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neuropathies secondary to the direct effects of malignancies

• The most common cause of neuropathy in patients with cancers is chemotherapy-induced neuropathy
  
• An infiltrative brachial plexopathy is more likely due to breast and lung cancers whereas infiltrative lumbosacral plexopathies are associated with colorectal and cervical cancers
  
• The presence of myokymic discharges on EMG are suggestive of radiation-induced plexopathy rather than metastatic disease.

Most physicians refer to paraneoplastic syndromes as “remote effects” of cancer on the nervous system that are not caused by direct invasion or other nonmetastatic complications. Paraneoplastic neurological syndromes usually precede the identification of cancer and, even if the related cancer is finally found, the cancer is usually small, indolent, and nonmetastatic. Often, the symptoms of the paraneoplastic neurological syndrome predominate while the cancer itself remains asymptomatic. Paraneo­plastic syndromes may simultaneously involve the central nervous system, resulting in a clinical picture of a multifocal neurological disease further complicating the diagnosis. Paraneo­plastic neurological syndromes are rare but exact frequency remains uncertain. Nevertheless, as paraneoplastic syndromes precede the detection of a neoplasm, early recognition can lead to detection of a cancer at an earlier and potentially more curable stage. Paraneoplastic syndromes are thought to be due to an immune-mediated process arising from cross-reacting antibodies against tumor antigens and the antigens in the neural tissues. Paraneoplastic neuromuscular disorders include paraneoplastic neuropathy, myopathy, motor neuron diseases, and neuromuscular junction diseases. This chapter addresses only paraneoplastic neuropathies.

Paraneoplastic Neuropathies

There are five major clinical presentations of the paraneoplastic neuropathies:

Although mixed sensorimotor neuropathies are more frequent paraneoplastic manifestations of cancer, pure sensory neuropathies due to neuronopathies and ganglionopathies are more specific and therefore more highly suggestive of the presence of an underlying malignancy.

Sensory Neuronopathy or Ganglionopathy

The symptoms are acute or subacute, progressive numbness, tingling, paraesthesiae, and loss of sensory functions. Pain can be prominent. Unlike length-dependent neuropathies, symptoms do not typically start in the toes or lower extremities but often start in the upper limbs, and progress to the lower limbs. In addition, sensory symptoms are often asymmetric and can involve the face, chest, or trunk. As the neuronopathy progresses, sensory ataxia and pseudoathetosis in the limbs can be seen. Motor symptoms are typically absent even though profound loss of proprioceptive sense can be mistaken for motor weakness, especially when a patient is unable to walk. Deep tendon reflexes are usually absent. Sensory deficits involve all modalities. Nerve conduction studies show a pattern of severe pure sensory involvement, often with absence of all sensory responses, whereas motor studies are normal or minimally changed. Cerebrospinal fluid (CSF) analysis may show elevated protein or other inflammatory findings. Although infrequently done, a nerve biopsy might reveal severe loss of myelinated fibers without evidence of inflammation. This syndrome is most commonly associated with small cell lung cancer (SCLC) or neuroendocrine tumors. Other tumors that have been reported also include breast and ovarian cancer and lymphoma. The sensory neuronopathy syndrome can precede the identification of the cancers for many months or years.

Paraneoplastic sensory neuronopathy is a disorder of the dorsal root ganglion sensory neurons. Pathology shows marked inflammatory infiltration around dorsal root ganglion neurons, which degenerate and are replaced by satellite cells (Nageotte’s nodule) suggesting an immune-mediated process as a likely pathogenesis. Serum anti-Hu antibodies are detected in about 80% of cases and are therefore an important dia­gnostic test. The main target of the antibody is the antigen Hu-D, which is expressed in both the sensory neurons and on the surface of the tumors.

The differential diagnosis of paraneoplastic sensory neuronopathies includes:

• Toxic, cisplatin-induced sensory neuronopathy. Although paraneoplastic sensory neuropathies are often asymmetric and usually painful, affecting small-fiber as well as large-fiber nerves, cisplatin neuronopathy is symmetric, usually large fiber, rarely painful, with sparing of pain and temperature sensation. Cisplatin neuronopathy usually stops progressing several months after the medication is stopped, although “coasting “may be seen initially. Paraneoplastic neuronopathy continues to progress.
  
• Dysimmune neuronopathies associated with Sjögren’s syndrome.
  
• Excessive intake of vitamin B₆ (pyridoxine toxicity).
  
• Friedreich’s ataxia, an inherited spinocerebellar disorder.
  
• Idiopathic sensory neuronopathy.

The prognosis of paraneoplastic sensory neuronopathy is poor. Despite an immune-mediated pathogenesis, the neuronopathy does not respond to immunotherapy and continues to progress relentlessly. Early detection and treatment of underlying cancer arrest progression but do not reverse the neuropathy. In cases presenting with the neurological syndrome alone, especially when anti-Hu is present, vigorous and continuous search for an underlying cancer is recommended. A positron emission tomography (PET) scan could be helpful in identifying an underlying cancer when computed tomography (CT) or magnetic resonance imaging (MRI) fail.

Autonomic Neuropathy

Paraneoplastic autonomic neuropathy presents with acute or subacute onset of orthostatic symptoms, ocular involvement, gastrointestinal dysmotility, bladder dysfunction, and anhidrosis. Orthostatic symptoms are found in more than 70% of cases and include lightheadedness, dizziness, and syncope on standing up. Ocular involvement includes abnormal pupillary reaction and dry eyes. Gastrointestinal dysmotility is prominent and causes early satiety, weight loss, bloating, intestinal pseudoobstruction, chronic constipation, recurrent vomiting, and ileus. Symptoms of autonomic neuropathy are more commonly associated with other paraneoplastic syndromes including sensory neuronopathy, limbic encephalitis, Lambert–Eaton myasthenic syndrome, and cerebellar degeneration. Auto­nomic dysfunction as the sole manifestation occurs in less than 10% of cases.

An autonomic reflex screening test assessing postganglionic sudomotor (sweat), cardiovagal, and cardioadrenergic functions usually shows varying abnormalities from limited autonomic neuropathy to widespread panautonomic failure. Gastrointestinal manometry often shows hypomotility, uncoordinated motility, and intense tonic contraction. In most cases, anti-Hu antibodies can be detected (less than 10% of anti-Hu-positive cases have autonomic symptoms) but other paraneoplastic antibodies such as CRMP-5 can also be seen. Most anti-Hu-positive cases will be associated with SCLC.

Recently, a specific antibody directed against the α₃ subunit of the acetylcholine receptor (AChR) was discovered in patients with dysautonomia. About 50% of those who have ganglionic AChR antibodies have underlying cancers, again most commonly SCLC. Other cancers associated with this antibody include thymoma, and bladder and rectal cancers. Ganglionic AChR antibody was shown to reduce the number of synaptic AChRs at the autonomic ganglia, possibly by crosslinking and internalization of the receptors, an effect that is reversible. Similar to other paraneoplastic syndromes, prognosis of paraneoplastic autonomic neuropathy is related to the underlying cancer. In cases of ganglionic AChR antibody-mediated cases, treatment of the underlying cancer has been shown to improve the autonomic symptoms as well as to lower the level of the antibody. Spontaneous remission of the symptoms without cancer treatment can also occur. It is unclear if treatment with immunotherapy helps improve the autonomic symptoms, although would seem to be warranted in light of the pathogenesis. In patients of Lambert–Eaton myasthenic syndrome, treatment with 3,4-diaminopyridine and of the underlying cancer has been shown to improve the autonomic symptoms.

Sensorimotor Neuropathy

Paraneoplastic sensorimotor neuropathy presents with acute, subacute, or chronic progressive weakness and sensory symptoms and deficits.

Acute Sensorimotor Neuropathies

An acute demyelinating neuropathy clinically identical to GBS is associated with Hodgkin’s disease. Other cancers associated with GBS include SCLC, and kidney, esophageal, and tongue cancer as well as melanoma. The typical syndrome consists of acute or subacute onset of progressive symmetric motor greater than sensory symptoms in an ascending pattern over 4–6 weeks, accompanied by loss of deep tendon reflexes, unilateral or bilateral facial weakness, elevated CSF protein, and demyelination on EMG. Treatment of GBS associated with cancers is the same as GBS without cancers.

Subacute Sensorimotor Neuropathies

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is rarely associated with pancreatic, colon, liver, and breast cancers. CIDP presents with subacute onset of weakness and sensory symptoms progressing over more than 8 weeks associated with elevated CSF protein and demyelination on EMG. Again, treatment is the same as CIDP without cancers.

Chronic Sensorimotor Neuropathies

Sensorimotor neuropathies associated with hematological malignancies are frequently associated with monoclonal gammopathy of uncertain significance and, less commonly, anti-MAG (myelin-associated glycoprotein) antibody. Lymphoma, multiple myeloma, osteosclerotic myeloma, and Castleman’s disease are all associated with paraproteinemic neuropathies. Most cases present with subacute or chronic progressive weakness and sensory symptoms, elevated CSF protein, and demyelinating or axonal changes on EMG. In cases of anti-MAG neuropathy, sensory symptoms, especially large-fiber symptoms, are more pronounced. The patients typically present with gait disturbance with minimal weakness but frequently tremor in the upper limbs. It is important to screen for monoclonal proteins in unexplained neuropathies in patients aged >50 and complete a skeletal survey looking for underlying hematological malignancy in patients who have an acquired demyelinating polyneuropathy.

In multiple myeloma, a predominantly small-fiber “amyloid” neuropathy can be seen in which case electrodiagnostic studies may be normal or minimally abnormal. Amyloid neuropathy seen in the setting of multiple myeloma is due to AL protein and typically present with a painful, subacute, progressive axonal sensorimotor neuropathy with weight loss, prominent autonomic symptoms, and involvement of other organs, such as heart, kidneys, and liver. Diagnosis requires tissue biopsy for diagnosis, and biopsy of peripheral nerves, rectum, kidney, bone marrow, or omental fat pad may be helpful.

Osteosclerotic myeloma may be challenging to diagnose. The hematological diagnosis may become more readily apparent when the features of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) are appreciated. A patient with POEMS typically presents in the fifth to seventh decades with weakness and paraesthesiae, and electrodiagnostic studies consistent with distal, sensorimotor, demyelinating polyneuropathy. Papil­ledema and hyperpigmented macules can be seen. Organomegaly usually involves the liver but splenomegaly and lymphadenopathy can be found. Hypogonadism, thyroid dysfunction, and diabetes mellitus are the more common features of endocrine involvement. Unlike multiple myeloma, hypercalcemia and renal failure are rarely seen in POEMS. Bone marrow biopsy showing abnormal plasma cell infiltration, lymph node biopsy showing angiofollicular hyperplasia (Castleman’s disease), bone biopsy showing osteosclerotic myeloma, or a blood test showing elevated plasma vascular endothelial growth factor is helpful in diagnosis.

Treatment of sensorimotor neuropathy asso­ciated with hematological malignancy usually requires treatment of the underlying cancers. Even if the cancer is in remission, the neuropathy may or may not improve. Focal diseases such as osteosclerotic myeloma may require local radiation but more diffuse diseases warrant systemic therapy. Treatment directed at neuropathy itself, such as intravenous immunoglobulin or plasmapheresis, is usually not helpful. It is also important to avoid cancer treatment that can affect peripheral nerves in these patients. Amyloid neuropathy seen in the setting of multiple myeloma has a poor prognosis with an unsatisfactory response to treatment and short survival.