Neuromuscular Dysfunction and Palliative Care

Dianna Quan

James W. Teener

John T. Farrar

The neuromuscular disorders experienced by patients with cancer may cause weakness, fatigue, muscle cramps, sensory loss, pain, or dysesthesias. To determine the etiology of these symptoms accurately and formulate a treatment strategy, physicians need a logical approach to assessment. First, a careful history is taken and a neurologic examination is performed to identify potential neuromuscular dysfunction presenting as part of the complex set of symptoms that occur with cancer. Second, a specific diagnosis is established through laboratory testing or appropriate consultation. Finally, appropriate evidence-based therapy is prescribed. This approach is explored in the subsequent text with reference to common cancer-associated neuromuscular diseases.

The term neuromuscular refers to both the muscle and the peripheral nervous system, including anterior horn cells, dorsal root ganglia, sensory and motor spinal nerve roots, plexi, peripheral nerves, and neuromuscular junctions. Patients with cancer can develop neuromuscular deficits due to compression or invasion of these structures by neoplasm, paraneoplastic effects of cancer, or toxic effects of antineoplastic therapies, including chemotherapy or radiation.

A careful history and examination of the patient help the practitioner differentiate a neuromuscular problem from a central nervous system (CNS) or non-neurologic problem. The tempo of symptom onset is important. Weakness or sensory dysfunction that develops abruptly may indicate a vascular injury in the central or peripheral nervous system, tumor impingement on neural structures, or fulminant autoimmune or inflammatory process. Patients with new and rapidly progressive neuromuscular symptoms require immediate attention. Regardless of tempo of onset, symptoms should be assessed in the context of the location and type of underlying malignancy, previous or current treatments and medications, and underlying comorbid conditions.

The nature and distribution of symptoms offer further diagnostic clues. For example, weakness of one side of the body may suggest a CNS lesion, whereas symmetrical weakness of distal leg and hand muscles is more likely caused by neuropathy. Proximal weakness is more typical of myopathies or defects of neuromuscular transmission. Both positive (e.g., tingling or pain) and negative (e.g., numbness) sensory complaints may occur with nervous system injury. A sensory level or sensory loss below a particular dermatome is typical of spinal cord compression, whereas foot and hand numbness in a “stocking and glove” pattern is more typical of a neuropathy. Reflexes are usually brisk when weakness is caused by a CNS lesion and reduced in cases of neuropathy. Deep tendon reflexes are often normal in myopathy but the magnitude of the reflex motor response may be reduced if the myopathy is severe.

If the history and physical examination are not definitive, other diagnostic procedures should be used. Electrodiagnostic studies, especially nerve conduction studies (NCS) and needle electromyography (EMG) can frequently help to localize the problem to nerve, muscle, or neuromuscular junction. Depending on the symptoms, additional laboratory studies, such as creatine phosphokinase level, hemoglobin A1C, 2-hour 75 g glucose tolerance test, thyroid function tests, vitamin B₁₂ level, Lyme antibody titers, HIV, cryoglobulins, or serum protein electrophoresis with immunofixation electrophoresis may identify a specific contributing cause. Even when the primary diagnosis is clear, identifying other treatable related factors may allow intervention to slow further deterioration.

Table 38.1 presents common symptoms of neuromuscular disorders. Some of the symptoms, such as fatigue or diffuse weakness, are not specific for neuromuscular disease. Others, such as muscle tenderness, focal pain or sensory loss, may lead to an anatomic localization.

Treatment strategies for neuromuscular disorders fall into two categories: etiologic and symptomatic. With our current state of knowledge, complete reversal of the underlying disease with effective etiologic therapy is rare. When available, etiologic treatments for the specific disease entity are described in the subsequent text. Symptomatic therapy, which is becoming more effective, is presented as a separate section. One important general point is that damaged tissues may require higher levels of nutrients and cofactors to support the maximum degree of recovery. Although there are no specific data, appropriate nutrition and supplementation of vitamins and trace minerals are likely to be important components in the treatment of all oncology-related neuromuscular disorders.

We do not specifically discuss any alternative or complementary therapeutic approaches because there is inadequate evidence to support the use of any of these particular treatments in this set of disorders. However, use of these treatments continues to increase and should be documented and reviewed in the course of caring for all patients with oncology-related neuromuscular disease (1).

Table 38.1 Common Symptoms of Neuromuscular Dysfunction

	Focal weakness	Diffuse weakness	Numbness/ Dysesthesia	Focal pain	Muscle cramps	Myalgias	Fatigue
Polyneuropathy	+	+	+	+	+	–	+
Mononeuropathy	+	–	+	+	+	–	–
Sensory neuropathy	–	–	+	–	–	–	–
Motor neuropathy	+	–	–	–	+	–	+
Plexopathy	+	–	+	+	+	–	–
Radiculopathy	+	–	+	+	+	–	–
NMJ defect	–	+	–	–	–	–	+
Myopathy	–	+	–	+	+	+	+
+, common; -, uncommon; NMJ, neuromuscular junction. Most symptoms also have a large number of non-neuromuscular causes.

Specific Neuromuscular Disorders

Neuropathy

Neuropathy is the most frequently encountered neuromuscular complication of cancer. Although neurotoxic chemotherapy is most commonly implicated, neuropathy may also be caused by direct extension or metastatic tumor infiltration of the nerve, or by remote (paraneoplastic) effects of cancer. Nerve involvement may be focal or widespread, and resulting symptoms and signs may be focal or diffuse. Dysesthetic pain, numbness, and weakness are frequent complaints. Fatigue and muscle cramps also may be troublesome. Reflexes are generally reduced or absent in affected areas.

It is useful to categorize neuropathies according to the distribution of the problem and the primary neurologic modalities affected: sensory, motor, or sensorimotor. Neuropathy may be further classified according to the predominant pathology: axonal loss, demyelination, or neuron cell body death. Although one deficit may predominate, both sensation and strength are usually involved to some degree in most neuropathies. Disorders that exclusively affect either sensation or strength are most often caused by lesions of the dorsal root ganglion cells or anterior horn cells, respectively, and therefore are described most accurately as neuronopathies.

The evaluation of neuropathy usually involves an EMG and NCS. These tests confirm the extent and distribution of nerve involvement and help differentiate primary neuronal or axonal injury from injury to the myelin sheathe. A careful history, neurologic examination, and high-quality electrodiagnostic testing will provide guidance for choosing other necessary tests. Nerve biopsy is occasionally indicated to help differentiate direct tumor invasion (which may be amenable to chemotherapy or radiation) from inflammation, radiation damage, amyloid deposition, or demyelination. Spinal magnetic resonance imaging (MRI) may reveal structural lesions, such as metastases, that can cause patterns of sensory and motor dysfunction that mimic peripheral neuropathy. In addition, spinal nerve root enhancement is often noted following the administration of gadolinium in patients with inflammatory demyelinating neuropathies. Examination of cerebrospinal fluid (CSF) reveals an elevated protein level in most patients with inflammatory demyelinating neuropathies. CSF may also be subjected to cytologic examination to search for evidence of malignancy involving the spinal subarachnoid space. It is also important to identify potential non-neoplastic causes of neuropathy. A useful general algorithm for evaluation of neuropathy has been presented by Brown (2).

The primary treatment of neuropathy should be directed at the specific underlying cause, if one can be identified. The palliative treatment of neuropathy depends primarily on the predominant symptom (e.g., weakness, sensory loss, pain) and is discussed in the Symptomatic Treatments section.

Cancer-Related Neuropathies

A group of clinically significant sensorimotor neuropathies not related to chemotherapy may accompany or even precede the diagnosis of cancer. Causes to consider in this setting include direct infiltration by tumor, amyloid deposition, and remote effects of cancer. The pathogenesis of neuropathy may remain unknown in some cases, despite extensive investigations. Electrodiagnostic testing is essential to help quantify the degree and pattern of involvement and to distinguish between demyelination and axonal injury. Some processes such as vasculitis or demyelination may have focal, multifocal, or symmetrical presentations. The pattern and tempo of involvement can provide important information to guide further evaluation. Common clinical patterns of neuropathy are presented in the subsequent text.

Polyneuropathy

Axonal Polyneuropathy

Idiopathic neuropathy

Patients with malignancy often develop a mild, symmetrical idiopathic sensorimotor polyneuropathy. This neuropathy typically presents with numbness and tingling in the feet. Symptoms may progress to more widespread sensory disturbances, as well as distal leg and hand weakness. NCS confirm an axonal neuropathy; CSF protein may be normal or, rarely, slightly elevated. The etiology of this typically mild neuropathy is uncertain and is likely to be multifactorial. Predisposing factors may include chemotherapeutic agents, weight loss, malnutrition, and organ failure.

Amyloid neuropathy

Patients with systemic amyloidosis due to plasma cell dyscrasia may develop a polyneuropathy that is predominantly sensory and typically involves small, unmyelinated or thinly myelinated fibers. Autonomic dysfunction is an early and prominent feature. The diagnosis is made by detection of amyloid material on nerve biopsy or may be inferred
if amyloid is detected in other locations such as bone marrow or fat pad aspirate. Even among these patients, however, genetic causes should be considered. Nearly, 10% of patients with suspected AL amyloidosis were noted to have familial amyloid polyneuropathy in one series (21). Failure to identify a genetically mediated neuropathy may result in unnecessary treatment of monoclonal gammopathy.

Paraneoplastic neuropathy

Paraneoplastic polyneuropathy is rare. One of the more common and well-studied syndromes is related to an antineuronal autoantibody referred to as anti-Hu. These antibodies are associated with small cell lung cancer, breast cancer, gynecological, and other malignancies. The syndrome is more properly characterized as a sensory neuronopathy, but may be clinically indistinguishable from a symmetrical sensory polyneuropathy in its initial stages. More recently described anti-CV2 antibodies may be present in small cell lung cancer, thymoma and other tumors and have been associated with mixed axonal and demyelinating polyneuropathies. Symptoms may be predominantly sensory, motor, or mixed (22).

Tumor infiltration

Widespread metastatic infiltration of nerves or spinal nerve roots by tumors, such as lymphoma or melanoma, may result in a confluent multifocal neuropathy that is indistinguishable from a length-dependent, symmetrical sensorimotor polyneuropathy. In some patients with non-Hodgkin’s lymphoma (and much less commonly Hodgkin’s disease), tumor infiltration of nerve roots and nerves has been detected on nerve biopsy (23). This has been termed neurolymphomatosis. These patients may respond to antineoplastic treatment.

Demyelinating Polyneuropathy

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré Syndrome)

Guillain-Barré syndrome has been associated with Hodgkin’s lymphoma and solid tumors, particularly those involving the lung (23, 24). Patients suspected of having this disorder require immediate hospitalization for monitoring their respiratory vital capacity and cardiac function. The rate of progression and severity of this disease is highly variable; at worst, patients can become quadriplegic and ventilator dependent within days. Less severely affected patients may have onset of sensory loss, dysesthesia, or weakness over a few weeks. Autonomic involvement can lead to fatal cardiac arrhythmias if not detected, making cardiac monitoring imperative during the initial period. Although untreated symptoms typically reach a nadir within 6 weeks, early treatment with intravenous immunoglobulin or plasmapheresis hastens recovery and may result in better long-term outcome. Patients with cancer appear to respond to the same therapies used for non–cancer-related Guillain-Barré syndrome.

Chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is rarely associated with cancer. Demyelinating neuropathies occur in patients with monoclonal gammopathies (25). A predominantly motor demyelinating neuropathy can be identified in up to 50% of patients with osteosclerotic myeloma. Most patients have elevated levels of monoclonal IgG or IgA lambda. The neuropathy may occur as part of a syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS). These neuropathies may improve markedly with treatment of the tumor (25).

Paraproteinemic neuropathy

In some patients with Waldenstrom’s macroglobulinemia or monoclonal gammopathy of undetermined significance, an IgM antibody directed against myelin-associated glycoprotein (MAG) can be detected in serum and in the myelin sheath. These patients have a predominantly sensory demyelinating neuropathy (25). The pattern of weakness and sensory loss may be symmetrical or asymmetrical, and NCS reveal classic demyelinating electrophysiology. CSF protein is frequently elevated. Remissions are reported after treatment of the tumor; the neuropathy may sometimes respond to corticosteroids or intravenous immunoglobulin, although the improvement is typically modest. Recent promising anecdotal data is also available for rituximab in this situation (26).

Focal Neuropathy

Isolated mononeuropathies also may develop in patients with cancer. Causes to consider in this setting include compression neuropathies, invasion of neural structures by tumor, vasculitis, or focal presentations of demyelinating neuropathies. The tempo of onset and clinical setting provide guidance for further evaluation and management.

Compression Neuropathy

Peroneal neuropathies at the fibular head typically develop in bedbound patients with weight loss. Loss of the usual fatty cushion predisposes the peroneal nerve to compression at this site. Nutritional, metabolic, and microcirculatory factors also may contribute to this neuropathy. Other nerves such as the ulnar nerve at the elbow may be similarly affected. Chronic arm and hand edema due to prior lymph node dissection may also predispose patients to median nerve compression at the wrist (carpal tunnel syndrome). Focal compression neuropathies generally improve with simple measures, such as careful positioning to avoid further trauma and padding of vulnerable areas such as the elbow and fibular head (27).

Tumor Infiltration

Other focal neuropathies arise when malignant cells invade nerves and cause axonal degeneration. Cranial neuropathies, resulting from invasion of these nerves as they traverse the subarachnoid space are common. Lumbar puncture and contrast-enhanced MRI of the affected area may demonstrate tumor. In cases where repeated lumbar punctures are nondiagnostic, nerve biopsy should be considered to provide histologic confirmation of tumor, especially if further antineoplastic therapy is an option.

Vasculitic Neuropathy

Peripheral nerves may be damaged by a cancer-associated vasculitis, which often causes either an acute or chronic sensorimotor polyneuropathy. The disorder may also begin as a painful mononeuropathy or mononeuritis multiplex and become confluent. Small cell cancer and adenocarcinoma of the lung, renal cell carcinoma, lymphoma, endometrial, and prostate cancer have all been associated with vasculitic neuropathy. Other lymphoproliferative disorders may be associated with cryoglobulinemic neuropathy, which may have a focal, or distal and symmetrical presentation. NCS demonstrate evidence of axonal damage. The diagnosis is confirmed by demonstration of lymphocytic infiltration and necrosis of blood vessels on nerve or muscle biopsy. Treatment with corticosteroids or other immunosuppressants may result in symptomatic improvement (28, 29).

Chemotherapy-Related Neuropathy

Chemotherapeutic agents are among the most common causes of neuropathy in patients with cancer. A wide variety of chemotherapeutic agents has been associated with the
development of neuropathy. Patients receiving vinca alkaloids, platinum-based agents, and taxanes may develop symptoms although the severity is highly variable. Other drugs toxic to peripheral nerves include suramin, thalidomide, cytosine arabinoside, etoposide, ifosfamide, and 5-fluorouracil (3). Less commonly used agents such as misonidazole and dolostatin-10 have also been reported to result in neuropathy (4, 5).

Vinca alkaloids, especially vincristine are a frequent cause of chemotherapy-induced neurotoxicity. Vincristine routinely causes a peripheral neuropathy when used at the usual weekly doses of 1.4 mg per m² or greater (6). Paresthesias may first become noticeable in the fingers. The first clinical sign is usually loss of ankle reflexes. Although mild sensory loss does not warrant a reduction in dosage, weakness may develop rapidly and is a dose-limiting side effect when severe. Signs of impending motor involvement include cramps and mild clumsiness. Weakness typically reverses when the dose is reduced or the drug is stopped; paresthesias take longer to disappear, and mild sensory deficits may persist. Occasionally, patients develop prolonged or permanent dysfunction. Less commonly peripheral neuropathy may occur with vinorelbine tartrate and vinblastine (3). In most cases of vinca alkaloid neuropathy, electrodiagnostic studies demonstrate a symmetrical sensorimotor polyneuropathy with predominant axonal involvement.

Cisplatin may begin to cause neurotoxicity or ototoxicity at a cumulative dose of approximately 300 mg per m², and more than 50% of patients who receive 600 mg per m² develop symptoms (7). The neuropathy is usually symmetrical and predominantly sensory; decreases in vibratory, light touch, and pinprick sensation are accompanied by progressive loss of deep tendon reflexes. The loss of proprioception may result in sensory ataxia. Despite discontinuation of the drug, neuropathic symptoms may continue to increase for weeks before stabilizing, a phenomenon known as “coasting.” Recovery occurs over months, but is often incomplete. Weakness is rare in all but the most severely affected patients. Similar symptoms are reported with carboplatinum, but are less frequent than with cisplatin (3). Oxaliplatin, a newer platinum derivative, mainly causes a completely or partially reversible sensory neuropathy at high cumulative doses. Acral, perioral, and pharyngeal dysesthesias, cramps, and stiffness may occur. Neuromyotonia related to peripheral nerve hyperexcitability has been observed on electrodiagnostic examination of oxaliplatin treated patients (8).

Paclitaxel and docetaxel commonly cause a symmetrical, predominantly large fiber sensory or sensorimotor polyneuropathy at usual doses. Pain, tingling, and numbness may begin within 1–3 days after a single high-dose treatment. The feet and distal legs are affected first, but sensory changes in the hands and face may present earlier than in other toxic neuropathies. Weakness and autonomic abnormalities occasionally develop (9, 10). Coasting occurs but most symptoms eventually improve when the drug is discontinued. Neurotoxicity may limit treatment, particularly with high-dose regimens. Risk factors for the development of neuropathy include an earlier neuropathy, high doses (>250 mg per m²), prolonged length of treatment, and possibly older age (11).

Combinations of multiple neurotoxic agents may result in cumulative peripheral nerve injury beyond that expected with the individual agents. For example, paclitaxel may cause a more severe neuropathy than usual in patients previously treated with cisplatin (12). Those with underlying nerve problems, such as diabetic neuropathy or Charcot-Marie-Tooth disease may also be especially predisposed to developing neuropathy from chemotherapy. Any patient with suspected chemotherapy-related neuropathy should also undergo a complete evaluation to identify other contributing causes of neuropathy, either related to the cancer itself or to underlying treatable conditions. It is occasionally useful to follow electrodiagnostic markers of nerve dysfunction prospectively to identify impending nerve disease early in the course of chemotherapy. Somatosensory-evoked responses are generally affected early, followed by a reduction in sensory amplitudes on NCS (13). NCS are a more reliable measure and can be performed serially to monitor the degree of nerve injury.

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