Journal Tumor

CANCER-RELATED NEUROPATHIES

Edward J. Dropcho, M.D.

December 2002

INTRODUCTION

         Peripheral neuropathies are among the most common neurologic complications of cancer.  The differential diagnosis of peripheral nervous system dysfunction in cancer patients is broad and includes: direct nerve compression or infiltration by tumor; neurotoxicity of cancer treatment; nutritional deficiencies; metabolic derangements; and paraneoplastic disorders.  In patients presenting with a peripheral neuropathy but no known cancer diagnosis, it is important to consider the possibility that the neuropathy is a remote effect of a previously undiagnosed neoplasm.

PARANEOPLASTIC NEUROPATHIES

         Most neurologic paraneoplastic disorders are believed to be autoimmune diseases. The central theory of autoimmunity for paraneoplastic disorders postulates that tumor cells express "onconeural" antigen(s) identical or antigenically related to molecules normally expressed by neurons, and that in rare instances an autoimmune response initially arising against the tumor subsequently attacks neurons expressing the same or related antigen(s).

         Since the mid-1980s there has been a steadily growing list of antineuronal autoantibodies identified in the sera of patients with paraneoplastic disorders.  Most paraneoplastic autoantibodies show widespread or pan-neuronal reactivity and are associated with a variety of clinical neurologic syndromes, or with a multifocal encephalomyeloneuritis.  Conversely, a given clinical syndrome may be associated with one of a number of different autoantibodies.  Antineuronal antibodies are a useful though not infallible clinical tool, both for diagnosing a patient’s condition as paraneoplastic, and for guiding the search for specific underlying tumor types.  With a few exceptions, antineuronal antibodies are believed to be "markers" for autoimmunity but probably do not directly mediate neuronal injury.  For some syndromes recent evidence implicates cellular-mediated autoimmune mechanisms, but the exact immunopathogenetic mechanisms underlying most paraneoplastic syndromes remain unclear.

         Taken as a group, peripheral neuropathies are the most common remote effect of systemic cancer on the nervous system.  Paraneoplastic neuropathies may be classified by their associated neoplasms, or by their clinical presentation.  Either classification scheme becomes complicated, in that a given clinical syndrome (eg, sensory neuropathy) occurs in association with a number of different neoplasms.  Conversely, a given tumor type can be associated with different neuropathy syndromes.  As with other neurologic paraneoplastic disorders, neuropathy is often the presenting feature of the patient's neoplasm.  It is therefore the neurologist's task to identify a paraneoplastic neuropathy as such.  This task is made more difficult by the rarity of paraneoplastic conditions, and by the fact that none of the paraneoplastic neuropathies have a pathognomonic clinical presentation.  For at least some paraneoplastic neuropathies there are serologic markers which may be used in diagnosis.

         For patients without a known neoplasm who present with a peripheral neuropathy, the likelihood of a paraneoplastic etiology is difficult to quantitate and depends on the particular neuropathy syndrome.  For example, severe rapidly progressive sensory neuronopathy is much more likely to be paraneoplastic than a mild, distal, slowly progressive axonal polyneuropathy [3-5].

Paraneoplastic Subacute Sensory Neuronopathy

         A large proportion of patients with paraneoplastic disorders can be grouped into the clinicopathologic entity of paraneoplastic encephalomyelitis (PEM).  Small cell lung carcinoma is by far the tumor most commonly associated with PEM, with a scattering of patients with a variety of other neoplasms.  In most patients with PEM the neurologic syndrome is the presenting feature of an otherwise occult tumor and precedes the discovery of the neoplasm by an average of several months.  PEM is characterized clinically and pathologically by patchy, multifocal involvement of any or all areas of the cerebral hemispheres, limbic system, cerebellum, brainstem, spinal cord, dorsal root ganglia, and autonomic ganglia.  

         The most common clinical manifestation of PEM is subacute sensory neuronopathy (SSN) reflecting involvement of the dorsal root ganglia [6-11].  SSN is the predominant feature of PEM in 50-60% of patients.  Early symptoms are patchy or asymmetric numbness and paresthesias, often involving face, trunk, or proximal limbs. The symptoms eventually spread to involve all limbs.  Burning dysesthesias and severe aching or lancinating pain are common and may be the most distressing feature of the disease.  Examination reveals severe sensory ataxia, predominant impairment of vibration sense and proprioception, frequent pseudoathetosis, and hypoactive or absent muscle stretch reflexes.  Many patients cannot walk unassisted due to pain and profound loss of proprioception.  Most patients with SSN also have signs and symptoms reflecting multifocal involvement of the limbic system, cerebellum, brainstem, or spinal cord.  Patients may additionally show involvement of the peripheral nervous system, including sensorimotor polyneuropathy, mononeuritis multiplex, autonomic system failure, or Lambert-Eaton myasthenic syndrome (see below).         

         The neuropathologic hallmark of paraneoplastic SSN is severe dropout of primary sensory neurons in the dorsal root ganglia and gasserian ganglia. The neuronal loss is diffuse but patchy and asymmetric, reflecting patients' clinical presentation. Large-diameter neurons are probably lost preferentially [12]. Remaining neurons occasionally show nonspecific degenerative changes. There is a highly variable degree of infiltration by T and B lymphocytes, plasma cells, and macrophages, often in a perivascular distribution [13, 14]. Severe depletion of myelinated fibers is present in dorsal columns, posterior nerve roots, and peripheral sensory nerves, believed to be secondary to the loss of dorsal root ganglia neurons.  The majority of patients additionally have multifocal patchy neuronal loss and variable inflammatory infiltrates in the cerebral hemispheres, brainstem, cerebellum, gray matter of the spinal cord, dorsal root ganglia, or autonomic ganglia.

         Brain MR scans in patients with SSN/PEM are usually normal, except in patients with predominant cerebellar involvement or limbic encephalopathy.  Most patients have abnormal CSF, including elevated protein, mild mononuclear pleocytosis, elevated IgG index, and/or oligoclonal bands, although at least 10% of patients have normal CSF [7].  Electrodiagnostic studies in paraneoplastic SSN characteristically show severely reduced amplitude or complete absence of sensory nerve potentials, with normal or only slightly reduced sensory nerve conduction velocities if a response is able to be elicited [4, 6]. Most patients do show at least some electrophysiologic abnormalities in motor nerve conduction studies, with or without symptoms of a mixed sensorimotor polyneuropathy [15], but motor conduction studies are almost always less affected than sensory nerve studies.  Needle EMG may show denervation in patients with a component of motor neuropathy or encephalomyelitis and anterior horn cell involvement. Sural nerve biopsy shows nonspecific axonal degeneration and a reduced population of myelinated fibers [4].

         When considering the differential diagnosis of paraneoplastic SSN it is important to keep in mind that patients generally have severe sensory deficits, areflexia, and sensory gait ataxia.  It patients without a known cancer diagnosis, the differential diagnosis of sensory neuronopathy or severe sensory neuropathy includes dorsal root ganglionitis associated with Sjogren syndrome, idiopathic sensory neuronopathy [16], and sensory neuropathy associated with anti-disialosyl ganglioside antibodies [17].  In patients with a known neoplasm the differential diagnosis also includes sensory neuropathy cause by cisplatin or paclitaxel (see below).

         The great majority of patients with SSN/PEM have one or more circulating antineuronal autoantibodies, the most common of which are polyclonal IgG anti-Hu antibodies (also called ANNA-1 antibodies) [7-10]. More than 90% of reported patients with anti-Hu antibodies and SSN/PEM have small cell lung carcinoma, with individual case reports of patients with neuroblastoma, non–small cell lung carcinoma, carcinoma of the breast or prostate, or thymoma.  In a disproportionately high proportion of patients with SSN/PEM and anti-Hu antibodies, the associated small cell lung carcinoma is limited to the lung and mediastinum as compared with neurologically unaffected small cell cancer patients [18]. Patients with anti-Hu antibody-associated SSN/PEM appear to have a longer survival than patients with small cell lung cancer but no paraneoplastic syndrome [9].  This is circumstantial evidence supporting an anti-tumor immune response, but an alternative explanation is that the occurrence of neurologic symptoms leads to early tumor diagnosis and treatment.

         Anti-Hu antibodies stain the nuclei and to a lesser degree the cytoplasm of all neurons in the dorsal root ganglia, autonomic ganglia, and central nervous system.  Anti-Hu antibodies react with a group of closely related 35-40 kD RNA-binding proteins, several of which have been cloned [19, 20].  Expression of one or more Hu autoantigens is common but is not universal among small cell lung carcinomas, including tumors from patients with SSN/PEM and anti-Hu antibodies as well as tumors from neurologically unaffected patients [21, 22].

         Occasionally, patients are false-positive or false-negative for anti-Hu antibodies. High-titer anti-Hu antibodies have been reported in a few patients with encephalomyeloneuritis in whom no tumor was detected, even at autopsy [10, 11].  Depending on the methodology used, low titers of anti-Hu antibodies can be detected in the sera of 15-40% of patients with small cell lung carcinoma but no overt clinical paraneoplastic disorder [23, 24].

         There is currently no definite evidence that anti-Hu antibodies directly cause neuronal injury.  Animals actively immunized with recombinant Hu antigens produce anti-Hu antibodies, but they do not develop the clinical or pathologic features of SSN/PEM [25].  Recent studies show cytotoxic anti-Hu T-lymphocytes in patients and other evidence for cellular immune mechanisms [26-29], but the exact immune-mediated mechanism(s) of neuronal injury in SSN/PEM remain unknown.   

         A minority of patients with SSN/PEM associated with small cell lung carcinoma or with another tumor either has no detectable antineuronal autoantibodies [5], or has antibodies with patterns of immunoreactivity distinct from anti-Hu antibodies (Table 1).  These include anti-CV2 (CRMP-5) antibodies directed against a group of proteins expressed by neurons and oligodendrocytes [30, 31], anti-amphiphysin antibodies   [32-34], anti-Ma antibodies [35], ANNA-3 antibodies [36], and other un-named antibodies.  The clinical features of SSN/PEM in anti-Hu antibody-negative patients do not reliably differ from the spectrum of signs and symptoms seen in patients with anti-Hu antibodies.  The presence of anti-Hu or other anti-neuronal antibodies in a patient with sensory neuropathy is a very strong (but not absolute) indicator of the presence of an underlying tumor.  Conversely, the absence of anti-neuronal antibodies does not rule out a paraneoplastic condition and the presence of an occult neoplasm.

Table 1. Antineuronal Antibodies in Paraneoplastic Sensory Neuronopathy

and Sensorimotor Polyneuropathy

 

Antineuronal Antibody	Associated Tumor(s)	Antibody Reactivity
anti-Hu (ANNA-1)	small cell lung carcinoma	pan-neuronal nuclei > cytoplasm; 35-40 kD RNA-binding proteins
anti-CV2 (CRMP-5)	small cell lung carcinoma, others	cytoplasm of neurons and oligodendrocytes; 66 kD CV2 protein
anti-amphiphysin	small cell lung carcinoma	neuropil; synaptic vesicle-associated    amphiphysin
ANNA-3	small cell lung carcinoma	Purkinje cell and dentate neuronal nuclei; 170 kD protein
anti-Ma	lung, other carcinomas	pan-neuronal nuclei and nucleoli; 37 kD Ma1 and 40 kD Ma2 proteins

 

         Patients with encephalomyelitis or sensory neuronopathy, with or without anti-neuronal antibodies, should undergo a workup looking for small cell lung carcinoma.  Chest CT or MR scanning is clearly more sensitive than "plain" chest X-rays in detecting a neoplasm [37].  Whole-body FDG-PET scanning may detect lung neoplasms in patients with suspected paraneoplstic syndromes but unrevealing or equivocal chest CT or MR scans [38, 39].  It is not uncommon for patients' initial evaluation for an occult lung tumor to be unrevealing; in these patients the workup should be repeated every several months and should include workup for other tumors, including lymphoma and carcinoma of the breast or prostate.  

         By far the most common clinical course of SSN/PEM is deterioration over a period of weeks to months, and then stabilization at a level of severe neurologic disability, regardless of treatment.  Subsequent stepwise or gradual neurologic deterioration is less common and tends to occur in patients with less than complete response of the associated small cell lung cancer to treatment [9]. Sudden death is not rare and is presumed to be caused by acute dysautonomia. Conversely, there are a few patients with minimal CNS manifestations and a sensory neuronopathy that takes a relatively indolent course independent of any treatment [40].  SSN/PEM associated with anti-Hu antibodies may rarely spontaneously improve without any specific treatment [41].

           Patients with SSN/PEM rarely show significant neurologic improvement despite successful tumor treatment and/or a variety of immunosuppressive therapies, including prednisone, cyclophosphamide, intravenous immunoglobulin (IVIg), or plasmapheresis [7, 10, 11, 42, 43].   It is difficult to interpret reports of "stabilization" of SSN/PEM with immunosuppression, considering that the disease in most patients stabilizes spontaneously.  There are a few patients with SSN/PEM and anti-Hu antibodies, fewer than 10%, who do in fact have significant neurological improvement with prednisone and/or IVIg [42, 44].  Patients with early diagnosis and successful treatment of the associated neoplasm may have a slightly better likelihood of neurologic stabilization or improvement [10].  With that possible exception, there is nothing distinctive about the clinical presentation of the few patients with SSN/PEM who improve after immunosuppression, tumor treatment, or both.  It is likely that, at the time of diagnosis, many patients have already suffered irreversible neuronal damage or loss.

         There is theoretical concern that if the paraneoplastic disorder arises from an immune response directed against the tumor, attempts to treat the neurologic disorder with immunosuppression may adversely affect the evolution of the tumor.  Presently there is no evidence that immunosuppressive treatment in patients with SSN/PEM is associated with a worse tumor outcome [9].

Paraneoplastic Motor Neuron Disease

         There is no convincing epidemiologic evidence that non-hematologic neoplasms occur in ALS patients any more frequently than would be expected in an age-matched control population [45].  Despite the absence of a clear epidemiologic link between motor neuron disease and neoplasia, the relationship in small subsets of patients is probably more than coincidental.  Lower motor neuron signs and symptoms are among the presenting or predominant manifestations in up to 25% of patients with multifocal PEM [7, 10, 46].  As with other manifestations of PEM, motor neuron involvement in these patients does not usually improve with treatment.  Autopsy demonstrates patchy loss of anterior horn cells and variable inflammatory infiltrates within the spinal cord.   In addition, there are several well-described patients with a lower motor neuron syndrome or combined upper and lower motor neuron syndrome who had significant neurologic improvement after resection of lung or renal carcinomas [47, 48].  There is a single report of a lower motor neuron syndrome in a patient with breast carcinoma and serum antibodies reacting with axons and nodes of Ranvier [49].

         There appears to be a special association between motor neuron disorders and lymphomas or plasma cell dyscrasias.  The prevalence of plasma cell dyscrasias among patients with motor neuron disease is higher than in age-matched control populations, but the vast majority of these patients have "monoclonal gammopathy of undetermined significance" and the etiologic association between the two conditions remains unclear.  The clinical syndrome and neuropathologic findings in reported patients with motor neuron disease and IgG or IgA paraproteinemias closely resemble classical ALS.  In most cases this probably a coincidental association, although there are reports of neurologic improvement after plasma exchange, corticosteroids, and alkylating agents such as melphalan or cyclophosphamide [50].

         There are more than 50 published patients with concurrent ALS or "progressive spinal muscular atrophy" and lymphoproliferative disease including Hodgkin's or non-Hodgkin's lymphoma and chronic lymphocytic leukemia [51]. The frequency of lymphoproliferative disease in patients with motor neuron disorders has been estimated as high as 2-5%. In roughly half of patients the neurologic symptoms precede diagnosis of the lymphoproliferative disease.  Some patients have no "systemic" signs or symptoms, and the lymphoma is discovered only by bone marrow biopsy.  Up to one-third of patients have an associated monoclonal IgA, IgG, or IgM paraprotein.  There is nothing clinically distinctive about the motor neuron disease in patients with lymphoproliferative disease, except for an elevated CSF protein without pleocytosis in up to 50%. Patients with an ALS-like syndrome generally have progressive weakness and often die a "neurologic" death despite treatment of the associated lymphoproliferative disease.

         The association of motor neuron disease and lymphoproliferative disease includes the syndrome of "subacute motor neuronopathy" described in patients with Hodgkin's or non-Hodgkin's lymphoma, or thymoma [52].  Patients develop a subacute lower motor neuron syndrome predominantly involving the legs, without pain, significant sensory loss, or upper motor neuron findings.  The neurologic deficits generally worsen over weeks to months independent of the course of the malignancy, but usually stabilize or improve (sometimes dramatically) after a period of months to years.  The few cases examined at autopsy have shown patchy degeneration and loss of anterior horn cells, occasional inflammatory infiltrates, secondary thinning of ventral nerve roots, and widespread patchy segmental demyelination of spinal roots, brachial and lumbosacral plexuses.

Paraneoplastic Neuromyotonia

         Patients with small cell lung carcinoma, thymoma, Hodgkin's lymphoma, or plasmacytoma may develop a syndrome of diffuse muscle stiffness, cramps, and myokymia similar to “neuromyotonia” or “continuous muscle fiber activity” (Isaacs' syndrome) [53-56].  Patients with thymoma may concurrently have myasthenia gravis, and some patients have a confusional state, dysautonomia, and/or CSF oligoclonal bands suggesting CNS involvement (termed "Morvan's fibrillary chorea") [57, 58].  Needle EMG shows repetitive bursts of rapidly firing motor unit discharges (myokymic potentials) and/or very high frequency trains of discharges.  Fibrillations and fasciculations may also be present.  Most patients have electrophysiologic evidence for a mild axonal sensorimotor polyneuropathy.  Some patients with neuromyotonia and thymoma have serum antibodies against voltage-gated potassium channels which have also been identified in patients with non-paraneoplastic neuromyotonia [59].  The antibodies are postulated to cause prolonged motor neuron depolarization leading to abnormal spontaneous muscle activity.  Successful tumor treatment may bring about significant neurologic improvement.  Patients may also benefit from phenytoin, carbamazepine, plasmaphersis, and/or other immunosuppresive treatment.

Paraneoplastic Demyelinating Neuropathies

         There are several reports of an acute,  predominantly motor polyradiculoneuropathy occurring in the setting of a number of primary neoplasms, particularly lymphomas Hodgkin's or non-Hodgkin's lymphoma.  The clinical features, electrophysiologic findings, CSF, and peripheral nerve pathology in these patients are indistinguishable from those of idiopathic Guillain-Barre syndrome [60, 61].  Improvement may follow steroid therapy or tumor resection, but many of these patients undergo dramatic spontaneous remission of the neuropathy independent of the status of their underlying tumor.  

         Patients with lymphoma or a variety of carcinomas may develop a sensorimotor polyneuropathy which closely resembles chronic demyelinating polyneuropathy (CIDP) [4, 61-63].  The neurologic syndrome may precede discovery of the neoplasm by up to several years.  Electrophysiologic studies show abnormal F-waves, conduction blocks, reduced nerve conduction velocities, and abnormal temporal dispersion.  Nerve biopsies demonstrate segmental demyelination and mononuclear cell infiltrates.  Neurologic improvement may follow tumor resection, IVIg, or corticosteroid therapy.  Several recently reported patients with CIDP and melanoma had vitiligo or serum antibodies against gangliosides and other antigens shared by tumor cell and peripheral nerve [64, 65].

         Acute or chronic inflammatory demyelinating polyneuropathy may occur up to several months following allogeneic bone marrow transplantation [66-69].  In approximately one-half of reported patients the neuropathy occurred in the setting of graft-versus-host disease.  The neuropathy generally improves with plasma exchange, IVIg, and immunosppressive therapy.

         Chronic demyelinating polyneuropathy can be associated with a variety of plasma cell dyscrasias.  Some affected patients have a paraprotein which reacts with peripheral nerve antigens.  These conditions are more fully described in another section of this course. 

Paraneoplastic Vasculitic Neuropathy

         Peripheral nerve microvasculitis may occur in association with lymphomas or with carcinoma of the lung, prostate, uterus, kidney, or stomach [70, 71].  Neurologic symptoms usually precede discovery of the tumor.  The clinical presentation is either that of mononeuritis multiplex, or of an asymmetric distal sensorimotor neuropathy.  Pain is common.  Patients usually have an elevated sedimentation rate but rarely have cutaneous vasculitis or other systemic symptoms.  Nerve conduction studies show a variable degree of axonal degeneration in motor and sensory nerves which reflects the asymmetric clinical involvement.  Sural nerve biopsy or autopsy demonstrate focal mononuclear cell infiltration of epineurial vessel walls and active nerve fiber degeneration.  There may additionally be arteriolar fibrinoid necrosis with obliteration of lumens.  Patients with peripheral nerve vasculitis and small cell lung cancer may also have clinical and pathologic features of  SSN/PEM [70, 72].  Patients with small cell lung cancer may have anti-Hu antibodies, with or without overt CNS involvement [73].  There are reports of neurologic improvement after tumor treatment and/or cyclophosphamide; corticosteroids alone do not seem to have much effect.

Other Paraneoplastic Neuropathies

         As described above, the most common peripheral nervous system syndrome associated with anti-Hu antibodies is sensory neuronopathy reflecting dorsal root ganglionitis.  Nerve conduction studies show, however, that only a minority of patients with clinically "pure" or predominantly sensory neuronopathy have conduction abnormalities totally restricted to sensory nerves.  Rather, most patients have at least some electrophysiologic abnormalities in motor nerves [15].  A minority of patients with anti-Hu antibodies has a clinical presentation suggestive of mixed sensorimotor polyneuropathy with a mixed axonal-demyelinating electrophysiologic pattern.  A few patients with anti-Hu antibodies have what appears to be a primary demyelinating polyneuropathy superimposed on sensory neuronopathy [74], or a mononeuritis multiplex with biopsy-proven nerve vasculitis [70, 73].

         Patients with anti-CV2 antibodies (most of whom have small cell lung carcinoma) may develop a sensorimotor polyneuropathy with mixed axonal-demyelinating electrophysiologic features [75].  Some of these patients have both anti-Hu and anti-CV2 antibodies.  Anti-CV2 antibodies immunocytochemically label peripheral nerve axons.  Sensorimotor polyneuropathy may also occur in patients with ANNA-3 antibodies [36].

Paraneoplastic Autonomic Insufficiency

         Paraneoplastic autonomic dysfunction most commonly occurs as a part of PEM in patients with small cell lung carcinoma.  Most patients have symptoms of a concurrent SSN or sensorimotor polyneuropathy, but in some patients the autonomic symptoms overshadow other manifestations of SSN/PEM.  These patients may develop severe and progressive gastrointestinal dysmotility, including gastroparesis, chronic intestinal pseudo-obstruction, and severe constipation/obstipation, presenting several months prior to discovery of the small cell lung tumor [78-80].  Orthostatic hypotension and other features of sympathetic dysfunction may also be present.  Some of these patients have anti-Hu antibodies.  The pan-neuronal reactivity of anti-Hu antibodies includes staining of neurons in the sympathetic ganglia and myenteric plexus.  Improvement in autonomic function follows tumor resection or chemotherapy in some patients with isolated dysautonomia or PEM.

         Acute or subacute dysautonomia involving cardiovascular, urinary, and/or gastrointestinal systems may rarely occur in association with other tumors, including bronchial carcinoid, thymoma, and Hodgkin's lymphoma [81, 82].

DIRECT TUMOR SPREAD

         The most common ways in which tumors directly infiltrate or compress elements of the peripheral nervous system are cauda equina involvement by leptomeningeal metastases, and brachial or lumbosacral plexopathy metastases.  These are beyond the scope of the present review.

         Neurolymphomatosis is a condition in which lymphoma cells directly infiltrate peripheral nerves and/or nerve roots in a diffuse but patchy pattern [61, 83, 84].  In one-half of reported cases neurologic symptoms preceded diagnosis of the lymphoma.  Patients most often present with a subacute progressive asymmetric polyneuropathy or polyradiculoneuropathy.  A minority of cases look like a rapidly progressive polyneuropathy resembling Guillain-Barre syndrome.  Cranial nerve involvement and/or dysesthetic pain may be present.  Electrodiagnostic testing shows nonspecific axonal or axonal/demyelinating features.  Definitive diagnosis requires nerve biopsy, but the yield of a sural nerve biopsy is limited by the patchy nature of the lymphomatous infiltration.  Biopsy of a symptomatic nerve (eg saphenous or superficial peroneal nerve) may be performed if feasible.  Unfortunately, in many reported patients the diagosis was made only at autopsy.  Patients may show significant neurologic improvement with corticosteroids or cytotoxic chemotherapy. 

NEURO          Cisplatin: Sensory neuropathy is the major dose-limiting toxicity of cisplatin when given for treatment of ovarian carcinoma or a number of other solid neoplasms [88, 89].  The incidence and severity of neuropathy are mainly determined by the cumulative cisplatin dose.  Sensory neurons in the dorsal root ganglia are believed to be the primary site of injury, though there may be an additional direct toxic effect on axons.  Patients develop subacute distal numbness and paresthesias, dysesthesias, areflexia, and sensory ataxia. Lhermitte's symptom and/or muscle cramps are common. The neuropathy often worsens and spreads proximally for several months after cisplatin is discontinued. Recovery is slow and usually incomplete.  Patients may be permanently disabled from severe proprioceptive loss and dysesthesias.  Electrophysiologic studies show diminished amplitude (or absence) of sensory nerve potentials and prolonged sensory nerve latencies.  Abnormalities in somatosensory evoked potentials, together with Lhermitte's symptom, indicate involvement of dorsal columns in some patients.  Several "neuroprotective" agents appear to ameliorate cisplatin neuropathy, including amifostine, glutathione, and the ACTH analog ORG 2766.  Oxaliplatin commonly causes transient perioral and acral dysesthesias aggravated by cold temperature, during or shortly after drug infusion.  A persistent mainly sensory polyneuropathy may occur at high cumulative doses [90], sometimes accompanied by bladder dysfunction or Lhermitte's phenomenon.  The neuropathy does not seem to be as severe or as long-lasting as occurs with cisplatin.  Carboplatin is much less likely than other platinum agents to cause neuropathy, although severe mainly sensory neuropathy has been reported in patients who received high-dose carboplatin after prior cisplatin-based regimens [91].

         Cytarabine given in high intravenous doses is occasionally associated with peripheral neuropathy including a distal sensorimotor polyneuropathy, brachial plexopathy, or a rapidly progressive, severe ascending demyelinating motor neuropathy resembling Guillain-Barre syndrome [92, 93].

         5-Fluorouracil may rarely cause peripheral neuropathy with distal pain, numbness and weakness that partially resolve after discontinuation of the drug [94].

         Ifosfamide given in high doses can induce rapid worsening of a pre-existing mild chemotherapy-related axonal polyneuropathy.

         Intrathecal methotrexate has been associated with lumbosacral polyradiculopathy.  Patients develop subacute flaccid leg weakness occurring after several methotrexate injections, without pain or sensory disturbance [95].  MR scanning shows enhancement of nerve roots in the cauda equina.  Patients slowly improve after methotrexate is discontinued.

         Suramin may cause a mild distal axonal sensorimotor polyneuropathy, and less commonly has caused a subacute demyelinating polyneuropathy with areflexia and moderate to severe weakness similar to Guillain-Barre syndrome [96].

         Taxanes: A predominantly sensory or sensorimotor axonal polyneuropathy is a dose-limiting toxicity of paclitaxel (taxol) [97, 98] or docetaxel (taxotere) [99, 100]. The incidence and severity of neuropathy are related to the cumulative drug dose, and probably to the single-dose intensity as well.  Axonal injury is caused by disruption of microtubules.  Sensory symptoms include numbness and dysesthesias that usually begin distally in the legs but can be asymmetric or involve the hands or face early in the course. Muscle stretch reflexes are diminished.  Autonomic involvement and distal or proximal weakness with myalgias can occur in more severely affected patients [101, 102].  Electrophysiologic studies show early reduction or disappearance of sural sensory nerve potentials, with evidence of more widespread sensorimotor axonal neuropathy in severely affected patients.  The signs and symptoms may continue to worsen for several weeks after discontinuation of the drug, and then improve gradually.  Neuropathy may be more common and severe among diabetic patients.  Patients who received prior cisplatin or vincristine are more likely to develop severe sensorimotor polyneuropathy after paclitaxel or docetaxel [97, 101].

         Thalidomide may cause a mainly sensory polyneuropathy whose incidence and severity increase with higher cumulative dose exposure [103].  Symptoms improve after drug discontinuation.

         Vinca alkaloids: The dose-limiting toxicity of vincristine is a symmetric sensorimotor axonal polyneuropathy whose incidence and severity are related to the cumulative drug dose.  Disruption of microtubule formation and axoplasmic transport are believed to lead to axonal degeneration.  Nearly all patients develop some degree of neuropathy during the course of vincristine treatment.  The initial manifestations are usually paresthesias in the fingers and feet and loss of Achilles reflexes [104].  Some patients have muscle cramps.  Muscle stretch reflexes are diminished or lost early in the course.  Autonomic symptoms are common and include constipation, ileus, and less commonly urinary retention or orthostatic hypotension.  Patients may have severe autonomic involvement without severe sensorimotor symptoms in the limbs, or vice versa.  Occasional patients have jaw pain, facial weakness, diplopia, or other evidence for cranial neuropathies.  With continued vincristine administration sensory symptoms in the limbs progress proximally and distal weakness occurs in more severely affected cases.  Symptoms may worsen for a few months after vincristine is discontinued, and then improve slowly.  Electrophysiologic studies show reduced amplitude of sensory nerve potentials and prolonged distal motor latencies with normal or mildly slowed conduction velocities, indicating a primary axonal degeneration [104].  Hepatic insufficiency is a risk factor for more severe vincristine neuropathy.  Patients with type 1 Charcot-Marie-Tooth hereditary neuropathy are at particular risk for developing rapidly progressive, severe neuropathy after low cumulative doses of vincristine [105].  Patients receiving concomitant granulocyte- or granulocyte-macrophage-colony stimulating factor may be at risk for developing severe vincristine neuropathy [106].  Peripheral neuropathy is rarely caused by vinblastine, but a distal dose-dependent axonal sensorimotor polyneuropathy has been described after treatment with vinorelbine [107].

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