Paraneoplastic Autonomic Neuropathy

Paraneoplastic Autonomic Neuropathy

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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:

The most common non-classical paraneoplastic neurological syndromes include:

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.

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.

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.

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 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.

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]

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.

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.

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]

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.

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

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

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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Stacy E Dixon, MD, PhD Assistant Professor of Neurology, University of Colorado School of Medicine

Stacy E Dixon, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Colorado Society of Clinical Neurologists

Disclosure: Nothing to disclose.

Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine

Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Jorge C Kattah, MD Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences

Disclosure: Nothing to disclose.

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Ronald G Wiley, MD, PhD Professor of Neurology and Pharmacology, Vanderbilt University, Chief of the Neurology Service, Veterans Affairs Tennessee Valley Healthcare System

Ronald G Wiley, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for the Advancement of Science, New York Academy of Sciences, Society for Neuroscience

Disclosure: Nothing to disclose.

Bjorn E Oskarsson, MD Assistant Professor, Department of Neurology, University of California, Davis, School of Medicine

Bjorn E Oskarsson, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Flex Pharma<br/>Serve(d) as a speaker or a member of a speakers bureau for: Grifols<br/>Received research grant from: Neuraltus, Glaxo, Eisai, Cytokinetics, Genentech,.

Daniel Mordechai Goldenholz, MD, PhD Resident Physician, Department of Neurology, University of California Davis Medical Center

Daniel Mordechai Goldenholz, MD, PhD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Paraneoplastic Autonomic Neuropathy

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