About Paraneoplastic Neurological Disorders (PND) > Information for Patients > Overview of Paraneoplastic Neurological Disorders (PND)

Overview of Paraneoplastic Neurological Disorders (PND)

About Paraneoplastic Neurologic Disorders

Definition

The terms "paraneoplastic neurologic disorders (PND)" or "paraneoplastic neurologic syndromes" (PNS) are used to describe many conditions that affect the nervous system (brain, spinal cord, nerves or muscles) in patients with cancer. "Paraneoplastic" means that the neurologic problem is not caused by the cancer itself, but by disturbances that the cancer causes in the body, particularly in the immune system.

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The Immune Disturbances in PND

The purpose of the immune system is to defend the body from being "attacked," by something such as an infection or a tumor. When the immune system detects a tumor or cancer it responds with a "counter attack" to fight the tumor. The immune system uses proteins ( antibodies) and cells ( lymphocytes) to fight the tumor.

In some patients, the tumor contains proteins that are like the proteins that are present in the nervous system (called neuronal antigens). When the immune system "detects" these proteins in the tumor, it mounts an attack, called an immune response, against them. During the attack, the lymphocytes and antibodies are directed against the tumor. But, they also find and attack the same proteins found in the normal brain or other parts of the nervous system.

The end result is that the patient's own immune system causes severe collateral damage to the nervous system.

Furthermore, in most patients the damage that the immune system causes in the nervous system is greater than the damage that it supposedly causes in the tumor.

This explains why patients with PND have neurological symptoms but also have a growing tumor that the immune system is usually unable to control, and therefore needs to be treated. A graphic summarizing this process is shown in Figure 1.

Paraneoplastic Neurological Disorders

Figure 1: Immunologic mechanism proposed for many PND

In addition to the process described above and in Figure 1, there are other "paraneoplastic mechanisms" in which immune disturbances are involved.

For example, some types of tumors or cancers are derived from cells of the blood, bone marrow or lymph nodes (such as plasma cells or B lymphocytes). These malignant tumors include lymphomas, leukemias, myelomas and others . They also can affect the nervous system, usually the peripheral nerves. This happens because the cancer cells themselves produce antibodies that attack and damage the nerves.

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Classification of paraneoplastic neurological disorders (PND)

The main PND are listed in Table 1. Historically these disorders were named according to:

  • the area of the nervous system that is affected, or
  • the type of immune response, or
  • the type of symptoms.

For example, "paraneoplastic cerebellar degeneration" is a PND that results in degeneration of the cells or tissue of the cerebellum (a part of the nervous system that controls movement, among other functions).

Another example is a PND called "paraneoplastic encephalitis"; in this case the patients develop an inflammation of the brain (encephalitis) caused by one or several immune attacks against neuronal antigens; when the immunel response is well known, it may be included in the name of the disease, such as "anti-Hu associated encephalitis" or "anti-Ma2 associated encephalitis."

Finally, some PND associate with symptoms or problems which are so characteristic, that the disorder is named after the symptoms. Examples of this are "paraneoplastic stiff-person syndrome" (a disorder that produces muscle stiffness and cramps) and "paraneoplastic opsoclonus" (a disorder also called "dancing eyes syndrome" because the eyes move uncontrollably in all directions).

As shown in Table 1, PND can affect any part of the nervous system, including eyes, brain, spinal cord, dorsal root ganglia, peripheral nerves, neuromuscular junction, muscle, and eyes and retina.

Furthermore, each of these areas can be affected by several PND related to a distinct immune response. In many instances an immune response is suspected, but little is know about the antibodies and the protein targets of these antibodies. These PND are usually more difficult to recognize than those for which the immuel responses are well known.

Table 1: Paraneoplastic neurological disorders

Area of the nervous system involved

Syndromes

Central nervous system
(Brain and spinal cord)

  • Limbic encephalitis
  • Cerebellar degeneration
  • Brainstem encephalitis
  • Myelitis
  • Encephalomyelitis
  • Ma2 encephalitis
  • NMDAR encephalitis
  • Stiff-person syndrome
  • Opsoclonus-myoclonus
  • Necrotizing myelopathy
  • Motor neuron disease

Dorsal root ganglia and peripheral nerves

  • Sensory neuronopathy
  • Paraneoplastic neuropathies Neuromyotonia
  • Vasculitis of the nerve and muscle

Neuromuscular junction

  • LEMS
  • Myasthenia gravis

Muscle

  • Polymyositis/ Dermatomyositis
  • Acute necrotizing myopathy

Eye and retina

  • Cancer-associated retinopathy
  • Melanoma-associated retinopathy
  • Optic neuropathy

Disorders in italics are not included in this review

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The Frequency of the PND

In general, PND are considered rare disorders. However, some PND such as the paraneoplastic neuropathies (or paraneoplastic polyneuropathy) are relatively frequent (affecting ~10% of patients with some cancers of the immunological system). While other PND are in fact, extremely rare.

In many instances PND are simply not recognized, either because:

  • the disorder has not been described,
  • a diagnostic test (such as the detection of antibodies) has not been developed,
  • the symptoms resemble many other diseases or complications of cancer or
  • the patient deteriorates or dies before the diagnosis is made or the cancer is discovered.

The last point is shown by our recent discovery of "paraneoplastic encephalitis" in young women with ovarian tumors (called teratomas). Before we described this disorder there were only 5 cases ever published in the English literature of women who might have had the same disorder. As soon as we reported how to identify this PND, a surprising number of patients were identified (17 in 9 months). The consequences are important, because this disorder is severe (potentially lethal) but if recognized and treated properly, patients usually recover completely.

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The Main Paraneoplastic Antibodies

An "immune response" is the response or attack that the immune system develops against any organism or tissue that does not form part of the body, such as infections by viruses or bacteria, foreign tissues from transplanted organs, or tumors (which are seen as not part of the body because they are made up of abnormal cells). The attack is carried out by antibodies and T-cells with the aim of killing or rejecting the infection, transplanted tissue, or tumor. In this review we will focus in the immunological responses triggered by tumors of patients with PND.

It turns out that there is no relation between the size of the tumor and the triggering of the immune system. In other words, the immune response may be triggered at early stages of tumor development, when the tumor is very small. In fact, this is what happens most of the time. Therefore, the tumor (or cancer) of patients with PND can initially be very difficult to find.

This explains the problem that doctors have in recognizing that the neurological symptoms of a patient are in fact a PND instead of another disease. For this reason, the discovery that many patients with PND have specific paraneoplastic antibodies, in their blood or spinal fluid, was very important.

If one of the paraneoplastic antibodies is found, it confirms that the patients' problems are a PND. It is important to understand that although some antibodies have been reported as "paraneoplastic antibodies," only some truly are. The usefulness of these antibodies can be summarized as follows:

  • The detection of one or several antibodies in the patient's blood or spinal fluid usually confirms that the neurological symptoms are from PND, whether the tumor has been detected or not.
  • The antibody detected often suggests the location of the tumor. This helps the doctor to select the best tests to demonstrate the tumor.
  • The type of antibody may suggest the best treatment approach for the PND. This treatment approach can be different if a tumor is found or not.

The main paraneoplastic antibodies are found in Table 2.

Table 2: Paraneoplastic antibodies

Antibody

Associated syndrome

Most frequent cancers

Well characterized paraneoplastic antibodies

Hu (ANNA1)

PEM, PSN, PCD, limbic encephalitis

Small Cell Lung Cancer (SCLC)

Yo (PCA1)

PCD

Ovary, breast

CV2/CRMP5

Several

SCLC

Ri (ANNA2)

Ataxia, OM, brainstem encephalitis

Breast, gynecologic, SCLC

Ma2*

Limbic, diencephalic, brainstem encephalitis

Testicular, lung

Amphiphysin

Stiff person syndrome, PEM

Breast, SCLC

NMDAR (NR2)

Encephalitis

Teratoma of the ovary or mediastinum

Partially characterized paraneoplastic antibodies

Tr

PCD

Hodgkin's disease

Zic4

PCD

SCLC

PCA2

Several

SCLC

ANNA3

Several

SCLC

PEM: paraneoplastic encephalomyelitis; PSN: paraneoplastic sensory neuronopathy; PCD: paraneoplastic cerebellar degeneration; SCLC: small-cell lung cancer.

*Some patients harbour Ma1 and Ma2 antibodies; the presence of Ma1 usually associates with predominant brainstem, cerebellar involvement, and tumors other than testicular neoplasms. The prognosis in patients with tumors other than testicular neoplasms is poorer than that of patients with Ma2 antibodies and testicular neoplasms.

The antibodies listed in Table 2 are usually detected in blood and spinal fluid, but in some patients the antibodies are easier to identify in the spinal fluid. The usefulness of these antibodies can be explained with one example:

Example 1: A 67 year-old man developed progressive numbness in one foot and then over the next 3 weeks, the numbness spread to affect the other foot and both hands. The symptoms were associated with pain and decreased ability to use his hands. Because he was a heavy smoker a chest XR and CT scan were obtained but both were normal. A PND was suspected and blood and spinal fluid tests for paraneoplastic antibodies were requested. These studies were positive for the anti-Hu antibody ( Figure 2). Detection of this antibody indicated that the patients' symptoms were due to a PND called paraneoplastic sensory neuronopathy. Because the anti-Hu antibody usually associates with small-cell lung cancer, the patient underwent further tests that uncovered a small area in his chest that contained the cancer. The patient was sent to an oncologist (a medical doctor that treats cancer) who gave him chemotherapy. The treatment was successful and the patient is free of cancer and the neurological symptoms have also improved.

In this case, the patients' neurological symptoms led him to be evaluated. This resulted in finding the cancer when it was still small, and this improved the chances of successful cancer treatment

. Paraneoplastic Neurological Disorders

The usefulness of other antibodies can be inferred from Table 2. It is extremely important to understand that not all patients with PND have paraneoplastic antibodies. Therefore, the absence of antibodies does not rule out that a neurological disorder is PND. In these patients, the decision that the neurological disorder is a PND can be difficult.

In addition, there are several other issues that must be taken into consideration when looking at paraneoplastic antibody results.

  • Some paraneoplastic antibodies may occur with several different types of PND. For example, one patient with Hu antibodies may have severe numbness and weakness while another patient with Hu antibodies may have seizures or memory loss.
  • Some paraneoplastic antibodies may occur in patients with cancer, but without symptoms of PND. The chance of this happening depends on the type of antibody; some antibodies (such as anti-Ma2) always occur in association with PND, while others (such as anti-Hu) may be detected in about 20% of patients with small-cell lung cancer without PND. When this occurs, the amount of antibody present in the blood (called antibody titer) is usually smaller than that identified in patients with PND.
  • Paraneoplastic antibodies may be absent but the patient does have a PND. This scenario is very frequent for PND of the peripheral nervous system (involving peripheral nerves and muscle). It is estimated that about 80% of patients with these types of PND do not develop paraneoplastic antibodies. In contrast, the PND that affect brain, cerebellum and spinal cord associate more frequently with paraneoplastic antibodies. The frequency of detecting paraneoplastic antibodies in these disorders varies with the area of the brain involved or with the type of PND.

For all the reasons mentioned above the presence or absence of antibodies should always be evaluated in the clinical context provided by other information. In other words, results of antibody testing do not supersede a careful neurological examination and some tests that are necessary for a comprehensive evaluation.

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The Cancers Associated with PND

Any type of cancerous (or malignant) tumor can cause a PND. Recent studies show that even benign tumors (such as some teratomas) can also cause PND.

Among the malignant tumors, there are some that are more frequently associated with PND than others. They include:

  • cancer of the lung (mainly the subtype called "small-cell lung cancer"),
  • cancer of the breast,
  • cancer of the ovary and other gynecological tumors,
  • tumors of the testis (called germ-cell tumors),
  • tumors of the thymus (such as thymomas), and
  • tumors of the cells of the blood and immune system.

In about 60% of patients with PND the neurological symptoms develop before the presence of a cancer is known. These patients are usually first seen by general practitioners or neurologists because there is no past history of cancer.

The other 40% of patients are already known to have cancer, and they develop the PND during or after treatment of the cancer. In these cases a common scenario is a patient whose cancer is believed to be in remission who develops neurologic symptoms. This strongly suggests that the cancer has relapsed.

In the majority of patients with PND, the tumor is localized to one site without having spread to distant parts of the body, and the size of the tumor is small. For this reason it can be very hard to find the tumor.

The type of PND and the type of paraneoplastic antibody (when present) help in some patients to focus the search for the tumor to one or a few organs. For example, if a patient develops paraneoplastic encephalitis and has anti-Hu antibodies, clinical experience indicates that the tumor is usually in the lung or lymph nodes between the lungs (an area called mediastinum). Therefore, in such a patient the diagnostic tests (for example, CT or PET cans) should be those that explore the lungs and mediastinum.

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Tests Frequently Used for the Diagnosis of PND

In addition to obtaining blood and spinal fluid to look for paraneoplastic antibodies, there are other tests that are usually required during the evaluation of a patient with a suspected PND. The selection of these tests is based on the type of neurological symptoms and sometimes, the type of paraneoplastic antibody identified. These tests can be divided in two groups: those used for the study of the neurological symptoms, and those used to find the tumor.

Tests used to study the neurological symptoms:

  • Spinal tap (also called a lumbar puncture) and analysis of the spinal fluid. These studies usually show abnormalities that suggest inflammation of the brain or spinal cord. They are not specific of a "paraneoplastic cause." However, analysis of the spinal fluid provides useful information for the diagnosis of PND, particularly when combined with other tests listed below.
  • One of the many studies performed in the spinal fluid is the analysis for paraneoplastic antibodies. If any of these antibodies is identified, then the diagnosis of PND is definitive.
  • Magnetic resonance imaging (MRI) of the brain is particularly useful to show areas of the brain that are abnormal due to inflammation or that become abnormal due to the loss of tissue (atrophy) caused by the inflammation. Some PND of the brain and spinal cord are associated with MRI abnormalities more frequently than others. For example, patients with a PND called "paraneoplastic limbic encephalitis" often have abnormal brain MRI findings early in the disease. While patients with "paraneoplastic cerebellar degeneration" often have normal MRI at this time. These patients only develop MRI findings at the late stages of the disease when the MRI will show atrophy of the cerebellum.
  • One of the most important uses of MRI is to rule out other neurological complications that can cause symptoms similar to a PND. For example, in patients with cancer, there are many complications such as metastasis (spread of the tumor to the brain and the meninges- the tissues that cover the brain) that can cause symptoms mimicking a PND. MRI is extremely sensitive to show these other complications.
  • MRI of the spinal cord, nerve roots, or networks of nerves leaving the spinal cord (called the plexuses) can be done in patients whose symptoms suggest involvement of these parts of the nervous system.
  • Electroencephalogram (EEG). This test is used when patients are suspected of having seizures. The EEG records the electric activity in the brain revealing information such as epileptic seizures, or slow activity, which may also occur as a result of seizures and other abnormal brain function.
  • Electromyography (EMG) and nerve conduction studies. These tests are particularly useful to assess the function of the cells in the spinal cord that are the origin of the peripheral nerves. The peripheral nerves carry the electric impulses from the spinal cord to the muscles, or in the opposite direction, from the skin and other receptors in muscles and tissues to the spinal cord. The EMG and nerve conduction studies tests the integrity of these circuits.
  • There are several blood antibodies that are frequently associated with specific neurological syndromes regardless of whether the syndrome is a PND or not ( Table 3). These antibodies may assist in the diagnosis of the neurological syndrome, but do not clarify whether the cause is paraneoplastic. In other words, detection of these antibodies do not predict the presence of a cancer, the patient may or may not have a tumor.

Table 3: Antibodies that help to diagnose the neurological syndrome but do not clarify whether it is a PND or not

Antibody

Syndrome

AChR (nicotinic, neuromuscular junction)

Myesthenia Gravis

AChR (ganglionic or neuronal)

Autonomic neuropathy

P/Q VGCC (frequently associates with PND)

Lambert Eaton Myasthenic Syndrome ( LEMS) and cerebellar degeneration

VGKC

Neuromyotonia, limbic encephalitis, Morvan's syndrome

*In patients with cerebellar degeneration, with or without associated LEMS, detection of these antibodies should prompt the search of a SCLC.

Tests used to identify the tumor:

  • Computed tomographic (CT) scanning of the chest, abdomen and pelvis: This test should be considered in all patients suspected to have a PND. It is useful to locate the tumor or demonstrate an abnormal area that can be considered for further evaluation (perhaps by biopsy).
  • Mammography is the initial test to consider when looking for a cancer of the breast.
  • Ultrasound of the pelvis is useful to assess abnormalities in the uterus, ovaries and related structures that may have been detected with CT.
  • Ultrasound of the testis may reveal tumors or abnormalities that suggest a tumor.
  • [18]Fluorodeoxyglucose positron emission tomography (PET) scan: This is a very sensitive test that usually complements the use of CT. It is particularly useful when there is strong suspicion of a tumor but all other tests are negative ( Figure 3). Of note, for some tumors the PET can be negative but the CT or ultrasound of pelvis or testis may reveal the tumor.
  • Blood cancer markers. These are proteins that when detected in the blood in certain amounts suggests the presence of a cancer (CA 125, CA 15-3, CA 19-9, CEA, a-fetoprotein, b-HCG, and others).

Paraneoplastic Neurological Disorders

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Presentation of symptoms

One frequent feature of PND is that patients usually develop the neurological symptoms rapidly over the course of a few days or weeks. In some instances this is a clue that the problem is a PND. For example, a patient who develops progressive memory problems over many months, most likely has another type of neurological disease (perhaps Alzheimer's disease) rather than a PND.

In some patients the neurological deficits develop a few days or weeks after a transient illness resembling a viral process. This is particularly frequent in patients who develop some types of limbic encephalitis or cerebellar degeneration. The significance of this is unclear, but it can create confusion and delay the diagnosis of the PND if one assumes that the new symptoms are simply a re-occurrence of the viral illness.

Further complicating the process of diagnosing PND is the fact that in some patients the presentation of symptoms is slow. While this is unusual it should be kept in mind when other causes of the patients' problems cannot be found.

As mentioned previously, in about 60% of patients with PND the neurological symptoms occur before the diagnosis of the cancer. For the 40% of patients already known to have cancer the initial symptoms of PND may resemble other complications of cancer or its treatment. For example, metastasis (spread of the cancer cells to the nervous system), infections, or problems in blood clotting may cause neurological symptoms or deficits similar to those caused by PND. Cancer treatments can also cause neurological symptoms that can be confused with PND.

Another feature frequent in many PND (particularly those that affect the brain and spinal cord) is that the patients' symptoms suggest that a single area of the nervous system is affected but careful examination demonstrates that other parts of the nervous system are also involved. In other cases only one area of the nervous system is involved initially but over time, other areas become affected. Therefore, careful and repeated neurologic examinations have to be done to follow the disease process.

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