Patients with malignancy can develop peripheral neuropathies as the result of (1) a direct effect of the cancer by invasion or compression of the nerves, (2) a remote or paraneoplastic effect including vasculitis, (3) a direct toxic effect of treatment, or (4) an alteration of immune status caused by immunosuppression (Table 19-1).^1,2 It is difficult to estimate the frequency of polyneuropathy in patients with cancer because it is dependent on a number of factors including the type, stage, and location of the malignancy, as well as confounding variables such as malnutrition, the toxic effects of therapy, and the background incidence of neuropathy in this frequently older population. Nevertheless, some series indicate that 1.7–5.5% of patients with cancer have clinical symptoms or signs of a peripheral neuropathy, while neurophysiologic testing (quantitative sensory testing and nerve conduction studies [NCS]) demonstrates evidence of peripheral neuropathy in as many as 30–40% of patients with cancer.³ The most common associated malignancy is lung cancer, but neuropathies also complicate carcinoma of the breast, ovaries, stomach, colon, rectum, and other organs including the lymphoproliferative system.

Neuropathies related to remote effects of carcinoma or the so-called paraneoplastic syndromes are quite interesting but quite rare.^1,2,4

PARANEOPLASTIC SENSORY NEURONOPATHY/GANGLIONOPATHY

In 1948, Denny-Brown reported two patients with small-cell lung cancer (SCLC) and sensory neuronopathy (SN).⁵ Autopsies revealed dorsal root ganglionitis with degeneration of the posterior columns as well as peripheral sensory axons. Subsequently, there have been many reports of patients presenting with paraneoplastic encephalomyelitis (PEM) and/or SN.^3,5–31 SCLC is the most common malignancy associated with PEM/SN, but cases of carcinoma of the esophagus, breast, ovaries, kidney, and lymphoma have also been reported.^3,5,6 Approximately 13% of patients with SCLC have another type of concomitant malignancy.³ Therefore, finding a malignancy other than SCLC in a patient with PEM/SN does not obviate the need to look for concurrent lung cancer.

Clinical Features

PEM/SN most commonly develops in the sixth or seventh decade.^3,5,6,32 The disease is more common in women than in men (up to a 2:1 ratio). The neurologic symptoms usually precede the diagnosis of cancer. Most malignancies are detected within 4–12 months, although there are reports of cancer being diagnosed 8 years or more following the onset of the neurologic symptoms.^3,5 Patients usually present with numbness, dysesthesia, and paresthesia, usually in the distal extremities. These symptoms begin in the hands in up to 60% and may be asymmetric in 27–40% of cases, a pattern that provides a helpful clue in distinguishing a SN from the more typical length-dependent axonal sensory polyneuropathy.^3,5 The onset can be quite acute or insidiously progressive. Diminished touch, pain, and temperature sensation and prominent loss of vibratory and position sense occur, resulting in sensory ataxia and pseudoathetosis. The causes of sensory ataxia are limited and should lead to a malignancy workup in any patient who exhibits such signs (Table 19-2). Muscle stretch reflexes are diminished or absent. While sensory symptoms predominate, mild weakness is evident in at least 20% of patients.³ Weakness can be secondary to an associated myelitis, motor neuronopathy, or concurrent Lambert–Eaton myasthenic syndrome (LEMS).^3,5,32 Autonomic neuropathy may occur as an isolated disturbance or as part of the spectrum of a paraneoplastic syndrome in up to 28% of patients and can be the presenting feature in as many as 12%.^3,5,32

Another clue suggesting a paraneoplastic etiology is the concomitant involvement of other anatomically unrelated neurologic systems. As many as 21% of affected individuals present with limbic encephalitis manifesting as confusion, memory loss, depression, hallucinations, or seizures.^3,5,32 Approximately 32% of patients develop brainstem dysfunction (e.g., diplopia, vertigo, nausea, and vomiting). Cranial neuropathies, especially of the eighth cranial nerve, occur in up to 15% of patients. Cerebellar ataxia, scanning dysarthria, tremor, and peduncular reflexes attributed to cerebellar dysfunction are evident in 25% of patients. Abnormal ocular movements such as nystagmus, opsoclonus, and internal and external ophthalmoplegia are seen in up to 32% of patients. Myoclonus develops in approximately 1% of patients. Myelitis with secondary degeneration of the anterior horn is the presenting feature in as many as 14% of those affected.

Laboratory Features

Polyclonal antineuronal antibodies (IgG) directed against a 35–40 kDa protein or complex of proteins, the so-called Hu antigen or antineuron nuclear antigen 1 (ANNA1), are found in the sera or cerebrospinal fluid (CSF) in the majority of patients with paraneoplastic PEM/SN.^3,5–13,32 The presence of anti-Hu antibodies in the serum correlates with SN,¹¹ while antibodies in the CSF are associated with the development of PEM.¹² In a study of 49 patients with paraneoplastic sensory neuropathy, anti-Hu antibodies were present in the serum of 40 out of 49 patients.⁶ In 77 patients with idiopathic sensory neuropathy, anti-Hu antibodies were found in only 1 patient.⁶ Thus, the sensitivity and specificity of the anti-Hu antibodies are high. However, 12% of patients with paraneoplastic SN did not have anti-Hu antibodies. Therefore, all patients suspected of having PEM/SN should undergo periodic screening for an underlying malignancy, regardless of their anti-Hu antibody status.

CSF may be normal or may demonstrate mild lymphocytic pleocytosis and elevated protein.^3,5,12,32 Oligoclonal bands and increased CSF IgG synthesis and index are evident in the majority of patients suggestive of intrathecal synthesis of the autoantibody. Magnetic resonance imaging (MRI) of the brain is usually unremarkable. However, some patients with encephalomyelitis have signal abnormalities on T2-weighted and FLAIR images in the temporal or frontal lobes.³ Periventricular white matter hypodensities, and atrophy of the frontal and temporal lobes and cerebellum also have been reported.

NCS in pure SN reveal low-amplitude or absent sensory nerve action potentials (SNAPs).³³ Compound muscle action potentials (CMAPs) and needle electromyography (EMG) are normal unless the patient has a concurrent motor neuropathy or LEMS. The blink reflex study is usually abnormal, while the masseter reflex study can be normal.^14,15

Histopathology

Sural nerve biopsies may demonstrate perivascular inflammation comprised of plasma cells, macrophages, B cells, and T cells.³³ Autopsy studies reveal inflammation and degeneration of the dorsal root ganglia with secondary degeneration of sensory neurons and the posterior columns (Fig. 19-1).^2,3,13,16,31 In addition, inflammation and degeneration of neurons in the autonomic ganglia, including the myenteric plexus, may be evident.^16,17,19 Lennon et al. reported autoantibodies (presumably anti-Hu) directed against a nuclear antigen of myenteric neurons in patients with intestinal pseudo-obstruction due to autonomic involvement.¹⁷ In patients with PEM, autopsies have revealed perivascular and perineuronal inflammation and degeneration of neurons in the brainstem and limbic system (medial temporal lobe, cingulate gyrus, piriform cortex, orbital surface of the frontal lobes, and the insular cortex) (Fig. 19-2).^3,8,13,32 The thalamus, hypothalamus, subthalamic nucleus, deep cerebellar nuclei, and Purkinje cells may also be involved. Inflammation and degeneration of the anterior horn cells and the ventral spinal roots are evident in patients with myelitis. In addition to deposition on tumor cells, deposits of anti-Hu antibody have been demonstrated in areas of the nervous system that correlate with the clinical symptoms.^13,16–19

Pathogenesis

PEM/SN is probably the result of antigenic similarity between proteins expressed in the tumor cells and the neuron cells (e.g., Hu antigens), leading to an immune response directed against both tumor and neuronal cells.^3,5,20,21,32 The Hu antigen is a family of four similar RNA-binding proteins (HuD, HuC/ple21, Hel-N1, and Hel-N2). The Hu antigen is expressed in the nuclei and to a lesser extent in the cytoplasm of neurons and SCLC cells.¹⁰ The function of this group of proteins is not known, but these are thought to be crucial in the development and maintenance of the nervous system.²¹ The role of the anti-Hu antibodies in the development of PEM/NS is also unclear. The antibodies appear to bind to CNS and PNS neurons affected in the syndrome.^13,16–19 There is a correlation of high anti-Hu titers in the CSF and the development of PEM,¹² and the serum titer with the occurrence of SN.¹¹ However, the anti-Hu antibodies have not been proved to be pathogenic. Passive transfer of autoantibodies from patients with PEM/SN and immunization with purified HuD protein have failed to reproduce the disease in animal studies.²⁴ Further, the anti-Hu antibodies exhibit only weak complement activation.^19,25

The cellular immune response also appears to be involved in the pathogenesis of PEM/SN.²⁶ The perivascular infiltrate in tumors and the nervous system consists mainly of CD4+ cells, B cells, and macrophages, while CD8+ cells, cytotoxic T cells, and microglia-like cells predominate in the tissue immediately surrounding neurons.^19,26 T-cell receptor studies on the inflammatory infiltrates in the nervous system and within the tumors of anti-Hu-positive PEM/SN patients reveal a limited Vβ repertoire and clonal expansion suggestive of an antigen-driven cytotoxic T-cell response.²⁷ Studies have demonstrated an increase of CD45RO+CD4+ memory helper T cells in the peripheral blood of patients with anti-PEM/SN.²⁶ Antigen-specific proliferation of these T cells occurs following in vitro stimulation of cultured lymphocytes with purified HuD antigen. In addition, the cells secreted interferon-γ, suggesting that these lymphocytes were primarily of the Th1 helper subtype. The authors speculated that neoplastic cells express the Hu antigen previously produced by fetal cells but lie sequestered in adult neurons. Autoreactive CD4+ T cells that escaped thymic deletion may become activated by the tumor expressing the Hu antigen. These cells, in turn, activate CD4+ Th1 T cells that migrate to the tumor and into the nervous system as well, inducing a direct cytotoxic effect on tumor cells and on neurons.

Treatment

Treatment of the underlying cancer generally does not affect the course of PEM/SN.^3,33 However, some patients may improve with treatment of the tumor. Unfortunately, plasmapheresis (PE), intravenous immunoglobulin (IVIg), rituximab, and immunosuppressive agents have been disappointing.^3,5,30,34

PARANEOPLASTIC SENSORIMOTOR POLYNEUROPATHY

Clinical Features

Sensorimotor polyneuropathies occasionally can be paraneoplastic in nature. While sensory symptoms predominate in PEM/SN, mild weakness is evident in many patients as noted above.⁶ It is unclear if there is truly a paraneoplastic sensorimotor polyneuropathy distinct from PEM/SN described previously. Besides generalized symmetric sensorimotor polyneuropathies, multiple mononeuropathies attributed to paraneoplastic vasculitis have been reported in patients with lymphoma, SCLC, adenocarcinoma of the lungs, endometrium, prostate, and kidneys.^35–40

Laboratory Features

Sensory NCS show absent or low-amplitude SNAPs with normal or only borderline slowing of conduction velocities and slightly prolonged distal latencies, while motor studies demonstrated normal or only mild abnormalities reflective of axon loss.⁴ A primarily demyelinating neuropathy may be seen as a complication of melanoma, lymphoma, and myeloma/plasmacytoma.^41,42 CV2/CRMP5-antibodies are associated mainly with SCLC and thymoma. Patients with CV2/CRMP5-Ab may present with a sensorimotor polyneuropathy but frequently also have cerebellar ataxia, chorea, uveo/retinal symptoms, and myasthenic syndrome (LEMS or myasthenia gravis).⁴³

Histopathology

Nerve biopsies may reveal a generalized reduction in numbers of myelinated fibers, often with perivascular inflammation.⁴ Necrotizing vasculitis is extremely rare.

Pathogenesis

The pathogenic basis of the neuropathy is not known. Perhaps, there is immune response directed at both the sensory and the motor components of peripheral nerves.

PARANEOPLASTIC AUTONOMIC NEUROPATHY

Autonomic dysfunction can occur as an isolated disturbance or as part of the spectrum of the anti-Hu–associated PEM/SN.^6,33 Autonomic neuropathy is most commonly described as a paraneoplastic effect of SCLC but has also occurred with adenocarcinoma and carcinoid tumor of the lungs, breast, testicular and ovarian cancer, pancreatic malignancy, and lymphoma.^6,44 Symptoms and signs of autonomic neuropathy include orthostatic hypotension, gastroparesis, intestinal pseudo-obstruction, urinary retention, dry eyes and mouth, and pupillary dysfunction. In a study of 71 patients with anti-Hu–associated PEM/SN, 10% presented with severe orthostatic hypotension and 28% had varying degrees of dysautonomia during the course of their illness.⁶ Autopsies have demonstrated loss of neurons and inflammatory infiltrate in the dorsal root and autonomic ganglia (e.g., myenteric plexus). Autoantibodies directed against a nuclear antigen in myenteric neurons have been shown.⁴⁴

COINCIDENTAL IDIOPATHIC SENSORY OR SENSORIMOTOR POLYNEUROPATHY ASSOCIATED WITH MALIGNANCY

Clinical Features

Idiopathic sensory or sensorimotor polyneuropathy complicating cancer is much more common than paraneoplastic neuropathies. The polyneuropathy is more frequent in individuals with SCLC but can be seen in most cancer. In the majority of cases, etiology of sensory or sensorimotor polyneuropathy complicating cancer remains unknown.

Most patients develop slowly progressive, distal, symmetric numbness beginning in the feet and later progressing to involve the hands. All sensory modalities can be affected, but the prominent sensory ataxia associated with PEM/SN does not occur. If weakness is appreciated it is usually mild and distal. Muscle stretch reflexes are diminished or absent distally.

Laboratory Features

There are no specific laboratory abnormalities. NCS demonstrate features of a length-dependent, axonal, sensory, or sensorimotor polyneuropathy with reduced or absent amplitudes and relatively preserved distal latencies and conduction velocities.² EMG may reveal mild denervation changes distally.

Histopathology

Nerve biopsies and autopsies reveal axonal degeneration and regeneration with secondary segmental demyelination and remyelination.

Pathogenesis

The pathogenic basis for this neuropathy is not known. Neuropathies can develop in untreated patients, so neurotoxicity from chemotherapies is not the cause in all. Patients with cancer may lose weight and appear cachectic; however, the neuropathy can manifest before they appear malnourished, and vitamin supplementation does not help. Perhaps, toxic or cytokine factors released by an inflammatory response to the tumor lead to neuronal damage. Alterations in protein and fat metabolism that are associated with cancers conceivably might cause neuropathy.

Treatment

There is no specific treatment for the neuropathy other than treating the underlying malignancy and maintaining adequate nutrition.

Malignant cells, in particularly leukemic and lymphomatous cells, can occasionally infiltrate peripheral nerves, leading to mononeuropathy, multifocal neuropathy/multiple mononeuropathies, polyradiculopathy, plexopathy, or even a generalized symmetric distal or proximal and distal polyneuropathy.^45–52 The neuropathy can begin acutely or have a more slow, insidious onset. Neuropathy related to tumor infiltration can be the presenting clinical manifestation of leukemia or lymphoma or the heralding of a relapse. The neuropathy may improve with treatment of the underlying leukemia or lymphoma or corticosteroids.

LEUKEMIA

Peripheral neuropathy occurs in up to 5.5% of patients with leukemia.^48,52–56 Mononeuropathy or multifocal neuropathy/multiple mononeuropathies can occur due to hemorrhage or leukemic infiltration into cranial or peripheral nerves, including the spinal roots. As one might expect, symmetric polyneuropathy due to leukemic infiltration of the nerves is unusual but has been described.

Electrophysiologic studies typically demonstrate features of a multifocal axonal sensorimotor neuropathy. Nerve biopsies can demonstrate leukemic infiltration of the nerve, axonal degeneration, and segmental demyelination. Vasculitic neuropathy may complicate hairy cell leukemia.^36,37

ANGIOTROPHIC LARGE-CELL LYMPHOMA

This rare malignancy is characterized by intravascular proliferation of large, atypical, lymphoid B cells.^{46,47,57–59} The CNS and skin are the most common sites of involvement. Nearly a quarter of patients develop a radiculopathy or polyradiculopathy, while 5% develop mononeuropathies. The diagnosis is made difficult by the absence of malignant cells in the peripheral blood or lymph nodes. Biopsy of affected nerves demonstrates intravascular and endoneurial lymphocytic infiltration (primarily B cells).

LYMPHOMATOID GRANULOMATOSIS

This angiocentric immunoproliferative disorder is associated with a pleomorphic lymphoid infiltrate of blood vessels. Infection of T cells by Epstein–Barr virus drives this inflammatory response of reactive T cells.⁶⁰ There is a predisposition for evolution into non-Hodgkin lymphoma. Distal symmetric polyneuropathy, multifocal neuropathy/multiple mononeuropathies, polyradiculoneuropathies, and cranial neuropathies develop in 10–15% of patients.^61–64 Electrophysiologic studies are suggestive of a multifocal axonal sensorimotor neuropathy. Nerve biopsies can demonstrate perivascular lymphoplasmatoid infiltrates in the epineurium, necrosis, thrombosis of the vessels, and asymmetric loss of axons between and within nerve fascicles due to ischemic injury.

INFILTRATING TUMORS

The leptomeninges, cranial nerves, and nerve roots can also be invaded by tumor cells. Polyradiculopathies manifest as radicular pain and sensory loss, weakness, and hypo- or areflexia. Widespread involvement can mimic a generalized sensorimotor polyneuropathy. If the spinal cord is involved, superimposed upper motor neuron signs are seen. Multiple cranial neuropathies can occur due to local spread of a tumor (i.e., nasopharyngioma) or by metastasis. The sixth and fifth cranial nerves are most commonly affected in nasopharyngiomas, while the sixth cranial nerve followed by the third, fifth, and seventh are more commonly affected in metastatic processes. The so-called “numb chin syndrome,” characterized by numbness of the lower lip and chin, is particularly worrisome for malignant invasion of the mental or alveolar branches of the mandibular nerve.

Imaging studies (e.g., MRI, CT, or PET) may demonstrate infiltration or compression of the nerve roots by the tumor (Figs. 19-3 and 19-4). CSF may be abnormal, revealing increased protein, an increased cell count, and malignant cytology. Electrodiagnostic studies can be useful to localize the site of the lesion(s).

Patients with leukemia and lymphoma may respond to irradiation and intrathecal chemotherapy. However, the response rate is much lower in other types of tumors with the possible exception of breast cancer.

BRACHIAL PLEXOPATHY

The brachial plexus can be involved due to regional spread of a local tumor (i.e., Pancoast tumor), metastases, or radiation-induced injury. Metastatic disease is responsible for most causes of brachial plexopathy in cancer patients, 78% in one large series.⁶⁵ Lung and breast cancers are the most common culprits. The tumors most often spread via the lymphatics to the lateral group of axillary lymph nodes, where divisions of the lower trunk of the brachial plexus are located. Lung cancers in the apices of the lungs may also invade the paravertebral space, the extraspinal C8–T3 mixed spinal nerves, the sympathetic chain, and the stellate ganglia.

Most patients complain of pain in the shoulder area radiating down the arm into the fingers, in particular the fourth and fifth digits. Sensory loss and weakness usually conform to the distribution of the lower trunk, and Horner’s syndrome may be seen due to involvement of the superior cervical sympathetic ganglionitis often seen. The arm may appear swollen because of associated lymphedema. Signs and symptoms attributable to involvement of the upper and middle trunk of the brachial plexus are much less common and, when present, suggest epidural extension of the tumor or radiation-induced injury.

Radiation plexitis is usually associated with doses greater than 6,000 rads and can present 3 months to 26 years (mean 6 years) following radiation treatment to the region.⁶⁵ Paresthesias and lymphedema of the affected arm are common. Pain occurs in only 15% of patients and is usually not severe, which may help distinguish radiation-induced plexitis from tumor invasion. Further, the upper plexus is involved in 77% and diffuse plexus involvement occurs in 23% of patients with radiation plexitis. Some studies note that the entire plexus is more commonly involved than just the upper trunk.

Imaging studies may demonstrate malignant invasion of the plexus and perhaps extension to the epidural space (Fig. 19-3). Motor and sensory NCS reveal reduced amplitudes of involved nerves. Myokymic discharges may be appreciated on EMG and, when seen, are highly suggestive of radiation-induced damage. However, the absence of myokymia does not exclude radiation plexopathy. When noninvasive testing cannot differentiate between metastatic and radiation diseases, surgical exploration and biopsy may be required for definitive diagnosis.

Neoplastic invasion of the brachial plexus can be treated with radiation therapy. Pain may be improved but the prognosis for return of motor function is poor. Treatment of the pain with transcutaneous stimulation, sympathetic blockage, and dorsal rhizotomies has been disappointing.

LUMBOSACRAL PLEXOPATHY

The lumbosacral plexus may be invaded by local extension of intra-abdominal tumors (73%) or metastasis of distant neoplasms (27%).⁶⁶ Colorectal, cervical, and breast cancers, lymphoma, and sarcoma are the most common associated malignancies. The lumbar plexus is involved in 31%, lumbosacral trunk in 51%, and entire lumbosacral plexus in 18% of patients with malignant invasion of the plexus.^66,67 Patients usually complain of an insidious onset of pain, numbness, weakness, and edema of the lower limb. Approximately 25% of patients have involvement of both legs. Fewer than 10% of patients develop bowel or bladder incontinence or impotence.

Radiation-induced lumbosacral plexopathy can develop 1–31 years (mean 5 years) after completion of treatment. It usually manifests as slowly progressive weakness, and, unlike plexopathy secondary to tumor invasion, pain is present in only half the patients and typically is not as severe. Typically, there is symmetrical involvement of both legs, with the distal muscles being more affected than proximal muscles. Bowel and bladder incontinence may occur secondary to nerve injury or due to radiation-induced proctitis or cystitis.

MRI or CT of the lumbosacral spine and pelvis can demonstrate the tumor invading the lumbosacral plexus and perhaps extension into the epidural space. On EMG, fibrillation potentials and positive sharp waves are found in the paraspinal muscles in approximately 50% of patients with radiation-induced damage, suggesting that the disorder is more appropriately termed a radiation-induced radiculoplexopathy. Myokymic discharges are seen on EMG in over 50% of patients with radiation-induced lumbosacral radiculoplexopathy.

There is increased incidence of monoclonal gammopathies in patients with peripheral neuropathy, and neuropathies may be more frequent in patients with monoclonal gammopathies than in the general population.⁶⁸ Approximately 10% of patients with otherwise idiopathic peripheral neuropathies have monoclonal proteins compared to 2.5% of patients with peripheral neuropathies secondary to other diseases.^69,70 A causal relationship of demyelinating sensorimotor polyneuropathy and monoclonal IgM has been established (see Chapter 14, and discussion on DADS neuropathy).^70,71 Antibodies directed against myelin-associated glycoprotein (MAG) are present in at least 50% of these patients. However, what relationship, if any, IgA and IgG monoclonal gammopathies have to the pathogenesis of the peripheral neuropathies is not clear. Unlike IgM-associated demyelinating neuropathies, IgA and IgG immunoglobulin deposition is generally not seen on nerve sheaths in patients with neuropathies and concurrent IgA or IgG monoclonal gammopathy.

We test all patients with peripheral neuropathies for the presence of monoclonal gammopathies in the serum and urine. Serum and urine protein electrophoresis (SPEP and UPEP) are useful screening tests but are not as sensitive as immunoelectrophoresis, immunofixation, or assessment of serum free light chains. Therefore, our workup of neuropathies includes serum and urine immunoelectrophoresis or immunofixation and assessment for serum free light chains. In patients with suspected POEMS (see below) we also order vascular endothelial growth factor (VEGF) levels. A workup for amyloidosis, multiple myeloma, osteosclerotic myeloma, plasmacytoma, Waldenström macroglobulinemia, lymphoma, leukemia, and cryoglobulinemia should be performed in any patient in whom a monoclonal gammopathy is identified.^70,72–75 We order a radiologic skeletal survey to assess for osteolytic or sclerotic lesions and hematology consultation to consider a bone marrow biopsy. Although most patients with monoclonal gammopathies have no underlying malignancy (deemed monoclonal gammopathies of undetermined significance or MGUS), approximately 20% of MGUS patients subsequently develop lymphoma, leukemia, myeloma, or plasmacytoma.⁷⁰ In our experience, an acutely or subacutely developing neuropathy in a patient with a monoclonal protein may herald the conversion of MGUS to one of these malignant disorders.

LYMPHOMA

Clinical Features

Lymphoma may cause neuropathy by infiltration or direct compression of nerves,⁵⁰ but the neuropathies can also be paraneoplastic in nature.⁷⁶ Both Hodgkin disease and non-Hodgkin lymphoma are associated with polyneuropathies.^{47,55,77–79} A prospective study reported clinical symptoms or signs of neuropathy in 8% and electrophysiologic evidence of neuropathy in 35% of patients with lymphoma.⁷⁶ The neuropathy can be purely sensory⁷⁶ or motor,⁷⁹ but most commonly is sensorimotor.⁷⁶ Autonomic neuropathy may also be seen. The pattern of involvement may be symmetric, asymmetric, or multifocal; the course may be acute,^55,77 subacute,^55,58 chronic progressive,^76,78 or relapsing and remitting.^77,78

Laboratory Features

CSF may reveal lymphocytic pleocytosis and elevated protein.^50,76 Motor and sensory NCS reveal reduced amplitudes with preserved conduction velocities suggestive of a generalized axonal sensorimotor neuropathy⁷⁶ or demonstrate prolonged distal and F-wave latencies, slow conduction velocities, temporal dispersion, and conduction block,⁵⁵ similar to those observed in acute inflammatory demyelinating polyneuropathy (AIDP) and chronic inflammatory demyelinating polyneuropathy (CIDP). MRI scans may show enhancement of the nerves.⁷⁹

Histopathology

Nerve biopsy may demonstrate endoneurial inflammatory cells in both the infiltrative and the presumed paraneoplastic neuropathies complicating lymphoma (Fig. 19-5). A monoclonal population of cells would favor lymphomatous invasion.^76,77

Pathogenesis

The paraneoplastic neuropathy associated with lymphomas is presumably autoimmune in nature, but the exact antigen(s) and trigger for the immune attack are not known.

Treatment

The neuropathy may respond to treatment of the underlying lymphoma or immunomodulating therapies.^50,55,80

MULTIPLE MYELOMA

Multiple myeloma usually presents in the fifth to seventh decade of life with fatigue, bone pain, anemia, and sometimes hypercalcemia. Clinical signs and symptoms of peripheral neuropathies develop in 3–13% of patients,^69,74,81,82 while NCS demonstrate that as many as 40% of patients have a subclinical peripheral neuropathy.⁸² The most common pattern is that of a distal, axonal, sensory, or sensorimotor polyneuropathy.^81,81 Less frequently, a chronic demyelinating polyneuropathy may develop.⁸¹ Multiple myeloma can be complicated by amyloid polyneuropathy, which should be considered in patients with painful paresthesias, loss of pinprick and temperature discrimination, and autonomic dysfunction (suggestive of a small fiber neuropathy) and/or patients who develop atypically rapid and severe carpal tunnel syndrome (CTS). Expanding plasmacytomas can compress cranial nerves and spinal roots as well.

Laboratory Features

Multiple myeloma is the most common hematologic malignancy associated with a monoclonal gammopathy. The monoclonal protein is usually γ heavy chains or κ light chains and may be identified in the serum or urine. Anemia and hypercalcemia are common. Skeletal survey typically reveals osteolytic lesions. Diagnosis of multiple myeloma requires the demonstration of at least 10% plasma cells on a bone marrow biopsy. Motor and sensory NCS usually reveal reduced amplitudes with normal or only mildly abnormal distal latencies and conduction velocities.^81,82 Superimposed median neuropathy at the wrist is common.

Histopathology

Abdominal fat-pad, rectal, or sural nerve biopsy can be performed to look for amyloid deposition. Nerve biopsies usually reveal axonal degeneration along with mild segmental demyelination,⁸² Amyloid deposition is seen in approximately two-thirds of nerve biopsies.⁸¹ In CTS, amyloid may be deposited in the flexor retinaculum of the wrist, which is worthwhile biopsying if a patient with suspected amyloidosis undergoes carpal tunnel release surgery.