TABLE 19-1. NEUROPATHIES ASSOCIATED WITH CANCERPatients 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.
TABLE 19-1. NEUROPATHIES ASSOCIATED WITH CANCER
Direct effect of the cancer by invasion or compression of the nerves
Paraneoplastic
Sensory ganglionopathy (anti-Hu syndrome)
Sensorimotor neuropathy
Autonomic neuropathy
Direct toxic effect of treatment
Neurotoxicity secondary to chemotherapy
Radiation toxicity
Alteration of immune status caused by immunosuppressive medications
Often occur in setting of bone marrow transplantation or treatment of GVHD
PARANEOPLASTIC NEUROPATHIESNeuropathies related to remote effects of carcinoma or the so-called paraneoplastic syndromes are quite interesting but quite rare.1,2,4
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.
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
TABLE 19-2. CAUSES OF SENSORY NEUROPATHY/GANGLIONOPATHY
Paraneoplastic (anti-Hu syndrome)
Sjögren’s syndrome
Human immunodeficiency virus infection
Toxic agents (e.g., chemotherapy, pyridoxine, antinucleosides)
Reproduced with permission from Amato AA, Anderson MP. A 51 year old women with lung cancer and neuropsychiatric abnormalities (Case 38—2001). N Engl J Med. 2001;345(24):1758–1765.
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.
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
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
Figure 19-1. (A) Dorsal-root ganglia of the cervical cord, showing marked parenchymal and perivascular inflammation, loss of ganglion cells, and fibrosis (H&E, ×100). (B) Section of cervical spinal cord showing marked pallor of the dorsal columns (arrows) (Luxol Fast Blue—H&E, ×5). (Reproduced with permission from Amato AA, Anderson MP. A 51 year old woman with lung cancer and neuropsychiatric abnormalities (Case 38—2001). N Engl J Med. 2001;345(24):1758–1765.)
Figure 19-2. Amygdalar complex with a perivascular lymphocytic infiltrate and microglial nodules (H&E, ×100). (Reproduced with permission from Amato AA, Anderson MP. A 51 year old woman with lung cancer and neuropsychiatric abnormalities (Case 38—2001). N Engl J Med. 2001;345(24):1758–1765.)
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 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
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
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
Nerve biopsies may reveal a generalized reduction in numbers of myelinated fibers, often with perivascular inflammation.4 Necrotizing vasculitis is extremely rare.
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.
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
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.
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.
Nerve biopsies and autopsies reveal axonal degeneration and regeneration with secondary segmental demyelination and remyelination.
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.
There is no specific treatment for the neuropathy other than treating the underlying malignancy and maintaining adequate nutrition.
NEUROPATHY SECONDARY TO TUMOR INFILTRATIONMalignant 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.
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
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).
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.
CRANIAL NEUROPATHIES AND RADICULOPATHIESThe 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).
Figure 19-3. MRI T1 without contrast (A) and with contrast (B) demonstrates lymphoma compressing the right brachial plexus. PET/CT scan shows increased signal highlighting the tumor in the plexus (C).
Figure 19-4. Lumbosacral MRI (T1 with contrast) demonstrates enhancement of roots in sagittal (A) and axial sections (B) in a patient with lymphomatous polyradiculopathy.
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.
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.
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.
NONINFILTRATIVE PERIPHERAL NEUROPATHIES ASSOCIATED WITH LYMPHOPROLIFERATIVE DISORDERS AND PLASMACYTOMASThere 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 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
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
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
Figure 19-5. Lymphoma. Sural nerve biopsy demonstrates perivascular and endoneurial infiltration of lymphomatous cells on routine H&E (A) and immunoperoxidase stain using CD3 antibody (B).
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.
The neuropathy may respond to treatment of the underlying lymphoma or immunomodulating therapies.50,55,80
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.
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.
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.
The mechanism of the neuropathy in multiple myeloma is multifactorial. The neuropathy may be related to primary amyloidosis with infiltration of the nerves. Other mechanisms of neuropathy may be due to the systemic consequences of multiple myeloma or (e.g., cytokines) or amyloidosis (e.g., renal failure). Chemotherapies employed to treat multiple myeloma (e.g., bortezomib and thalidomide) are commonly associated with neuropathy. A paraneoplastic effect is speculated in demyelinating neuropathies associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome (discussed next).
Unfortunately, the treatment of the underlying multiple myeloma does not usually affect the course of the neuropathy.
Osteosclerotic myeloma is rare and is responsible for less than 3% of myelomas. Symptomatic polyneuropathy develops in near 50% of patients with osteosclerotic myeloma and often is the presenting feature.83 Systemic manifestations include hepatosplenomegaly, cutaneous pigmentation, hypertrichosis, edema, pericardial and pleural effusions, leukonychia, finger clubbing, gynecomastia, testicular atrophy with impotence in men, amenorrhea in women, diabetes mellitus, arterial occlusive disease, and hypothyroidism. This complex constitutes the Crow–Fukase or POEMS syndrome.74,83–91 Importantly, not every patient displays all the features of POEMS syndrome. Most individuals with POEMS syndrome have osteosclerotic myeloma, but the syndrome can also occur with Castleman disease (angiofollicular lymphoid hyperplasia), extramedullary plasmacytomas, Waldenström macroglobulinemia, and solitary lytic plasmacytoma. Some patients have no identifiable malignancy.
POEMS syndrome usually presents as symmetric tingling, numbness, and weakness that gradually progresses to involve proximal and distal arms and legs similar to CIDP. Rarely, the onset may be acute or subacute such that it resembles AIDP/Guillain–Barré syndrome (GBS).90 The sensory modalities mediated by large fibers are affected most, with decreased but relative sparing of pain and temperature sensation. Muscle stretch reflexes are reduced or absent. The cranial nerves and respiratory muscles can be affected. Papilledema is evident in 29–55% of patients,88 a finding that is uncommon in idiopathic CIDP. Patients can also develop a myopathy secondary to associated hypothyroidism or rarely an inflammatory myopathy.91
POEMS is usually associated with an IgG or IgA lambda chain monoclonal gammopathy, but in up to 20% of patients, the monoclonal protein is demonstrated in the urine but not in the serum.74 Further, because the amount of monoclonal protein can be small, immunoelectrophoresis and immunofixation are much more sensitive than protein electrophoresis.88,89 In addition, CSF protein levels are often markedly elevated, even more so than typical CIDP. POEMS syndrome is associated with high levels of serum VEGF and, conversely, low levels of serum erythropoietin.92,93 Serum levels of VEGF and erythropoietin normalize with a response to therapy.92
Skeletal survey reveals characteristic sclerotic (two-thirds of cases) or mixed sclerotic and lytic bony lesions (one-third of cases) usually in the vertebral bodies, pelvis, or ribs (Fig. 19-6). In 50% of cases, these skeletal lesions are multiple and represent focal plasmacytomas. NCS can demonstrate features of a primary demyelinating or mixed axonal and demyelinating sensorimotor peripheral neuropathy.81–83,86,94–97 NCS are usually indistinguishable from CIDP. However, conduction block is much less common in POEMS as compared to idiopathic CIDP.
Figure 19-6. POEMS. Pelvic x-ray demonstrates a large osteosclerotic lesion (arrow) in the left iliac crest.
Nerve biopsies usually reveal a combination of segmental demyelination and axonal degeneration.86,98 A few endomysial or perivascular inflammatory cells may be seen. VEGF is highly expressed in blood vessels and some non–myelin-forming Schwann cells in nerve biopsies of patients with POEMS.92 Light microscopy reveals an increased thickness of the basal lamina and a narrowing of the lumina of endoneurial vessels, while electron microscopy (EM) demonstrates proliferation of endothelial cells and opening of tight junctions.92 EM may also reveal uncompacted myelin.98
The pathogenesis of POEMS syndrome is not clear, but likely autoimmune in nature. Various cytokines including VEGF and matrix metalloproteinases are elevated in patients with POEMS syndrome and appear to correlate with the severity of the neuropathy.92,93,99,100 Over expression of VEGF may increase nerve microvascular permeability, thereby inducing endoneurial edema and allowing neurotoxic cytokines and other chemicals access the nerve parenchyma, which lead to demyelination and secondary axonal degeneration.90
The neuropathy is difficult to treat but may respond to radiation or surgical excision of the isolated plasmacytoma or to chemotherapy. The neuropathy can also improve with usual treatment given to patients with idiopathic CIDP (e.g., corticosteroids). However, the neuropathy is more refractory to treatment than typical CIDP, and POEMS needs to be suspected and re-evaluated for in all cases of refractory CIDP with repeated serum and urine immunofixation/immunoelectrophoresis and skeletal surveys. Refractory cases may respond to autologous peripheral blood stem cell transplantation.93,100
Castleman disease or angiofollicular lymph node hyperplasia is characterized by lymphoid hyperplasia associated with capillary proliferation and can be associated with POEMS syndrome (except for absence of the osteosclerotic lesions).94 The angiofollicular lymph node hyperplasia and neuropathy may be related to increases in serum cytokine levels and VEGF, which are associated with the disorder.
Waldenström macroglobulinemia is associated with a malignant proliferation of lymphoplasmacytoid cells, which produce an IgM monoclonal protein, usually with a κ light chain.74,101–105 It most commonly occurs in men between the ages of 50 and 70 years and usually presents with an insidious onset of progressive fatigue, weight loss, lymphadenopathy, hemorrhages (especially nose bleeds), anemia, and weakness. It commonly evolves from a patient with known IgM-MGUS. Hepatomegaly and splenomegaly may be appreciated on physical examination. Nearly 50% of patients have symptoms or signs of neuropathy on clinical examination and/or electrophysiologic testing.105 Patients initially complain of numbness and paresthesias beginning in the feet, which then progresses proximally in the lower limbs and also affects the hands. Patients may develop difficulty in walking and loss of fine motor control of the fingers due to a sensory ataxia. Strength is normal or only slightly affected distally.
Waldenström macroglobulinemia is responsible for about 2% of cases of monoclonal gammopathies with over 80% associated with a κ light chain. Diagnosis requires demonstration of an IgM monoclonal protein in a concentration greater than 3 g/L. The disorder is distinguished from IgM myeloma by the absence of lytic bone lesions and hypercalcemia and by the presence of hepatosplenomegaly and lymphadenopathy. Antibodies directed against MAG or sulfatide can be detected in the serum in as many as 38% of patients.74 NCS may demonstrate features of a demyelinating sensorimotor polyneuropathy, of an axonal sensorimotor neuropathy, or may be normal suggesting a small fiber polyneuropathy.74,101–105
In cases of demyelinating neuropathy with MAG antibodies, nerve biopsies may show prominent demyelination and IgM deposition on the outer myelin membranes and occasionally in the periaxonal space but not on compact myelin.105 Deposition of light chains in the endoneurium and epineurium resulting in massive fascicular hyalinosis and epineural arteries disruption has also been reported.106
The mechanism of the neuropathy is unknown. The demyelinating neuropathy may be related to MAG antibodies, although a causal relationship has not been established. Some neuropathies are associated with POEMS syndrome or caused by secondary amyloidosis or nerve fiber ischemia related to serum hyperviscosity.87
Some patients benefit from corticosteroids, chlorambucil, or plasma exchange. However, prospective, blinded, controlled trials have not been performed. Rituximab, a monoclonal antibody directed against CD20 that is present on B lymphocytes, can be an effective treatment for Waldenström macroglobulinemia. However, there have been a few reports that rituximab may initially paradoxically worsen the associated neuropathy, rather than improve it.107,108
MGUS neuropathy is heterogeneous in regards to clinical, laboratory, and electrophysiologic features.70,74,109–111 Neuropathies associated with an IgM monoclonal protein are typically demyelinating, while IgG and IgA monoclonal gammopathies can be axonal or demyelinating in nature. Patients with a demyelinating neuropathy can present with proximal and distal weakness and sensory symptoms typical of CIDP or just distal symptoms of distal acquired demyelinating sensory (DADS) neuropathy (see Chapter 14).73,74,110–113 Individuals who are affected describe numbness and tingling in both the upper and the lower limbs beginning in the distal regions and progressing proximally. Weakness can also develop but is usually restricted to the distal limbs in the IgM-MGUS neuropathies, while patients with demyelinating neuropathies associated with IgG- and IgA-MGUS are more likely to have symmetrical proximal and distal weakness typical of idiopathic CIDP. Deep tendon reflexes are reduced or absent throughout.
Patients with an axonal neuropathy usually present with sensory symptoms in a length-dependent fashion. Their clinical, laboratory, histopathology, and electrophysiologic features are indistinguishable from idiopathic sensory or sensorimotor polyneuropathies.
At least 50% of the patients with IgM-MGUS neuropathy have antibodies directed against MAG.70,112,113 Elevated CSF levels are common in patients with a demyelinating neuropathy. NCS in patients with IgG- and IgA-MGUS neuropathies can be either axonal or demyelinating in nature. The IgM-MGUS neuropathies are typically demyelinating with marked prolonged distal latencies, and moderately slow conduction velocities are variably reduced. Motor NCS reveal markedly prolonged distal latencies with moderate slowing of conduction velocities, but there is usually no evidence of temporal dispersion or conduction block.72,111–114
Nerve biopsy reveals a loss of large myelinated nerve fiber population, with relative sparing of the small myelinated and unmyelinated fibers. Segmental demyelination and remyelination are also appreciated in some patients. In some patients, there is a predominance of demyelination, while in others axonal loss may be somewhat more significant. In patients with IgM-MGUS, immunohistochemistry reveals immunoglobulin deposition on the outer myelin membranes and occasionally in the periaxonal space but not on compact myelin.75 On EM the myelin sheaths appear to be separated, and IgM deposits are evident in these zones of myelin splitting.
IgM-MGUS is typically associated with a demyelinating neuropathy. Endoneurial injection or passive transfer of serum from patients with IgM-MAG antibodies to animals leads to conduction block and demyelination. However, response to PE and other immunotherapies is less satisfactory in this IgM-MGUS subgroup than in IgG/IgA demyelinating neuropathies where a causal link is even less well established.
Except for cases of amyloid neuropathy, there is no pathogenically proven causal relationship of monoclonal gammopathy and axonal sensorimotor polyneuropathy.
Patients with MGUS neuropathy who fulfill clinical and electrophysiologic criteria for CIDP with proximal and distal weakness can improve with immunotherapy (discussed in Chapter 14).112,113 However, those demyelinating neuropathies with mainly sensory symptoms and only mild distal weakness, particularly the IgM-MAG neuropathies, are usually refractory to treatment. Rare patients may respond to rituximab.115,116 The demyelinating sensorimotor polyneuropathies associated with IgG-MGUS and IgA-MGUS are more amenable to treatment than the IgM-MGUS neuropathies.117 There is no strong medical evidence that treating the MGUS in patients has any impact on axonal neuropathies.
NEUROPATHY AS A COMPLICATION OF BONE MARROW TRANSPLANTATION/GRAFT-VERSUS-HOST DISEASENeuropathies may develop in patients who undergo bone marrow transplantation because of toxic effects of chemotherapy, radiation, infection, or an autoimmune response directed against the peripheral nerves.35,118,119 Carcinomatous or infectious meningitis with infiltration of nerves, malnutrition, and sepsis with multiorgan failure are other causes of polyneuropathy in critically ill patients. Many cranial neuropathies and radiculopathies are related to herpes zoster infection. Thrombocytopenia can lead to hemorrhage within the nerve or plexus.
Peripheral neuropathy in bone marrow transplantation patients is often associated with graft-versus-host disease (GVHD).35 Chronic GVHD shares many features with a variety of autoimmune disorders, and it is possible that an immune-mediated response can be directed against peripheral nerves. Patients with chronic GVHD may develop cranial neuropathies including loss of olfactory and gustatory sensation,120 sensorimotor polyneuropathy, multifocal neuropathy/multiple mononeuropathies, and severe generalized peripheral neuropathy resembling GBS118,121,122 or CIDP.35 Myositis, myasthenia gravis, and Lambert-Eaton myasthenic syndrome can also complicate GVHD. In patients with neuropathy, NCS may demonstrate primarily axonal, demyelinating, or mixed features. Some cases of GBS have been attributed to chemotherapy, cytomegalovirus, or Campylobacter jejuni infections and have improved with plasma exchange121 or IVIg. The neuropathy may also improve with increased immunotherapy and resolution of the GVHD.35
TOXIC NEUROPATHIES SECONDARY TO CHEMOTHERAPYMany of the commonly used chemotherapy agents can cause a toxic neuropathy (Table 19-3).1,2 The mechanisms by which these agents cause toxic neuropathies vary, as can the specific type of neuropathy. The risk of developing a toxic neuropathy or more severe neuropathy appears to be greater in patients with a pre-existing neuropathy (e.g., Charcot–Marie–Tooth disease and diabetes) and in those who concomitantly take more than one neurotoxic drugs (e.g., nitrofurantoin, isoniazid, disulfiram, pyridoxine, etc.). Chemotherapeutic agents usually cause a sensory greater than motor length-dependent axonal neuropathy or SN/ganglionopathy.
TABLE 19-3. TOXIC NEUROPATHIES SECONDARY TO CHEMOTHERAPY
Cisplatin is used for a variety of cancers and can cause a predominantly sensory neuropathy (ganglionopathy), usually at cumulative doses of 225–500 mg/m2.123–131 There is a predilection for involvement of large myelinated nerve fibers leading to paresthesia, hypesthesia, loss of vibratory perception and proprioception, often resulting in gait ataxia and pseudoathetoid movements. Muscle stretch reflexes are reduced or absent throughout. Interestingly, as many as 40% of patients can develop Lhermitte’s sign, perhaps due to demyelination and edema of the posterior columns. Only a few patients (approximately 2%) develop weakness.125 Onset of symptoms can appear as late as 8 weeks after the drug has been stopped and may progress up to 6 months following discontinuation of cisplatin, a phenomenon known as coasting.
NCS demonstrate low-amplitude or absent SNAPs with normal or only slightly prolonged distal latencies and slow sensory conduction velocities.127–129 Vibratory perception is usually impaired on quantitative sensory testing. Motor NCS and needle EMG are usually normal.
Sural nerve biopsies reveal a predominant loss of large myelinated nerve fibers with axonal degeneration, segmental demyelination, and regenerating axonal sprouts.124,126,127 Degeneration of neurons in the dorsal root ganglion and secondary axonal degeneration on both central and peripheral nerve processes are seen in rats given toxic doses of cisplatin.128
Cisplatin covalently binds DNA creating inter- and intrastrand cross-links. Pathologic and electrophysiologic studies suggest that neurons in the dorsal root ganglion are preferentially affected. Binding of the drug to neuronal DNA may inhibit transcription of important proteins and impair axonal transport.
Oxaliplatin is a third-generation platin derivative used mainly for treatment of colorectal cancer. Oxaliplatin has been associated with an acute sensory neuropathy that is often, but not always, reversible132,133 The neuropathic symptoms are often aggravated by exposure to cold. NCS demonstrate features of a sensory greater than motor, axonal neuropathy. A reduction of intraepidermal nerve fiber density is evident with skin biopsy.133
Vincristine is commonly associated with a toxic sensorimotor and autonomic neuropathy.134–136 Affected patients develop paresthesias and numbness, which can at times occur in the fingers before the toes. The loss of ankle jerks often precedes the subjective loss of sensation. Weakness of the hands and feet may occur in 25–35% of patients with increased dosage. Autonomic neuropathy characterized by constipation, urinary retention, impotence, and orthostatic hypotension may occur as well. Cranial neuropathies are uncommon, but optic neuropathy, oculomotor palsies, facial weakness, hearing loss, and laryngeal paralysis have been described. Neuropathic symptoms and signs are more prominent after a cumulative dose of 12 mg of vincristine.113 However, neuropathy can develop as early as 2 weeks following a single 2 mg/m2 dose. A coasting effect can be seen such that 24–30% of patients continue to worsen the first month after discontinuation of vincristine.134 The median duration of symptoms after stopping the medication is around 3 months.134
Sensory and motor NCS reveal diminished amplitudes or absent responses with normal or only mildly prolonged distal latencies and slow conduction velocities.134,137 The SNAP and CMAP amplitudes improve usually following discontinuation of cisplatin, but do not usually return to pretreatment levels. Active denervation in the form of fibrillation potentials and positive sharp waves may be seen on EMG in distal muscles.
Nerve biopsies demonstrate axonal degeneration and loss of myelinated and unmyelinated nerve fibers and clusters of regenerating axonal sprouts.
Vinca alkaloids inhibit microtubule formation by binding to tubulin. This, in turn, impairs axoplasmic transport and leads to cytoskeletal disarray and axonal degeneration.138
Vinorelbine is a semisynthetic vinca alkaloid that causes a dose-related peripheral neuropathy in 20–50% of patients.139–141 It is less neurotoxic than vincristine, and the associated neuropathy is severe in only 1% of cases. Patients present with distal sensory loss and paresthesia, and motor weakness can occur after 3–6 months of treatment. After 12 cycles of vinorelbine, most patients have reduced or absent muscle stretch reflexes at the ankles.141 As with vincristine, symptoms and signs of autonomic neuropathy may develop but are less common.
Serial NCS reveal a dose-dependent reduction of SNAP and CMAP amplitudes, with preservation of distal latencies and conduction velocities.141 The SNAP and CMAP amplitudes improve following discontinuation of the vinorelbine.
Nerve pathology has not been reported.
The pathogenesis is presumably similar to that of vincristine.
Etoposide is a semisynthetic derivative of podophyllotoxin, which causes a moderate-to-severe predominantly sensory axonal neuropathy or ganglionopathy in 4–10% of patients.142 Severe autonomic neuropathy can develop, leading to orthostatic hypotension and gastroparesis. The neuropathy gradually improves over several weeks or months following discontinuation.
NCS reveal low-amplitude SNAPs and CMAPs.
In mice, etoposide causes degeneration of the cell bodies within the dorsal root ganglion.142 However, histopathology has not been well described in humans with the neuropathy.
Etoposide inhibits microtubule function, and the pathogenic basis of the neuropathy is probably similar to vincristine and vinorelbine.
Taxol is used as adjuvant treatment of breast cancer and has been associated with a dose-dependent, predominantly sensory neuropathy.143–152 A subclinical or mild neuropathy develops in up to 85% of patients after three to seven cycles of taxol at doses of 135–200 mg/m2. A severe neuropathy occurs in 2% of patients at this lower dose range. However, at doses between 250 and 350 mg/m2, neuropathic symptoms develop after first or second cycle, sometimes within 24 hours of the initial infusion. As many as 70% of patients have a severe neuropathy after high-dose paclitaxel with cumulative doses above 1,500 mg/m2.145,146 Pre-existing neuropathy and prior or concurrent exposure to neurotoxic agents are additional risk factors for developing a severe neuropathy.146
Sensory and motor NCS demonstrate reduced SNAP and CMAP amplitudes, which correlate with the cumulative dose of taxol.143–159 Distal latencies and conduction velocities are usually normal, although demyelinating features have been described.144,148 NCS abnormalities may predate occurrence of neuropathic symptoms.152 Quantitative sensory testing reveals impairment of vibratory perception more often than abnormal thermal thresholds.143,149 Needle EMG may reveal fibrillation potentials in distal limb muscles.144,147
Sural nerve biopsies reveal a preferential loss of large myelinated nerve fibers along with axonal degeneration with secondary demyelination and remyelination.147,148 Regenerating axonal sprouts are uncommon. On EM, one may find accumulation of tubular and membranous structures within the axons.147
Taxol may have a toxic effect on the neuronal cell body, the axon, or both. In contrast to the vinca alkaloids, which disassemble microtubules, the taxanes (taxol and taxotere) promote microtubule assembly by increasing tubulin polymerization. The subsequent aggregation and accumulation of abnormal bundles of microtubules in dorsal root ganglia, axons, and Schwann cells impair axoplasmic transport.153
Taxotere, a semisynthetic analogue of taxol, is also associated with a dose-dependent, predominantly sensory neuropathy. Neuropathies are less frequent and severe than that seen with taxol.154–158 Patients describe pain in the hands and feet and also may have a Lhermitte’s sign. On examination, large fiber sensory modalities are preferentially affected and most patients have reduced or absent muscle stretch reflexes at the ankles. Mild proximal and distal weakness is evident in 5–19% of patients. Most patients improve 1–2 months after cessation of the chemotherapy; however, neuropathic symptoms can continue to worsen for several months after discontinuation of the docetaxel.
Sensory and motor NCS reveal diminished amplitudes with only mild slowing of conduction velocities.154,156
Sensory nerve biopsy may reveal a loss of large myelinated fibers, with scattered fibers undergoing axonal degeneration.156
The pathogenic mechanism is presumably similar to taxol.
Suramin is a hexasulfonated naphthylurea that causes a peripheral neuropathy in 25–90% treated patients.159–161 Neurotoxicity is the dose-limiting side effect, and there appears to be two distinct types of toxic neuropathy: (1) a dose-dependent, distal, axonal sensorimotor polyneuropathy and (2) a subacute demyelinating polyradiculoneuropathy.
The distal axonopathy is more common and manifests with distal numbness and paresthesias.159,161 Examination reveals reduced light touch, pain, and vibratory perception; mild weakness of the distal limbs (e.g., toe extensors); and diminished ankle reflexes. This neuropathy is reversible upon suramin discontinuation.
A subacute sensorimotor demyelinating polyradiculoneuropathy is more severe and develops in 10–20% of patients after 1–5 months of treatment.159–161 It is associated with peak plasma concentrations of over 300 μg/L, exposure to greater than 200 μg/L for more than 25 days per month, or cumulative dose of 40,000 mg/L. Patients present with numbness and paresthesias of the distal limbs or face, followed by symmetric, proximal greater than distal weakness. Muscle stretch reflexes are decreased or absent throughout. The weakness is insidiously progressive and can involve the respiratory muscles. Up to 25% of affected patients become bedridden and require mechanical ventilation. The neuropathy can continue to progress for 1 month following suramin discontinuation. It can take several months for patients to recover, and there frequently are residual numbness and weakness. Plasma exchange has been tried in an uncontrolled fashion with mixed results.
CSF protein may be elevated in patients with subacute demyelinating polyradiculoneuropathy.159,161 NCS in the more common distal sensorimotor polyneuropathy reveal decreased amplitudes of SNAPs and CMAPs with relatively preserved distal latencies and conduction velocities.159,161 Abnormal vibratory and cooling thresholds are seen with quantitative sensory testing.159 Needle EMG may reveal fibrillation potentials and neurogenic MUAPs in distal muscles.
Electrodiagnostic studies in the subacute sensorimotor polyradiculoneuropathy reveal features of demyelination: prolonged distal latencies and F-waves, slow conduction velocities, temporal dispersion, and conduction block.159–161 As in the distal axonopathy, quantitative sensory testing shows increased vibratory and cooling thresholds.159 EMG demonstrates decreased recruitment of MUAPs in proximal and distal muscles and occasional fibrillation potentials.
Sural nerve biopsies in patients with the subacute demyelinating polyradiculoneuropathy demonstrate loss of large and small myelinated nerve fibers, demyelination and remyelination, and secondary axonal degeneration.159–161 Epi- and endoneurial mononuclear inflammatory infiltrates may be seen. In animal models, suramin induces a length-, dose-, and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.162
The mechanism of neurotoxicity is unknown. Suramin may inhibit the interaction of neurotrophic factors with its peripheral nerve receptors163 or induce a form of lysosomal storage disease. The demyelinating neuropathy may be immune mediated, related to the immunomodulating effects of suramin.164
Cytosine arabinoside (ARA-C) is an antimetabolite used in the treatment of leukemia and lymphoma. Sensory neuropathy and severe sensorimotor polyneuropathy resembling GBS165–170 have been reported with cumulative doses ranging from 60 mg/m2 to 36 g/m2. These neuropathies can begin within hours or weeks following treatment.
Patients with a GBS-like neuropathy have increased CSF protein.168 EMG and NCS can be compatible with a primary axonal169 or an acquired demyelinating sensorimotor polyneuropathy.166
Sural nerve biopsies may reveal demyelination or axonal degeneration.165,168,169
The pathophysiologic mechanism(s) for the neuropathies are not known. The antimetabolite action of ARA-C may inhibit proteins necessary for myelin production, axonal structure, or axonal transport. Alternatively, the immunomodulating effects of ARA-C may predispose patients to an immune attack against the peripheral nerves.
Ifosfamide, a cyclophosphamide analog, has been associated with polyneuropathy with total doses of 14 g/m2 or more.171 Patients manifest numbness, and painful paresthesias that begin in the hands and feet 10–14 days after treatment and gradually resolve but recur if they are rechallenged with the chemotherapy. Electrodiagnostic and histopathologic data are lacking, but the occasional onset beginning in the hands rather than the feet is suggestive of a ganglionopathy.
Bortezomib, a selective, reversible inhibitor of the proteasome, is most commonly used for treatment of multiple myeloma.172 Treatment-emergent neuropathy or symptomatic worsening of a pre-existent neuropathy developed in a third to two-thirds of myeloma patients in treatment trials.172–176 Polyneuropathy also occurred in 9 out of 21 patients with renal cell carcinoma treated with bortezomib.174 The risk of neuropathy correlates with the cumulative dose of bortezomib. Patients usually complain of paresthesia, burning dysesthesia, and numbness in a length-dependent distribution. The neuropathy usually improves when the dose is reduced or drug is discontinued. The electrophysiologic characteristics of the treatment-emergent neuropathy suggest a length-dependent, axonal, sensory polyneuropathy.173,175 The absence of electrophysiologic changes in some patients with symptoms of burning and dysesthesias in their feet suggests involvement of small-diameter nerve fibers (i.e., a small fiber neuropathy) as well.
NCS may demonstrate a reduction or loss of amplitudes of SNAPs in a length-dependent pattern.173,176 Motor studies are usually spared and EMG is typically normal. Autonomic studies, in particular, quantitative sweat testing may be abnormal.
Skin biopsies have shown a reduction in intraepidermal nerve fiber density.176,177 Nerve biopsies of patients with the characteristic toxic neuropathy have not been reported. However, in Wistar rats, pathologic examination reported shows a dose-dependent axonopathy of the unmyelinated fibers in nerves of treated animals.178 In mice, histopathologic findings have demonstrated a mild reduction of myelinated and unmyelinated fibers), mostly involving large and C fibers, with abnormal vesicular inclusion bodies in unmyelinated axons.179 In addition, degeneration of dorsal root ganglia has been observed in mice treated with bortezomib.180
The pathophysiologic mechanism is not known. Bortezomib may block the ubiquitin–proteasome pathway, possibly causing a “toxic” buildup of proteins that should be degraded by the proteasome, resulting in impairment of neuronal function, initially in the dorsal root ganglia, and then leading to a retrograde (or “dying-back”) axonopathy of small nerve fibers followed by larger nerve fibers.
Carfilzomib is a second-generation selective proteasome inhibitor that is also used to treat refractory multiple myeloma. Peripheral neuropathy can occur, but appears to be less common in patients receiving carfilzomib compared to bortezomib.181
SUMMARYNeuropathy is not an uncommon complication in a cancer patient. Although a paraneoplastic etiology is often considered, most neuropathies in the setting of cancer are not the result of a remote, immune-mediated effect of cancer. The neuropathy is more commonly due to a direct, adverse side effect of chemotherapeutic agents (toxic neuropathy), or as a consequence of nutritional deficiency. In some cases, it may be due to compression or infiltration of the tumor. Treatment and prognosis are dependent on the etiology and mechanism of the neuropathy.
1. Briemberg HR, Amato AA. Neuromuscular complications of cancer. Neurol Clin. 2003;21(1):141–165.
2. Amato AA, Dumitru D. Acquired neuropathies. In: Dumitru D, Amato AA, Swartz MJ, eds. Electrodiagnostic Medicine, 2nd edn. Philadelphia, PA: Hanley & Belfus; 2002:937–1041.
3. Amato AA, Collins MP. Neuropathies associated with malignancy. Semin Neurol. 1998;18:125–144.
4. Campbell MJ, Paty DW. Carcinomatous neuromyopathy: 1. Electrophysiological studies. J Neurol Neurosurg Psychiatry. 1974;37:131–141.
5. Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry. 1948;11:73–87.
6. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine. 1992;71:59–72.
7. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–657.
8. Molinuevo JL, Graus F, Serrano C, Rene C, Guerrero C, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol. 1998;44:976–980.
9. Wilkinson PC, Zeromski J. Immunofluorescent detection of antibodies in sensory carcinomatous neuropathy. Brain. 1965;88:529–583.
10. Graus F, Elkon KB, Cordon-Cardo C, Posner JB. Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor. Am J Med. 1986;80:45–52.
11. Graus F, Elkon KB, Lloberes P, et al. Neuronal antinuclear antibody (anti-Hu) in paraneoplastic encephalomyelitis simulating acute polyneuritis. Acta Neurol Scand. 1987;75:249–252.
12. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the Hu (encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol. 1992;141;881–886.
13. Dalmau J, Furneaux HM, Rosenblum MK, Kris MG, Posner JB. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer. A quantitative western blot analysis. Ann Neurol. 1990;27:544–552.
14. Vega F, Graus F, Chen QM, Poisson M, Schuller E, Delattre JY. Intrathecal synthesis of the anti-Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy: Clinical–immunological correlation. Neurology. 1994;44:2145–2147.
15. Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology. 1991;41:1757–1764.
16. Auger RG. The role of the masseter reflex in the assessment of subacute sensory neuropathy. Muscle Nerve. 1998;21:800–801.
17. Auger RG, Windebank AJ, Lucchinetti CF, Chalk CH. Role of the blink reflex in the evaluation of sensory neuronopathy. Neurology. 1999;53:407–408.
18. Wanschitz J, Hainfellner JA, Kristoferitsch W, Drlicek M, Budka H. Ganglionitis in paraneoplastic subacute sensory neuronopathy: A morphologic study. Neurology. 1997;49:1156–1159.
19. Lennon VA, Sas DF, Busk MF, et al. Enteric neuronal autoantibodies in pseudo-obstruction with small-cell lung carcinoma. Gastroenterology. 1991;100:137–142.
20. Altermatt HJ, Rodriguez M, Scheithauer BW, Lennon VA. Paraneoplastic anti-Purkinje and type-1 anti-neuronal nuclear autoantibodies bind selectively to central, peripheral, and autonomic nervous system cells. Lab Invest. 1991;65:412–420.
21. Jean WC, Dalmau J, Ho A, Posner JB. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis. Neurology. 1994;44:140–147.
22. Rosenblum MK. Paraneoplastic and autoimmunologic injury of the nervous system: The anti-Hu syndrome. Brain Pathol. 1993;3:199–212.
23. Voltz RD, Graus F, Posner JB, Dalmau J. Paraneoplastic encephalomyelitis: An update on the effects of the anti-Hu immune response. J Neurol Neurosurg Psychiatry. 1997;63:133–136.
24. Sillevis-Smith PA, Manley GT, Posner JB. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause disease in mice. Neurology. 1995;45:1873–1878.
25. Panegyres PK, Reading MC, Esiri MM. The inflammatory reaction of paraneoplastic ganglionitis and encephalitis: An immunohistochemical study. J Neurol. 1993;240:93–97.
26. Benyahia B, Liblau R, Merle-Béral H, Tourani JM, Dalmau J, Delattre JY. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol. 1999;45:162–167.
27. Voltz R, Dalmau J, Posner JB, Rosenfeld MR. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology. 1998;51:1146–1150.
28. Bastson OA, Fantle DM, Stewart JA. Paraneoplastic encephalomyelitis. Dramatic response to chemotherapy alone. Cancer. 1992;69:1291–1293.
29. Keime-Guibert F, Graus F, Broët P, et al. Clinical outcome of patients with the anti-Hu-associated encephalomyelitis after treatment of the cancer. Neurology. 1999;53:1719–1723.
30. Graus F, Vega F, Delattre JY, et al. Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes and antineuronal antibodies. Neurology. 1992;42:536–540.
31. Antoine JC, Mosneir JF, Honnorat J, et al. Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: Clinicopathological study of an autopsy case. Muscle Nerve. 1998;21:850–857.
32. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: Analysis of 200 patients. Brain. 2001;124:1138–1148.
33. Amato AA, Anderson MP. A 51 year old woman with lung cancer and neuropsychiatric abnormalities (Case 38—2001). N Engl J Med. 2001;354:1758–1765.
34. Antoine JC, Camdessanché JP. Treatment options in paraneoplastic disorders of the peripheral nervous system. Curr Treat Options Neurol. 2013;15:210–223.
35. Amato AA, Barohn RJ, Sahenk Z, Tushka PJ, Mendell JR. Polyneuropathy complicating bone marrow and solid organ transplantation. Neurology. 1993;43:1513–1518.
36. Gabriel SE, Conn DL, Phyliky RL, Pittelkow MR, Scott RE. Vasculitis in hairy cell leukemia: Review of literature and consideration of possible pathogenic mechanisms. J Rheumatol. 1986;13:1167–1172.
37. Hasler P, Kistler H, Gerber H. Vasculitis in hairy cell leukemia. Semin Arthritis Rheum. 1995;25:134–142.
38. Johnson PC, Rolak LA, Hamilton RH, Laguna JF. Paraneoplastic vasculitis of the nerve: A remote effect of cancer. Ann Neurol. 1979;5:437–444.
39. Kurzrock R, Cohen PR, Markowitz A. Clinical manifestations of vasculitis in patients with solid tumors: A case report and review of the literature. Arch Neurol. 1994;154:334–340.
40. Oh SJ, Slaughter R, Harrell L. Paraneoplastic vasculitic neuropathy: A treatable neuropathy. Muscle Nerve. 1991;14:152–156.
41. Bird SJ, Brown MJ, Shy ME, Scherer SS. Chronic inflammatory demyelinating polyneuropathy associated with malignant melanoma. Neurology. 1996;46:822–824.
42. Weiss MD, Luciano CA, Semino-Mora C, Dalakas MC, Quarles RH. Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma. Neurology. 1998;51:1738–1741.
43. Honnorat J, Cartalat-Carel S, Ricard D, et al. Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry. 2009;80:412–416
44. Levin KH, Lutz G. Angiotrophic large-cell lymphoma with peripheral nerve and skeletal muscle involvement: Early diagnosis and treatment. Neurology. 1996;47:1009–1011.
45. Grisold W, Piza-Katzer H, Jahn R, Herczeg E. Intraneural nerve metastasis with multiple mononeuropathies. J Peripher Nerv Syst. 2000;5(3):163–167.
46. Oei ME, Kraft GH, Sarnat HB. Intravascular lymphomatosis. Muscle Nerve. 2002;25(5):742–746.
47. Kelly JJ, Karcher DS. Lymphoma and peripheral neuropathy: A clinical review. Muscle Nerve. 2005;31:301–313.
48. Bobker DH, Deloughery TG. Natural killer cell leukemia presenting with a peripheral neuropathy. Neurology. 1993;43: 1853–1854.
49. Borit A, Altrocchi PH. Recurrent polyneuropathy and neurolymphomatosis. Arch Neurol. 1971;24:40–49.
50. Krendel DA, Stahl RL, Chan WC. Lymphomatous polyneuropathy. Biopsy of clinically involved nerve and successful treatment. Arch Neurol. 1991;48:330–332.
51. Thomas FP, Vallejos U, Foitl DR, et al. B cell small lymphocytic lymphoma and chronic lymphocytic leukemia with peripheral neuropathy: Two cases with neuropathological findings and lymphocyte marker analysis. Acta Neuropathol (Berl). 1990;80: 198–203.
52. Aregawi DG, Sherman JH, Douvas MG, Burns TM, Schiff D. Neuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia. Muscle Nerve. 2008;38:1196–1200.
53. Créange A, Theodorou I, Sabourin JC, Vital C, Farcet JP, Gherardi RK. Inflammatory neuromuscular disorders associated with chronic lymphoid leukemia: Evidence for clonal B cells within muscle and nerve. J Neurol Sci. 1996;137:35–41.
54. Krendel DA, Albright RE, Graham DG. Infiltrative polyneuropathy due to acute monoblastic leukemia in hematologic remission. Neurology. 1987;37:474–477.
55. Sumi SM, Farrell DF, Knauss TA. Lymphoma and leukemia manifested by steroid-responsive polyneuropathy. Arch Neurol. 1983;40:577–582.
56. Vital C, Bonnaud E, Arne L, Barrat M, Leblanc M. Polyneuritis in chronic lymphoid leukemia. Ultrastructural study of the peripheral nerve. Acta Neuropathol. 1975;32:169–172.
57. Vital C, Heraud A, Coquet M, Julien M, Maupetit J. Acute mononeuropathy with angiotropic lymphoma. Acta Neuropathol (Berl). 1989;78:105–107.
58. Dubas F, Saint-Andre JP, Poulard BA, Delestre F, Emile J. Intravascular malignant lymphomatosis (so-called malignant angioendotheliomatosis): A case confined to the lumbosacral spinal cord and nerve roots. Clin Neuropathol. 1990;9:115–120.
59. Glass J, Hochberg FH, Miller DC. Intravascular lymphomatosis: A systemic disease with neurologic manifestations. Cancer. 1993;71:3156–3164.
60. Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein–Barr viral infection of B lymphocytes and response to interferon-α2B. Blood. 1996;87:4531–4537.
61. Calatayud T, Vallejo AR, Dominguez L, Sotelo T, Peña P, Jimenez M. Lymphomatoid granulomatosis manifesting as a subacute polyradiculoneuropathy: A case report and review of the neurological manifestations. Eur Neurol. 1980;19:213–223.
62. Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: A clinicopathologic study of 152 cases. Cancer. 1979;43:360–373.
63. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid granulomatosis. Hum Pathol. 1972;3:457–558.
64. Kasamon YL, Nguyen TN, Chan JA, Nascimento AF. EBV-associated lymphoma and chronic inflammatory demyelinating polyneuropathy in an adult without overt immunodeficiency. Am J Hematol. 2002;69(4):289–293.
65. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology. 1981;31:45–50.
66. Jaeckle KA, Young DF, Foley KM. The natural history of lumbosacral plexopathy in cancer. Neurology. 1985;35:8–15.
67. Evans RJ, Walton CPN. Lumbosacral plexopathy in cancer patients. Neurology. 1985;35:1392–1393.
68. Vrethem M, Cruz M, Wen-Xin H, Malm C, Holmgren H, Ernerudh J. Clinical, neurophysiological and immunological evidence of polyneuropathy in patients with monoclonal gammopathies. J Neurol Sci. 1993;114:193–199.
69. Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ. Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981; 31:1480–1483.
70. Latov N. Prognosis of neuropathy with monoclonal gammopathy. Muscle Nerve. 2000;23:150–152.
71. Latov N, Sherman WH, Nemni R, Galassi G, Shyong JS, Penn AS. Plasma cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral nerve myelin. N Engl J Med. 1980;303:618–621.
72. Kelly JJ. The electrodiagnostic findings in peripheral neuropathy associated with monoclonal gammopathy. Muscle Nerve. 1983;6:504–509.
73. Kelly JJ. Peripheral neuropathies associated with monoclonal proteins: A clinical review. Muscle Nerve. 1985;8:138–150.
74. Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. Neuromuscul Disord. 1996;6:3–18.
75. Vital A, Vital C, Julien J, Baquey A, Steck AJ. Polyneuropathy associated with IgM monoclonal gammopathy. Acta Neuropathol (Berl). 1989;79:160–167.
76. Walsh JC. Neuropathy associated with lymphoma. J Neurol Neurosurg Psychiatry. 1971;34:42–50.
77. Cameron DG, Howell DA, Hutchinson JL. Acute peripheral neuropathy in Hodgkin’s disease. Neurology. 1958;8:575–577.
78. Lisak RP, Mitchell M, Zweiman B, Orrechio E, Asbury AK. Guillain–Barre syndrome and Hodgkin’s disease: Three cases with immunological studies. Ann Neurol. 1977;1:72–78.
79. Flanagan EP, Sandroni P, Pittock SJ, Inwards DJ, Jones LK Jr. Paraneoplastic lower motor neuronopathy associated with Hodgkin lymphoma. Muscle Nerve. 2012;46:823–827.
80. Sagar HJ, Read DJ. Subacute sensory neuropathy with remission: An association with lymphoma. J Neurol Neurosurg Psychiatry. 1982;45:83–85.
81. Kelly JJ Jr, Kyle RA, Miles JM, O’Brien PC, Dyck PJ. The spectrum of peripheral neuropathy in myeloma. Neurology. 1981;31:24–31.
82. Walsh JC. The neuropathy of multiple myeloma. An electrophysiological and histological study. Arch Neurol. 1971;25: 404–414.
83. Kelly JJ Jr, Kyle RA, Miles JM, Dyck PJ. Osteosclerotic myeloma and peripheral neuropathy. Neurology. 1983;33:202–210.
84. Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes: The POEMS syndrome. Medicine (Baltimore). 1980;59:311–322.
85. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow–Fukase syndrome: A study of 102 cases in Japan. Neurology. 1984;34:712–720.
86. Ohi T, Kyle RA, Dyck PJ. Axonal attenuation and secondary segmental demyelination in myeloma neuropathies. Ann Neurol. 1985;17:255–261.
87. Kihara Y, Hori H, Murakami H, et al. A case of POEMS syndrome associated with reactive amyloidosis and Waldenström’s macroglobulinaemia. J Intern Med. 2002;252(3):255–258.
88. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: Definitions and long-term outcome. Blood. 2003;101(7):2496–2506.
89. Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011;86:591–601.
90. Isose S, Misawa S, Kanai K, et al. POEMS syndrome with Guillain-Barré syndrome-like acute onset: A case report and review of neurological progression in 30 cases. J Neurol Neurosurg Psychiatry. 2011;82:678–680.
91. Goebels N, Walther EU, Schaller M, Pongratz D, Mueller-Felber W. Inflammatory myopathy in POEMS syndrome. Neurology. 2000;55:1413–1414.
92. Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: Role of angiogenic factors in the pathogenesis. Brain. 2005;128:1911–1920.
93. Kuwabara S, Misawa S, Kanai K, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology. 2006;66(1):105–107.
94. Donaghy M, Hall P, Gawler J, et al. Peripheral neuropathy associated with Castleman’s disease. J Neurol Sci. 1989;89:253–267.
95. Donofrio PD, Albers JW, Greenberg HS, et al. Peripheral neuropathy in osteosclerotic myeloma: Clinical and electrodiagnostic improvement with chemotherapy. Muscle Nerve. 1984;7:137–141.
96. Ohi T, Nukada H, Kyle RA, et al. Detection of an axonal abnormality in myeloma neuropathy. Ann Neurol. 1983;14:120.
97. Sung JY, Kuwabara S, Ogawara K, Kanai K, Hattori T. Patterns of nerve conduction abnormalities in POEMS syndrome. Muscle Nerve. 2002;26(2):189–193.
98. Vital C, Vital A, Ferrer X, et al. Crow–Fukase (POEMS) syndrome: A study of peripheral nerve biopsy in five new cases. J Peripher Nerv Syst. 2003;8(3):136–144.
99. Michizono K, Umehara F, Hashiguchi T, et al. Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 are increased in POEMS syndrome. Neurology. 2001;56(6):807–810.
100. Dyck PJ, Engelstad J, Dispenzieri A. Vascular endothelial growth factor and POEMS. Neurology. 2006;6(1):10–12.
101. Gotham JE, Wein H, Meyer JS. Clinical studies of neuropathy due to macroglobulinemia (Waldenström’s syndrome). Can Med Assoc J. 1963;89:806–809.
102. Iwashita H, Argyrakis A, Lowitzsch K, et al. Polyneuropathy in Waldenström’s macroglobulinemia. J Neurol Sci. 1974;21:341–354.
103. Propp RP, Means E, Deibel R, Sherer G, Barron K. Waldenström’s macroglobulinemia and neuropathy. Neurology. 1975; 25:980–988.
104. Vital C, Vallat JM, Deminiere C, Loubet A, Leboutet MJ. Peripheral nerve damage during multiple myeloma and Waldenström’s macroglobulinemia. Cancer. 1982;50:1491–1497.
105. Levine T, Pestronk A, Florence J, et al. Peripheral neuropathies in Waldenström’s macroglobulinaemia. J Neurol Neurosurg Psychiatry. 2006;77(2):224–228.
106. Luigetti M, Frisullo G, Laurenti L, et al. Light chain deposition in peripheral nerve as a cause of mononeuritis multiplex in Waldenström’s macroglobulinaemia. J Neurol Sci. 2010;291:89–91.
107. Gironi M, Saresella M, Ceresa L, et al. Clinical and immunological worsening in a patient affected with Waldenström macroglobulinemia and anti-mag neuropathy after treatment with rituximab. Haematologica. 2006;91(6 suppl):ECR17.
108. Noronha V, Fynan TM, Duffy T. Flare in neuropathy following rituximab therapy for Waldenström’s macroglobulinemia. J Clin Oncol. 2006;24(1):e3.
109. Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30:54–61.
110. Kelly JJ, Adelman LS, Berkman E, Bhan I. Polyneuropathies associated with IgM monoclonal gammopathies. Arch Neurol. 1988;45:1355–1359.
111. Suarez GA, Kelly JJ. Polyneuropathy associated with monoclonal gammopathy of undetermined significance: Further evidence that IgM-MGUS neuropathies are different than IgG-MGUS. Neurology. 1993;43:1304–1308.
112. Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ. Distal acquired demyelinating symmetric (DADS) neuropathy. Neurology. 2000;54:615–620.
113. Saperstein DS, Katz JS, Amato AA, Barohn RJ. The spectrum of the acquired chronic demyelinating polyneuropathies. Muscle Nerve. 2001;24:311–324.
114. Donofrio PD, Kelly JJ Jr. AEE case report #17: Peripheral neuropathy in monoclonal gammopathy of undetermined significance. Muscle Nerve. 1989;12:1–8.
115. Niermeijer JM, Eurelings M, Lokhorst HL, et al. Rituximab for polyneuropathy with IgM monoclonal gammopathy. JNNP. 2009;80:1036–1039.
116. Dalakas MC, Rakocevic G, Salajegheh M, et al. Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol. 2009;65:286–293.
117. Larue S, Bombelli F, Viala K, et al. Non-anti-MAG DADS neuropathy as a variant of CIDP: Clinical, electrophysiological, laboratory features and response to treatment in 10 cases. Eur J Neurol. 2011;18:899–905.
118. Eliashiv S, Brenner T, Abramsky O, et al. Acute inflammatory demyelinating polyneuropathy following bone marrow transplantation. Bone Marrow Transplant. 1991;8:315–317.
119. Openshaw H, Hinton DR, Slatkin NE, Bierman PJ, Hoffman FM, Snyder DS. Exacerbation of inflammatory demyelinating polyneuropathy after bone marrow transplantation. Bone Marrow Transplant. 1991;7:411–414.
120. Greenspan A, Deeg HG, Cottler-Fox M, Sirdofski M, Spitzer TR, Kattah J. Incapacitating peripheral neuropathy as a manifestation of chronic graft-versus-host disease. Bone Marrow Transplant. 1990;5:349–352.
121. Bashir RM, Bierman P, McComb R. Inflammatory peripheral neuropathy following high dose chemotherapy and autologous bone marrow transplantation. Bone Marrow Transplant. 1992;10:305–306.
122. Myers SE, Williams SF, Iveson T, Treleaven J, Powles R. Guillain–Barré syndrome after bone marrow transplantation. Bone Marrow Transplant. 1994;14:165–167.
123. Ashraf M, Scotchel PL, Krall JM, Flink EB. Cis-platinum induced hypomagnesemia and peripheral neuropathy. Gynecol Oncol. 1983;16:309–318.
124. Barajon I, Bersani M, Quartu M, et al. Neuropeptides and morphological changes in cis-platin-induced dorsal root ganglion neuronopathy. Exp Neurol. 1996;138:93–104.
125. Cerosimo RJ. Cisplatin neurotoxicity. Cancer Treat Rev. 1989;16:195–211.
126. Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: The relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol. 1992;10:795–803.
127. Krarup-Hansen A, Fugleholm K, Helweg-Larsen S, et al. Examination of distal involvement in cisplatin-induced neuropathy in man. Brain. 1993;116:1017–1041.
128. LoMonaco M, Milone M, Batocchi AP, Padua L, Restuccia D, Tonali P. Cisplatin neuropathy: Clinical course and neurophysiological findings. J Neurol. 1992;239: 199–204.
129. Mollman JE, Hogan WM, Glover DJ, McCluskey LF. et al. Unusual presentation of cis-platinum neuropathy. Neurology. 1988;38:488–490.
130. Mollman JE, Glover DJ, Hogan WM, Furman RE. Cisplatin neuropathy: Risk factors, prognosis, and protection by WR-2721. Cancer. 1998;61:2192–2195.
131. Russell JW, Windebank AJ, McNiven MA, Brat DJ, Brimijoin WS. Effect of cisplatin and ACTH4-9 on neural transport in cisplatin induced neurotoxicity. Brain Res. 1975;676:258–267.
132. Grothey A. Oxaliplatin-safety profile: Neurotoxicity. Semin Oncol. 2003;30(4 suppl 15):5–13.
133. Burakgazi AZ, Messersmith W, Vaidya D, Hauer P, Hoke A, Polydefkis M. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77:980–986.
134. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related vincristine-induced neuropathy with unexpected off-therapy worsening. Neurology. 2005;64:1076–1077.
135. Casey EB, Jellife AM, Le Quense M, Millett YL. Vincristine neuropathy: Clinical and electrophysiological observations. Brain. 1973;96:69–86.
136. Legha SS. Vincristine neurotoxicity: Pathophysiology and management. Med Toxicol. 1986;1:421–427.
137. Pal PK. Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol. 1999; 39:323–330.
138. Sahenk Z, Brady ST, Mendell JR. Studies on the pathogenesis of vincristine-induced neuropathy. Muscle Nerve. 1987;10:80–84.
139. Goa KL, Faulds D. Vinorelbine: A review of its pharmacological properties and clinical use in cancer chemotherapy. Drugs Aging. 1994;5:200–234.
140. O’Reilly S, Kennedy MJ, Rowinsky EK, Donehower RC. Vinorelbine and the topoisomerase 1 inhibitors: Current and potential roles in breast cancer chemotherapy. Breast Cancer Res Treat. 1994;33:1–17.
141. Pace A, Bove L, Nistico C, et al. Vinorelbine neurotoxicity: Clinical and neurophysiological findings in 23 patients. J Neurol Neurosurg Psychiatry. 1996;61:409–411.
142. Bregman CL, Buroker RA, Hirth RS, Crosswell AR, Durham SK. Etoposide- and BMY-40481-induced sensory neuropathy in mice. Toxicol Pathol. 1994;22:528–535.
143. Forsyth PA, Balmaceda C, Peterson K, Seidman AD, Brasher P, DeAngelis LM. Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. J Neurooncol. 1997;35:47–53.
144. Lipton RB, Apfel SC, Dutcher JP, et al. Taxol produces a predominantly sensory neuropathy. Neurology. 1989;39:368–373.
145. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced peripheral neuropathy. Ann Oncol. 1995;6:489–494.
146. Rowinsky EK, Chaudhry V, Forastiere AA, et al. Phase 1 pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulation factor: Neuromuscular toxicity is dose-limiting. J Clin Oncol. 1993;11:2010–2020.
147. Sahenk Z, Barohn RJ, New P, Mendell JR. Taxol neuropathy: An electrodiagnostic and sural nerve biopsy finding. Arch Neurol. 1994;51:726–729.
148. van den Bent MJ, van Raaij-van den Aarssen VJ, Verweij J, et al. Progression of paclitaxel-induced neuropathy following discontinuation of treatment. Muscle Nerve. 1997;20:750–752.
149. van Gerven JM, Moll JW, van den Bent MJ, et al. Paclitaxel (Taxol) induces cumulative mild neurotoxicity. Eur J Cancer. 1994;30A:1074–1077.
150. Kuroi K, Shimozuma K. Neurotoxicity of taxanes: Symptoms and quality of life assessment. Breast Cancer. 2004;11(1):92–99.
151. Makino H. Treatment and care of neurotoxicity from taxane anticancer agents. Breast Cancer. 2004;11(1):100–104.
152. Park SB, Lin CS, Krishnan AV, Friedlander ML, Lewis CR, Kiernan MC. Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy. Muscle Nerve. 2011;43:367–374.
153. Roytta M, Raine CS. Taxol-induced neuropathy: Chronic effects of local injection. J Neurocytol. 1986;15:483–496.
154. Freilich RJ, Balmaceda C, Seidman AD, Rubin M, DeAngelis LM. Motor neuropathy due to docetaxel and paclitaxel. Neurology. 1996;47:115–118.
155. Hilkens PH, Verweij J, Stoter G, et al. Peripheral neurotoxicity induced by docetaxel. Neurology. 1996;46:104–108.
156. New PZ, Jackson CE, Rinaldi D, Burris H, Barohn RJ. Peripheral neuropathy secondary to docetaxel (Taxotere). Neurology. 1996;46:108–111.
157. Hsu Y, Sood AK, Sorosky JI. Docetaxel versus paclitaxel for adjuvant treatment of ovarian cancer: Case-control analysis of toxicity. Am J Clin Oncol. 2004;27(1):14–18.
158. Guastalla JP III, Dieras V. The taxanes: Toxicity and quality of life considerations in advanced ovarian cancer. Br J Cancer. 2003;89(suppl 3):S16–S22.
159. Chaudhry V, Eisenberber MA, Sinibaldi VJ, et al. A prospective study of suramin-induced peripheral neuropathy. Brain. 1996;119:2039–2052.
160. La Rocca RV, Meer J, Gilliat RW, et al. Suramin-induced polyneuropathy. Neurology. 1990;40:954–960.
161. Soliven B, Dhand UK, Kobayashi K, et al. Evaluation of neuropathy in patients on suramin treatment. Muscle Nerve. 1997;20:83–91.
162. Russell JW, Gill JS, Sorenson EJ, Schultz DA, Windebank AJ. Suramin-induced neuropathy in an animal model. J Neurol Sci. 2001;192(1–2):71–80.
163. Sullivan KA, Kim B, Buzdon M, Feldman EL. Suramin disrupts insulin-like growth factor-II (IGF-II) mediated autocrine growth in human SH-SY5Y neuroblastoma cells. Brain Res. 1997;744:199–206.
164. Czernin S, Gessl A, Wilfing A, et al. Suramin affects human peripheral blood mononuclear cells in vitro: Inhibition of Y cell growth and modulation of cytokine secretion. Int Arch Allergy Immunol. 1993;101:240–246.
165. Borgeat A, De Muralt B, Stalder M. Peripheral neuropathy associated with high-dose Ara-C therapy. Cancer. 1986; 58:852–853.
166. Johnson NT, Crawford SW, Sargar M. Acute acquired polyneuropathy with respiratory failure following high-dose systemic cytosine arabinoside and bone marrow transplantation. Bone Marrow Transplant. 1987;2:203–207.
167. Nevill TJ, Benstead TJ, McCormick CW, Hayne OA. Horner’s syndrome and demyelinating peripheral neuropathy caused by high-dose cytosine arabinoside. Am J Hematol. 1989;32:314–315.
168. Openshaw H, Slatkin NE, Stein AS, Hinton DR, Forman SJ. Acute polyneuropathy after high-dose cytosine arabinoside in patients with leukemia. Cancer. 1996;78:1899–1905.
169. Paul M, Joshua D, Rehme N, et al. Fatal peripheral neuropathy associated with high-dose cytosine arabinoside in acute leukemia. Br J Haematol. 1991;79:521–523.
170. Russell JW, Powles RL. Neuropathy due to cytosine arabinoside. Br Med J. 1974;4:652–653.
171. Patel SR, Forman AD, Bejamin RS. High-dose ifosfamide-induced exacerbation of peripheral neuropathy. J Natl Cancer Inst. 1994;86:305–306.
172. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–2617.
173. Richardson PG, Briemberg H, Jagganath S, et al. The frequency, severity, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113–3120.
174. Davis NB, Taber DA, Ansari RH, et al. Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago phase II consortium study. J Clin Oncol. 2004;22:115–119.
175. Stubblefield MD, Slovin S, MacGregor-Cortelli B, et al. An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib. Clin Oncol (R Coll Radiol). 2006;18:410–418.
176. Richardson PG, Xie W, Mitsiades C, et al. Single-agent bortezomib in previously untreated multiple myeloma: Efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol. 2009;27:3518–3525.
177. Giannoccaro MP, Donadio V, Gomis Pèrez C, Borsini W, Di Stasi V, Liguori R. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: An immunofluorescence study. Neurol Sci. 2011;32:361–363.
178. Meregalli C, Canta A, Carozzi VA, et al. Bortezomib-induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats. Eur J Pain. 2010;14:343–350.
179. Bruna J, Udina E, Alé A, et al. Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice. Exp Neurol. 2010;223:599–608.
180. Carozzi VA, Canta A, Oggioni N, et al. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. Exp Neurol. 2010;226:301–309.
181. Lue J, Goel S, Mazumder A. Carfilzomib for the treatment of multiple myeloma. Drugs Today (Barc). 2013;49:171–179.
