Paraneoplastic syndromes are rare disorders caused by substances that are secreted by a benign tumor, a malignant (cancerous) tumor, or a malignant tumor's metastases. The disturbances caused by paraneoplastic syndromes occur in body organs at sites that are distant or remote from the primary or metastatic tumors. Body systems that may be affected by paraneoplastic syndromes include neurological, endocrine, cutaneous, renal, hematologic, gastrointestinal, and other systems. The most common manifestations of paraneoplastic syndromes are cutaneous, neurologic, and endocrine disorders. An example of a cutaneous paraneoplastic disorder are telangiectasias, which can be caused by breast cancer and lymphomas. Eaton-Lambert syndrome is a neurologic paraneoplastic syndrome that can be caused by a variety of tumors including small cell lung cancer, lymphoma , breast, colon and other cancers. Syndrome of inappropriate antidiuretic hormone (SIADH) is an endocrine paraneoplastic syndrome, which is seen in as many as 40% of patients diagnosed with small cell lung cancer.
Approximately 15% of patients already have a paraneoplastic disorder at the time of initial diagnosis with cancer. As many as 50% of all cancer patients will develop a paraneoplastic syndrome at some time during the course of their disease. Some clinicians categorize the anorexia , cachexia, and fever which occur as a result of cancer as metabolic paraneoplastic syndromes. Virtually all patients diagnosed with cancer are affected by at least one of these metabolic paraneoplastic syndromes.
Paraneoplastic syndromes can occur with any type of malignancy. However, they occur most frequently with lung cancer, specifically small-cell lung carcinoma . Other types of cancer that commonly cause paraneoplastic syndromes are breast cancer and stomach cancer . With the exception of Wilms' tumor and neuroblastoma , paraneoplastic syndromes do not usually occur in children diagnosed with cancer.
In general, paraneoplastic syndromes may be present in the patient before a diagnosis of cancer is made, or, as stated earlier, may be present at the time the patient is first diagnosed with cancer. Most paraneoplastic syndromes appear in the later stages of the disease. Frequently, the presence of a paraneoplastic syndrome is associated with a poor prognosis. Paraneoplastic syndromes are difficult to diagnose and are often misdiagnosed. Some paraneoplastic syndromes may be confused with metatastic disease or spread of the cancer. The presence of the syndrome may be the only indication that a patient has a malignancy or that a malignancy has recurred. Paraneoplastic syndromes may be useful as clinical indicators to evaluate the response of the primary cancer to the treatment. Resolution of the paraneoplastic syndrome can be correlated with tumor response to treatment. That is, if the paraneoplastic syndrome resolves, the tumor has usually responded to the treatment.
Paraneoplastic syndromes occur when the primary or original tumor secretes substances such as hormones, proteins, growth factors, cytokines, and antibodies. The substances are referred to as mediators. These mediators have effects at remote or distant body organs, which are termed target organs. Mediators interfere with communication between cells in the body. This miscommunication results in abnormal or increased activity of the cell's normal function. For example, a lung tumor may cause the paraneoplastic syndrome, ectopic Cushing's syndrome , which is the result of abnormal functioning of the pituitary gland located in the brain. In this example, the lung cancer is the primary tumor and the pituitary gland is the target organ. Ectopic Cushing's Syndrome is caused by overproduction of the mediator, adrenocorticotropic hormone (ACTH).
There are usually two approaches taken in the treatment of paraneoplastic syndromes. The first step is treatment of the cancer that is causing the syndrome. This treatment can be surgery, administration of chemotherapy , biotherapy, radiation therapy , or a combination of these therapies. The next approach is to suppress the substance or mediator causing the paraneoplastic syndrome. Often treatment targeted to the underlying cancer and to the paraneoplastic syndrome occur at the same time. However, even with treatment, irreversible damage to the target organ can occur.
Selected Paraneoplastic Syndromes
SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH).
SIADH is a common paraneoplastic syndrome that affects the endocrine system. This syndrome is most often associated with small-cell lung cancer; however, other cancers such as brain tumors, leukemia, lymphoma, colon, prostate, and head and neck cancers can lead to SIADH. SIADH is caused by the inappropriate production and secretion of arginine vasopressin or antidiuretic hormone (ADH) by tumor cells. Patients with SIADH may not have symptoms, especially in the early stages. When symptoms do occur they are usually related to hyponatremia, which leads to central nervous system toxicity if left untreated. Signs and symptoms associated with hyponatremia include fatigue , anorexia, headache and mild alteration in mental status in early stages. If SIADH remains untreated, symptoms can progress to confusion, delirium, seizures, coma, and death. Treatment approaches for SIADH are to treat the underlying tumor and restriction of fluids. More severe cases may require the administration of medications.
EATON-LAMBERT SYNDROME (ELS).
ELS has been associated with a number of cancers including small cell lung cancer, lymphoma, breast, stomach, colon, and prostate cancers. Potential mediators associated with paraneoplastic ELS are antibodies that interfere with release of acetylcholine at the neuromuscular junction. This interference prevents the flow of calcium, which results in decreased or absent impulse transmission to muscle. The disruption in muscular impulse transmission leads to mild symptoms including weakness in the legs and thighs, muscle aches, muscle stiffness, and muscle fatigue. Treatment of ELS includes administration of corticosteroids , intravenous immunoglobulin, and plasma-pheresis. Depending on the extent of damage, irreversible loss of function may occur even with treatment.
ECTOPIC CUSHING'S SYNDROME.
Cushing's Syndrome is most often associated with small-cell lung cancer, ovarian cancer , and medullary cancers of the thyroid. ACTH precursors are activated by tumor cells that results in overproduction of ACTH by the pituitary gland. Signs and symptoms of ectopic Cushing's Syndrome include hypertension, hyperglycemia, hypokalemia, edema, muscle weakness, and weight loss . The primary approach to treating ectopic Cushing's Syndrome is to treat the underlying cancer. In early stages, surgery is the treatment of choice. However, surgery is not usually an option for patients diagnosed with small-cell cancer of the lung. If the tumor is unable to be removed or controlled, or if the patient has severe symptoms, then treatment targeted to the syndrome is initiated. Medical therapy is usually focused on inhibiting cortisol production and involves the use of medications such as ketoconazole and aminoglutethimide .
Block, J. B. "Paraneoplastic Syndromes" In Cancer Treatment, edited by J. S. Berek. Philadelphia: Saunders, 1995, pp. 245-264.
John, W. J., K. A. Foon, and R. A. Patchell. "Paraneoplastic Syndromes" In Cancer: Principles and Practice, edited by V. T. DeVita, S. Hellman, and S. A. Rosenberg. Philadelphia: Lippincott-Raven, 1997, pp. 2, 397-2, 422.
Midthun, D. E., and J. R. Jett. "Clinical Presentation of Lung Cancer" In Lung Cancer: Principles and Practice, edited by H. I. Pass, J. B. Mitchell, D. H. Johnson, and A. T. Tau ris. Philadelphia: Lippincott-Raven, 1996, pp. 421-435.
Nathensen, L. and T. C. Hall. "Introduction: Paraneoplastic Syndrome." Seminars in Oncology (1997): 265-268.
Zumsteg, M. M. and D. S. Casperson. "Paraneoplastic Syn dromes in Metastatic Disease." Seminars in Oncology Nursing (1998): 220-229.
"Neoplastic and Paraneoplastic Syndromes." Lung Cancer Online 1999-2001. Lung Cancer Online. 3 April 2001. 27 June 2001. <http://www.lungcanceronline.org/syndrom.html>.
"10 Most Commonly Asked Questions about Paraneoplastic Syndromes." Williams and Wilkins 1998. 3 April 2001. 27 June 2001. <http://www.wwilkins.com/theneurologist/articles/paraneoplastic.html>.
Melinda Granger Oberleitner, RN, DNS
—Loss of appetite.
—Severe malnutrition, emaciation, muscle wasting and debility associated with the inability to absorb the nutritional value of food eaten.
—Disorders affecting the skin.
—Decreased levels of the electrolyte potassium in the blood.
—Decreased levels of the electrolyte sodium in the blood.
—Tumors which originate from the primary or original tumor at distant locations in the body; secondary tumors.
—Disorders affecting the nervous system.
"Paraneoplastic Syndromes." Gale Encyclopedia of Cancer. . Encyclopedia.com. (April 22, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/paraneoplastic-syndromes
"Paraneoplastic Syndromes." Gale Encyclopedia of Cancer. . Retrieved April 22, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/paraneoplastic-syndromes
Paraneoplastic syndromes (PS) are rare disorders triggered by the immune system's response to cancer cells, or by remote effects of tumor-derived factors. These syndromes are believed to occur when cancer-fighting anti-bodies or white blood cells, known as T-cells, mistakenly attack normal body cells. These disorders typically affect middle-aged to older people and are most common in patients with lung, ovarian, lymphatic, or breast cancer.
Paraneoplastic syndromes are defined as clinical syndromes involving non-cancerous effects in the body that accompany malignant disease, and can affect any part of the nervous system from the cerebral cortex to peripheral nerves and muscles. In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, occurring far away from the tumor itself. When a tumor arises, the body may produce antibodies to fight it, by binding to and helping in the destruction of tumor cells. Unfortunately, in some cases, these antibodies cross-react with normal tissues and destroy them, which may stimulate the onset of PS. However, not all PS are associated with such antibodies.
Neurological symptoms generally develop over a period of days to weeks, and usually occur prior to the discovery of cancer, which can complicate diagnosis. In these cases, additional information should raise the possibility that the patient may have a hidden cancer and that neurological symptoms could be paraneoplastic. Symptoms include fatigue , weakness, muscular pain in upper arms, difficulty walking, burning, numbness or tingling sensations in the limbs (peripheral paresthesia), dry mouth, sexual function difficulty, and drooping eyelids.
Neurological signs may include dementia with or without brain stem signs, rapid and irregular eye movements, and ophthalmoplegia (weakness or paralysis in muscles that move the eye). Paraneoplastic syndromes involving the nervous system include: Lambert-Eaton myasthenic syndrome (LEMS), stiff person syndrome (SPS), encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis (MG), cerebellar degeneration (CD), limbic and/or brain stem encephalitis, neuromyotonia, opsoclonus myoclonus (OM), and sensory neuropathy.
Most paraneoplastic syndromes are rare, affecting less than 1% of persons with cancer. Exceptions include LEMS, which affects about 3% of patients with small-cell lung cancer; MG, which affects about 15% of persons with thymoma; and demyelinating peripheral neuropathy , which affects about 50% of patients with the rare osteosclerotic form of plasmacytoma. No race, age, or sex preference has been reported.
Causes and symptoms
Most or all paraneoplastic syndromes are activated by the body's immune system. In response to a tumor, the immune system produces an antigen that is normally expressed exclusively in the nervous system. The tumor antigen is identical to the normal antigen, but for unknown reasons the immune system identifies it as foreign and mounts an immune response.
In general (although not always), PS develops in an acute or subacute fashion, over days or weeks. Symptoms may include difficulty in walking and/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. The nervous system disability is usually severe.
Currently, paraneoplastic syndromes are diagnosed using two different technologies in testing blood. Blood testing with western blot using recombinant human antigens is a highly specific method; it can clearly distinguish between different paraneoplastic antibodies. Immunohistochemistry can detect paraneoplastic antibodies in blood serum, providing a general diagnosis, but cannot distinguish between the different PS antibodies.
The physician should search for cancer using the most sensitive technology available, including magnetic resonance imaging (MRI) and a fluorodeoxyglucose body positron emission tomography (PET) scan.
Due to the many manifestations of paraneoplastic syndromes, PS should be evaluated clinically by a coordinated team of doctors, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, and dermatologists.
Because PS are considered to be immune-mediated disorders, two treatment approaches have been used: removal of the source of the antigen by treatment of the underlying tumor, and suppression of the immune response. For many PS, the first approach is the only effective treatment. In the LEMS and MG, plasma exchange or intravenous immune globulin is usually effective in suppressing the immune response.
Physicians often also prescribe a combination of either plasma exchange or intravenous immune globulin and immunosuppressive agents such as corticosteroids, cyclophosphamide, or tacrolimus. For most paraneoplastic syndromes, immunotherapy is not effective.
Recovery and rehabilitation
Some disorders such as the LEMS and MG respond well to immunosuppressant drugs and to treatment of the underlying tumor. The peripheral neuropathy associated with osteosclerotic myeloma generally resolves when the tumor is treated with radiotherapy. A few disorders may respond to treatment of the underlying tumor, immuno-suppression, or both, or they may resolve spontaneously. In many instances, it is not clear whether the PS resolve spontaneously or in response to treatment. Disorders involving the central nervous system , such as encephalomyelitis associated with cancer or paraneoplastic cerebellar degeneration, usually respond poorly to treatment, although they may stabilize when the underlying tumor is treated.
As of mid-2004, the numerous clinical trials recruiting participants for the study and treatment of paraneo-plastic syndromes include:
- Interferon and Octreotide to Treat Zollinger-Ellison Syndrome and Advanced Non-B Islet Cell Cancer
- Evaluating Pancreatic Tumors in Patients with Zollinger-Ellison Syndrome
- Treatment of Zollinger-Ellison Syndrome
- The Use of Oral Omeprazole and Intravenous Pantoprazole in Patients with Hypersecretion of Gastric Acid
Updates information on these and other ongoing trials can be found at the National Institutes of Health web-site for clinical trials at <http://www.clinicaltrials.gov>.
The prognosis for persons with paraneoplastic syndromes depends on the specific type of PS, and the progression of the underlying cancer. LEMS and MG are neuromuscular junction diseases, which can recover function once the causal insult is removed, because there is no neuronal loss. Disorders such as CD are usually associated with neuronal damage, and because they evolve subacutely and treatment is often delayed, neurons die, making recovery much more difficult. Some central nervous system disorders such as OM may not involve cellular loss and, thus, patients with these disorders, like those with LEMS, have the potential for recovery.
It is important that caregivers for those with paraneo-plastic syndromes receive adequate support. The disorder typically emerges suddenly and without warning. The neurological manifestations of PS are complex and often require 24-hour patient care. Many caregivers will require quick access to information on caring for a disabled person. This includes information on social security benefits, insurance coverage, handicapped license plates, evaluations for physical therapy; medical equipment such as hospital beds, ultra-light wheelchairs, handheld showerheads, and home healthcare and visiting nurses; and social workers and other support services.
Ruter, U., et al. Paraneoplastic Syndromes. Basel: S. Karger Publishing, 1998.
Robert, B. D., and P. B. Jerome. "Paraneoplastic Syndromes Involving the Nervous System." New England Journal of Medicine 349 (2003): 1543–1554.
Sutton, I., and J. B. Winer. "The Immunopathogenesis of Paraneoplastic Neurological Syndromes." Clinical Science 102 (2002): 475–486.
"NINDS Paraneoplastic Syndromes Information Page." National Institute of Neurological Disorders and Stroke. May 1, 2004 (June 2, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/paraneoplastic.htm>.
Santacroce, Luigi. "Paraneoplastic Syndromes." eMedicine. May 1, 2004 (June 2, 2004). <http://www.emedicine.com/med/topic1747.htm>.
American Autoimmune Related Diseases Association. 22100 Gratiot Avenue, Eastpointe, MI 48201-2227. (586) 776-3900 or (800) 598-4668; Fax: (586) 776-3903. firstname.lastname@example.org. <http://www.aarda.org>.
National Cancer Institute (NCI)—National Institutes of Health. Bldg. 31, Rm. 10A31, Bethesda, MD 20892-2580. (301) 435-3848. email@example.com. <http://cancernet.nci.nih.gov>.
Francisco de Paula Careta
Iuri Drumond Louro, MD, PhD
"Paraneoplastic Syndromes." Gale Encyclopedia of Neurological Disorders. . Encyclopedia.com. (April 22, 2017). http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/paraneoplastic-syndromes
"Paraneoplastic Syndromes." Gale Encyclopedia of Neurological Disorders. . Retrieved April 22, 2017 from Encyclopedia.com: http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/paraneoplastic-syndromes
Syndrome of Inappropriate Antidiuretic Hormone
Syndrome of inappropriate antidiuretic hormone
The syndrome of inappropriate antidiuretic hormone production (SIADH) is a condition in which the body develops an excess of water and a decrease in sodium (salt) concentration, as a result of improper chemical signals. Patients with SIADH may become severely ill, or may have no symptoms at all.
A syndrome is a collection of symptoms and physical signs that together follow a pattern. SIADH is one of the paraneoplastic syndromes , in which a cancer leads to widespread ill effects due to more than just the direct presence of tumor.
The body normally maintains very tight control over its total amount of water and its concentration of sodium. Many organs including the kidneys, heart, and the adrenal, thyroid, and pituitary glands participate in this regulation. One important contribution is the release of a chemical substance, or hormone, by the pituitary gland into the bloodstream. This chemical substance, called antidiuretic hormone (ADH), is also known as arginine vasopressin, or AVP.
The pituitary releases ADH into the bloodstream when receptors in various organs detect that the body has too little water or too high a concentration of salt. ADH then affects the way the kidneys control water and salt balance. ADH causes the kidneys to decrease their output of urine. The body thus saves water by undergoing antidiuresis, that is, not excreting urine.
Simultaneously, the concentration of sodium in the body serum decreases. This decrease results from a second effect of ADH on the kidneys. When the kidneys retain extra water, the existing concentration of sodium in the body decreases slightly as a result of dilution. These functions are all part of the body's extremely precise control over water and salt balance in health.
Abnormal physiology in SIADH
Certain disease states can upset the delicate balance of water and salt in the body. If there is too much ADH in the body, or if the kidneys overreact to the ADH they receive, the body retains excess water and the serum sodium concentration becomes diluted and falls to abnormal levels. The patient with SIADH develops symptoms based on the degree of abnormality in the serum sodium concentration and the speed with which this concentration falls.
Normal serum sodium concentration is 135-145 mEq/L (milliEquivalents of sodium per liter of body fluid). When the sodium concentration is 125-135 mEq/L the patient may have mild nausea, loss of appetite, fatigue , headache, or still remain free of symptoms. As the sodium level drops below 120 mEq/L, the patient experiences greater weakness, confusion, sleepiness, vomiting, and weight gain. As the sodium concentration approaches 110 mEq/L, the patient may suffer seizures, coma, and death.
SIADH has many known causes, some of which particularly relate to cancer or its treatment. These causes include specific types of cancer, drugs used to treat cancer itself, drugs used to treat the effects of cancer, and conditions that arise as a consequence of cancer or its treatment.
Specific types of cancer
SIADH results from numerous different types of cancer. The malignancies known to cause SIADH include:
- Lung cancer, small cell type
- Gastrointestinal cancers (pancreatic cancer, exocrine ; duodenal or stomach cancer )
- Genitourinary cancer (bladder cancer , prostate cancer , ovarian cancer)
- Lymphoma, including Hodgkin's disease
- Head and neck cancers (oral cancers , laryngeal cancer , nasopharyngeal cancer )
- Brain and central nervous system tumors
- Breast cancer
Certain cancers produce and secrete ADH themselves. This production occurs without regard for the needs of the body. Thus, the kidneys receive repeated signals to save water, even when the body already has a marked excess of fluid. Of all the types of cancer that produce ADH themselves, small cell lung cancer is by far the most common. Small cell cancer of the lung is the cause in 75% of cases of SIADH caused directly by a tumor. In some cases, the appearance of SIADH may be the first indication that a cancer exists.
Also, primary or metastatic tumors in the brain may lead to SIADH. SIADH here results from an increase in intracranial pressure (pressure within the head), or from other effects of intracranial disease on the brain. Increased intracranial pressure commonly causes various parts of the brain to work improperly.
Drugs used to treat cancer itself
A variety of drugs used in cancer treatment may lead to SIADH. The mechanism of this effect may be that the drug causes the abnormal release of ADH, or that the drug makes existing ADH work in a stronger fashion than usual. Chemotherapy drugs that cause SIADH include:
- Vincristine , vinblastine , vinorelbine and other vinca alkaloids (Oncovin, Velban, Navelbine)
- Cyclophosphamide , ifosfamide , melphalan and other nitrogen mustards (Cytoxan, Ifex, Alkeran)
- Cisplatin (Platinol-AQ)
- Levamisole (Ergamisol)
Drugs used to treat the effects of cancer
SIADH may occur as a reaction to drugs used to treat effects of cancer such as pain, depression , or seizures. SIADH also may result from general anesthesia.
- Narcotic pain medications (morphine, Oramorph SR, fentanyl, Duragesic)
- Tricyclic antidepressants (amitriptyline , Elavil)
- Carbamazepine (Tegretol)
- General anesthetics
Conditions that arise as a consequence of cancer
SIADH may result from some of the debilitating consequences of cancer. For example, a person with cancer who is weak or unsteady will have a tendency to fall and hit the head. Skull fracture and other types of head injury may damage the brain or increase the intracranial pressure, and thus lead to SIADH.
Also, cancer patients who are weak, malnourished, receiving chemotherapy, or spending excessive time in bed have an increased risk of pneumonia and other infections. Infections including pneumonia, meningitis, and tuberculosis can cause SIADH.
The treatment of SIADH involves relief of the urgent symptoms and correction of the underlying problem. For immediate improvement, all patients with SIADH require sharp restriction of their daily water intake. As little as two cups of liquid, about 500 ml, may be the daily limit for some patients. In cases where the sodium concentration is already dangerously low, doctors may cautiously give an intravenous infusion of fluid with a high concentration of sodium (hypertonic saline solution). However, this treatment carries some risk of damaging the brain. Physicians may also use a medicine such as furosemide (Lasix) that promotes water excretion (diuresis). Another drug, demeclocycline , blocks the action of ADH in the kidney.
The most definitive way to relieve SIADH is to address the underlying problem itself. Thus, if a tumor produces abnormal ADH, then surgery, radiation therapy , or chemotherapy may help by reducing tumor size. If SIADH results from use of a drug, then the patient must discontinue the medicine. Finally, doctors try to identify and treat any other correctable cause, such as an infection.
The prognosis of SIADH depends largely on its cause. Until recently, many physicians believed that the appearance of SIADH indicated a poor prognosis for cancer. However, more recent reports contradict this idea. The patient's ability to observe severe restriction of fluid intake may determine the degree of ongoing symptoms. SIADH usually improves after stopping a drug or curing an infection when that is the cause. When cancer is the direct cause of SIADH, one hopes for similar improvement of SIADH from treatments that reduce the amount of cancer in the body.
DeVita, Vincent T. Jr., Samuel Hellman, and Steven A. Rosen berg, eds. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins, 2001.
Fauci, Anthony S., et al., ed. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 1998.
Kenneth J. Berniker, M.D.
Antidiuretic hormone (ADH)
—A chemical hormonal signal sent by the pituitary gland to the kidneys through the bloodstream, telling the kidneys to conserve water in the body.
—The excretion of urine.
—A chemical signal released into the bloodstream that affects one or more other organs.
Hypertonic saline solution
—Fluid that contains salt in a concentration higher than that of healthy blood.
—Within the head.
—A small organ, located at the base of the brain, that regulates many body functions.
—Syndrome of inappropriate antidiuretic hormone production
—The clear yellowish liquid part of whole blood, after it is separated into solid and liquid components. It may be found within the vascular system or in body tissue itself.
—A collection of symptoms and physical signs that together follow a pattern.
"Syndrome of Inappropriate Antidiuretic Hormone." Gale Encyclopedia of Cancer. . Encyclopedia.com. (April 22, 2017). http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/syndrome-inappropriate-antidiuretic-hormone
"Syndrome of Inappropriate Antidiuretic Hormone." Gale Encyclopedia of Cancer. . Retrieved April 22, 2017 from Encyclopedia.com: http://www.encyclopedia.com/medicine/encyclopedias-almanacs-transcripts-and-maps/syndrome-inappropriate-antidiuretic-hormone