Paraneoplastic Syndrome

Welcome to PT 635 Pathophysiology of Complex Patient Problems This is a wiki created by and for the students in the School of Physical Therapy at Bellarmine University in Louisville KY. Please do not edit unless you are involved in this project, but please come back in the near future to check out new information!!

Original Editors - Brittany Chorley & Seth Chorley from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Lead Editors - Your name will be added here if you are a lead editor on this page.  Read more.

Definition/Description

Paraneoplastic syndrome is a group of rare disorders that is triggered by an abnormal immune system response caused by a neoplasm. It is hypothesisized that Paraneoplastic syndrome occurs when cancer-fighting antibodies or white blood cells (known as T cells) mistakenly attack normal cells in the nervous system.  Neurologic symptoms can develop over a period of days to weeks and usually occur prior to the tumor being discovered. Paraneoplastic syndrome presents with symptoms that include difficulty in walking or swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, sensory loss in the limbs, and vertigo or dizziness. Paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis, myasthenia gravis, cerebellar degeneration, limbic or brainstem encephalitis, neuromyotonia, opsoclonus, and sensory neuropathy.

Prevalence

You will see symptoms of this disorder typically in the middle-aged to older population. Specifically, it is most common in individuals with lung, ovarian, lymphatic, or breast cancer.  The most common cancer associated with paraneoplastic syndrome is small cell cancer of the lungs.

Characteristics/Clinical Presentation

Paraneoplastic syndrome presents with symptoms that include difficulty in walking or swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, sensory loss in the limbs, and vertigo or dizziness. Paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis, myasthenia gravis, cerebellar degeneration, limbic or brainstem encephalitis, neuromyotonia, opsoclonus, and sensory neuropathy.

Paraneoplastic syndromes most commonly occur in patients not known to have cancer, as well as in those with active cancer and those in remission after treatment. A complete history and physical examination findings can suggest neoplasia. Persons with a family history of malignancies such as breast or colon cancer may be at an increased risk and should be screened for cancer.

Because of their complexity and variety, the clinical presentations of Paraneoplastic syndrome may vary greatly. In general, paraneoplastic syndromes are divided into the following categories: (1) miscellaneous (nonspecific), (2) rheumatologic, (3) renal, (4) gastrointestinal, (5) hematologic, (6) cutaneous, (7) endocrine, and (8) neuromuscular.

Miscellaneous (nonspecific)
Fever, dysgeusia, anorexia, and cachexia are included in this category.
Fever is frequently associated with lymphomas, acute leukemias, sarcomas, renal cell carcinomas (Grawitz tumors), and digestive malignancies (including the liver).

Rheumatologic
Paraneoplastic arthropathies arise as rheumatic polyarthritis or polymyalgia, particularly in patients with myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the colon, pancreas, prostate, and CNS.
Hypertrophic osteoarthropathy may be observed in patients with lung cancers, pleural mesothelioma, or phrenic neurilemmoma.
Scleroderma may precede direct evidence of tumor
The widespread form is typical of malignancies of the breast, uterus, and lung (both alveolar and bronchial forms).
The localized form is characteristic of carcinoids and of lung tumors (bronchoalveolar forms).
Systemic lupus erythematosus (SLE) may develop in patients with lymphomas or cancers of the lung, breast, or gonads.
Secondary amyloidosis of the connective tissues is a rare presentation in patients with myeloma, renal carcinoma, and lymphomas.

Renal
Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20 mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone (ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the lung (ie, small cell lung cancer ).
Hypokalemia, hyponatremia or hypernatremia, hyperphosphatemia, and alkalosis or acidosis may result from other types of tumors that produce ACTH, antidiuretic hormone (ADH), or gut hormones (see Endocrine and neuromuscular, below).
Nephrotic syndrome is observed, although infrequently, in patients who have Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); leukemias; melanomas; or malignancies of lung, thyroid, colon, breast, ovary, or pancreatic head.
Secondary amyloidosis of the kidneys, heart, or CNS may rarely be a presenting feature in patients with myeloma, renal carcinoma, or lymphomas. The clinical picture of secondary amyloidosis is related to renal and cardiac injuries.

Gastrointestinal
Watery diarrhea accompanied by an electrolyte imbalance leads to asthenia, confusion, and exhaustion.
These problems are typical of patients with proctosigmoid tumors (both benign and malignant) and of medullary thyroid carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2 and F2) that lead to malabsorption and, consequently, unavailability of nutrients.
These alterations also can be observed in patients with melanomas, myelomas, ovarian tumors, pineal body tumors, and lung metastases.

Hematologic
Symptoms related to erythrocytosis or anemia, thrombocytosis, disseminated intravascular coagulation (DIC), and leukemoid reactions may result from many types of cancers.
In some cases, symptoms result from migrating vascular thrombosis (ie, Trousseau syndrome) occurring in at least 2 sites.
Leukemoid reactions, characterized by the presence of immature WBCs in the bloodstream, are usually accompanied by hypereosinophilia and itching. These reactions are typically observed in patients with lymphomas or cancers of the lung, breast, or stomach.
Cryoglobulinemia may occur in patients with lung cancer or pleural mesothelioma.

Cutaneous
Itching is the most frequent cutaneous manifestation in patients with cancer.
Herpes zoster, ichthyosis, flushes, alopecia, or hypertrichosis also may be observed.
Acanthosis nigricans and dermic melanosis are characterized by a blackish pigmentation of the skin and usually occur in patients with metastatic melanomas or pancreatic tumors.

Endocrine
Endocrine symptoms related to paraneoplastic syndromes usually resemble the more common endocrine disorders (eg, Cushing syndrome). Neuromuscular symptoms may mimic common neurological conditions (eg, dementia).
Cushing syndrome, accompanied by hypokalemia, very high plasma ACTH levels, and increased serum and urine cortisol concentrations, is the most common example of an endocrine disorder linked to a malignancy. This is related to the ectopic production of ACTH or ACTH-like molecules from many tumors (eg, small cell cancer of the lung).

Neuromuscular
Neuromuscular disorders related to cancers are now included among the paraneoplastic syndromes. Such disorders affect 6% of all patients with cancer and are prevalent in ovarian and pulmonary cancers. Examples include the following:
Myasthenia gravis is the most common paraneoplastic syndrome in patients with thymoma, a malignancy arising from epithelial cells of the thymus. Indeed, thymoma is the underlying cause in approximately 10% to 15% of cases of myasthenia gravis. Rarely, hypogammaglobulinemia and pure red cell aplasia occur as paraneoplastic syndromes in patients with thymoma.
Lambert-Eaton myasthenic syndrome (LEMS), which manifests as asthenia of the scapular and pelvic girdles and a reduction of tendon reflexes. LEMS sometimes can be accompanied by xerostomia, sexual impotence, myopathy, and peripheral neuropathy. It is associated with cancer 40-70% of the time, most commonly small cell lung cancer (SCLC). It seems to result from interference with the release of acetylcholine due to immunologic attack against the presynaptic voltage-gated calcium channel.
Opsoclonus-myoclonus syndrome usually affects children younger than 4 years. It is associated with hypotonia, ataxia, and irritability. One in two patients has neuroblastoma.
Paraneoplastic limbic encephalitis is characterized by depression, seizures, irritability, and short-term memory loss. The neurologic symptoms develop rapidly and can resesmble dementia. Paraneoplastic limbic encephalitis is most commonly associated with SCLC.
Paraneoplastic encephalomyelitis is characterized by a complex of symptoms derived from brainstem encephalitis, limbic encephalitis, cerebellar degeneration, myelitis, and autonomic dysfunction. Such neurologic deficits and signs seem to be related to an inflammatory process involving multiple areas of the nervous system.
Paraneoplastic cerebellar degeneration causes gait difficulties, dizziness, nausea, and diplopia, followed by ataxia, dysarthria, and dysphagia. Paraneoplastic cerebellar degeneration is frequently associated with Hodgkin lymphoma, breast cancer, SCLC, and ovarian cancer; it may occur in association with prostate carcinoma.
Paraneoplastic sensory neuropathy affects lower and upper extremities and is characterized by progressive sensory loss, either symmetric or asymmetric. It seems to be related to the loss of the dorsal root ganglia with early involvement of major fibers responsible for detecting vibration and position.

Associated Co-morbidities

-HTN

-Endocarditis

-Anorexia

-Thrombophlebitis

-Polyarthritis

-Anemia

Medications

Medications will depend on what type of paraneoplastic syndrome the patient has.  In addition to chemotherapy for the underlying cancer, medications could include:

Corticosteroids, such as prednisone, inhibit inflammation. Long-term use of corticosteroids may cause weakening of the bones (osteoporosis), diabetes, high blood pressure, high cholesterol and other serious side effects.

Immunosuppressants inhibit the production of disease-fighting white blood cells. Side effects include an increased risk of infections. Drugs with immunosuppressant properties that may be used include azathioprine (Imuran) and cyclophosphamide (Cytoxan).

Anti-seizure medications may help control seizures associated with syndromes affecting nerve cells in the brain. A number of anti-seizure medications are available, including carbamazepine (Tegretol, Carbatrol, others) and valproic acid (Depakene, Stavzor).

Medications to enhance nerve to muscle transmission may improve symptoms of syndromes affecting muscle function. Some drugs, such as 3,4-diaminopyridine, enhance the release of a chemical messenger that transmits a signal from nerve cells to muscles. Other drugs, such as pyridostigmine (Mestinon, Regonol), prevent the breakdown of these chemical messengers.

File:Paraneoplastic Syndromes Treatment Pros and Cons.gif

Diagnostic Tests/Lab Tests/Lab Values

First, a health care provider will perform a clinical exam that would include a general physical and neurological screening. Tests that would be involved in the neurological screening could include reflexes, sensation, myotomes, balance, and coordination.

Laboratory tests that could be utilized to diagnose paraneoplastic syndrome include:

Blood tests: This may identify antibodies typically associated with paraneoplastic syndrome. However, some people who have the syndrome do not have the antibody, and some people who do not have the syndrome actually have the antibody. Blood tests can also identify an infection, disorder of nutrient processing, or hormone disorder.

Spinal tap: A neurologist or nurse will insert a needle into your lumbar spine to extract a small amount of cerebrospinal fluid (CSF). At times, paraneoplastic antibodies may be present in the CSF but not in the blood.

Imagine tests that could be utilized to diagnose paraneoplastic syndrome include:

CT Scan

MRI

PET Scan

PET-CT, which may enhance the detection rate of small cancers

"If no malignant tumor is located or no other cause identified, the problem may be a tumor that's still too small to find. You'll likely have follow-up imaging tests every three to six months for a few years or until a cause is identified. " (Mayo Clinic)

Etiology/Causes

"Paraneoplastic syndromes occur among a small percentage of people who have cancer, but these syndromes aren't caused by cancer cells directly disrupting nerve function.

Instead, they're believed to be caused by cancer-fighting antibodies or certain white blood cells, known as T cells, that the body activates to combat the cancer. Instead of attacking only the cancer cells, these immune system agents also attack normal cells of the nervous system."

QUOTE FROM MAYO CLINIC

Systemic Involvement

-Renal

-Gastrointestinal

-Hematologic

-Cutaneous

-Endocrine

-Neuromuscular

Medical Management (current best evidence)

Treatment varies with the type and location of the paraneoplastic disorder.

Treatment of the underlying tumor
In general, the therapeutic protocols used are those that are applied in patients without paraneoplastic syndromes (ie, surgery, radiation, or chemotherapy, alone or in combination).

Treatment of the presumptive immune-mediated disorder
The second therapeutic option is based on immunosuppression (by intravenous immunoglobulins, steroids or other immunosuppressive drugs, or by plasma exchange).
This treatment should be reserved for patients with clearly identifiable antibodies in their serum.
Some patients with paraneoplastic pemphigus seem to derive some benefit from rituximab, but further studies are necessary to confirm this observation.

Plasmapheresis

This process — also known as plasma exchange — separates the fluid part of the blood, called plasma, from your blood cells with a device known as a cell separator. The red and white blood cells, along with your platelets, are returned to your body, while the plasma, which contains unwanted antibodies, is discarded and replaced with other fluids.
Intravenous immune globulin (IVIg). Immune globulin contains healthy antibodies from blood donors. High doses of immune globulin accelerate the destruction of damaging antibodies in your blood.

Physical Therapy Management (current best evidence)

People with Paraneoplastic syndrome can have difficulty with walking, coordination, muscle tone, sensory of where the body is in space, and vertigo. All of these symptoms the physical therapist can treat with traditional therapy. Precautions must be taken to account for the cancer or neoplasm that is involved.

Alternative/Holistic Management (current best evidence)

-Speech therapy

-Aquatherapy specifically for those patients who have ataxia as a result of their paraneoplastic syndrome

-Cytotoxin (chemo)

-Intravenous gamma globulin

-ACTH a steriod stimulating hormone

Differential Diagnosis

Abdominal Aortic Aneurysm
Anemia
Antithrombin Deficiency
Attention Deficit Hyperactivity Disorder
Bone Marrow Failure
Chronic Fatigue Syndrome
Dermatomyositis
Diabetes Mellitus, Type 1
Glomerulonephritis, Acute
Mixed Connective-Tissue Disease
Myelodysplastic Syndrome
Nephrotic Syndrome
Personality Disorders
Polycythemia Vera
Polymyalgia Rheumatica
Scleroderma
Superficial Thrombophlebitis
Systemic Lupus Erythematosus
Undifferentiated Connective-Tissue Disease

Case Reports/ Case Studies

add links to case studies here (case studies should be added on new pages using the case study template)

Resources

add appropriate resources here

Recent Related Research (from Pubmed)

Failed to load RSS feed from http://www.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=1z_pxc-9fhPQGO3O_wUPIHn9g0TvgRt5zhdAuv7LxIMLxABktq|charset=UTF-8|short|max=10: Error parsing XML for RSS

References

see adding references tutorial.