and sensory ataxia which may be severely disabling. Rarely, acute forms may mimic Guillain-Barré syndrome, or less disabling chronic forms may progress slowly over years.⁶ Onset of sensory symptoms is often in the arms (60%) and asymmetric (40%), but eventually all limbs are involved and all sensory modalities are affected. Strength is usually normal but reflexes are reduced or absent. Other paraneoplastic manifestations such as encephalitis, cerebellar degeneration, myelopathy, autonomic neuropathy, or gastrointestinal dysmotility frequently coexist with sensory neuronopathy.²

The differential diagnosis of subacute sensory neuronopathies includes Sjogren's syndrome, idiopathic, and cis-platinum and B₆ toxicities.² Diagnosis of paraneoplastic sensory neuronopathy is confirmed primarily by ANNA-1/anti-Hu seropositivity. Nerve conduction studies demonstrating absent or low-amplitude sensory responses and the presence of a neoplasm, especially SCLC, are also confirmatory.  ANNA-1/anti-Hu positive patients with sensory neuronopathy without known cancer should be closely watched for the appearance of a neoplasm, especially SCLC. Chest x-ray every three months, with CT or MR imaging of the chest every six months is recommended.² No specific treatment is available. Tumor removal and immunosuppressive therapy are of no benefit in regards to the sensory disturbance.³

Motor Neuron Disease

A subacute motor neuronopathy is seen occasionally in association with Hodgkin's or non-Hodgkin's lymphoma. Patients typically present with asymmetric, subacute lower motor neuron weakness (accompanied by atrophy, fasciculations, areflexia) affecting predominately the lower limbs and sparing bulbar muscles.⁷ This disorder may initially worsen, but then may stabilize or improve after treatment of the lymphoproliferative disorder. Rarely, a lower motor neuron syndrome occurs in association with SCLC and ANNA-1/anti-Hu antibodies.⁷ A syndrome resembling amyotrophic lateral sclerosis, with both upper and lower motor neuron signs, has been rarely reported in association with lymphoma, lung cancers, and renal cell carcinoma, but these may be chance associations.⁸

Sensorimotor Peripheral Neuropathies

Cancer-related sensorimotor neuropathies may occur in association with solid tumors or with hematologic malignancies and monoclonal proteins. Patients present with subacute or chronic numbness, paresthesias, and weakness of the distal extremities without prominent sensory ataxia.

Solid tumor-related paraneoplastic syndromes are a rare cause of neuropathy and a search for occult malignancy is usually not indicated in the workup of a sensorimotor peripheral neuropathy, but paraneoplastic antibody studies are frequently obtained. Where they do occur, autoantibody markers, especially ANNA-1/anti-Hu or anti-calcium channel, may be present, as may coexisting neurologic syndromes such as encephalopathy, cerebellar ataxia, or myelopathy.⁹ Associated small cell lung cancers are most frequent, followed by stomach, breast, colon, pancreas, and testis.¹⁰ Patients may respond to plasma exchange or corticosteroids.¹⁰

Sensorimotor neuropathies are also seen in patients with monoclonal gammopathies, with or without a hematologic malignancy.⁶ Sensory loss, paresthesias, and weakness of the distal extremities are typical features although patients with osteosclerotic myeloma may have proximal as well as distal weakness resembling chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).⁶ Any patient with a neuropathy of uncertain cause should be checked for monoclonal proteins, as 10% will have a monoclonal gammopathy.

Disorders Of Neuromuscular Transmission

Lambert-Eaton Myasthenic Syndrome

Patients with Lambert-Eaton myasthenic syndrome (LEMS) typically present with fatigue and weakness predominately affecting proximal muscles, especially the lower extremities, and little or no bulbar or extraocular muscle involvement.⁵ Autonomic dysfunction, especially xerostomia and impotence, are very common.¹¹ Strength may improve transiently after brief exercise and then may wane with continued activity. Reflexes are typically reduced or absent, but may improve or normalize transiently after brief strenuous muscle activity. LEMS may be difficult to distinguish clinically from myasthenia gravis, especially when bulbar involvement is present. About one-half of LEMS patients have cancer and 80% of these are small cell lung cancers. Other associated neoplasms include non-small cell lung, ovarian, and breast. Most patients are over 40, although any age group may be affected.⁵

Diagnosis is confirmed with nerve conduction studies (NCS) and seropositivity for P/Q-type voltage-gated calcium channel (VGCC) autoantibodies, which are present in 95% of LEMS patients and in essentially all LEMS patients that have cancer.⁹ N-type VGCC autoantibodies are present in about one-half of LEMS patients.⁹ NCS may show reduced compound muscle action potential amplitudes that improve two-fold or more after brief (10 second) maximal exercise, or with high-frequency (20-50 Hz) repetitive stimulation. Once a diagnosis of LEMS is made a rigorous search for occult malignancy, especially SCLC, should be undertaken. In smokers with negative imaging bronchoscopy is recommended.⁵ If a malignancy is not detected then serial follow-up including chest imaging should be performed, especially for the first two years.⁵

P/Q-type VGCCs are present on presynaptic nerve endings at the neuromuscular junction and are also expressed by small cell lung cancer cells.^1,9 Antibodies directed against the VGCC decrease the calcium influx into nerve terminals in response to an action potential resulting in reduced acetylcholine release producing neuromuscular weakness.

Improvement or resolution of weakness and autonomic symptoms often occurs with treatment of SCLC. In cases that do not respond to tumor removal or that are not associated with cancer, treatment may include cholinesterase inhibitors or 3,4-diaminopyridine (3,4-DAP).¹² 3,4-DAP acts by blocking presynaptic voltage-gated potassium channels, keeping nerve terminals depolarized longer and augmenting calcium influx. If symptoms are severe, then immunosuppressive therapy may be considered; plasma exchange, intravenous immune globulin (IVIG), corticosteroids, azathioprine, or cyclosporin. As for myasthenia gravis, drugs that interfere with neuromuscular transmission should be avoided or used with caution. These include D-penicillamine, neuromuscular blocking or depolarizing agents, aminoglycoside antibiotics, beta blockers, and calcium channel antagonists.¹³

Myasthenia Gravis

Some cases of autoimmune myasthenia gravis (MG) may be considered paraneoplastic since a thymoma is found in 10%, usually in patients with onset under 60 years of age.⁵ MG is usually not associated with a tumor. Thymic hyperplasia is present in 70% of cases. MG produces fluctuating, fatigueable weakness of muscle strength, not simply generalized fatigue. Symptoms usually worsen later in the day or after prolonged use of specific muscles. In contrast with LEMS, most MG patients have ocular or bulbar weakness. MG is thoroughly reviewed elsewhere.⁵

All patients suspected of having MG should have chest CT or MR imaging to exclude thymoma. Thymectomy is indicated for any patient with thymoma, and generally for any low surgical-risk patient with moderate or severe MG under age 60 without thymoma. Symptoms often improve following thymectomy. Striational antibodies (StrAb), directed against skeletal muscle proteins, are a marker for thymoma, although relatively insensitive and nonspecific. StrAb are found in 30% of all MG patients, 80% of MG patients with thymoma, and in 24% of patients with thymoma but not MG.¹⁴

Diseases Of Muscle

Polymyositis And Dermatomyositis

Polymyositis and adult dermatomyositis are associated with a four- to fivefold increase in the incidence of malignancy.¹⁵ Associated carcinomas include stomach, ovary, and in China, nasopharyngeal. The incidence is higher in patients with dermatomyositis over age 40, where 10% or more may have cancer. The typical presentation is insidious weakness most prominently involving shoulder and pelvic girdle muscles. Patients may have dysphagia and respiratory weakness. Muscle pain and tenderness may be present. Dermatomyositis patients have erythematous skin lesions and subcutaneous edema over the periorbital, malar, and perioral regions, and over extensor surfaces of the extremities, especially elbows, knuckles and knees. Creatine kinase levels are usually very high, but may be normal. Diagnosis is established with electromyography and muscle biopsy. Corticosteroids are the treatment of choice. Paraneoplastic primary myopathies are extremely rare and not well described.

Commonly Tested Paraneoplastic Autoantibody Markers

Type 1 Antineuronal Nuclear Autoantibodies (ANNA-1/anti-Hu)

ANNA-1/anti-Hu antibodies are strongly associated with small cell lung carcinoma (SCLC) and a variety of neurologic and gastrointestinal paraneoplastic syndromes. In the study by Lucchinetti, et al malignancy was present in 88% of 162 ANNA-1/anti-Hu seropositive patients, most of whom (81%) had SCLC.³ Nearly all had a history of tobacco use. Other associated neoplasms were prostate, breast, and squamous cell lung carcinomas, lymphoma, and prostate carcinoma with melanoma. Thirteen percent of SCLC ANNA-1/anti-Hu positive patients had other coexisting tumors, most often renal cell, prostate, breast, or other lung primary carcinoma. Thus, patients should be evaluated for possible SCLC even if a non-SCLC has been identified. In over one-half of the cases eventually found to have SCLC, a tumor was not identified at initial workup, underscoring the importance of continued surveillance.³ Cancer was not identified in 12% of the ANNA-1/anti-Hu seropositive patients having a presumed paraneoplastic syndrome, while 6% of SCLC patients without neurologic symptoms or signs were ANNA-1 positive. ANNA-1 seropositivity is more common in women. Calcium channel autoantibodies accompany ANNA-1 in about 30% of cases.⁹

A paraneoplastic disorder preceded the diagnosis of SCLC in 97% of ANNA-1/anti-Hu positive patients.³ The most common neuromuscular problem was neuropathy (72%); 40% sensory, 30% sensorimotor, 3% motor, and 18 % autonomic. Other less common neuromuscular manifestations were cranial neuropathies, Lambert-Eaton syndrome, polyradiculopathy, motor neuronopathy, brachial plexopathy, and myopathy. Twelve percent of ANNA-1 positive patients presented with gastrointestinal dysmotility, most commonly gastroparesis or intestinal pseudo-obstruction. Immunosuppressive therapies were of no benefit in patients so treated.

Type 2 Antineuronal Nuclear Autoantibodies (ANNA-2/anti-Ri/nova)

ANNA-2/anti-Ri autoantibodies are very rare and are associated with breast, gynecologic, and small cell lung carcinomas. They are more commonly associated with brainstem encephalitis and cerebellar dysfunction, and only rarely with peripheral neuropathies.^1,16 These antibodies may be accompanied by calcium channel antibodies in 28% of patients.⁹

Type 1 Anti-Purkinje Cell Cytoplasmic Autoantibodies (PCA-1/anti-Yo)

PCA-1/anti-Yo antibodies are almost exclusively seen in women, usually in association with ovarian or breast carcinomas along with a subacute syndrome of cerebellar ataxia.^2,16 Six percent of patients present with a peripheral neuropathy.¹⁶ PCA-1/anti-Yo is strongly associated with malignancy, so much so that some recommend prophylactic hysterectomy and salpingo-oopherectomy in postmenopausal PCA-1 positive patients with negative mammography and pelvic imaging.⁴

Amphiphysin

Anti-amphiphysin autoantibodies are associated with breast carcinoma along with stiff-man syndrome or encephalomyelitis, or very rarely with small cell lung cancer and sensory or sensorimotor peripheral neuropathies.¹⁷

Voltage-gated Calcium Channels

P/Q and N-type voltage-gated calcium channels (VGCC) are present at nerve terminals and are expressed by small cell lung cancer cells.^1,9 P/Q-type VGCC antibodies are highly sensitive markers for Lambert-Eaton syndrome (LEMS) with cancer, but are somewhat nonspecific. N-type VGCC antibodies are less sensitive. Autoantibodies directed against the VGCC of either type may be seen in the following situations:

1. LEMS, with or without cancer. As described in the section on LEMS, P/Q-type VGCC autoantibodies are present in essentially all LEMS patients with cancer, and nearly all without an identified cancer (91%). About one-half of patients with LEMS and P/Q-type VGCC antibodies are identified as having a cancer, usually SCLC.⁹
2. Cancer without a neurologic disorder. Twenty-eight percent of patients with SCLC and 11% of patients with ovarian cancer had either P/Q or N-type VGCC autoantibodies.⁹
3. Coexisting with other paraneoplastic antibodies. 54% percent of patients with ANNA-1/anti-Hu, ANNA-2/anti-Ri/Nova, or PCA-1/anti-Yo markers and paraneoplastic neurological disorders other than LEMS had coexisting VGCC autoantibodies. In decreasing order of frequency, associated neoplasms were small cell lung, ovarian, breast, and uterine cervix.⁹
4. Amyotrophic lateral sclerosis (ALS). Calcium channel autoantibodies were found in 23% of 78 patients with sporadic ALS in the study by Lennon, et al.⁹
5. False positives may result from hypergammaglobulinemia in association with autoimmune disorders, chronic liver disease or infection, or from technical factors (e.g., repeated freeze-thawing of samples). A small proportion of healthy patients (<3%) have either antibody (P/Q or N-type).¹⁶

Summary

Neurologic paraneoplastic syndromes may be the presenting feature of an occult malignancy. A particular neurologic syndrome or paraneoplastic autoantibody marker can often direct the search for a neoplasm to a specific site. Lambert-Eaton syndrome is strongly associated with small cell lung cancer (SCLC) and P/Q-type voltage-gated calcium channel antibodies. Paraneoplastic subacute sensory neuronopathy is strongly associated with SCLC or gynecologic malignancies and ANNA-1/anti-Hu antibodies. Weaker associations exist between myasthenia gravis, thymoma, and striational antibodies, and between sensorimotor peripheral neuropathies and either SCLC and ANNA-1/anti-Hu or monoclonal gammopathies with or without hematologic malignancy. It is worthwhile to consider these neurologic paraneoplastic disorders in the differential diagnosis of patients presenting with weakness or sensory loss, especially in those with risk factors for malignancy.

REFERENCES

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Jacksonville Medicine / August, 2000

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