History
Patients may present with autonomic neuropathy prior to diagnosis of cancer, at the time of cancer diagnosis, or after the treatment of cancer. Autonomic neuropathy often presents as orthostatic hypotension. This may be profound, keeping patients bedridden in spite of aggressive therapy to maintain blood pressure. However, careful evaluation may reveal more widespread disturbances. Abnormal gastrointestinal motility may cause a spectrum of problems from mild constipation and nausea to intestinal pseudo-obstruction [40] due to autoimmune attack on myenteric neurons. Urinary incontinence, erectile dysfunction, cardiac arrhythemias, dry eyes, dry mouth, pupillary changes (sluggish or fixed pupils), and abnormalities of sweating are also common.
Concomitant somatic neuropathy is common and may cause pain and sensory loss, often in a length-dependent "stocking and glove" pattern but occasionally in a patchy distribution. Pain may be lightning like or burning. When motor nerves are affected, patients may report weakness.
If the paraneoplastic process involves the CNS, symptoms can include reduced level of consciousness, seizures, impaired memory or cognitive problems, personality change (ie, limbic encephalitis), ataxia, or even focal signs such as aphasia. CNS involvement may occur early or late; it often is responsible for profound morbidity and death.
One of the minor symptoms seen in LEMS is an unpleasant metallic taste. In the setting of weakness this symptom is suggestive of LEMS, but it may not be reported by the patient and often it needs to be solicited.
A patient may manifest a paraneoplastic syndrome with any combination of autonomic, peripheral, or CNS involvement. [15]
As with any paraneoplastic neurological degeneration, autonomic dysfunction has been described in many types of cancer. These include small-cell lung cancer and other lung tumors, thymoma, and ovarian and breast carcinoma. In some cases, paraneoplastic autonomic dysfunction occurs in the apparent absence of cancer. In patients without known cancer, any clinical history suggesting an underlying tumor (e.g., unexplained weight loss) or high risk for particular cancers (eg, heavy smoking, personal or family history of cancer) can help suggest a link between autonomic symptoms and an underlying malignancy. Finding the primary tumor can prove very difficult in some patients.
The clinical course is usually subacutely progressive over weeks to months, leading to a bedridden condition in severe cases if untreated, and often in spite of treatment.
Physical
Physical findings in patients with paraneoplastic autonomic failure resemble those of any patient with autonomic dysfunction, and include the following:
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Orthostatic hypotension, often profound, in the absence of volume depletion
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Impaired pupillary light responses
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Absence of heart rate changes with respiration
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Abnormal Valsalva response
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Abnormal cold pressor response
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Dysrhythmias such as bradycardia, tachycardia, or asystole [23]
Peripheral sensory neuronopathy often is evident as patchy superficial sensory loss and asymmetrically abnormal stretch reflexes.
Patchy asymmetric weakness and dyscoordination, or abnormal mental status, may occur in patients with CNS involvement.
Proximal muscle weakness is seen in LEMS.
It is important to note that some physical signs may be due directly to the oncological process or from treatment of the malignancy. For instance, chemotherapy with vincristine typically causes areflexia that is diffuse and symmetric. Cisplatin can cause a sensory neuropathy and hearing loss, both of which are typically symmetric. Carcinomatous meningitis can closely mimic the presentation of paraneoplastic encephalomyeloneuropathy.
Causes
Paraneoplastic autonomic dysfunction is a secondary effect of cancer. Small-cell lung cancer is particularly likely to cause paraneoplastic syndromes, but many types of malignancy can cause these types of syndromes, including teratoma, neuroblastoma, retinoblastoma, oligodendroglioma, melanoma, leiomyosarcoma, hematological tumors, and cancers of the thymus, gastrointestinal tract, rectum, prostate, breast, fallopian tubes, uterus, bladder, kidney, pancreas, testicles, malignancies and ovary. [9, 15, 41, 22, 16, 29]
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Paraneoplastic autonomic neuropathy. Histopathology of peripheral nerve and sympathetic ganglion from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive anti-HU antibody titer. (a) Peripheral nerve in longitudinal section stained with Luxol fast blue-periodic acid-Schiff (PAS) showing scattered wallerian degeneration (arrowheads). (b) Low-power view of a paravertebral sympathetic ganglion stained with hematoxylin and eosin (H&E). Arrowhead indicates perivascular mononuclear infiltrates. (c) High-power view of the same sympathetic ganglion showing degenerating neurons (single arrowheads) and mononuclear infiltrates (double arrowhead). Magnification bars in a and b indicate 100 mm; c is 50 mm.
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Paraneoplastic autonomic neuropathy. Hematoxylin and eosin (H&E)–stained sections from dorsal root ganglion showing the hallmark histopathology of anti-HU disease; a and c are from a healthy patient; b and d are from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies. The arrowheads in b and d indicate degenerating sensory neurons. Also note the interstitial hypercellularity and decreased numbers of neurons in b and d. Magnification bar in b indicates 100 mm and applies also to a. Similarly, the magnification bar in d indicates 50 mm, which also applies to c.
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Paraneoplastic autonomic neuropathy. Central nervous system sections from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies stained with hematoxylin and eosin (H&E). (a) Inferior olive showing a cluster of mononuclear cells (arrowhead); (b) hippocampus showing perivascular mononuclear infiltrate (arrowhead); (c) midbrain section showing a vessel encased in a mononuclear infiltrate; (d) ventral horn of the thoracic spinal cord showing clusters of mononuclear cells around degenerating motor neurons (arrowheads). Magnification bars indicate 100 mm. The bar in b applies also to a and the bar in d also applies to c.
