Last updated:
August 01, 2016
Years published: 2007, 2012, 2016
NORD gratefully acknowledges Josep Dalmau, MD, PhD, Research Professor, ICREA (Catalan Institution of Research and Advanced Studies) and IDIBAPS (Institution for Biomedical Research August Pi i Sunyer); Hospital Clinic, University of Barcelona, Spain; Adjunct Professor, Neurology, University of Pennsylvania, for assistance in the preparation of this report.
Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. It is believed that the body’s normal immunological system interprets the tumor as an invasion. When this occurs, the immunological system mounts an immune response, utilizing antibodies and lymphocytes to fight the tumor. The end result is that the patient’s own immune system can cause collateral damage to the nervous system, which can sometimes be severe. In many patients, the immune response can cause nervous system damage that far exceeds the damage done to the tumor. The effects of PNS can remit entirely, although there can also be permanent effects.
Paraneoplastic neurologic syndromes can manifest themselves in different ways, such as encephalitis (inflammation of the brain), ataxia (loss of balance), neuropathy (progressive numbness/ weakness of feet and hands), myoclonus/opsoclonus (body jerks and irregular rapid eye movements), psychiatric disturbances, or myasthenia gravis (a neuromuscular disorder that causes extreme weakness of several muscle groups, including those that control breathing). It is the presence of specific paraneoplastic antibodies that often leads to the diagnosis of a paraneoplastic neurologic syndrome.
Symptoms of PNS can develop rapidly, over the course of a few days or weeks, or they may develop slowly. Often, they seem to follow what may appear to have been a transient viral illness. In about 60% of patients with PNS, the symptoms occur before the diagnosis of cancer is made. For about 40% of patients already known to have cancer, the initial symptoms of PNS may appear to resemble other complications of cancer. In addition, some cancer treatments can also cause neurological symptoms that can be mistaken for PNS.
PNS can frequently appear to affect only a single area of the nervous system. In some cases of PNS, only one area of the nervous system is involved initially, but over time, other areas can become affected. Therefore, careful and repeated neurologic examinations are required to follow and monitor the disease process.
In the majority of patients with PNS, the tumor is localized to one site without having metastasized (spread) to distant parts of the body. Usually, the size of the tumor at this stage is small. For this reason, it can be very difficult to find the tumor. The combination of symptoms, lab studies, and the paraneoplastic antibodies that may be found in the blood and/or spinal fluid, helps to make the diagnosis of a paraneoplastic neurologic syndrome. The specific antibodies, if detected, can help focus the search for the tumor to one or a few organs.
Broadly speaking, paraneoplastic neurologic syndromes (PNS) are categorized by (1) the area of the nervous system that is principally affected; (2) the type of symptoms manifested; or (3) the type of immunological response.
Paraneoplastic Limbic Encephalitis
This disorder results from an inflammation of the brain and, in particular, the limbic system, which includes the hippocampus, amygdala, hypothalamus, and several other related areas. This part of the brain is involved in memory, emotion and behavior, and controls reactions of fear and anger. It can also involve the emotions of sexual behavior. The hypothalamus participates in the functioning of the autonomic nervous system, which regulates bodily functions such as blood pressure control, heart rate, pupil reactivity, endocrine/hormone function, body temperature, food and water intake, and sleeping and wakefulness. These functions can each be adversely affected in the setting of any type of encephalitis.
A variety of symptoms can result from paraneoplastic limbic encephalitis, such as mood changes, problems sleeping, and severe, short-term memory deficits. In addition, many patients with limbic encephalitis develop seizures or seizure-like spells, or sometimes grand mal seizures resulting in a total loss of consciousness.
The combination of clinical symptoms, analysis of blood and spinal fluid, and brain MRI and EEG findings can suggest the diagnosis of limbic encephalitis. However, it is the specific presence of paraneoplastic antibodies (in particular, Hu, Ma2, and CRMP5, NMDA receptor, GABA(B) receptor, AMPA receptor, Caspr2, mGluR5 antibodies) in the blood and/or spinal fluid that usually forms the diagnosis of paraneoplastic limbic encephalitis.
The cancers more often associated with paraneoplastic limbic encephalitis are cancers of the lung and testis and tumors of the thymus (thymoma) although other cancers can also be involved.
Symptoms identical to paraneoplastic limbic encephalitis may occur without cancer; these patients often have antibodies to LGI1 (previously known as voltage-gated potassium channel antibodies or VGKC).
Paraneoplastic Cerebellar Degeneration
Patients with this form of PNS develop severe problems in fine motor coordination of the arms, legs, and the muscles that control the eyes, speech and swallowing. In general, all movements will become fragmented and a tremor (shaking of the hands) may develop. Due to problems controlling the movement of the eyes, patients develop double vision or a sensation of “jumpiness” of the visual field (“opscillopsia”). Ordinary activities such as reading or watching TV can become difficult or impossible, and simple chores like writing, feeding oneself or dressing can also become impossible to perform.
The brain MRI, at the onset of this type of PNS, can appear normal. However, several months after the presentation of neurological symptoms, the brain MRI will usually show atrophy (shrinkage) of the cerebellum.
Several different paraneoplastic antibodies have been associated with paraneoplastic cerebellar degeneration, including among others Yo, Tr, or mGluR1 antibodies. The associated tumors include, but are not limited to, gynecologic cancers (mainly ovarian cancer), breast, lung, and Hodgkin’s lymphoma.
Paraneoplastic cerebellar degeneration is one of the most difficult of the PNS to treat. Although there may be some mild improvement after treatment of the primary tumor, the majority of patients do not improve. Treatment may result in stabilization of symptoms. In very rare instances, dramatic improvements can occur.
Paraneoplastic Encephalomyelitis
This disorder affects multiple areas of the brain, cerebellum, brainstem and spinal cord.
Patients with paraneoplastic encephalomyelitis usually develop symptoms or deficits that combine those found in both “limbic encephalitis” and “cerebellar degeneration” In addition, due to involvement of the brainstem, patients may develop double or blurry vision, slurred speech, vertigo and/or dizziness, changes in heart rhythms, tremor, and slow movements. The symptoms may initially resemble Parkinson’s disease, and can progress to loss of consciousness and coma. There can also be a malfunction of the nerves that carry information and signals to and from the brain/arms/legs.
Depending upon which of the paraneoplastic antibodies is present, some patients may develop difficulty in moving the lips. When they try to talk, their voice may be barely audible to the point that they may appear mute. However, they are able to understand other people and answer commands with signals, such as with a thumbs up or down.
When the affected patient is a man younger than 50 years, the tumor is often in the testis. If the patient, male or female, is older than 50 years, the associated tumor is likely to be in the lung or other part of the body.
Various paraneoplastic antibodies are associated with paraneoplastic encephalomyelitis, including Hu, CRMP5, Ma2, and amphiphysin.
Prompt diagnosis of this type paraneoplastic encephalomyelitis is important because some patients improve with treatment.
Paraneoplastic Encephalitis associated with anti-NMDAR Antibodies
This syndrome usually affects teenagers or young women in whom other diseases or problems are frequently suspected. Many of these young patients will at first be thought to be manifesting either an acute psychiatric process or a drug abuse reaction. In general, the progression of severe symptoms leads the practitioner to the suspect the patient has an encephalitis.
The symptoms may include anxiety, insomnia, mood changes, bizarre behavior, delusions/hallucinations, episodes of near catatonia (absence of movement), episodes of mumbling or talking gibberish, and/or confusion. Over the course of time, fine muscle twitching can progress to more pronounced abnormal movements and postures of the arms and legs (choreoathetosis). Many patients develop abnormal movements with the face, mouth or tongue (orofacial dyskinesias). Autonomic nervous system dysfunction becomes apparent, and a high temperature (as a result of autonomic dysfunction) can occur, leading to suspect an infection.
This type of encephalitis can be paraneoplastic or not. When paraneoplastic the most common tumor found is a teratoma. The presence of a tumor varies according to the age of the patient, sex, and ethnicity. For example, about 50% of young women (between 18 years and 45 years) have an ovarian teratoma. Older women and men may have other types of tumors or cancer. In contrast, most children (younger than 12 years) male or female, do not have a tumor. Removal of the tumor (when identified) and immunotherapy result in decreased levels of NMDAR antibodies, and improvement or full neurological recovery.
In summary, the encephalitis associated with anti-NMDAR antibodies is one of the most commonly identified autoimmune encephalitis and can occur as a paraneoplastic or non-paraneoplastic disorder. Both forms of encephalitis are highly responsive to immunotherapy and tumor removal (if present).
Paraneoplastic Stiff-Person Syndrome
This type of PNS presents as muscle stiffness and rigidity, along with painful spasms. The symptoms usually present in the muscles of the lower back and legs, but may also affect the arms and legs, and then progress to affect other parts of the body. The spasms can be enhanced or triggered by anxiety, loud noises, or simply by touch or trying to move.
Paraneoplastic stiff-person syndrome should not be confused with the non-paraneoplastic form of stiff-person syndrome. When the disorder is the paraneoplastic type, a specific antibody called anti-amphiphysin is usually found in the blood and spinal fluid of the patient. The tumors usually associated with this PNS are cancer of the breast or lung.
Patients with non-paraneoplastic stiff-person syndrome more often develop other type of antibodies, such as GAD or Glycine receptor (GlyR) antibodies. In rare instances, these antibodies can also occur in patients with paraneoplastic stiff-person syndrome.
Paraneoplastic Opsoclonus-Myoclonus or Opsoclonus-Ataxia
Opsoclonus is a neurological symptom in which the patient’s eyes move rapidly from one direction to another in an uncontrolled fashion. Myoclonus is a neurological symptom of uncontrolled muscle body jerks that can affect the face, arms or legs. Ataxia is a neurological symptom of difficulty controlling the muscles of the trunk and or arms or legs, leading to an uncoordinated, swerving gait. These symptoms can affect children or adults.
In children, opsoclonus is the most common paraneoplastic syndrome. It usually affects patients younger than four years of age, and presents with sudden development of staggering and falling (ataxia) often followed by body jerks, drooling, refusal to walk or sit, opsoclonus, irritability and sleep disburbances. The associated tumor is neuroblastoma (about 50% of children with similar symptoms do not have a tumor). Although symptoms may resolve or improve after treatment of the tumor and immunotherapy, many children are left with behavioral abnormalities and other developmental abnormalities.
While no specific antibody has been identified for pediatric paraneoplastic opsoclonus-myoclonus, there is a large amount of evidence that as-of-yet unidentified antibodies are involved.
In adults with opsoclonus-myoclonus, there are usually fewer behavioral abnormalities, but ataxia is often prominent. The cancers most often associated with these symptoms in adults are usually located in the lung, breast, and ovary. Sometimes, in approximately 20% of adults with this disorder, well-known paraneoplastic antibodies are discovered. The best known of these antibodies is called “anti-Ri”.
Treatment of the tumor and immunotherapy usually results in improvement or stabilization of the neurologic symptoms.
Sensory Neuronopathy
This term refers to the neurons from which the sensory nerves originate. These neurons are clustered in the “dorsal root ganglia” which are located along the sensory nerve roots close to the spinal cord.
Symptoms of sensory neuronopathy usually start in an asymmetric fashion. That is, they will begin on one side, and in a matter of days and weeks progress to involve the other side, eventually becoming symmetric. The symptoms most frequently described by patients include lancinating pain (short-lasting, electric shock type pain), a sensation of walking on sand, cold, numbness, or a feeling of burning in hands and feet. Sensations in the face, as well as the taste and hearing, can be affected. In the advanced stage of sensory neuronopathy, all sensations can be severely diminished or lost. Sensory ataxia can occur, which diminishes the ability to know where the limbs are when the eyes are closed, making it difficult to reach out for something or to walk.
The antibodies most often associated with paraneoplastic sensory neuronopathy are the “anti-Hu” antibodies. There is often an association with small-cell lung cancer, although other cancers can be associated.
Paraneoplastic Neuropathies
There are two main types of peripheral nerves: motor and sensory. Motor nerves make the muscles move and are important in muscle strength. Sensory nerves allow for the feeling of different sensations, such as touch, pain, heat, cold and vibration. Most neuropathies affect both sides of the body equally, with the worse symptoms in the hands and feet, rather than in the hip or shoulders.
It is important to note that patients with cancer can develop peripheral neuropathy as a result of other complications of cancer, or from side-effects of the cancer treatments. The cancers most often associated with paraneoplastic neuropathies are lung cancer, myeloma, B-cell lymphoma, and Waldenstrom’s macroglobulinemia. Only a small number of patients have paraneoplastic neuropathies with associated antibodies. The two antibodies that are associated with this PNS are “anti-Hu” and “anti-CV2/CRMP5;” patients with these antibodies often have lung cancer.
Vasculitis of the Nerve and Muscle
This is a very rare disorder that consists of inflammation of the small blood vessels of the peripheral nerves and muscles. Patients often develop symptoms of peripheral neuropathy that may initially affect only one arm or leg before involving both sides. Pain often occurs.
Several types of tumors have been associated with this type of paraneoplastic neurologic syndrome, including cancers of the lung, kidney, prostate and lymphomas. There are no specific paraneoplastic antibodies associated with this disorder.
Lambert Eaton Myasthenic Syndrome (LEMS)
This disorder results from impaired release of the neurotransmitter acetylcholine. Because of this deficit, the muscles do not contract well, causing weakness that usually presents in the hips and shoulders. A transient drooping of the eyelids (ptosis) and double vision (diplopia) can occur. The muscles of the neck, and sometimes, the respiratory muscles that control breathing, can be affected.
LEMS is also associated with symptoms of autonomic nervous system dysfunction, including dry mouth, rapid decrease of blood pressure on standing up (orthostatic hypotension), constipation, difficulty controlling bladder dysfunction, and erectile dysfunction.
Patients with LEMS have antibodies called voltage-gated calcium channel (VGCC) antibodies. However, it should be noted that the VGCC antibodies do not indicate that the specific cause of LEMS is paraneoplastic, as the disorder can occur in the absence of cancer. Approximately 60% of all patients with LEMS have small-cell lung cancer.
Myasthenia Gravis (MG)
This is a well-known disorder of the neuromuscular junction. The symptoms of MG may resemble those of patients with LEMS, but the muscles of the eyes, eyelids, face, swallowing, speech and respiratory muscles are more frequently and severely involved.
In contrast to LEMS, in which many patients have cancer, only 10-15% of patients with myasthenia gravis have a tumor, in which case it is in the thymus gland (thymoma). While there is an antibody associated with myasthenia gravis (AChR antibodies), this is not a paraneoplastic antibody.
Polymyositis/Dermatomyositis
These are two different disorders of the muscle. The term “myositis” means inflammation in the muscle. “Polymyositis” means that multiple muscles are affected by the inflammation. “Dermatomyositis” means that in addition to the muscles, there is also involvement of the skin.
Both disorders cause similar muscle symptoms, including pain or soreness of the shoulders and thighs, along with weakness. The weakness predominantly affects the hips and shoulders, and can also affect the neck, causing difficulty in holding the head up, and muscles of the throat and esophagus causing difficulty swallowing. Inflammation of the heart (myocarditis), joints (arthralgias), and lungs (interstitial lung disease) can occur.
Patients with dermatomyositis develop skin changes usually characterized by a purplish discoloration of the eyelids (heliotrope rash) with swelling. In addition, a crusty red rash can occur over the knuckles. Some patients develop itchiness and ulcerations in the skin.
Most patients with polymyositis do not have an associated cancer, so this disorder is rarely paraneoplastic. However, dermatomyositis is more likely to be associated with a malignant tumor. There are several tumors that can be involved, including but not limited to lung, breast, ovary, and gastrointestinal tract tumors. It has been shown that patients with dermatomyositis positive for either anti-transcriptional intermediary factor 1-gamma or anti-nuclear matrix protein 2 antibodies have increased risk of having cancer.
Necrotizing Autoimmune Myopathy
This is a disease that associates with prominent muscle weakness at the level of the shoulders and hips. The muscle destruction (necrosis) is more prominent than the presence of inflammation. There are several antibodies that have been reported in patients with this disease including anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and anti-signal recognition particle (SRP). Studies have shown that patients without antibodies or with antibodies against HMGCR are more likely to have an associated cancer than patients with antibodies against SRP. No specific type of cancer was found to predominate.
The specific cause of PNS is unknown. The findings in the serum or cerebrospinal fluid (CSF) of antibodies (onconeural antibodies) to specific malignant tumors suggest that the cause of some PNS is the immune response against the tumor being misdirected against the nervous system.
In general, PNS are considered rare disorders. However, some PNS such as the paraneoplastic neuropathies are relatively frequent, affecting approximately 10% of patients with some cancers of the immunological system. In many instances, PNS are not recognized and the patients’ complaints attributed to other more common problems.
PNS affect males and females in equal numbers. In general PNS are more common in older patients as they more frequently develop those cancers associated with PNS. However, PNS can occur in children and teenagers and as noted above there are some PNS (e.g., paraneoplastic anti-NMDAR encephalitis) that more commonly affect younger patients.
Patients with a suspected paraneoplastic syndrome should receive a complete panel of laboratory studies, including blood, urine, and CSF. In addition, the use of an MRI, EEG (electroencephalogram), and EMG (electromyogram) can further display abnormalities that help to diagnose PNS.
Many (but not all) patients with PNS have paraneoplastic antibodies in their blood and/or CSF. If any of these antibodies are identified, then the diagnosis of PNS is strongly supported or definite (depending on the type of antibody).
It should be understood that there are three types of antibodies that associate with neurological syndromes. There is one type that associates with specific neurological syndromes but not with cancer. Another type includes antibodies that almost always associate with the presence of cancer. The third type of antibodies includes those that may occur with or without cancer. Therefore, it is important to understand the relative value of each category of antibodies in suggesting that the neurological syndrome is paraneoplastic or not.
Once a diagnosis of or a suspicion of a paraneoplastic syndrome is apparent, other tests are used to identify the location and type of tumor. These include CT scanning (usually of the chest, abdomen, and pelvis), mammography, ultrasound, PET scan, and blood tests for specific tumor markers (such as the CA125, for ovarian cancer). The type of paraneoplastic antibody often helps to direct the search of the tumor to a specific organ (for example, most patients with Hu antibodies have lung cancer).
Treatment
Except for a few PNS of the peripheral nerves and neuromuscular junction, there is no general consensus yet for treating many of these syndromes. However, there are several principles in which most investigators agree upon:
The tumor is the main trigger for all PNS. Therefore, in general, prompt identification and treatment of the tumor is essential. Thus, the first therapeutic option is usually surgery, radiation, or chemotherapy (singly or in combination).
Because many PNS are immune-mediated, immunotherapy should be considered based on the type of antibody involved. PNS in which the antibody attacks the cell-surface of neurons respond better to immunotherapies than PNS in which the antibodies react with proteins that are inside the neurons (or intracellular antigens).
The usage, timing, and type of immunotherapy will vary depending on the specific type of PNS and/or whether the tumor is being treated at the same time.
In a patient who has been in remission from a cancer treated within the prior five years, symptoms that appear to be a PNS imply a high likelihood of tumor recurrence. Repeat cancer screening should be undertaken.
Similarly, a relapse or sudden worsening of neurological symptoms in a patient known to have a PNS, but whose cancer was thought to be in remission, should raise a high index of suspicion for cancer recurrence.
Clinical research on PNS is being conducted at the University of Pennsylvania, Department of Neurology, USA and the Biomedical Research Institute, University of Barcelona, Spain.
For information, contact:
Josep Dalmau, MD, PhD
Department of Neurology
Research Assistant: Lindsey McCracken ([email protected])
University of Pennsylvania
3400 Spruce Street, Philadelphia, PA 19104
Phone: 215-746-8511
Fax: 215-746-9122
Website: https://www.pennmedicine.org/providers/profile/josep-dalmau
and
ICREA-IDIBAPS, Service of Neurology, Hospital Clinic
Research Assistant: Maria Rodes ([email protected])
University of Barcelona
Neuroimmunology Lab P3A
c/ Casanova, 143
Barcelona 08036 (Spain)
Phone: +34 932 271 738
Fax: +34 932 271 726
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
JOURNAL ARTICLES
Allenbach Y, Keraen J, Bouvier A-M, et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain 2016;139;2131-2135.
Graus F, Titulaer MJ, Balu R, et al. Clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis: a cohort study. Lancet Neurol 2013;12:157-165.
Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-N-methyl-D-aspartate receptor encephalitis. Neurology 2013;81:1058-1063.
Titulaer, MJ, Soffietti R, Dalmau J, et al. Screening for malignancies in paraneoplastic syndromes: report of an EFNS Task Force. Eur J Neurol. 2011;18:19-e3.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Experience and investigations on anti-NMDA receptor encephalitis. Lancet Neurol. 2011;10:63-74.
Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77:179-189.
McKeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010;67:322-329.
Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7:327-340.
Antoine JC, Camdessanche JP. Peripheral nervous system involvement in patients with cancer. Lancet Neurol. 2007;6:75-86.
Darnell RB, Posner JB. Paraneoplastic syndromes affecting the nervous system. Semin Oncol. 2006;33:270-298.
Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the peripheral nerves. Curr Opin Neurol. 2005;18:598-603.
Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135-1140.
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