Chemotherapy-induced neuropathy

Abstract Neurotoxic side effects of cancer therapy are second in frequency to hematological toxicity. Unlike hematological side effects that can be treated with hematopoietic growth factors, neuropathies cannot be treated and protective treatment strategies have not been effective. For the neurologist, the diagnosis of a toxic neuropathy is primarily based on the case history, the clinical and electrophysiological findings, and knowledge of the pattern of neuropathy associated with specific agents. In most cases, toxic neuropathies are length‐dependent, sensory, or sensorimotor neuropathies often associated with pain. The platinum compounds are unique in producing a sensory ganglionopathy. Neurotoxicity is usually dependent on cumulative dose. Severity of neuropathy increases with duration of treatment and progression stops once drug treatment is completed. The platinum compounds are an exception where sensory loss may progress for several months after cessation of treatment (“coasting”). As more effective multiple drug combinations are used, patients will be treated with several neurotoxic drugs. Synergistic neurotoxicity has not been extensively investigated. Pre‐existent neuropathy may influence the development of a toxic neuropathy. Underlying inherited or inflammatory neuropathies may predispose patients to developing very severe toxic neuropathies. Other factors such as focal radiotherapy or intrathecal administration may enhance neurotoxicity. The neurologist managing the cancer patient who develops neuropathy must answer a series of important questions as follows: (1) Are the symptoms due to peripheral neuropathy? (2) Is the neuropathy due to the underlying disease or the treatment? (3) Should treatment be modified or stopped because of the neuropathy? (4) What is the best supportive care in terms of pain management or physical therapy for each patient? Prevention of toxic neuropathies is most important. In patients with neuropathy, restorative approaches have not been well established. Symptomatic and other management are necessary to maintain and improve quality of life.     

Ataxic sensory neuropathy and Lyme disease

INTRODUCTION: The clinical spectrum of peripheral neuropathies in Lyme disease is very wide. We report a case which was revealed by an ataxic sensory neuropathy. OBSERVATION: A 77-year-old patient presented with a subacute ataxic sensory neuropathy which occurred 2 weeks after a skin lesion involving the right lower limb. He fully recovered after specific antibiotic treatment. EMG was suggestive of a predominantly axonal neuropathy. Diagnosis of Lyme disease was assessed by progressive elevation of serum antibodies, demonstration of a lymphocytic meningitis and intrathecal synthesis of antibodies. CONCLUSION: Lyme disease may be added to the list of diseases which may induce subacute sensory neuropathies.     

Autoantibodies associated with peripheral neuropathy.

High titers of serum antibodies to neural antigens occur in several forms of neuropathy. These include neuropathies associated with monoclonal gammopathy, inflammatory polyneuropathies, and paraneoplastic neuropathies. The antibodies frequently react with glycosylated cell surface molecules, including glycolipids, glycoproteins, and glycosaminoglycans, but antibodies to intracellular proteins have also been described. There are several correlations between antibody specificity and clinical symptoms, such as anti-MAG antibodies with demyelinating sensory or sensorimotor neuropathy, anti-GM1 ganglioside antibodies with motor nerve disorders, antibodies to gangliosides containing disialosyl moieties with sensory ataxic neuropathy and Miller-Fisher syndrome, and antibodies to the neuronal nuclear Hu antigens with paraneoplastic sensory neuronopathy. These correlations suggest that the neuropathies may be caused by the antibodies, but evidence for a causal relationship is stronger in some examples than others. In this review, we discuss the origins of the antibodies, evidence for and against their involvement in pathogenic mechanisms, and the implications of these findings for therapy.     

Update on hereditary neuropathy]

Hereditary neuropathies are classified into several subtypes according to clinical, electrophysiologic and pathologic findings. Recent genetic studies have revealed their phenotypic and genetic diversities. In the primary peripheral demyelinating neuropathies (CMT1), at least 15 genes have been associated with the disorders; altered dosage or point mutation of PMP22, GJB1, MPZ, EGR2, MTMR2, NDRG1, PRX, SOX10, GDAP1 and MTMR13/SBF2. In the primary peripheral axonal neuropathies (CMT2), at least 10 genes have been associated with these disorders; NEFL, KIF1B, MFN2, GAN1, LMNA, RAB7, GARS, TDP1, APTX, and SETX. In addition, some mutations in GJB1, MPZ, GDAP1 and NEFL also present with clinical and electrophysiologic findings of CMT2. Patients with TDP1, APTX or SETX mutations share common clinical findings; autosomal recessive inheritance, cerebellar ataxia, and axonal neuropathy. These genes are suspected to be related to DNA/RNA repair and induce cell death especially in neuronal cells. In addition to the above diseases, we have reported a new type of NMSNP (MIM# * 604484) characterized by proximal dominant neurogenic atrophy, obvious sensory nerve involvement and the gene locus on 3q12.3. Here, we summarize the genetic bases of hereditary neuropathies and attempt to highlight significant genotype-phenotype correlations with a special interest in nonsense-mediated mRNA decay pathway.     

A new animal model of vincristine-induced nociceptive peripheral neuropathy

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague-Dawley rats. In order to validate the model, three different doses (50, 100 and 150 microg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 microg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.     

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.     

Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy

The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection.We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.     

Chronic dysimmune neuropathy

The Chronic Dysimmune neuropathies (CDN) are a clinically heterogeneous group of polyneuropathies united by their presumed immune mediated aetiology. At present such neuropathies are classified as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Multifocal Motor Neuropathy (MMN) and the Neuropathies in association with serum Paraproteins (Paraproteinaemic Neuropathies). This classification fails to recognise other distinctive syndromes and is limited by heterogeneity within, and overlap between, subgroups. We have refined this clinical subclassification by a review of a consecutive series of 102 unselected patients with CDN referred to a single neurologist. We recognise 6 clinical subtypes of CDN: one sensory ataxic group; three motor-sensory subgroups (chronic motor sensory demyelinating neuropathy, subacute motor sensory demyelinating neuropathy and a multifocal motor sensory neuropathy); and two pure motor subgroups (symmetric pure motor demyelinating neuropathy and multifocal motor neuropathy). This subclassification allows distinct syndromes to be recognised and helps resolve problems of heterogeneity and overlap. Distinction between these subgroups is of immediate practical relevance to patient management. Although steroids are beneficial for most of the subgroups, this is not so for both of the pure motor syndromes which should be treated with intravenous immunoglobulin. Patients with chronic development of Motor Sensory Demyelinating Neuropathy respond less well to steroids than those with a subacute onset. An association was found between elderly patients with Subacute Motor Sensory Demyelinating Neuropathy and carcinomas. Within any clinical subgroup patients behave similarly regardless of the presence of associated paraproteins or nerve specific antibodies. Received: 19 March 2002, Received in revised form: 2 January 2003, Accepted: 13 January 2003 Correspondence to: Dr. M. Donaghy     

Recent advances in HIV neuropathy

PURPOSE OF REVIEW: To describe recent advances in HIV neuropathy. RECENT FINDINGS: Epidemiologic studies since highly active antiretroviral therapy was introduced have shown that the incidence of HIV-associated distal sensory polyneuropathy is reduced. Studies have also shown the relationship between distal sensory polyneuropathy and the use of neurotoxic antiretroviral drugs. Skin punch biopsy for assessment of epidermal nerve fiber density is valuable both for diagnosis of distal sensory polyneuropathy and as a predictor of the condition occurring in the future. An in-vitro model of antiretroviral toxic neuropathy showed that dideoxynucleoside analogues that cause neuropathy exert direct mitochondrial toxicity that is not mediated indirectly through the inhibition of DNA polymerase-gamma. HIV envelope protein gp120 exerts axonal toxicity directly or indirectly via perineuronal Schwann cells. A feline model of HIV, infection of neonatal cats with the feline immunodeficiency virus, showed development of peripheral neuropathy characterized by loss of epidermal innervation. SUMMARY: While epidemiological studies of HIV-associated peripheral neuropathy continue to provide useful information, pathogenic studies are moving forward. Animal models of the disease will allow researchers to 'manipulate' the system. It is hoped that these types of studies will translate to an improved understanding of the pathogenesis of HIV-associated neuropathies leading to better treatments.     

Animal Models of Peripheral Neuropathies

Peripheral neuropathies are common neurological diseases, and various animal models have been developed to study disease pathogenesis and test potential therapeutic drugs. Three commonly studied disease models with huge public health impact are diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, and human immunodeficiency virus-associated sensory neuropathies. A common theme in these animal models is the comprehensive use of pathological, electrophysiological, and behavioral outcome measures that mimic the human disease. In recent years, the focus has shifted to the use of outcome measures that are also available in clinical use and can be done in a blinded and quantitative manner. One such evaluation tool is the evaluation of epidermal innervation with a simple skin biopsy. Future clinical trials will be needed to validate the translational usefulness of this outcome measure and validation against accepted outcome measures that rely on clinical symptoms or examination findings in patients.     

Antidisialosyl antibodies in chronic idiopathic ataxic neuropathy

Antidisialosyl antibodies were found in two out of 13 patients with chronic idiopathic ataxic neuropathy (CIAN) and not in 32 patients with different sensory neuropathies of known cause. This finding confirms the association of antidisialosyl antibodies and CIAN regardless of the absence of the M band. These antibodies may have pathogenic relevance; however, larger series are needed to establish their clinical significance.     

Pathogenetic mechanism of experimental autoimmune neuropathy induced by sensitization with a ganglioside]

Antiganglioside antibodies are frequently present in sera from patients with autoimmune neuropathies. To elucidate the pathogenetic mechanisms of autoimmune neuropathies mediated by antiganglioside antibodies, we established a rabbit model of sensory ataxic neuropathy induced by sensitization with ganglioside GD1b (GD1b-SAN). Degeneration of primary sensory neurons extending the central axons to the dorsal column of spinal cord was observed pathologically. No lymphocytic cell infiltration was seen. Anti-GD1b antibody therefore should be an essential factor to induce GD1b-SAN. In sera from rabbits immunized with GD1b, two types of antibodies were present; antibodies monospecific to GD 1 b and those cross-reactive with GM1. Of 22 rabbits sensitized with GD1b, 12 developed GD1b-SAN. The level of IgG antibody monospecific to GD1b was higher in the sera from affected rabbits than in those from unaffected ones. The GD1b-positive neuronal cytoplasms of rabbit dorsal root ganglia had larger diameters than the GD1b-negative ones. Markedly reduced expression of trkC in dorsal root ganglia from rabbits with GD1b-SAN in acute phase was found. IgG antibody monospecific to GD1b may cause GD1b-SAN by preferentially binding to large primary sensory neurons mediating proprioceptive sensation. Anti-GD1b antibody-mediated downregulation of trkC expression could be one of the pathogenesis of GD 1 b-SAN.     

Skin biopsy in the management of peripheral neuropathy

Skin biopsy has been widely used in recent years for the investigation of small-calibre sensory nerves, including somatic unmyelinated intraepidermal nerve fibres, dermal myelinated nerve fibres, and autonomic nerve fibres in peripheral neuropathies, with different techniques for tissue processing and nerve fibre assessment. Here, we review the techniques for skin biopsy, the processing and assessment of the biopsy sample, their possible uses in different types of peripheral neuropathy, and their use in the follow-up of patients and in clinical trials. We also review the association between morphological measures of skin innervation and function and the limits of this method in the aetiological classification of peripheral neuropathies.     

Infectious neuropathy

PURPOSE OF REVIEW: Infectious neuropathy affects a large number of people worldwide. There is evidence of direct involvement of nerves by the infective agent, from the immune reaction of the patient or secondary to the toxicity of the drugs used during treatment. This group of neuropathies is often treatable or preventable. RECENT FINDINGS: There is a complex clinical picture of the neuropathy of leprosy, different pathological features and immunological mechanisms. If the skin is unaffected in leprosy it is not always easy to demonstrate that the neuropathy is due to leprosy. Peripheral neuropathy in patients with chronic infection with hepatitis C virus may be due to the virus, the development of vasculitis or direct neurotoxic effects of the treatment. Peripheral neuropathy has become the chief neurological syndrome in individuals infected with HIV-1. The antiretroviral therapies themselves can cause peripheral neuropathies clinically indistinguishable from those caused by the virus. The occurrence of chronic polyneuropathy as a late manifestation in Lyme disease is extremely rare and is not well understood. SUMMARY: Although infectious neuropathies are very frequent, mainly in developing countries, further studies are needed to elucidate their mechanisms of action, focusing on preventive interventions.     

A high-dose bortezomib neuropathy with sensory ataxia and myelin involvement

Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, is known to induce an axonal, dose-dependent neuropathy clinically characterized by pain, paresthesias, burning dysesthesias and numbness. In this study, we describe a patient treated with high-dose bortezomib whose main clinical feature was severe sensory ataxia. Electrodiagnostic studies showed, other than axonal changes, myelin involvement.     

Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci

OBJECTIVE: To elucidate genetic heterogeneity in ulcero-mutilating neuropathy. BACKGROUND: Ulcero-mutilating features and sensory loss have been observed in hereditary sensory neuropathy (HSN) and hereditary motor and sensory neuropathy (HMSN). HSN is characterized by marked distal sensory loss, frequent toe and foot ulcerations, osteomyelitis, and necrosis, which may be complicated by toe or limb amputations. Motor and autonomic nerve involvement can also occur to a variable degree. Recently, autosomal-dominant HSN type I was mapped to chromosome 9q22 in four families. In two other families with ulcero-mutilating neuropathy, a gene locus was assigned to chromosome 3q13-q22. Because motor symptoms were prominent in these latter two kinships, the disease was designated HMSN type IIB or Charcot-Marie-Tooth type 2B (CMT2B) neuropathy. METHODS: We report detailed clinical, electrophysiologic, and genetic data on a large Austrian family with ulcero-mutilating neuropathy, sensory loss, and amputations. RESULTS: Linkage analysis with chromosomal markers representing the HSN I and HMSN IIB loci excluded these gene loci in our family. CONCLUSIONS: These findings therefore indicate the existence of a third gene locus in autosomal-dominant inherited ulcero-mutilating neuropathies, showing that these neuropathies are genetically highly heterogeneous.     

Recent advances in hereditary sensory and autonomic neuropathies

PURPOSE OF REVIEW: This review summarizes the genetic advances of hereditary sensory neuropathies and hereditary sensory and autonomic neuropathies, and provides information on phenotype-genotype correlation and on possible underlying pathomechanisms. RECENT FINDINGS: Hereditary sensory neuropathies, also known as hereditary sensory and autonomic neuropathies, are a clinically and genetically heterogeneous group of disorders. These disorders are characterized by prominent sensory loss with acro-mutilating complications and a variable degree of motor and autonomic disturbances. Based on age at onset, clinical features and mode of inheritance, these disorders have originally been subdivided into five types. The identification of eight loci and six disease-causing genes for this group of disorders, however, has shown that this present classification has to be refined. SUMMARY: This review will discuss each of the different loci and genes of these disorders, showing glimpses into a possible underlying pathomechanism leading to the degeneration of sensory and autonomic neurons.     

Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy.

In previous work we demonstrated little effect of aging on the density and spatial pattern of epidermal innervation, however, this was restricted to two sites proximal and distal in the leg. To expand on these observations, we used punch skin biopsy in ten healthy controls to examine the variation in intra-epidermal nerve fiber (IENF) density at multiple specific sites in the leg. There was a consistent gradient in IENF from proximal to distal sites in all subjects, but minimal effect of age was noted. In the older age group (> or =70 years), the IENF densities ranged from 28.6+/-1.9 IENF/mm at the trunk to 15.5+/-1.5 at the distal leg. In a group of six patients with painful sensory neuropathy, we confirmed a length-dependent reduction in IENF. We observed what may be a predegenerative change, namely increased branching of epidermal nerve fibers at clinically unaffected sites. These data suggest little age-related change in IENF, at least up to age 75 years, in healthy normals. The increased branching complexity noted in unaffected sites in patients with sensory neuropathies implies that this may be a predegenerative change, preceding the actual loss of nerve fibers. Skin biopsy may be a useful tool for assessing the topographic extent and degree of nerve fiber damage in sensory neuropathies and its quantitative interpretation should be little affected by aging changes.     

Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line

Development of neuroprotective strategies for peripheral neuropathies requires high-throughput drug screening assays with appropriate cell types. Currently, immortalized dorsal root ganglion (DRG) sensory neuronal cell lines that maintain nociceptive sensory neuronal properties are not available. We generated immortalized DRG neuronal lines from embryonic day 14.5 rats. Here, we show that one of the immortalized DRG neuronal lines, 50B11, has the properties of a nociceptive neuron. When differentiated in the presence of forskolin, these cells extend long neurites, express neuronal markers, and generate action potentials. They express receptors and markers of small-diameter sensory neurons and upregulate appropriate receptor populations when grown in the presence of glial cell line-derived neurotrophic factor or nerve growth factor. Furthermore, they express capsaicin receptor transient receptor potential vanilloid family-1 (TRPV-1) and respond to capsaicin with increases in intracellular calcium. In a 96-well plate format, these neurons show a decline in ATP levels when exposed to dideoxycytosine (ddC) in a proper time- and dose-dependent manner. This ddC-induced reduction in ATP levels correlates with axonal degeneration. The immortalized DRG neuronal cell line 50B11 can be used for high-throughput drug screening for neuroprotective agents for axonal degeneration and antinociceptive drugs that block TRPV-1.     

Autonomic dysfunction in peripheral nerve disease

Autonomic neuropathies are inherited or acquired neuropathies in which autonomic nerve fibers are selectively or disproportionately affected. Generally, sympathetic and parasympathetic fibers are both affected but there are exceptions. Acquired cases can be autoimmune; due to diabetes, amyloidosis, drugs, or toxins; or idiopathic. Autoimmune autonomic neuropathy is often subacute, sometimes associated with a neoplasm, and associated with high titers of antibody to ganglionic nicotinic acetylcholine receptor in about half of the severe cases. The molecular basis of inherited autonomic neuropathies is better known, including recent identification of the loci and genes of hereditary sensory and autonomic neuropathies types I, III, and IV. The inherited amyloid neuropathies are due to mutations of three proteins: transthyretin, apolipoprotein A1, and gelsolin. Non-invasive autonomic testing complements clinical and electrophysiological characterization of the autonomic neuropathies.