Chronic Sensory Neuropathy Research Articles

Mitotoxicity in distal symmetrical sensory peripheral neuropathies.

Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor--that is, intraepidermal nerve fibres--of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.

Treatment of notalgia paresthetica with botulinum toxin A: A double-blind randomized controlled trial

To the Editor: Notalgia paresthetica (NP) is a chronic sensory neuropathy affecting the interscapular area, especially the T2-T6 dermatomes and characterized by pruritus on the upper back with cutaneous signs associated with rubbing and scratching.1,2 Botulinum toxin A (BTX-A) could have beneficial effects on localized pruritus, possibly by preventing the release of substance P, a mediator involved in pain and itch.3,4 One publication reports complete resolution of pruritus in 2 patients with NP treated with BTX-A.

The search for treatments to reduce chemotherapy-induced peripheral neuropathy

Oxaliplatin, a commonly used chemotherapeutic agent, is associated with both acute and chronic neurotoxicity. Chronic sensory neuropathy can be dose limiting and may have detrimental effects on patients' quality of life. Preclinical studies provide an understanding of the pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) and may be important for developing effective preventative interventions. In this issue of the JCI, Coriat and colleagues used an animal model and a human pilot trial to evaluate the use of mangafodipir to reduce CIPN. Although many pilot clinical studies have reported promising data, larger clinical trials have repeatedly been unable to confirm these preliminary results. Thus, no agents are currently clinically recommended for the prevention of CIPN.

Anti-voltage-gated potassium channel antibody is associated with chronic autonomic and sensory neuropathy

Anti-voltage-gated potassium channel antibody is associated with chronic autonomic and sensory neuropathy

Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy

Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1–2days after and 3–4weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.

Management of peripheral neuropathy for cancer patients

Neuropathy in cancer patients or patients with peripheral neuropathy is a common and often difficult and debilitating complication of cancer or the treatment-related. Chemotherapy-Induced Peripheral Neuropathy (CIPN) is most widely reported and has been the focus of research efforts among the various types of neuropathies in cancer patients. Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies, but their acute and motor neurotoxicities are less well characterized. Multidisciplinary team was charged with the review the literature and discussion intervention strategies currently available to patients as well as areas that require research efforts for the possible prevention, diagnosis, and management of peripheral neuropathy. Effective management of neuropathy or CIPN depends on early diagnosis and an understanding of its underlying causes in the individual patient. Patients with neuropathic pain (NP) are also challenging to manage and evidencebased clinical recommendations for pharmacologic management are needed. The objectives of this article are to discuss: Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated in prevention, assessment and treatment of the various types of neuropathies in cancer patients

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BackgroundOxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity- acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na+ channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na+ channel dysfunction.Methodology/Principal FindingsSpecifically the function of transient and persistent Na+ currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na+ channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na+ conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = −.65; P<.05; Sensory correlation coefficient = .67; P<.05).Conclusions/SignificanceIt is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na+ conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.

Chondroitin beta-1,4-N-acetylgalactosaminyltransferase-1 missense mutations are associated with neuropathies

Chondroitin sulfate proteoglycans (CSPGs) in the peripheral nervous system likely participate as regulatory molecules in the process of axonal degeneration and regeneration. We investigated the chondroitin beta1,4-N-acetylgalactosaminyltransferase-1 (ChGn-1) gene in 114 patients affected with neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, hereditary motor and sensory neuropathy (HMSN) and unknown etiology. The controls were 196 patients with other neurological diseases. We found novel missense mutations in two patients with neuropathy (Bell's palsy, unknown HMSN) in exons 5 (H234R) and 10 (M509R), respectively. None of the patients with other neurological diseases had either of these mutations. We then synthesized the two soluble forms of ChGn-1, containing each of the above mutations. Each of the soluble mutants was expressed in COS-1 cells and the mutant proteins were purified. The purified mutant proteins were used for western blotting analysis using an anti-ChGn-1 antibody and evaluated for glycosyltransferase activities. Although the expression of the ChGn-1 mutant proteins was confirmed by western blotting, they exhibited no N-acetylgalactosamineT-II activities. It is possible that these mutations are associated with the pathogenetic mechanisms of the peripheral neuropathies.

PATU2 Novel truncation mutation of PRNP causes chronic diarrhoea, sensory neuropathy and autonomic failure associated with prion protein deposition in the cerebral blood vessels and small bowel

The inherited prion diseases (IPD) are a group of dominantly inherited neurodegenerative disorders caused by mutation of the prion protein gene (PRNP). Although clinically heterogeneous, IPDs are generally associated with...

European Federation of Neurological Societies/Peripheral Nerve Society Guideline* on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision

The aim of this guideline is to update the 2006 EFNS/PNS guideline on management of patients with a demyelinating neuropathy and a paraprotein (paraproteinemic demyelinating neuropathy [PDN]) by review of evidence and expert consensus. In the absence of adequate evidence, the panel agreed on good practice points: (1) patients with PDN should be investigated for a malignant plasma cell dyscrasia; (2) a monoclonal gammopathy of undetermined significance is more likely to be causing the neuropathy if it is immunoglobulin (Ig)M, anti-neural antibodies are present, and the clinical phenotype is chronic distal sensory neuropathy; (3) patients with IgM PDN usually have predominantly distal sensory impairment, prolonged distal motor latencies, and often anti-myelin-associated glycoprotein antibodies; (4) IgM PDN may respond to immunomodulatory therapies. Their potential benefit should be balanced against possible side effects and the usually slow disease progression; (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy; and (6) Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes syndrome is a multi-system malignant PDN.

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

BackgroundPlatinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.MethodsTwenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.ResultsAbnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).ConclusionsAbnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.

Motor neuropathies and serum IgM binding to NS6S heparin disaccharide or GM1 ganglioside

BackgroundSerum IgM binding to GM1 ganglioside (GM1) is often associated with chronic acquired motor neuropathies. This study compared the frequency and clinical associations of serum IgM binding to a different...

Achalasia, chronic sensory neuropathy, and N-type calcium channel autoantibodies: beneficial response to IVIG.

Autoimmune gastrointestinal dysmotility (AGID) can result from paraneoplastic onconeuronal antibodies. Patients may present with regional hypomotility anywhere along the gastrointestinal tract. We report a case of a woman who developed an insidious sensory neuropathy and achalasia. She was found to have a high-titer of N-type voltage gated-calcium channel (VGCC) antibodies. She demonstrated clinical and electrophysiological improvement of her neuropathy, as well as improvement of her swallowing and gait, after treatment with intravenous immunoglobulins.

The efficacy of ogikeishigomotsuto on chronic cumulative sensory neuropathy induced by Oxaliplatin - case report and literature view.

The efficacy of ogikeishigomotsuto on chronic cumulative sensory neuropathy induced by Oxaliplatin - case report and literature view.

Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy

Objective:To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies.Methods:Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in...

Neurological morbidity in survivors of childhood acute lymphoblastic leukemia (ALL)

9529 Background: The majority of children diagnosed with ALL over the past two decades have achieved long-term survival. This remarkable success is attributed in part to intensive central nervous system (CNS)-directed therapy that effectively prevents CNS relapse. Because treatment-related neurological morbidity is recognized but poorly characterized, the objective of this cross-sectional study was to estimate the prevalence of neurological symptoms and signs in long-term survivors of childhood ALL. Methods: After obtaining IRB approval, all long-term ALL survivors (≥ 5 years since diagnosis) aged 6–28 years who remained active patients at our institution were identified. All participants completed a questionnaire consisting of independent (and when possible validated) instruments designed to identify various neurological symptoms, as well as, a comprehensive and standardized neurologic examination by a board-certified neurologist. Results: Of the 433 potentially eligible subjects, 162 (37.4%) were enrolled. Participant demographic information and previous treatment exposure were similar to those not enrolled in the study. The rates of endorsed neurological symptoms were: neuropathy (40.1%), dizziness (33%), back pain (22.8%), fatigue (19.1%), falls (15.4%), headache (14.8%), seizures (10.5%), urinary incontinence (8.6%), and stroke (1.2%). Neurological examination confirmed an underlying sensory neuropathy in 44 patients (27.3%). Otherwise, signs of chronic cranial nerve dysfunction (1.9%) and motor weakness (5.6%) were rare. Conclusions: Symptoms and signs of a chronic sensory neuropathy, presumably from previous vincristine exposure, were evident in many patients. Complaints of fatigue, dizziness, and chronic back pain were also relatively common. The number of patients who routinely fall is of concern. Whether these falls are associated with symptoms/signs of neuropathy, weakness, and/or dizziness will require further analysis. Although headache was a common complaint, its prevalence may not differ significantly from a normal age-matched population. No significant financial relationships to disclose.

Neuropathy with anti-disialosyl IgM antibodies and multifocal persistent motor conduction blocks

In 1985, circulating IgM antibodies reacting with NeuAc(alpha2–8)NeuAc(alpha2–3)Gal-configured disialosyl gangliosides (including GD1b, GD3, GT1b, and GQ1b) were first described in a patient with chronic sensory neuropathy.1 The typical clinical picture...

Early detection of oxaliplatin-induced neurotoxicity: Getting it before it hurts

15015 Background: Neurotoxicity is the major dose-limiting toxicity of oxaliplatin, presenting acutely and as a chronic sensory neuropathy at higher cumulative doses. We utilized a novel neurophysiological assessment tool to examine both the pathophysiology and development of oxaliplatin-induced neurotoxicity. Methods: Sensory excitability studies were undertaken in 25 patients with colorectal cancer receiving oxaliplatin, before and within 2–3 days after infusion (88 treatment cycles). A subset of 12 patients were followed longitudinally across all cycles. Conventional sensory nerve action potentials (SNAPs) were recorded from the second digit, stimulating the median nerve at the wrist. Multiple excitability parameters (threshold electrotonus (TE), refractoriness (RF) and superexcitability (SX)) were recorded as indices of axonal ion channel function. Neurotoxicity was graded using the National Cancer Institute scale. Results: Most patients developed acute neuropathic symptoms (92%). With a mean cumulative dose of 726 ± 57 mg/m2, 44% of patients developed neurotoxicity with a NCI rating of ≥ 2. Immediate changes occurred in nerve excitability after each infusion, particularly in measures related to Na+ channel activity (RF p<.05; SX p<.001). Lower single doses produced less change in nerve excitability (p<.05). Longitudinal assessment demonstrated progressive changes in nerve excitability with increasing cumulative doses (TE p<.05; RF p<.01; SX p≤.001). By the final dose, peak SNAP amplitude had decreased by 45% (p≤.005), confirming loss of sensory axons. Importantly, nerve excitability parameters changed by mid treatment (cycles 5 - 7), before changes in SNAP and clinical symptoms (cycles 8 -12) - predicting subsequent development of neuropathy (p<.05). Conclusions: These findings present a means of early identification of at-risk patients prior to the development of neuropathy, providing a significant advantage over conventional neurophysiological measures. The technique also yields insight into the pathophysiology of oxaliplatin-induced neurotoxicity, supporting previous in-vitro studies implicating Na+ channel dysfunction, and will aid development of future neuroprotective strategies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

Oxaliplatin Acts on IB4-Positive Nociceptors to Induce an Oxidative Stress-Dependent Acute Painful Peripheral Neuropathy

The toxicity profile of oxaliplatin, a platinum derivative currently used in the treatment of colorectal cancer, differs from those of the other platinum compounds, cisplatin and carboplatin. Oxaliplatin treatment induces an acute neurotoxicity characterized by a rapid onset of cold-induced distal dysesthesia and a chronic sensory peripheral neuropathy. A single intravenous dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia and heat and cold allodynia; repeated administration intensified symptoms. A single intradermal dose of oxaliplatin produced a dose-dependent mechanical hyperalgesia. A single dose intravenous oxaliplatin also lowered thresholds and increased responses of C-fiber nociceptors to mechanical stimulation, confirming a peripheral site of action. Whereas peripheral administration of inhibitors of second messengers implicated in models of other painful peripheral neuropathies (PKA, PKC, NO, Ca(2+), and caspase) had no effect; both systemic and local administration of antioxidants (acetyl-L-carnitine, alpha-lipoic acid or vitamin C), all markedly inhibited oxaliplatin-induced hyperalgesia. Intrathecal administration of the neurotoxin for IB4-positive nociceptors, IB4-saporin, markedly attenuated IB4 staining in the dorsal horn of the spinal cord and completely prevented oxaliplatin-induced hyperalgesia. We suggest that oxaliplatin acts on IB4 (+)-nociceptors to induce oxidative stress-dependent acute peripheral sensory neuropathy. Many drugs used to treat cancer produce pain as their dose-limiting side effect. We used a model of this pain syndrome induced by oxaliplatin to demonstrate that pain is produced by action on a subset of nociceptors, the IB4-positive DRG neurons. This information could help define cellular targets against which protective therapies could be developed.

Die akute Neurotoxizität von Oxaliplatin: Häufigkeit und Ausprägung

BACKGROUND: Oxaliplatin is a new generation platinum derivative, and has become a part of the medical treatment for solid cancer. It induces two distinct forms of neurotoxicity. An acute reversible syndrome shortly after the infusion is attributed to the transient hyperexcitability of the peripheral nerves and a dose-limiting chronic sensory neuropathy results from the cumulative toxic doses. This study was undertaken to evaluate the incidence and pattern of the clinical and electrophysiological abnormalities with the transient hyperexcitability syndrome. METHODS: 22 patients received Oxaliplatin as part of the FOLFOX schedule for anticancer therapy. Clinical symptoms were assessed by a standardized questionnaire. Electrophysiological investigations included sensory and motor nerve conduction studies of the median nerve and an electromyogram of the thenar. Investigations were performed 24 hours following Oxaliplatin and 13 days thereafter. RESULTS: 72% of the patients reported symptoms after Oxaliplatin, predominantly cold-induced painful parethesias of the hands, legs and throat and muscle cramps in the respective regions. They were more frequent in the second or further FOLFOX cycles and more disabling with higher cumulative doses. Myokymia and muscle twitching was seen in 47%. Thirteen days thereafter the above-mentioned symptoms had resolved completely. Nerve conduction studies did not differ at both times. After Oxaliplatin, single motor nerve stimuli induced repetitive muscle action potentials in 70% of the patients and the EMG disclosed neuromyotonic discharges in 85%. The more severe the clinical complaints, the more prominent were the electrophysiological abnormalities. However, even in 5 out of 6 asymptomatic patients electrophysiological abnormalities were evident. 13 days thereafter, except one patient, all abnormalities had subsided. CONCLUSION: This study confirms the high incidence of acute but reversible adverse events with Oxaliplatin therapy and highlights the nerve conduction studies and the EMG as valuable tools to disclose this hyperexcitablity syndrome of the peripheral nerve.