Syndrome of Inappropriate Secretion of Antidiuretic Hormone

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a paraneoplastic condition that is associated with malignant tumors (particularly SCLC), central nervous system disease (eg, infection, intracerebral lesions, head trauma, and subarachnoid hemorrhage), and pulmonary disorders (eg, tuberculosis, pneumonia, and abscess).

Signs and Symptoms

Hyponatremia

Hyponatremia is the most common presenting sign of SIADH. Patients who experience a rapid fall in plasma sodium levels are usually the most symptomatic.

Other presentations

Patients with SIADH can also experience malaise, altered mental status, seizures, coma, and occasionally, death. Focal neurologic findings can occur in the absence of brain metastases.

Diagnosis

To make a diagnosis of SIADH, certain criteria must be met (Table 2). In addition to those criteria, patients should have normal renal, adrenal, and thyroid function, along with normal extracellular fluid status.

Drug history

It is important to obtain a full list of medications that the patient is taking, because certain drugs can impair free water excretion either by acting on the renal tubule or by inducing pituitary arginine vasopressin expression. These drugs include morphine, cyclophosphamide, vincristine, chlorpropamide, amitriptyline, and clofibrate.

Treatment

The major focus of treatment for SIADH related to malignancy is successful treatment of the underlying cancer.

Acute treatment

Acute treatment is indicated in patients who are symptomatic and who have severe hyponatremia (eg, serum sodium level < 125 mEq/L). The goals of therapy in these patients are to initiate and maintain rapid diuresis with intravenous furosemide (1 mg/kg of body weight) and to replace the sodium and potassium lost in the urine. Usually, the latter goal can be achieved by administering 0.9% saline with added potassium.

This rapid correction should not exceed a 20 mEq/L rise in serum sodium concentration during the first 48 hours. Patients who experience too rapid a rise in serum sodium concentration may suffer neurologic damage and central pontine myelinolysis.

Chronic treatment

The mainstay of chronic therapy is water restriction to 500 to 1,000 mL/d. When this measure alone is unsuccessful, demeclocycline, 300 to 600 mg orally bid, may be used in patients without liver disease. The onset of action may be more than 1 week. Agents from a new class of pharmacologic agents, vasopressin receptor antagonists, have been approved for the treatment of euvolemic and hypervolemic hyponatremia. Only tolvaptan (Samsca) and conivaptan (Vaprisol) are approved by the US Food and Drug Administration; they can be initiated in a hospital setting, where the serum sodium can be monitored closely because of the risk of overly rapid correction of hyponatremia. Further studies are needed to guide their optimal use.

Lambert-Eaton Syndrome

The Lambert-Eaton syndrome is strongly associated with SCLC. It is caused by antibodies that interfere with the release of presynaptic acetylcholine at the neuromuscular junction.

Signs and Symptoms

This syndrome is characterized by fatigue and proximal muscle weakness, particularly of the pelvic girdle and thighs.

Many patients with this disorder have autonomic symptoms, one of the most common of which is dry mouth.

Other possible symptoms include diplopia or blurred vision, ptosis, dysarthria, dysphagia, and paresthesias.

Diagnosis

Patients with Lambert-Eaton syndrome show an improvement in muscle strength with exercise.

Electromyographic studies

These studies are helpful in making the diagnosis. They reveal an increase in the muscle action potential, with repeated nerve stimulation at rates faster than 10 per second.

Edrophonium test

In addition, in contrast to individuals with myasthenia gravis, patients with Lambert-Eaton syndrome have a poor response to the edrophonium test.

Treatment

Chemotherapy

This is the first line of treatment, because 90% of patients with SCLC will respond to this measure.

Other therapies

For patients in whom chemotherapy fails to improve symptoms, 3,4-diaminopyridine has been reported to improve muscle strength in four small randomized controlled trials involving 54 participants in total. One trial involving only 9 participants showed that intravenous immunoglobulin also improved muscle strength up to 8 weeks from treatment. Randomized controlled trials involving plasma exchange, steroids, and immunosuppressive agents are needed.

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Polymyositis/Dermatomyositis

The relationship between polymyositis/dermatomyositis and malignancy was established long ago. The most commonly associated malignancies are breast, lung, and ovarian cancers. An increased incidence of cancer patients with dermatomyositis (10%) has been observed, but the association of cancer with polymyositis is less clear.

Signs and Symptoms

Muscle weakness

Patients with this syndrome typically experience proximal muscle weakness that progresses over weeks to months. Weakness in the hips, thighs, and shoulder girdle may cause patients to have difficulties in getting out of a chair, climbing stairs, or combing their hair. Patients also may experience dysphagia as well as weakness of the flexor muscles of the neck.

In the majority of cases, the distal muscles of the extremities are not involved. Also, most patients do not have involvement of the extraocular muscles.

Rashes

Patients with dermatomyositis can have involvement of the eyelids, forehead, cheeks, chest, elbows, knees, and knuckles, with the classic heliotrope rash. A more diffuse rash may also occur.

Diagnosis

Patients with polymyositis/dermatomyositis usually have an elevation in their serum muscle enzyme levels and erythrocyte sedimentation rate.

In addition, electromyography tracings are abnormal and muscle biopsies reveal minimal inflammatory changes, along with muscle fiber necrosis, in patients with polymyositis/dermatomyositis.

Treatment

Corticosteroids

In addition to treatment of the underlying malignancy, patients with polymyositis or dermatomyositis are treated with high-dose oral corticosteroids (eg, prednisone, 60 to 80 mg/d). Other supportive measures, such as range of motion exercises, are also prescribed.

Immunosuppressives

In patients who do not respond to corticosteroid therapy, immunosuppressive therapy is often added. This type of therapy needs to be tailored to the individual patient, and consultation with a rheumatologist should be considered.

Therapy for skin disease

The skin disease of dermatomyositis can be treated with a variety of measures, such as topical corticosteroids, antimalarials, photoprotection, and at times, low-dose methotrexate.

Suggested Reading

On Superior Vena Cava Syndrome

Fagedet D, Thony F, Timsit JF, et al: Endovascular treatment of malignant superior vena caba syndrome: Results and predictive factors of clinical efficacy. Cardiovasc Intervent Radiol 36:140–149, 2013.

Liang Z, Han R, Qu Y, et al: Role of prophylactic filter placement in the endovascular treatment of symptomatic thrombosis in the central veins. Thromb Res 134:57–62, 2014.

On Venous Thromboembolic Complications of Cancer

Lotsch F, Konigsbrugge O, Posch F, et al: Statins are associated with low risk of venous thromboembolism in patients with cancer: A prospective and observational cohort study. Thromb Res 134:1008–1013, 2014.

Petterson TM, Marks RS, Ashrani AA, et al: Risk of site-specific cancer in incident venous thromboembolism: A population-based study. Thromb Res 135:472–478, 2015.

Lyman GH, Bohlke K, Khorana AA, et al: Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol Jan 20, 2015. [Epub ahead of print]

On Spinal Cord Compression

Lee CH, Kwon JW, Lee J, et al: Direct decompressive surgery followed by radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression: A meta-analysis. Spine 39:E587–E592, 2014.

Fehlings MG, Nater A, Holmer H: Cost-effectiveness of surgery in the management of metastatic epidural spinal cord compression: A systematic review. Spine 39(22 suppl 1):S99–S105, 2014.

On Hypercalcemia

Hu MI, Glezerman IG, Leboulleux S, et al: Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab 99:3144–3152, 2014.

On Hyperuricemia and Tumor Lysis Syndrome

McBride A, Lathon SC, Boehmer L, et al: Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome. Pharmacotherapy 33:295–303, 2013.

Galardy PJ, Hochberg J, Perkins SL, et al: Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: A Children’s Oncology Group Report. Br J Haematol 163:365–372, 2013.

On Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Elhassan E, Schrier R: Hyponatremia: Diagnosis, complications, and management including V2 receptor antagonists. Curr Opin Nephrol Hypertens 20:161–168, 2011.

Esposito P, Piotti G, Bianzina S, et al: The syndrome of inappropriate antidiuresis: Pathophysiology, clinical management and new therapeutic options. Nephron Clin Pract 119:c62–c73, 2011.

On Lambert-Eaton Syndrome

Antoine JC, Camdessanché JP: Treatment options in paraneoplastic disorders of the peripheral nervous system. Curr Treat Options Neurol 15:210–223, 2013.

Hülsbrink R, Hashemolhosseini S: Lambert-Eaton myasthenic syndrome - diagnosis, pathogenesis and therapy. Clin Neurophysiol 125:2328–2336, 2014.

On Polymyositis/Dermatomyositis

Yang Z, Lin F, Qin B, et al: Polymyositis/dermatomyositis and malignancy risk: A metaanalysis study. J Rheumatol 42:282–291, 2015.