Paraneoplastic Autonomic Neuropathy

Background

Autoimmune paraneoplastic autonomic neuropathy is a rare paraneoplastic neurological syndrome (PNS), which manifests as disturbance in sympathetic and/or parasympathetic nervous system function. Most often, autonomic problems in cancer patients are attributable to prolonged bed rest, neurotoxic chemotherapy, high-dose analgesics, and malnutrition. However, paraneoplastic autonomic neuropathy should be considered in all cancer patients who present with signs or symptoms of autonomic nervous system dysfunction. Patients may develop autonomic disturbances at any time relative to the diagnosis of cancer. The autonomic problems can precede the cancer diagnosis, and a high level of suspicion is then required to identify the underlying neoplasm.

An international expert group established diagnostic criteria in 2004 that divided patients with a suspected paraneoplastic neurological syndrome into "definite" and "probable" categories.^[1] These criteria are based on the presence or absence of cancer, the presence of well-characterized paraneoplastic (onconeural) antibodies, and the type of clinical syndrome.

The clinical syndromes are divided into classical and non-classical categories.^[1]

Classical paraneoplastic neurological syndromes include:

• Encephalomyelitis
• Limbic encephalitis
• Subacute cerebellar degeneration
• Opsoclonus-myoclonus
• Subacute sensory neuronopathy
• Chronic gastrointestinal pseudo-obstruction
• Lambert-Eaton myasthenic syndrome (LEMS)
• Dermatomyositis

The most common non-classical paraneoplastic neurological syndromes include:

• Brainstem encephalitis
• Optic neuritis
• Cancer- or melanoma-associated retinopathy
• Stiff person syndrome
• Necrotizing myelopathy
• Motor neuron diseases
• Acute sensorimotor neuropathies (ie, Guillain-Barre syndrome or brachial neuritis)
• Subacute/chronic sensorimotor neuropathies
• Neuropathies associated with paraproteinemia or vasculitis
• Autonomic neuropathies
• Myasthenia gravis
• Acquired neuromyotonia
• Acute necrotizing myopathy

Patients with a definite PNS include those with the following:

• A classical syndrome and cancer that develops within 5 years of the diagnosis of the neurological disorder, regardless of the presence of paraneoplastic antibodies,
• A nonclassical syndrome that objectively improves or resolves after cancer treatment, provided that the syndrome is not susceptible to spontaneous remission,
• A nonclassical syndrome with paraneoplastic antibodies (well characterized or not) and cancer that develops within 5 years of the diagnosis of the neurological disorder, or
• A neurological syndrome (classical or not) with well-characterized paraneoplastic antibodies (ie, anti-Hu, anti-Yo, anti-Ri, antiamphiphysin, anti-CV2, anti-Ma2), and no cancer.

Patients with a possible PNS include those with the following:

• A classical syndrome without paraneoplastic antibodies and no cancer but at high risk to have an underlying tumor (eg, smoking history),
• A neurological syndrome (classical or not) without cancer but with partially characterized paraneoplastic antibodies, or
• A nonclassical neurological syndrome, no paraneoplastic antibodies, and cancer that presents within 2 years of the neurological syndrome.

The main paraneoplastic syndromes associated with autonomic dysfunction include paraneoplastic autoimmune autonomic gangliopathy (AAG), paraneoplastic sensory neuropathies and neuronopathies, paraneoplastic encephalomyeloneuropathies, and Lambert-Eaton myasthenic syndrome (LEMS). Each one of these disorders may have other distinct symptoms and findings in addition to autonomic disturbances.

• References

Pathophysiology

It has long been known that patients with small-cell lung cancer^[2] develop neurological signs and symptoms with increased frequency^[3] ; however, many cancers including other lung tumors^[4] , thymoma, Hodgkin disease^[5] , other lymphomas^[6] , testicular, ovarian, and breast carcinoma can also cause paraneoplastic neurological syndromes.^[7]

Exactly how cancers result in paraneoplastic neurological symptoms is incompletely understood. The development of these syndromes are not due to direct tumor invasion. Expression of onconeural antigens by the cancer cells resulting in autoimmunity appears to be the mechanism. The classical paraneoplastic antibodies are directed at intracellular antigens^[8] and may not be directly pathogenic. Passive transfer experiments have generally been unsuccessful. However, antibodies directed against exposed antigens, namely ganglionic acetylcholine receptors and voltage-gated calcium and potassium channels, appear more directly pathogenic. With these antibody types, several passive transfer experiments have been positive, confirming the antibodies direct pathogenic effect.

Autoantibodies to these extracellularly exposed membrane proteins often occur without an underlying malignancy. A search for a malignancy should still be undertaken, but these conditions may occur through an idiopathic autoimmune process.

Many antineuronal antibodies have been described to date, and new antibodies are described each year. Sometimes, more than 1 type of antibody is found in a single patient, and the same type of antibody may be associated with very different syndromes in other patients.^[9] It is also entirely possible that a patient who lacks identifiable autoantibodies but has a tumor known to express epitopes similar to neuronal structures (eg, small-cell lung cancer), may suffer from paraneoplastic autonomic dysfunction due to an antibody that has not been identified.

Autonomic dysfunction can occur when this autoimmune process causes sufficient damage to the autonomic nervous system. Limited data are available regarding the immune attack on preganglionic neurons or central autonomic pathways. Typical pathological changes include lymphocytic infiltrates^[10] and vascular cuffing; as is shown in the image below from a case of anti-Hu encephalomyeloneuropathy. Similar attacks on autonomic postganglionic and myenteric neurons can occur with antineuronal antibodies.

View Image

Paraneoplastic autonomic neuropathy. Central nervous system sections from a patient with autonomic failure, oat-cell carcinoma of the lung, and positi....

The best understood syndromes involving paraneoplastic autonomic dysfunction are paraneoplastic autoimmune autonomic gangliopathy (AAG), paraneoplastic sensory neuropathy and/or neuronopathy, paraneoplastic encephalomyeloneuropathy, and Lambert-Eaton myasthenic syndrome.

Anti-ganglionic acetylcholine receptor antibodies

These antibodies directed at nicotinic acetylcholine in receptors containing the α3 subunit expressed on sympathetic and parasympathetic ganglia cause paraneoplastic AAG.^[11] Ganglionic acetylcholine receptor antibodies do not bind to muscle acetylcholine receptors and are not known to cause myasthenia gravis (MG). These anti-ganglionic acetylcholine receptor antibodies are likely directly pathogenic and have an associated clinical picture that is usually characterized by autonomic failure. Only about 20% of cases with AAG appear to be paraneoplastic in origin^[12] , relating to small-cell lung carcinoma, thymoma, bladder carcinoma, and rectal carcinoma^[13] ; many of the remaining cases appear to be postinfectious analogues to Gullian-Barre syndrome. A case of paraneoplastic AAG coexisting with antibodies against muscle acetylcholine receptors has been reported.^[14]

Anti-Hu

Anti-Hu antibodies (which are also called antineuronal nuclear antibody type 1 [ANNA-1])^[2] are the second most pertinent to autonomic dysfunction; and are often seen in the setting of small-cell lung cancer. These antibodies can also be seen in non–small-cell lung cancer, neuroblastoma, and malignant disorders of the gastrointestinal tract, prostate, breast, bladder, kidney, pancreas, testicle, and ovary.^{[15, 13, 16]} The autoimmune response is directed to the Hu antigen, an AU-rich 3′-untranslated m-RNA sequence that is expressed by many small-cell lung cancer cells and by all neurons.

Antibodies to the Hu onconeuronal antigen can affect almost any portion of the central nervous system (CNS) or peripheral nervous system.^[17] The anti-Hu antibody is most often associated with a paraneoplastic sensory neuronopathy, which involves destruction of primary sensory neurons.^[18] When anti-Hu is present, about 25% of patients have some form of dysautonomia, most frequently gastrointestinal manifestations.^[19] This antibody is diagnostically useful, but the exact role of humoral immunity in causing neural degeneration remains uncertain.

Anti-NMDA receptor

A recently discovered antibody to the NMDA receptor has been found to be associated with psychosis, seizures, and autonomic instability. In a case series, it was found to be the cause of 4% of encephalitis cases.^[20] The antibody is found in cerebrospinal fluid (CSF) in 94% of cases.^[21] In one case series, 55% of patients were found to have a teratoma containing neural tissue with NMDA receptors expressed.^[22] Typically, the tumor is an ovarian teratoma; however, testicular germ cell tumors, neuroblastoma, and Hodgkin lymphoma have also been reported.^[21] There is some evidence that NMDA-receptor antibody encephalitis may result in centrally mediated sinus node dysregulation, including cardiac arrest.^{[23, 24]}

Anti-VGCC

In Lambert-Eaton myasthenic syndrome (LEMS), antibodies against P/Q type voltage-gated calcium channels (VGCC) are present. These antibodies lead to impaired presynaptic calcium release at the neuromuscular junction, resulting in predominantly proximal muscle weakness. These antibodies not only block the voltage-gated calcium channels at the neuromuscular junction but also block them at parasympathetic and sympathetic nerve terminals, thus creating autonomic insufficiency and autonomic symptoms. This syndrome is associated with malignancy 50-60% of the time, typically small-cell lung cancer, but also non–small-cell lung cancer, malignant thymoma, lymphoma, leukemia, and carcinomas of the breast, prostate, larynx, and gallbladder.^{[15, 25, 19]} Autonomic dysfunction in LEMS is normally mild.

Other paraneoplastic antibodies

Collapsin response-mediator protein (CRMP-5), also known as CV-2, is another paraneoplastic antibody that has associated autonomic dysfunction in 33% of cases.^[19] CRMP-5 is most often seen with small-cell lung cancer. Purkinje cell antibody-2 (PCA-2) frequently causes cerebellar degeneration but can also be associated with autonomic failure.^[26] Antibodies against synaptophysin may be associated with lung cancer and gastrointestinal disturbances from the myenteric plexus.^[27] Voltage-gated potassium channel (VGKC) antibodies^[28] have been reported to cause autonomic failure in 33% of cases. VGKC antibodies are associated with neuroendocrine tumors including small-cell lung carcinoma, retinoblastoma, oligodendroglioma, melanoma, leiomyosarcoma, and hematologic malignancies.^[29] . There is a VGKC antibody-complex associated with contractin associate protein 2 (CASPR2) that has been observed with autonomic dysfunction with thymoma or small cell lung cancer.^[30]

Gastric dysmotility paraneoplastic disorders can often be seen with antibodies such anti-Yo, anti-Hu, anti-ganglionic acetylcholine receptor, CRMP-5, anti-VGCC, anti-VGKC, GAD65, islet cell antigen 512 (IA-2), gastric parietal cell, muscle striational, thyroid peroxidase, or thyroglobulin autoantibodies.^[31] . One case report documents a patient with functional colonic obstruction ultimately resulting from paraneoplastic ocular myasthenia associated with a thymoma.^[32]

Stiff person syndrome, when caused by a paraneoplastic disorder (about 5% of cases), has been reported to associate with anti-GAD65, amphiphysin antibodies, anti-Ri (ANNA-2 antibodies), anti-gephyrin, anti ICA 105, and anti-17-B-hydroxysteroid dehydrogenase type 4. Associated tumors are found in breast, thymus, lung, and kidney cancers as well as multiple myeloma.^[33]

Progressive encephalomyelitis with rigidity and myoclonus (PERM) has been found to have a paraneoplastic cause in 20% of patients associated with anti-Ri (ANNA-2), anti-amphiphysin, and anti-GAD65. Autonomic symptoms such as pyrexia and diaphoresis are exhibited in 66% of patients with PERM.^[33]

Anti-Yo, also known as Purkinje cell antibody 1 (PCA-1) is associated with breast, ovarian, fallopian tube, or uterine cancers.^[9] It targets an intracellular antigen called CDR2. The typical presentation is gastric dysmotility.^[15]

Many other autoantibodies may also play a role in paraneoplastic dysautonomia, with more being found every year. Recent examples include synaptophysin, SOX, ZIC, anti-AMPA, and anti-GABA, and antibodies to inositol 1,4,5-trisphosphate receptor type 1 (ITRP1) and dipeptidyl-peptidase-like protein-6 (DPP6, also known as DPPX).^{[34, 35, 36, 37]}

The autoimmunity in paraneoplastic neurological syndromes does appear to confer some degree of antitumor effect. Inflammation similar to what is seen in the nervous system also affects the tumor.

There have been several reported cases in which Hu antibody has occurred with classical paraneoplastic symptoms that spontaneously resolved without an underlying tumor being identified.^[38] This could be due to a spontaneous cure of the underlying cancer, possibly due to an anti-tumor effect of the paraneoplastic antibodies.

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Epidemiology

Frequency

United States

In the United States, the precise incidence of paraneoplastic autonomic disorders in patients with cancer is not known, but the current best estimate is that less than 1% of patients with solid tumors develop any kind of PNS.

International

In the United Kingdom, a national screening program found 63 patients with paraneoplastic neurological symptoms (not including LEMS) from 2000-2001.^[7]

Mortality/Morbidity

Morbidity and death can result from severe failure of autonomic function. However, milder autonomic disturbances may be obscured by prominent symptoms of systemic cancer, anticancer therapy, or other peripheral nervous system and CNS damage.

Race

No data suggests differences in frequency or outcomes based on race.

Sex

Conflicting evidence exists with many case series suggesting higher frequency in women^{[7, 39]} but others suggesting higher frequency in men.

Age

PNS can occur at any age, many case series have recorded median age of onset in the sixth^[7] or seventh decade. Anti-NMDA receptor antibodies tend to affect much younger patients with a median age in the early 20s.^[22]

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History

Patients may present with autonomic neuropathy prior to diagnosis of cancer, at the time of cancer diagnosis, or after the treatment of cancer. Autonomic neuropathy often presents as orthostatic hypotension. This may be profound, keeping patients bedridden in spite of aggressive therapy to maintain blood pressure. However, careful evaluation may reveal more widespread disturbances. Abnormal gastrointestinal motility may cause a spectrum of problems from mild constipation and nausea to intestinal pseudo-obstruction^[40] due to autoimmune attack on myenteric neurons. Urinary incontinence, erectile dysfunction, cardiac arrhythemias, dry eyes, dry mouth, pupillary changes (sluggish or fixed pupils), and abnormalities of sweating are also common.

Concomitant somatic neuropathy is common and may cause pain and sensory loss, often in a length-dependent "stocking and glove" pattern but occasionally in a patchy distribution. Pain may be lightning like or burning. When motor nerves are affected, patients may report weakness.

If the paraneoplastic process involves the CNS, symptoms can include reduced level of consciousness, seizures, impaired memory or cognitive problems, personality change (ie, limbic encephalitis), ataxia, or even focal signs such as aphasia. CNS involvement may occur early or late; it often is responsible for profound morbidity and death.

One of the minor symptoms seen in LEMS is an unpleasant metallic taste. In the setting of weakness this symptom is suggestive of LEMS, but it may not be reported by the patient and often it needs to be solicited.

A patient may manifest a paraneoplastic syndrome with any combination of autonomic, peripheral, or CNS involvement.^[15]

As with any paraneoplastic neurological degeneration, autonomic dysfunction has been described in many types of cancer. These include small-cell lung cancer and other lung tumors, thymoma, and ovarian and breast carcinoma. In some cases, paraneoplastic autonomic dysfunction occurs in the apparent absence of cancer. In patients without known cancer, any clinical history suggesting an underlying tumor (e.g., unexplained weight loss) or high risk for particular cancers (eg, heavy smoking, personal or family history of cancer) can help suggest a link between autonomic symptoms and an underlying malignancy. Finding the primary tumor can prove very difficult in some patients.

The clinical course is usually subacutely progressive over weeks to months, leading to a bedridden condition in severe cases if untreated, and often in spite of treatment.

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Physical

Physical findings in patients with paraneoplastic autonomic failure resemble those of any patient with autonomic dysfunction, and include the following:

• Orthostatic hypotension, often profound, in the absence of volume depletion
• Impaired pupillary light responses
• Absence of heart rate changes with respiration
• Abnormal Valsalva response
• Abnormal cold pressor response
• Dysrhythmias such as bradycardia, tachycardia, or asystole^[23]

Peripheral sensory neuronopathy often is evident as patchy superficial sensory loss and asymmetrically abnormal stretch reflexes.

Patchy asymmetric weakness and dyscoordination, or abnormal mental status, may occur in patients with CNS involvement.

Proximal muscle weakness is seen in LEMS.

It is important to note that some physical signs may be due directly to the oncological process or from treatment of the malignancy. For instance, chemotherapy with vincristine typically causes areflexia that is diffuse and symmetric. Cisplatin can cause a sensory neuropathy and hearing loss, both of which are typically symmetric. Carcinomatous meningitis can closely mimic the presentation of paraneoplastic encephalomyeloneuropathy.

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Causes

Paraneoplastic autonomic dysfunction is a secondary effect of cancer. Small-cell lung cancer is particularly likely to cause paraneoplastic syndromes, but many types of malignancy can cause these types of syndromes, including teratoma, neuroblastoma, retinoblastoma, oligodendroglioma, melanoma, leiomyosarcoma, hematological tumors, and cancers of the thymus, gastrointestinal tract, rectum, prostate, breast, fallopian tubes, uterus, bladder, kidney, pancreas, testicles, malignancies and ovary.^{[9, 15, 41, 22, 16, 29]}

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Laboratory Studies

Serum analysis for the presence of onconeural autoantibodies using immunohistochemistry and immunoblotting is the key to diagnosis. Since there is an overlap between the clinical picture of individual paraneoplastic autoantibodies, screening for them using a panel of autoantibodies is appropriate. Lumbar puncture is often indicated, with ample volume of cerebrospinal fluid (CSF) sent for cytologic analysis in addition to the other usual tests. The spinal fluid often reveals a mononuclear pleocytosis, elevated protein, oligoclonal bands, and paraneoplastic onconeural antibodies.

Evidence of another process (eg, diabetes, scleroderma, amyloidosis, thyroid disease) should be considered and excluded by appropriate serologic tests and/or biopsies.

Serological markers of malignancies (eg, CEA, PSA, NSE, CA19-9, AFP, β-HCG, and ProGRP, if available) can help to identify a cancer that is not readily apparent by imaging.

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Imaging Studies

If the patient is not known to harbor a malignancy, then chest imaging (eg, high resolution CT scan) is indicated, since small-cell lung cancer is most often the associated tumor. If any abnormalities are seen, then bronchoscopic or transthoracic needle biopsy is usually required. If no tumor is found, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered as it markedly increases the detection rate of malignancy.^[42] Imaging of the abdomen, pelvis, and brain is normally indicated to look for a primary tumor or metastasis. Mammography and gynecological ultrasonographic examinations can be of value in women, and testicular ultrasonography in men. If no malignancy is found at presentation, repeating the work-up every 3-6 months is advisable^[41] for the first 4 years (or the first 2 years in the case of LEMS).^[42]

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Other Tests

Electromyography (EMG)/nerve conduction velocity (NCV) studies can identify a neuropathy or defect of neuromuscular transmission if present. Heart rate variability and autonomic skin responses can be performed in most laboratories. More extensive autonomic testing may be helpful to prove autonomic dysfunction in milder cases, although it is usually not necessary.

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Histologic Findings

The images below show typical histologic findings from a patient with small-cell lung cancer and autoimmune paraneoplastic autonomic failure. Loss of neurons is evident in autonomic ganglia and dorsal root ganglia, as well as within the CNS. Inflammatory infiltrates are also typical in the vicinity of neuron loss. Similar findings have been reported for autoimmune-mediated paraneoplastic autonomic dysfunction caused by other cancers.

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Paraneoplastic autonomic neuropathy. Histopathology of peripheral nerve and sympathetic ganglion from a patient with autonomic failure, oat-cell carci....

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Paraneoplastic autonomic neuropathy. Hematoxylin and eosin (H&E)–stained sections from dorsal root ganglion showing the hallmark histopathology of ant....

View Image

Paraneoplastic autonomic neuropathy. Central nervous system sections from a patient with autonomic failure, oat-cell carcinoma of the lung, and positi....

The underlying tumor is often heavily infiltrated by inflammatory cells.

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Medical Care

Care of patients with paraneoplastic autonomic neuropathy depends on severity of autonomic dysfunction and status of associated malignancy.

• Malignancy

  • The most important aspect of medical care in a patient with paraneoplastic autonomic dysfunction is treatment of the underlying malignancy. If the malignancy can be cured, progression of autonomic dysfunction may cease and potentially even reverse. If a cure is not possible and chemotherapy is a consideration, then a non-neurotoxic immunosuppressive regimen such as cyclophosphamide and doxorubicin (Adriamycin) is theoretically appealing. However, no data show superiority of any particular regimen, as long as the tumor is controlled.
  • In exceptional cases, patients presenting with typical encephalomyeloneuropathy, including autonomic failure and positive antineuronal antibody titers, may be considered for chemotherapy even in the absence of a tissue diagnosis. The risk of an occult malignancy in this specific situation is very high.

   

  

   
• Autoimmune process: In general, immunosuppressive or immunomodulation treatments directed against the paraneoplastic antibodies (eg, plasmapheresis, IVIG, steroids, immunoadsorption) have been disappointing. However, for some specific types of paraneoplastic disorders, such as LEMS, stiff-person syndrome, anti-NMDA receptor encephalitis, and gastric dysmotility disorders, some reports have shown benefits of immunotherapy.^{[43, 22, 44, 16, 33]}
• No therapy directed at suppressing the immune system has been shown to be reliably effective; however, successful treatment of the associated malignancy by resection and/or chemotherapy may slow or stop the progression of the neurologic syndrome.
• In the case of LEMS, drugs that increase available acetylcholine (such as 3,4-diaminopyridine, which increases acetylcholine release, or cholinesterase inhibitors like pyridostigmine that prevent acetylcholine destruction) have been helpful for symptom control.^{[13, 16]}
• Autonomic failure

  • Nonpharmacologic measures are useful for all patients with autonomic dysfunction:
    • Discontinue antihypertensive medications and other medications known to lower blood pressure, if feasible.
    • Increase fluid and salt intake.
    • Equipment aids may be helpful; these include tight support stockings, abdominal binders or antigravity suits for symptomatic hypotension, and bladder catheterization for urinary retention.
    • Dietary fiber and enemas may help improve bowel motility and decrease straining during defecation.
    • Patients with decreased sweating should limit their physical activity, particularly in hot weather. Sponging with water during activity may help prevent overheating.
    • Large meals may exacerbate hypotension and should be avoided.
    • Positional changes, such as standing, should be performed slowly and gradually.
    • Elevate the head of the bed and avoid prolonged recumbency.
  • Many pharmacological interventions directed against symptoms of autonomic failure are helpful; please see the article on Idiopathic Orthostatic Hypotension and Other Autonomic Failure Syndromes for a discussion.

   

  

   

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Surgical Care

Temporary pacing of unstable cardiac rhythms has been found to be helpful in certain cases of NMDA receptor antibody encephalitis.^{[23, 24]}

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Consultations

If no known underlying cancer is present, consider seeking consultation from a pulmonary medicine specialist. A pulmonologist can help in finding an obscure small-cell lung cancer or other lung tumor. A medical oncology specialist can be of diagnostic help, in addition to assisting in the treatment of the associated malignancy.

Gastroenterology and urology consultation may be needed if intestinal dysmotility and urinary incontinence are part of the clinical manifestations.

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Diet

High fluid and salt intake is of potential value for orthostatic hypotension. A fiber-rich diet can help some gastric dysmotility symptoms.

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Medication Summary

No specific drug treatment is of proven value; however, cytotoxic chemotherapy for the associated malignancy is rational. For symptomatic management of autonomic failure, see article on Idiopathic Orthostatic Hypotension and Other Autonomic Failure Syndromes for details.

In the case of LEMS, drugs that increase available acetylcholine (such as 3,4-diaminopyridine, which increases acetylcholine release, or cholinesterase inhibitors like pyridostigmine that prevent acetylcholine destruction) have been helpful for symptom control.^{[13, 16]}

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Further Outpatient Care

Custodial nursing home care may be needed if the autonomic failure is severe, and patients are bedridden and completely disabled.

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Further Inpatient Care

Typically, the disorder is progressive, although stabilization with antineoplastic therapy has been reported. Subsequent follow-up is devoted to assessing adequacy of blood pressure support and bowel and bladder management.

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Inpatient & Outpatient Medications

Medications are the same as those used in inpatient care, except doses are adjusted with time and disease progression. See article Idiopathic Orthostatic Hypotension and Other Autonomic Failure Syndromes for specific suggestions.

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Deterrence/Prevention

No known method is effective in deterring or preventing occurrence of autonomic paraneoplastic failure, except to prevent exposure to known carcinogens such as tobacco smoke.

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Complications

Sudden death, often due to cardiac causes, can occur. Intestinal pseudo-obstruction and urinary tract infections from incomplete bladder emptying are possible. Overheating due to reduced sweat function can occur in hot temperatures or with physical exertion.

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Prognosis

Prognosis is generally poor. Prompt and effective treatment of the underlying malignancy may arrest progression of autonomic dysfunction, but in many cases, no improvement occurs. Survival is dependent on underlying cancer, patient age, and extent of nervous system involvement. The median survival of all patients with paraneoplastic syndromes has been estimated to be 1 to 3 years.^[7] The two major exceptions are LEMS and NMDA receptor antibody disease. In Lambert-Eaton myasthenic syndrome, effective treatment often results in remission of the mild autonomic symptoms and better than expected survival.^{[45, 46, 47]} In NMDA receptor antibody disease, treatment results in recovery 75% of the time; however, this disease is still poorly characterized and likely underdiagnosed, so these numbers may change as more data become available.^[22]

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