eMedicine Specialties > Neurology > Neuro-oncology

Paraneoplastic Autonomic Neuropathy

Author: Bjorn E Oskarsson, MD, Assistant Professor, Department of Neurology, University of California Davis
Coauthor(s): Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center; Ronald G Wiley, MD, PhD, Chief, Professor, Department of Neurology, Veterans Affairs Medical Center, Vanderbilt University
Contributor Information and Disclosures

Updated: Jul 12, 2006

Introduction

Background

Autoimmune paraneoplastic autonomic neuropathy is a rare Paraneoplastic syndrome (PNS), which manifest as disturbance in sympathetic and/or parasympathetic nervous system function. More 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 disease. Patients may develop autonomic disturbances at any time relative to the diagnosis of cancer. The autonomic problems can even 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 divide patients with a suspected paraneoplastic syndrome into "definite" and "probable" categories¹ . These criteria are based on the presence or absence of cancer, the presence of well-characterized antibodies, and the type of clinical syndrome.

Patients with a definite PNS include those with the following:

• A classical syndrome (ie, encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus myoclonus, subacute sensory neuronopathy, chronic gastrointestinal pseudo-obstruction, LEMS, or dermatomyositis) 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
• A neurological syndrome (classical or not) with well-characterized paraneoplastic antibodies (ie, anti-Hu, anti-Yo, anti-Ri, antiamphiphysin, anti-CV2, anti-Ma2)

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
• 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 neuropathy include paraneoplastic peripheral neuropathies, paraneoplastic encephalomyeloneuropathies, and Lambert-Eaton myasthenic syndrome (LEMS). Each one of these may have other distinct symptoms and findings in addition to autonomic disturbances.

Pathophysiology

It has long been known that especially patients with small-cell lung cancer² develop neurological signs and symptoms with greatly increased frequency³ ; however, many other cancers including other lung tumors⁴ , thymoma, Hodgkin disease⁵ , other lymphoma⁶ , testicular, and ovarian and breast carcinoma also cause paraneoplastic neurological syndromes.

Exactly how cancers result in paraneoplastic neurological symptoms is incompletely understood. Expression of onco-neuronal antigens by the cancer cells resulting in autoimmunity appears to be the mechanism. The classical paraneoplastic antibodies are directed at intracellular antigens⁷ 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 and with these antibody types several passive transfer experiments have been positive, confirming the antibodies direct pathogenic effect.

Auto antibodies to these extracellularlly 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 one type of antibody is found in a single patient, and the same type of antibody may associated with very different syndromes in different patients⁸ . 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 failure due to an antibody that has not been identified.

Autonomic failure can occur when this autoimmune process causes sufficient damage to the autonomic nervous system. Limited data is available regarding the immune attack on preganglionic neurons or central autonomic pathways. Typical pathological changes include lymphocytic infiltrates⁹ and vascular cuffing such 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.

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

Anti ganglionic Acetylcholine Receptor antibodies

These antibodies directed at nicotinic acetylcholine in receptors expressed on sympathetic and parasympathetic ganglia cause paraneoplastic autoimmune autonomic gangliopathy¹⁰ . Ganglionic acetylcholine receptors antibodies do not bind muscle acetylcholine receptors and are not known to cause Myasthenia Gravis. These anti ganglionic acetylcholine receptor antibodies are likely directly pathogenic and have an associated clinical picture which predictably and normally exclusively is characterized by autonomic failure. Only about 20 % of cases with AAG appear to be paraneoplastic in origin¹¹ , many of the remaining cases appear to be post infectious analogues to Gullian-Barre.

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. The autoimmune response is directed to the Hu antigen, an AU-rich 3′-untranslated m-RNA sequence which 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 system¹² . The anti-Hu antibody is most often associated with a paraneoplastic sensory neuronopathy, which involves destruction of primary sensory neurons¹³ . This antibody is diagnostically useful, but the exact role of humoral immunity in causing neural degeneration remains uncertain.

Anti VGCC

In Lambert-Eaton myasthenic syndrome (LEMS), antibodies against voltage-gated calcium channels 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 theneuromuscular junction but also block them at parasympathetic and sympathetic nerve terminals, thus creating autonomic insufficiency and autonomic symptoms.

Autonomic dysfunction in LEMS is normally mild.

Other

Autonomic failure can also be seen in stiff person syndrome with antibodies directed against Glutamic acid decarboxylase (GAD) or amphiphysin; this syndrome occasionally can be paraneoplastic in nature. Collapsin response-mediator protein (CRMP-5), also known as CV-2, is another paraneoplastic antibody associated with autonomic dysfunction. CRMP-5 is also most often seen with small cell lung cancer. Purkinje cell antibody-2 frequently causes cerebellar degeneration, but can also be associated with autonomic failure¹⁴ . Antibodies against synaptophysin¹⁵ and voltage-gated potassium channel antibodies¹⁶ have also been reported to cause autonomic failure.

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 identified¹⁷ . This could be due to a spontaneous cure of the underlying cancer, possibly due to an anti-tumor effect of the paraneoplastic antibodies.

Frequency

United States

In the US: The precise incidence of paraneoplastic autonomic failure 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 UK: A national screening program found 63 patients with paraneoplastic neurological symptoms (not including LEMS) from 2000 to 2001¹⁸ .

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 (PNS) 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^18,19 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 sixt¹⁸ or seventh decade.

Clinical

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-obstruction²⁰ due to autoimmune attack on myenteric neurons.  Urinary incontinence, erectile dysfunction, 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 lightninglike 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 (i.e., 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 and CNS involvement²¹ .

As with any paraneoplastic neurological degeneration, autonomic dysfunction has been described with 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 (e.g. 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 usually is subacutely progressive over weeks to months, leading to a bedridden condition if untreated, and often in spite of treatment.

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
• Impotence

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.

Prior 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.

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 syndromes²² .

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