Thalidomide Neuropathy Research Articles

One-year prospective nerve conduction study of thalidomide neuropathy in lupus erythematosus: Incidence, coasting effect and drug plasma levels.

Few prospective studies in cutaneous and systemic lupus erythematosus (CLE/SLE) assessed thalidomide-induced peripheral neuropathy (TiPN) incidence/reversibility, and most have not excluded confounding causes neither monitored thalidomide plasma levels. To evaluate TiPN incidence/reversibility, coasting effect and its association with thalidomide plasma levels in CLE/SLE. One-year prospective study of thalidomide in 20 CLE/SLE patients without pregnancy potential, with normal nerve conduction study (NCS), and excluded other PN causes. Thalidomide levels were determined by high-performance liquid chromatography/tandem mass spectrometry. Twelve patients (60%) developed TiPN: 33.3% were symptomatic and 66.6% asymptomatic. Half of this latter group developed coasting effect (TiPN symptoms 1-3 months after drug withdrawal). The main predictive factors for TiPN were treatment duration ≥6 months (p = 0.025) and cumulative dose (p = 0.023). No difference in plasma thalidomide levels between patients with/without TiPN was observed (p = 0.464). After drug withdrawal, 75% symptomatic TiPN patients improved their symptoms. Seven TiPN patients underwent an additional NCS after drug withdrawal: 42.8% worsened NCS, 14.2% was stable, and 42.8% had improved NCS. Our data provides novel evidence of coasting effect in half of asymptomatic patients with TiPN. The irreversible nature of this lesion in 25% of TiPN patients reinforces the relevance of early NCS monitoring, and suggests thalidomide use solely as a bridge for other effective therapy for refractory cutaneous lupus patients.

Longitudinal Patterns of Thalidomide Neuropathy in Children and Adolescents

To characterize the longitudinal clinical and electrophysiological patterns of thalidomide neuropathy in children and adolescents. Retrospective analysis of clinical records at a tertiary care children's hospital, including serial electrophysiological studies. Sixteen patients aged 6-24 years received thalidomide to treat Crohn's disease from 2002 to 2012. Nine subjects had electrophysiological evidence of sensorimotor axonal polyneuropathy, 8 of whom had sensory and/or motor symptoms. The patients with polyneuropathy received thalidomide for 5 weeks to 52 months, with cumulative doses ranging from 1.4 to 207.7 g. All subjects with cumulative doses greater than 60 g developed polyneuropathy, and 4 of the 5 subjects who received thalidomide for more than 20 months developed polyneuropathy. The 7 subjects who had normal neurophysiological studies received therapy for 1 week to 25 months, with cumulative doses ranging from 0.7 to 47 g. In contrast to some previous reports, several patients had sensorimotor polyneuropathies, rather than pure sensory neuropathies. In patients with neuropathy who received therapy for more than 24 months and had 3 or more electromyography studies, the severity of the neuropathy plateaued. Factors in addition to the total dose may contribute to the risk profile for thalidomide neuropathy, including pharmacogenetic susceptibilities. The severity of the neuropathy does not worsen relentlessly. Children, adolescents, and young adults receiving thalidomide should undergo regular neurophysiological studies to monitor for neuropathy.

Toxic neuropathy

This paper examines recent research on toxic neuropathy and potential therapeutic developments. It also summarizes reports of new agents reported to cause peripheral neuropathy. Gene therapy with vasoactive endothelial growth factor, neurotrophic substances such as nerve growth factor and neurotrophin-3 are reported to reverse or protect against neurotoxicity in animal models. The neuroprotective effects of more established therapeutic agents like vitamin E, tacrolimus (FK 506) and erythropoietin hold promise for the immediate future. Cisplatin and high-dose pyridoxine are used more frequently to produce robust models of peripheral neuropathy in animals. Statins do appear to cause peripheral neuropathy. The incidence is low, however, and compared to its benefits in terms of cardiovascular protection, relatively innocuous. The profile of thalidomide neuropathy is becoming clearer as the indications for this drug increases. The incidence of thalidomide neuropathy is high, up to three quarters in some series, and although the information on dose dependency is variable, lower cumulative doses appear to be less toxic. Like thalidomide bortezomib, a novel proteosome inhibitor, is reportedly effective in the treatment of multiple myeloma and is associated with peripheral neuropathy. Oxaliplatin and epothilone are emerging anticancer drugs with neurotoxic potential. Similarly, leflunomide, a new disease modifying-agent approved for the treatment of rheumatoid arthritis, is reported to cause neuropathy. The study of toxic neuropathy is not only enhancing our knowledge of the mechanisms of neurotoxicity but also the neurobiology of peripheral neuropathy in general; and is likely to reveal avenues for therapeutics.

Thalidomide neuropathy in childhood

Thalidomide was withdrawn from world markets in 1961 following recognition of its teratogenic effects. More recently, however, thalidomide treatment has been reintroduced to adult and paediatric practice for a variety of dermatologic, immunologic, rheumatologic and neoplastic disorders. Neuropathy is a significant side effect of thalidomide therapy, which may limit its clinical use. We report four cases of sensorimotor axonal neuropathy in children aged 10–15 years, treated with thalidomide for myxopapillary ependymoma, Crohn's disease and recurrent giant aphthous ulceration. Thalidomide neuropathy is often associated with proximal weakness and may progress even after discontinuation of treatment, in the phenomenon of ‘coasting’. Children treated with thalidomide should undergo regular neurophysiologic studies in order to detect presymptomatic or progressive peripheral neuropathy.

Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features.

Thalidomide is a promising therapy for multiple myeloma. Sensory neuropathy is a side effect of thalidomide and resulted to be partially reversible in 50% of cases, suggesting a sensory ganglionopathy. Spinal cord magnetic resonance imaging (MRI) was found to be useful in the diagnosis of sensory ganglionopathies and we use it to determine if thalidomide neuropathy has features of a ganglionopathy. Six patients with multiple myeloma developed thalidomide-induced polyneuropathy. Nerve conduction studies, somatosensory-evoked potentials (SEPs) and cervical and dorsal spinal cord MRI were obtained in all. All patients had a sensory neuropathy, with clinical or electrophysiological abnormalities involving all four limbs. Spinal cord MRI showed high signal intensity in the posterior columns in only one patient, with abnormal central conduction time at SEPs. Our results suggest that thalidomide can induce either an axonal length-dependent neuropathy or, less frequently, a ganglionopathy.

Incidence and Risk Factors for Thalidomide Neuropathy: a Prospective Study of 135 Dermatologic Patients

Thalidomide is effective in several cutaneous diseases. Peripheral neuropathy is the most important adverse event limiting its use. Its incidence rate and its relation to thalidomide doses remain unclear. We prospectively monitored 135 patients treated with thalidomide for various dermatologic diseases for 2 y in order to estimate the annual incidence rate and risk factors for neuropathy. Patients underwent standardized neurologic examination and nerve conduction studies prior to, and regularly during treatment. Risk factors for neuropathy were assessed using a Cox proportional-hazards model. Clinical and electrophysiologic evidence of a thalidomide-induced neuropathy were present in 25.2% of the patients; however, when considering all potential cases, this rate reached 55.6%. The incidence rate was maximal during the first year of treatment (20%). The risk of neuropathy was related to the daily dose whatever the duration of treatment (p<10-3). Considering a daily dose < or =50 mg per day as reference, the relative risk for thalidomide neuropathy was 8.2 for a daily dose comprised between 50 and 75 mg per day and 20.2 for a daily dose >75 mg per day (p<10-3). No neuropathy occurred for daily doses < or =25 mg per day. The neuropathy was subclinical in nearly a quarter of patients with such an adverse event. These data confirm the high rate of thalidomide neuropathy and identify the daily dose as the main risk factor. The risk of neuropathy seems to be negligible for doses less than 25 mg per day, whatever the duration of therapy.

DIFFERENT PATHOGENESIS OF THALIDOMIDE NEUROPATHY IN MULTIPLE MYELOMA.

Background: In the past few years thalidomide became one of the most interesting chemotherapeutic drugs in the treatment of multiple myeloma. However a predominantly sensory neuropathy is a well‐known side effect of thalidomide in a substantial amount of patients. Peripheral nerve damage resulted to be at lest partially reversible only in 50% of cases suggesting a possible toxic effect on dorsal rot ganglion neurons. Spinal cord MRI was indicated as a useful tool in the diagnosis of sensory ganglionopathy. We described MRI findings in 6 patients with thalidomide neuropathy and multiple myeloma. Patients: Six patients (4 men, 2 women, mean age 61.2 ± 8.6 years) were included: two had non‐secretory, 3 osteolytic and 1 osteosclerotic myeloma. Thalidomide was administered orally at a dose of 200 mg/day in 4 patients, and at a dose of 100 mg/day in 2. All patients where asymptomatic for peripheral neuropathy before treatment. Five of them were previously treated with vincristine and 4 with cisplatin, both at low doses. Positive sensory symptoms developed 6 to 19 months after treatment beginning: all patients had paresthesia; 2 had pain in stocking and glove distribution. One patient developed sensory ataxia. On nerve conduction studies, all patients had decreased or absent sensory action potential both at upper and lower limbs. Methods: Cervical spine routine MRI was performed in all patients with a 1 T system, with sagittal T2 FSE spin echo (TR/TE excitations 3909 / 112), axial gradient echo (630/22/30)—weighted images. Results: Cervical spine MRI was normal in 5 patients. In 1 patient, however, MRI disclosed a small T2‐weighted high signal intensity in the posterior columns. Discussion: Our results suggest that thalidomide could have a different toxic effect on the peripheral nervous system than on dorsal root ganglion neurons and axons.

Thalidomide neuropathy in patients treated for metastatic prostate cancer

We prospectively evaluated thalidomide-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic androgen-independent prostate cancer in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection.

Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet's disease: use of neurophysiological studies to detect thalidomide neuropathy.

To examine the efficacy, dose, and safety profile, including neurophysiological testing of thalidomide used in 59 patients (including 23 with Behçet's disease) to treat severe oral or genital ulceration (OGU). We identified prospectively subjects (including women of childbearing potential) who had persistent OGU over periods lasting one to 40 years and whose active ulceration was not controlled by other therapies. They were treated with thalidomide. Retrospectively, we identified the number of subjects with complete resolution of the ulcers at one and two months of thalidomide therapy, and the dose required to maintain that improvement in those individuals who relapsed after stopping thalidomide. The decrease from the baseline sensory nerve action potential (baseline SNAP) amplitude value (derived from median, radial and sural nerve SNAPs) at which the development of paraesthesiae was likely to occur was also determined. Complete resolution of the ulcers occurred in 81% of patients within one month of thalidomide therapy at doses of 200 mg/day. No further thalidomide was required by 20% of patients responding and in the remainder improvement was maintained with smaller doses (7-200 mg/day). Using an approximate 50% decrease from baseline SNAP as an indication to discontinue thalidomide, the incidence of symptomatic neuropathy was 13.5%. No patients with a decrease of less than 42% developed neuropathy, and a further 13.5% were asymptomatic with a decrease in SNAP between 42 and 69%. Other side effects were seen in 44% of patients. There were no pregnancies and no requirement for urgent pregnancy testing. Thalidomide provided a useful therapeutic option in severe oral and genital ulceration which had not responded to other therapies. The physician must remain vigilant to the continuing danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy.

Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients

Thalidomide therapy was shown to be effective in numerous dermatologic diseases. As reliable methods of contraception are now available, neurotoxicity has become the most important side effect limiting the use of thalidomide. The incidence of this neuropathy and its relationship to thalidomide doses are still matters of debate. In a retrospective study, we reviewed the files of 42 patients who had received thalidomide between 1987 and 1992 for various dermatologic diseases. The incidence and the conditions of occurrence of the neuropathy were analyzed. Evidence of a thalidomide-induced neuropathy was present in nine patients (21%), who had both clinical and electrophysiologic typical abnormalities. Twelve other patients (28%), however, presented with isolated clinical or electrophysiologic signs. Thus, the diagnosis of thalidomide neuropathy could not be affirmed. The occurrence of the neuropathy did not appear to be related to the daily dose nor to the duration of treatment. The highest risk of developing a thalidomide neuropathy was found in female and elderly patients. Two monozygotic twin sisters, who received thalidomide for Behçet's disease, both developed a neuropathy. These data suggest that the incidence of thalidomide neuropathy may be between 21% and 50%. Individual susceptibilities with possible genetic predisposition seem to be more important than daily dose and duration of thalidomide therapy.

Thalidomide Neuropathy Incidence and Clinicoelectrophysiologic Findings in 42 Patients

Background and Design: Thalidomide therapy was shown to be effective in numerous dermatologic diseases. As reliable methods of contraception are now available, neurotoxicity has become the most important side effect limiting the use of thalidomide. The incidence of this neuropathy and its relationship to thalidomide doses are still matters of debate. In a retrospective study, we reviewed the files of 42 patients who had received thalidomide between 1987 and 1992 for various dermatologic diseases. The incidence and the conditions of occurrence of the neuropathy were analyzed. Results: Evidence of a thalidomide-induced neuropathy was present in nine patients (21%), who had both clinical and electrophysiologic typical abnormalities. Twelve other patients (28%), however, presented with isolated clinical or electrophysiologic signs. Thus, the diagnosis of thalidomide neuropathy could not be affirmed. The occurrence of the neuropathy did not appear to be related to the daily dose nor to the duration of treatment. The highest risk of developing a thalidomide neuropathy was found in female and elderly patients. Two monozygotic twin sisters, who received thalidomide for Behcet's disease, both developed a neuropathy. Conclusions: These data suggest that the incidence of thalidomide neuropathy may be between 21% and 50%. Individual susceptibilities with possible genetic predisposition seem to be more important than daily dose and duration of thalidomide therapy. (Arch Dermatol. 1994;130:66-69)

P 109 Thalidomide neuropathy: incidence and clinico-electrophysiological features in 42 patients

P 109 Thalidomide neuropathy: incidence and clinico-electrophysiological features in 42 patients

Experimental thalidomide neuropathy: the morphological correlate of reduced conduction velocity.

Morphological studies of experimental thalidomide neuropathy have thus far failed to show any significant structural changes. The present investigation was performed on sural nerves of female New Zealand white rabbits showing a reduction of sensory conduction velocity after oral treatment with thalidomide (100 mg/kg b. wt. per day) for a period of 33 weeks. Rabbits of the same strain and equal sex, weight, and number served as controls. Very few nerve fibers were undergoing Wallerian degeneration in both groups, experimental animals and controls. Morphometry, however, revealed a statistically significant reduction of the mean myelin thickness of sural nerve fibers in the thalidomide group of rabbits as compared to controls. The mean myelin thickness of the largest nerve fibers was also significantly smaller than in the control group. On the other hand, axonal diameters were not significantly altered. The association between the decrease of the sensory conduction velocity, the reduction of the myelin sheath thickness, and the chronic thalidomide application is discussed.

Abstracts

Intracellular calcium and freeze fracture plasmalemmal changes of skeletalmuscle cells in Duchenne muscular dystrophy (DMD). The evolution of muscle cell necrosis in early stages and in male fetuses at risk U.‐P. KetelsenExperimental mitochondriopathy by electric stimulation of skeletal muscle in rats R. Kleinert, M. Beck‐Simmler and G. F. WalterEnzymhistochemistry in normal pelvic sphincters E. Reske‐Nielsen and H. Daa SchraderEffects of vitamin E deficiency on skeletal muscle in the rat* W. Roggendorf and J. Nelson'Mixed nemaline‐core myopathy with adult‐onset R. J. Seitz. K. V. Toyka and W. WechslerNerve fiber lesions and the consequences interpreted by enzyme histochemistry E. ThomasExperimental thalidomide neuropathy: the morphological correlate of reduced conduction velocity J. M. Schroder and T. Matthiesen

Thalidomide neuropathy: a clinical electrophysiological, and histological follow-up study.

Thalidomide neuropathy: a clinical electrophysiological, and histological follow-up study.