Showing papers in "Journal of The Peripheral Nervous System in 2008"
TL;DR: The neurologist managing the cancer patient who develops neuropathy must answer a series of important questions as follows: Are the symptoms due to peripheral 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.
583 citations
TL;DR: The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on the understanding of demyelinating disease and mechanisms that control nerve repair.
Abstract: Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non-myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann cell dedifferentiation involves activation of specific receptors, intracellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann cell, times Schwann cell generation, controls Schwann cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.
203 citations
TL;DR: The Utah Early Neuropathy Scale (UENS) is validated, a sensitive and reproducible clinical measure of sensory and small‐fiber nerve injury and may be useful in trials of early neuropathy.
Abstract: Early neuropathy is often sensory predominant and prominently involves small-diameter nerve fibers. Established neuropathy examination scales such as the Michigan Diabetic Neuropathy Scale (MDNS) and the Neuropathy Impairment Score-Lower Leg (NIS-LL) focus primarily on large-fiber sensory and motor function. Here, we validate the Utah Early Neuropathy Scale (UENS), a physical examination scale specific to early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. UENS, MDNS, and NIS-LL were compared in 215 diabetic or prediabetic subjects, with (129) or without neuropathy (86), and repeated in 114 neuropathy subjects after 1 year of follow-up. Neuropathy severity was also evaluated with nerve conduction studies, quantitative sensory testing, quantitative sudomotor axonal reflex testing, and intraepidermal nerve fiber density determination. The UENS had a high degree of interrater reliability (interclass correlation of 94%). UENS correlated significantly to MDNS and NIS-LL (p < 0.01), and more significantly than MDNS or NIS-LL to confirmatory tests. In this cohort, UENS had a superior profile to receiver operating characteristic analysis across a range of scores, with a sensitivity (92%) higher than MDNS (67%) or NIS-LL (81%), without sacrificing specificity. UENS more closely correlated with change in ancillary and small-fiber neuropathy measures over 1 year follow-up than did MDNS or NIS-LL. UENS is a sensitive and reproducible clinical measure of sensory and small-fiber nerve injury and may be useful in trials of early neuropathy.
170 citations
TL;DR: It is concluded that bortezomib and thalidomide combination chemotherapy induces a reversible length‐dependent sensory>motor, predominantly axonal, large‐fiber>small-fiber polyneuropathy in a subset of patients with previously untreated multiple myeloma.
Abstract: Dose-limiting peripheral neuropathy (PN) is frequently reported with the use of thalidomide and bortezomib, novel proteasome inhibitors. While these two agents have significant activity in multiple myeloma (MM), the combination and the associated PN have not been fully examined in untreated patients. The objective of this study was to report the baseline prevalence and occurrence of PN in newly diagnosed MM patients treated with bortezomib and thalidomide. Twenty-seven patients (11 men and 16 women) with previously untreated MM were prospectively monitored for PN. Total neuropathy score reduced (TNSr) was calculated at baseline and after every two cycles of bortezomib treatment. The median cumulative dose of bortezomib was 35.6 mg/m(2) (median 8 cycles) and of thalidomide was 16.8 g. Only three subjects showed mild PN at baseline (whole group median TNSr 0). At the end of treatment, PN developed in 26 patients (median TNSr 8). PN was of mild to moderate severity (TNSr grade 1 = 11, grade 2 = 10, grade 3 = 5, and grade 4 = 0). Nerve conduction studies showed axonal physiology in all except three subjects in whom demyelinating physiology was noted. The median TNSr was 17 in the demyelinating group and 9 in the axonal group. There was no significant correlation of TNSr with cumulative bortezomib or thalidomide dose. At follow-up, 80% of patients had become asymptomatic after discontinuation of the chemotherapy. We conclude that bortezomib and thalidomide combination chemotherapy induces a reversible length-dependent sensory>motor, predominantly axonal, large-fiber>small-fiber polyneuropathy. In a subset, a more severe demyelinating polyneuropathy may develop.
156 citations
TL;DR: During the progressive or the relapsing phases of CIDP, the number of Tregs was reduced, and the suppressive function of them decreased, which may be helpful to the understanding of the possible role of T Regs in the pathogenesis of C IDP.
Abstract: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral nervous system disease. CD4+CD25+ T regulatory cells (Tregs) have been unequivocally shown to be critical in maintaining immune tolerance and preventing auto-immune diseases by suppressing self-reactive T cells. Thus, we hypothesized that the numbers and/or the function of Tregs would be deranged during the progressive or relapse phases of CIDP. The number of Tregs was determined by flow cytometry according to their characteristic CD4+CD25(high) membrane phenotype. Functional characterization of Tregs was analyzed by suppression of proliferation and secretion of cytokines by co-cultured effector CD4+CD25- T cells. FOXP3 message expression level was assessed by quantitative real-time polymerase chain reaction. The results showed significant reduction in both the number and the suppressive function of Tregs in the patients with CIDP compared with healthy controls. Also, Tregs isolated from CIDP patients expressed lower levels of FoxP3 mRNA. During the progressive or the relapsing phases of CIDP, the number of Tregs was reduced, and the suppressive function of them decreased. These findings may be helpful to our understanding of the possible role of Tregs in the pathogenesis of CIDP.
68 citations
TL;DR: The results showed that although there were no differences between the groups regarding the Static Sciatic Index values, TENS led to nerves with morphological signs of impaired regeneration, and these effects were more pronounced on high‐frequency TENS nerves.
Abstract: The stimulation of peripheral nerve regeneration has been studied in different
ways, including the use of electrical fields. The capacity of this modality to enhance nerve
regeneration is influenced by the parameters used, including current type, frequency,
intensity, and means of administration. Transcutaneous electrical nerve stimulation (TENS)
is a frequently used form of administering electrical current to the body, but its effects on
peripheral nerve regeneration are not known. This study assessed the influence of TENS
on sciatic nerve regeneration, using a model of crush lesion in the mouse. Mice were
stimulated 30 min a day, 5 days a week, for 5 weeks with both high- (100 Hz) and low- (4
Hz) frequency TENS. Control animals had the sciatic nerve crushed but were not stimulated.
Assessment was performed weekly by functional analysis using the Static Sciatic
Index for the mouse and at the end of the experiment by light and electron microscopy.
The results showed that although there were no differences between the groups regarding
the Static Sciatic Index values, TENS led to nerves with morphological signs of
impaired regeneration. At light microscopy level, TENS nerves presented more axons with
dark axoplasm, signs of edema, and a less organized cytoarchitecture. Electronmicrographs
showed fewer and thinner thick myelinated fibers and increased number of
Schwann cell nuclei. Myelinated axon diameters and density and diameter of nonmyelinated
fibers were not affected by TENS, leading to the conclusion that this regimen of electrical
stimulation leads to a delayed regeneration after a crush lesion of the sciatic nerve in
the mouse. All these effects were more pronounced on high-frequency TENS nerves.
62 citations
TL;DR: This review examines the putative role of glucose in the etiology of diabetic neuropathies, finding that excessive glucose generates several secondary metabolic anomalies that trigger cellular responses that are inappropriate to normal function.
Abstract: This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies - principally oxidative stress (via both the polyol pathway and glucoxidation) and non-enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen-activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain.
62 citations
TL;DR: Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy‐dependent pumps, and ion exchange processes activated during the process of impulse conduction.
Abstract: Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.
61 citations
TL;DR: The results indicate that the course of bortezomib‐induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.
Abstract: We investigated a series of bortezomib-treated patients and correlated the course of bortezomib-induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty-eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty-three patients had a baseline TNSr = 0–2, and 25 patients had a baseline TNSr >2 (median = 6, range 3–13). The course of bortezomib-induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib-induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.
55 citations
TL;DR: Motor conduction slowing progresses through the first 6 years of life and thereafter remains stable, and CMAP amplitude is reduced from an early age, and the normal physiologic increase with age is attenuated.
Abstract: Although Charcot-Marie-Tooth disease type 1A (CMT1A) initially manifests in the first decade, there are no large studies describing its neurophysiologic features in childhood. We report neurophysiologic findings in 80 children aged 2-16 years with CMT1A who underwent median motor and sensory nerve conduction studies. Neurophysiologic abnormalities were present in all children. Median motor nerve conduction velocity was invariably less than 33 m/s (mean 18.7 m/s, range 9.0-32.9 m/s), with conduction velocities significantly slower in children aged 7-16 years compared with children aged 6 years and below. All children had prolonged distal motor latencies (mean 7.3 ms, range 4.0-12.3 ms). The compound muscle action potential (CMAP) amplitude was reduced from an early age (mean 7.1 mV, range 2.1-13.5 mV), and its normal increase with age was attenuated. Median sensory responses were present in only seven children, all aged less than 9 years and with slowed sensory conduction. Neurophysiologic abnormalities are present in all children with CMT1A from the age of 2 years. Motor conduction slowing progresses through the first 6 years of life and thereafter remains stable. CMAP amplitude is reduced from an early age, and the normal physiologic increase with age is attenuated. Median sensory responses may be recorded in younger children, and their presence does not exclude the diagnosis of CMT1A.
54 citations
TL;DR: It is demonstrated that rEV576 effectively prevents development of neuronal and pSC damage in experimental murine neuropathy.
Abstract: Guillain-Barre syndrome and its clinical variants, including the anti-GQ1b ganglioside-mediated Miller Fisher syndrome (MFS), comprise the world's leading cause of acute neuromuscular paralysis. Presently, no specific drug therapies exist. The complement cascade, which is activated in these patients, forms an attractive drug target. In this study, we tested whether the complement C5-inhibiting recombinant protein, rEV576, was able to prevent neural injury in a previously developed in vitro mouse model for MFS. Mouse hemidiaphragm preparations were treated with anti-GQ1b antibody and normal human serum as a source of complement with added rEV576 or control protein. Immunohistology in control tissue showed deposition of C3c and membrane attack complex at neuromuscular junctions (NMJs), along with terminal motor axonal neurofilament degradation as well as ethidium homodimer-2 staining showing perisynaptic Schwann cell (pSC) injury. Electrophysiological and functional analyses showed block of synaptic transmission at the NMJ after an initial period of a dramatically high level of asynchronous acetylcholine release. In tissue treated with rEV576, all these indicators of motor neuronal damage were absent, except for the presence of C3c, indicating effective inhibition of C5. These results demonstrate that rEV576 effectively prevents development of neuronal and pSC damage in experimental murine neuropathy.
TL;DR: This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain‐Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy‐related neuropathies.
Abstract: Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy-related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.
TL;DR: The ability to ambulate independently as well as toe and heel walk correlated well with QoL measures in patients with Charcot‐Marie‐Tooth disease type 1A, the most common form of CMT.
Abstract: Quality of life (QoL), as defined by the Short Form 36, has previously been shown to be abnormal in patients with Charcot-Marie-Tooth disease (CMT), both for Physical Composite Scores (PCS) and Mental Composite Scores (MCS). We have now extended these observations in a multicenter evaluation of 89 patients with Charcot-Marie-Tooth disease type 1A, the most common form of CMT. Both the PCS and MCS were abnormal also in this cohort, compared with the Italian population at large. In particular, the ability to ambulate independently as well as toe and heel walk correlated well with QoL measures in our patients.
TL;DR: There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerveaction potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls, and diabetes was associated with more severe motor and sensory impairment in patients with CMT 1A.
Abstract: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a duplication of PMP22 on chromosome 17 and is the most commonly inherited demyelinating neuropathy. Diabetes frequently causes predominantly sensory neuropathy. Whether diabetes exacerbates CMT1A is unknown. We identified 10 patients with CMT1A and diabetes and compared their impairment with 48 age-matched control patients with CMT1A alone. Comparisons were made with the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) and by electrophysiology. The CMTNS was significantly higher in patients with diabetes (20.25 +/- 2.35) compared with controls (15.19 +/- 0.69; p = 0.01). Values were particularly higher for motor signs and symptoms. Seven of the 10 diabetic patients had CMTNS >20 (severe CMT), while only 7 of the 48 age-matched controls had scores >20. There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerve action potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls. Diabetes was associated with more severe motor and sensory impairment in patients with CMT1A.
TL;DR: 2D digital video motion analysis can be used to quantify movement of the wrist and the MP joint in rats and is a valid method to evaluate functional deficit and recovery after nerve injury and repair in the forelimb.
Abstract: The object of this study was to demonstrate that digital video motion analysis is a quantitative, valid, and reproducible method for evaluation of function in the rat model of forelimb nerve transection and repair. Median, ulnar, and radial nerves were transected and directly repaired in 220 g Sprague-Dawley rats. Normal rats and sham-operated rats served as controls (six rats in each group). Two-dimensional (2D) digital video motion analysis was used to capture the gait cycle and quantify joint movement and changes in toe spread. Recordings were made preoperatively and at 1, 4, 8, 12, and 16 weeks postoperatively. Wrist and metacarpophalangeal (MP) joint extension decreased after radial nerve injury, and wrist and MP joint flexion decreased after combined median and ulnar nerve injury or injury to the median nerve only. Toe spread decreased after combined median and ulnar nerve injury and after radial nerve injury. Median or ulnar nerve injury alone did not lead to a significant change in toe spread. 2D digital video motion analysis can be used to quantify movement of the wrist and the MP joint in rats. It is a valid method to evaluate functional deficit and recovery after nerve injury and repair in the forelimb.
TL;DR: Isokinetic strength relates to measures of function, impairments, gait performance, and physical components of health‐related quality of life in long‐term CIDP.
Abstract: The aim of the present study was to determine the severity and distribution of assessed muscle weakness and to relate muscle performance to measures of function and quality of life in long-term chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Fourteen patients with 8.7 years (3.3-11.5) of confirmed CIDP consecutively referred to the referral center for CIDP patients at Aarhus University Hospital, Denmark, during the period 1992-2002 were compared with matched healthy controls. The main outcome parameter was muscle performance assessed with isokinetic dynamometry. Overall disability sum score (ODSS), neurological symptom score (NSS), neuropathy impairment score (NIS), health-related quality-of-life survey (SF-36), nerve conduction studies, physical fitness, hand and walking performance, and quantitative sensory testing were secondary variables. The mean (95% CI) isokinetic strength of all measured muscles was reduced by 19.4% (5.9-32.8%) (p < 0.01). In the legs, distal weakness was predominant, strength at ankle being 37.0% (14.7-59.2%) reduced. Isokinetic strength was closely related to manual muscle strength, ODSS, NIS, walking performance, and physical components of SF-36. In conclusion, isokinetic strength relates to measures of function, impairments, gait performance, and physical components of health-related quality of life in long-term CIDP. Furthermore, a detailed characterization of severity and distribution of weakness has been provided using this technique.
TL;DR: Whether pain also occurs in the pure motor variant of Guillain-Barré syndrome in a large group of GBS patients from Europe and Curacxao is investigated to increase awareness and ultimately improve insight into mechanisms of pain in GBS.
Abstract: Dear Editor, In Guillain-Barré syndrome (GBS), pain is frequently present and can even be misleading in making the diagnosis (Ropper and Shahani, 1984; Pentland and Donald, 1994; Moulin et al., 1997; Ruts et al., 2007). Clinicians generally associate pain with affected sensory nerves and not with a pure motor neuropathy. We investigated whether pain also occurs in the pure motor variant of GBS in a large group of GBS patients from Europe and Curacxao because this could increase awareness and ultimately improve insight into mechanisms of pain in GBS. The European GBS patients (predominantly Dutch; GBS disability score 3) were recruited from a doubleblind, placebo-controlled randomized, multicenter study between 1994 and 2000 (van Koningsveld et al., 2004). The presence and severity of pain were prospectively collected. In Curacxao, where we previously described the predominant occurrence of pure motor GBS, we retrospectively screened the medical records of all GBS cases who had been admitted to the island’s only neurological department between 1987 and 2006 (van Koningsveld et al., 2001). In all cases, the presence of pain had been collected from the period ranging from hospital admission until 4 weeks later. The clinical differentiation between the motor and the sensory-motor variant was made on the presence of sensory signs or symptoms by standard neurological examination. On the basis of electromyographic (EMG) studies, performed within 4 weeks after admission, we also tried to classify the patients as demyelinating [acute inflammatory demyelinating polyneuropathy (AIDP)] or axonal [acute motor axonal neuropathy (AMAN)] (Ho et al., 1995; Hadden et al., 1998). When the EMG was not conclusive, the patient was classified as ‘not conclusive.’ Because we were primarily interested in whether pain also occurs in GBS patients with pure motor neuropathy, only the clinical pure motor neuropathy and AMAN patients were further specified in this study. We studied 225 European and 83 GBS patients from Curacxao. Age, sex, maximum GBS disability score, and the percentage of patients reporting pain were not significantly different between the two groups (Table 1). The percentage of patients with a clinically pure motor neuropathy (72 vs. 8%) and AMAN based on the available EMG data (16 vs. 2%) was higher in the GBS population from Curacxao comparable with an earlier study, suggesting a probable relationship with an increased percentage of preceding gastroenteritis (van Koningsveld et al., 2001). Also in the present study, the percentage of preceding diarrhea was higher in the GBS patients from Curacxao. Of the total group of 77 patients from Europe and
TL;DR: The results indicate that PIO promotes peripheral nerve remyelination possibly through CD36 and it may be possible to apply PIO to the remedy against demyelinating neuropathies.
Abstract: In our previous study, we found that CD36-deficient mice showed significant delays in peripheral nerve remyelination after sciatic nerve crush injury and suggested that CD36 played an important role in the restoration of injured peripheral nerves. The aim of this study was to investigate whether CD36 upregulation can promote peripheral nerve remyelination. We made crush injury that caused demyelination and mild axonal degeneration to sciatic nerves and investigated the effect of pioglitazone (PIO) on the remyelination post-injury in C57Bl/6 wild-type and CD36-deficient mice. The immunohistochemistry with anti-CD36 antibody showed that CD36 was upregulated in macrophages infiltrating peripheral nerves from the wild-type mice by PIO administration at 1 week post-injury. The lectin histochemistry represented that infiltrating macrophages lessened in the wild-type mice at 3 weeks post-injury by PIO administration. General histopathology and morphometry indicated that thinly myelinated fibers and naked axons diminished in PIO-treated wild-type mice compared with non-treated wild-type mice at 3 weeks post-injury. No significant differences were observed in remyelination and number of infiltrating macrophages between PIO-treated and non-treated CD36-deficient mice. These results indicate that PIO promotes peripheral nerve remyelination possibly through CD36. It may be possible to apply PIO to the remedy against demyelinating neuropathies.
TL;DR: The goal of the workshop was to identify areas where additional research could lead to the development of new therapeutics in the next 5 years and to form a working group for neuropathy, the Peripheral Neuropathy Study Group, and to translate new scientific findings into therapies and complete clinical trials.
Abstract: National Institute of Neurological Disorders and Stroke sponsored a meeting to explore the current status of basic and clinical research in peripheral neurobiology and clinical neuropathy. The goal of the workshop was to identify areas where additional research could lead to the development of new therapeutics in the next 5 years. Participants discussed the current understanding of disease mechanisms of axonal and demyelinating neuropathies, existing techniques in research, disease biomarkers, and assessment of neuropathy. Painful neuropathies were discussed at the basic scientific and clinical levels in relation to new insights into etiology and treatment. The meeting concluded with a discussion on therapeutic development in neuropathy and the need for a unified approach to multicenter trials. Short-term goals of the workshop were to form a working group for neuropathy, the Peripheral Neuropathy Study Group, and to translate new scientific findings into therapies and complete clinical trials.
TL;DR: None of the findings of this study are disease specific but as a pattern may help support the diagnosis of inflammatory neuropathy in patients with serological evidence for Borrelia infection.
Abstract: Peripheral neuropathy is a recognized but incompletely understood manifestation of borreliosis. As the pathology of this neuropathy has been described only in small case series, the value of nerve biopsy findings for the pathologic diagnosis of Borrelia-associated neuropathy is unclear. We collected and investigated 21 patients with peripheral neuropathy and with typical clinical and serologic signs of neuroborreliosis [Borrelia neuropathy (BN)]. Standard histology and immunohistochemistry were performed on sural nerve biopsies using antibodies to CD4, CD68 and membrane attack complex C5b-9, intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6. Nine patients with idiopathic vasculitic neuropathy (VN) and 14 with idiopathic axonal neuropathy (AN) served as disease controls. In BN, the characteristic histology was that of an AN with transmural or perivascular lymphocytic infiltration of nerve vessels. In BN, but less in VN and AN, perineurial thickening and neovascularization were observed. For BN but not for VN, this thickening correlated with increased perineurial immunoreactivity (IR) to TNF-alpha, C5b-9, and ICAM-1. In comparison to AN, both BN and VN displayed increased perineurial T-cell infiltration and human leukocyte antigen (HLA)-DR3-IR. In the endoneurium, cytokine (IL-1beta, IL-6, TNF-alpha), HLA-DR3, and ICAM-1 expression was more pronounced in VN but not in BN. The neuropathy in patients with neuroborreliosis resembles idiopathic VN but shows some distinctive features. None of the findings of this study are disease specific but as a pattern may help support the diagnosis of inflammatory neuropathy in patients with serological evidence for Borrelia infection.
TL;DR: Buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third‐line treatment, which needs to be confirmed by a controlled trial.
Abstract: Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open-label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score � 5 under stable analgesic treatment were entered. The starting dosage of 35 mg/h was increased up to 70.0 mg/h in case of unsatisfactory pain control as assessed by fort- nightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients drop- ped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved .30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 mg/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 mg/h, and four patients withdrew consent to continue the study before day 42 visit because of a 'fear to become addicted,' although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third-line treatment.
TL;DR: Touch sensibility thresholds recorded in a large group of Indians were higher than that reported in other populations, having clinical implications for the diagnosis of early nerve impairment in the elderly and in disease states drawing attention to geographic variations in touch sensation.
Abstract: Touch sensibility testing is a cost-effective, psychophysical measure of peripheral nerve function and impairment. However, there is limited information regarding the natural variability in touch sensibility across different populations and different age groups. We studied 568 healthy Indian volunteers without any clinical evidence of peripheral nerve disease. Touch sensibility was evaluated bilaterally in palms, feet, and heels, using Semmes-Weinstein monofilaments, with target forces ranging from 0.008 to 300 g. No differences were observed between the right and the left limbs. The lowest target force detected ranged from 0.4 to 2 g in the palms and 1.4 to 15 g in the feet. These values showed further increase with age. Women compared with men had higher sensibility in the palms in most age groups. Touch sensibility thresholds recorded in a large group of Indians were higher than that reported in other populations. These findings have clinical implications for the diagnosis of early nerve impairment in the elderly and in disease states drawing attention to geographic variations in touch sensation.
TL;DR: An unusually young patient is described who demonstrated wild-type TTR systemic amyloidosis with a predominant clinical picture of bilateral CTS, and abnormal findings were obtained on laboratory examinations.
Abstract: Dear Editor, Bilateral carpal tunnel syndrome (CTS) accompanies various systemic diseases, including rheumatoid arthritis, myxedema, acromegaly, and amyloidosis. Amyloidosis comprises a large group of protein misfolding diseases. There are over 20 secreted human proteins whose misfolding and misassembly outside the cell are linked to amyloidosis. CTS could appear as an initial symptom in long-term hemodialysis-related (b2 microglobulin) amyloidosis and transthyretin (TTR) amyloidosis (Stein et al., 1987; Wallace et al., 1988; Kyle et al., 1992; Nakamichi and Tachibana, 1996; Takei et al., 2002; Connors et al., 2003). It was reported that amyloid deposition was found in 27 of 140 biopsied tissue specimens obtained from patients undergoing carpal tunnel release, and TTR amyloid deposits were present in 16 of 27 (Stein et al., 1987). Misfolding of variant TTR induces an autosomal dominant genetic disorder, familial amyloid polyneuropathy (FAP) (Connors et al., 2003; Sekijima et al., 2005), while misfolding of wild-type TTR leads to sporadic amyloid disease, senile systemic amyloidosis, which usually affects the population over 80 years of age (Cornwell et al., 1983; Westermark et al., 1990; Johansson and Westermark, 1991; Kyle et al., 1996). In this report, we describe an unusually young patient who demonstrated wild-type TTR systemic amyloidosis with a predominant clinical picture of bilateral CTS. At age 44, this man developed tingling and numbness in the right hand, especially the thumb, index, and middle fingers. He noticed a similar symptom in his left hand at the age of 47. He was diagnosed as having CTS and underwent bilateral surgical carpal ligament release. Tenosynovial tissues were obtained at surgery, and pathological studies detected amyloid deposition. His 76-year-old father and 72-year-old mother were both healthy, and there was no family history of cardiac disease or neuromuscular disorders. At age 48, neurologic examination demonstrated decreased pinprick sensation in the first, second, and third fingers of both hands and thenar muscle atrophy of the right hand. Tinel’s sign and Phalen’s maneuver were positive bilaterally. Nerve conduction studies were normal. Normal findings were obtained on laboratory examinations, including complete blood cell count, liver and kidney function tests, urine and stool analysis, serum c-reactive protein, serum amyloid A protein, b2-microgloblin, TTR, and immunoglobulin A, M, and G levels. M protein was undetectable in serum. Bence Jones protein was not detected in his urine. Electrocardiogram showed first-degree atrioventricular block and low voltage in standard limb leads. Echocardiogram and myocardial scintigram using technetium-99m pyrophosphate did not detect any abnormal findings. Tenosynovial tissues obtained at surgery were reanalyzed at our institution, and amyloid deposition was confirmed with Congo red staining (Figs. 1A and 1B). Immunohistochemical analysis was performed as follows. After deparaffinization, sections were treated with peroxidase-blocking solution (Dako) to inhibit endogenous peroxidase activity and with serum-free protein block (Dako) to inhibit non-specific binding. Anti-l (118–134), anti-k (116–133) (Hoshii et al., 2001), antiAA (Imada, 1981), anti-TTR (115–124) (Gustavsson et al., 1994), and anti-b2 microglobulin (Nordic Immunological Laboratories) antibodies were applied to the sections as primary antibodies for 30 min at room temperature. Then, sections were incubated with EnVisionþ (Dako) as the secondary antibody for 30 min at room temperature. Immunoreactivity was visualized with 3,30-diaminobeneidineþ (Dako). Amyloid in the tenosynovial tissue was specifically immunolabeled only by anti-TTR antibody (Fig. 1C). TTR amyloid deposition was also detected in biopsied gastroduodenal tissue (Figs. 1D and 1E). Abdominal fat aspirate biopsy was negative for amyloid deposition. Matrixassisted laser desorption ionization/time-of-flight mass spectrometry was used to detect serum variant TTR. However, only wild-type TTR was observed (Fig. 1F). Direct DNA sequencing of all four exons of the TTR gene did not detect any mutation. Address correspondence to: Yoshiki Sekijima, Department of Neurology and Rheumatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Tel: þ81-263-37-2673; Fax: þ81-263-37-3427; E-mail: sekijima@hsp.md.shinshu-u.ac.jp Journal of the Peripheral Nervous System 13:148–150 (2008)
TL;DR: Clinico-electrophysiological features and magnetic resonance imaging (MRI) patterns of lower limb amyotrophy in subclinically affected CMT1A adult patients are described and electrophysiology study is essential to distinguish between both disorders.
Abstract: Dear Editor, Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating polyneuropathy usually associated with a large DNA duplication on the short arm of chromosome 17 (Lupski et al., 1991; Raeymaekers et al., 1991). Symptoms are present during the first decade of life in over 60% of cases (Harding and Thomas, 1980; Garcı́a et al., 1998). Whereas absence of signs on physical examination may occur in 50% of presymptomatic CMT1A children under 5 years of age (Garcı́a et al., 1998; Berciano et al., 2003), this is an extremely rare situation in adult patients (Lupski et al., 1991; Kaku et al., 1993). We describe clinico-electrophysiological features and magnetic resonance imaging (MRI) patterns of lower limb amyotrophy in subclinically affected CMT1A adult patients. We reviewed the clinical records of our cohort of 126 CMT1A duplication cases, aged from 10 to 93 years coming from 25 unrelated pedigrees, and found two subclinical patients (patient 1 and patient 2), both studied originally as asymptomatic secondary cases. We administered the functional disability scale (FDS) (Birouk et al., 1997) and the Charcot-Marie-Tooth disease neuropathy score (CMTNS) (Shy et al., 2005). MRI study of lower limb musculature and electrophysiological studies were performed as reported elsewhere (Garcı́a et al., 1998; Gallardo et al., 2006). Patient 1 is aged 48 years and has been serially evaluated since age 17; her repeated physical examinations revealing mild pes cavus (Figs. 1A and 1B) with no other neuropathic signs. Patient 2 is aged 58 years and has been serially evaluated since age 48; her repeated physical examinations revealing mild pes cavus. Both patients showed normal FDS score and CMTNS of 3. MRI showed a pattern of intrinsic foot musculature involvement (Figs. 1C and 1D) with distal fatty atrophy of lower leg musculature, which was more apparent in patient 2. Motor conduction velocity was uniformly reduced (25–32 m/s in median and ulnar nerves and 25–29 m/s in peroneal and tibial nerves) with normal (Figs. 1E and 1F) or reduced foot compound muscle action potential (CMAP) amplitudes. Sensory conduction velocity was reduced in median and ulnar nerves (from 23 to 27 m/s) with reduced sensory nerve action potential amplitudes; sural nerve showed similar findings in patient 1 and was absent in patient 2. F-wave latencies were prolonged in median, ulnar, and tibial nerves and absent in peroneal nerve. Myoelectric deep tendon reflex (T-reflex) responses from biceps and gastrocnemius muscles were preserved though delayed. The single electromyographic abnormality in patient 1 was a moderate increase of polyphasic potentials in tibialis anterior muscle. Patient 2 showed a reduced recruitment pattern with long-duration and high-amplitude action potentials in extensor digitorum brevis muscle; the recording in tibialis anterior being normal. Fibrillation and positive waves were not present in either patient. While pes cavus is a cardinal manifestation of Charcot-Marie-Tooth disease (Harding and Thomas, 1980), it is also the hallmark of ‘idiopathic’ pes cavus that represents one third of cases attended in any pes cavus clinic (Brewerton et al., 1963). Electrophysiological study is essential to distinguish between both disorders, especially if, as reported here, there is evidence of positive family history with well-defined electrophysiological phenotype. Although adult patients with mild disease constitute a significant subset in any CMT1A series, the situation described here of repeated normal neurologic examination in adult patients is unusual. In a large French Acadian CMT1A pedigree (HOU1), there were three at-risk individuals, of ages 19, 26, and 27 years, who appeared clinically normal; each was found to have symmetrically reduced nerve conduction velocities and 17p duplication (Lupski et al., 1991; Kaku et al., 1993). In contrast with the cases in this pedigree, clinical data from eight large CMT1A cohorts, comprising 523 patients with at least 188 of them being secondary cases, have corroborated the Harding and Thomas paradigm of absence of affected individuals with completely normal clinical findings (Hoogendijk et al., 1994; Birouk et al., 1997; Thomas et al., 1997; Fabrizi Address correspondence to: Prof. José Berciano, MD, PhD, Service of Neurology, University Hospital ‘‘Marqués de Valdecilla’’, IFIMAV and CIBERNED, University of Cantabria, 39008 Santander, Spain. Tel: 34-942-202520; Fax: 34-942-202655; E-mail: jaberciano@humv.es Journal of the Peripheral Nervous System 13:310–312 (2008)
TL;DR: This review will focus on recent advances using synergistic approaches that led to the identification of small Rho GTPases and their regulators as crucial functional players in proper development and function of myelinated peripheral nerves, with a particular emphasis on the cell biology of Schwann cells in health and disease.
Abstract: A thorough knowledge of the cellular and molecular basis of the structure and function of peripheral nerves is of paramount importance not only for a better understanding of the fascinating biology of the peripheral nervous system but also for providing critical insights into the various diseases affecting peripheral nerves as the firm foundation of potential treatments. Genetic approaches in model organisms, in combination with research on hereditary forms of neuropathies, have contributed significantly to our progress in this field. In this review, we will focus on recent advances using these synergistic approaches that led to the identification of small Rho GTPases and their regulators as crucial functional players in proper development and function of myelinated peripheral nerves, with a particular emphasis on the cell biology of Schwann cells in health and disease.
TL;DR: It is concluded that rejection is suppressed by costimulation blockade, and treatment improves recovery of target muscle and myelination after nerve allografting.
Abstract: Costimulation blockade can prevent rejection of nerve allografts in short-term studies. We tested if costimulation blockade also prevented rejection of nerve allografts in long-term experiments, thereby improving functional recovery. A 7-mm sciatic nerve defect in C57/BL6 mice was bridged either by nerve allografts from Balb/C mice or by isogenic nerve grafts (isografts) from C57/BL6 mice. Costimulation blockade in the form of a triple treatment with anti-LFA-1, anti-CD40L, and CTLA4Ig was given at post-operative days 0, 2, 4, and 6 (intraperitoneal). Control mice (placebo; allografts) with nerve grafts were treated with isotype antibodies during the same time period. After 49 days, tetanic muscle force, wet weight of gastrocnemius muscle, histology, and morphometry in the tibial nerve were evaluated. Costimulation blockade diminished rejection of the nerve allografts. Axons bridged the graft. Treatment increased wet weight of the gastrocnemius muscle and resulted in a higher mean myelin area/nerve fiber in the tibial nerve distal to the nerve grafts. Tetanic muscle force and number of axons in tibial nerve showed no differences between groups. We conclude that rejection is suppressed by costimulation blockade. Treatment improves recovery of target muscle and myelination after nerve allografting.
TL;DR: This work presents a unique example of GS presenting as an ulnar neuropathy and evolving into a lower trunk predominant brachial plexopathy without evidence of systemic disease.
Abstract: Dear Editor, Granulocytic sarcoma (GS) is a focal, invasive, and destructive tumor mass composed of immature myeloid cells of granulocytic lineage. It most commonly occurs in patients with acute myelogenous leukemia (AML) but is also reported in chronic myelogenous leukemia and myelodysplastic disorders. GS can also occur in patients without evidence of a systemic hematologic disorder. We present a unique example of GS presenting as an ulnar neuropathy and evolving into a lower trunk predominant brachial plexopathy without evidence of systemic disease. Our patient’s neuropathy improved markedly with intrathecal methotrexate, systemic chemotherapy, and radiation. A 70-year-old man presented with the subacute onset of aching pain in his left upper arm and elbow. Over the next 3 months, numbness appeared on the extensor surface of his fourth and fifth digits. Electrophysiological studies demonstrated a left ulnar neuropathy at the elbow. Over the next 2 months, he developed weakness of finger flexion and extension andworsening numbness in the ulnar distribution. Ulnar nerve transposition was performed without benefit. Subsequently, magnetic resonance imaging (MRI) and computed tomography (CT) myelography demonstrated left C7 root compression, and anterior cervical spine decompression was performed. His weakness continued to worsen. Further MRI imaging of the cervical spine and brachial plexus was reportedly normal. This patient was referred to our institution 2 years after symptom onset. He denied constitutional symptoms. He could not feed himself, write, or manipulate tools with his left hand. He reported numbness in the ulnar distribution of his left hand and medial forearm. He had aching pain in his elbow and contact allodynia with pressure on the arm. Neurological examination demonstrated a positive Tinel’s sign in the infraclavicular brachial plexus radiating to the ulnar digits. Neurological examination demonstrated moderate weakness of wrist flexion and digital extension and severe weakness of digital flexion, thumb abduction, and finger abduction. There was claw deformity of his hand with intrinsic hand muscle atrophy and fasciculations. The left triceps reflex was reduced. All sensory modalities were reduced in the ulnar distribution and medial forearm. Left upper extremity nerve conduction studies (NCS) demonstrated normal medianmotor and sensory nerve conductions. Ulnarmotor amplitudewas reduced (3.0 mV) with a slightly reduced conduction velocity (46 m/s) and absent F-wave response. Ulnar sensory amplitude was reduced (4 mV) with reduced conduction velocity (51 m/s) and slightly prolonged distal latency (3.3 ms). Medial antebrachial sensory nerve action potential (SNAP) was absent on the left. Electromyography demonstrated neurogenic changes in the left extensor indicis proprius, first dorsal interosseous and flexor pollicis longus, and less so in C8 paraspinal muscles. There were fibrillation potentials in the first dorsal interosseous and flexor pollicis longus. Extensive laboratory testing was normal. Cervical spine MRI demonstrated a markedly enlarged left C8 nerve root with expansion of the surrounding neural foramen. A portion of the mass was intradural and extramedullary and demonstrated enhancement with contrast (Fig. 1). Brachial plexus MRI demonstrated marked diffuse fusiform enlargement of the entire left brachial plexus extending distally into the ulnar and median nerves. There were mild heterogeneous T2weighted abnormalities and enhancement with intravenous gadolinium (Fig. 1). Spinal fluid examination showed 53 white blood cells, 99% atypical cells, and mildly elevated protein (48 mg/dl). Auer rods were present. Cytology and flow cytometry demonstrated these cells were myeloblasts of granulocytic lineage expressing CD13, CD15, CD34, CD33, and CD117. This was not considered sufficient to support a diagnosis of malignancy without evidence of leukemia and especially because a bone marrow biopsy demonstrated normocellular marrow with normal karyotype. Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan demonstrated avid FDG uptake Address correspondence to: P. James B. Dyck, MD, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Tel: 507-284-8205; Fax: 507-284-3133; E-mail: dyck.pjames@mayo.edu Journal of the Peripheral Nervous System 13:153–156 (2008)
TL;DR: It is suggested that an increase in NO production generated by systemic inflammatory response pathways after burn injury contributes to the development of structural and functional deficits in peripheral motor axons.
Abstract: The systemic inflammatory response produced by a full-thickness dermal burn injury is associated with a peripheral motor neuropathy. We previously reported that a 20% body surface area (BSA) full-thickness dermal burn in C57BL6 mice produced structural and functional deficits in motor axons at a distance from the burn site. The etiology of the neuropathy, however, is not well characterized. Burn injury leads to an increase in production of a number of proinflammatory mediators, including nitric oxide (NO). We tested the hypothesis that dermal burn-induced motor neuropathy is mediated by increased production of NO. NO synthase (NOS) activity was inhibited following a 20% BSA full-thickness burn by injection of non-specific NOS inhibitor, nitro-L-arginine methyl ester or inducible NOS (iNOS) inhibitors, L-N6-(1-iminoethyl) lysine, and aminoguanidine. NOS inhibitors also prevented the reduction in ventral roots mean axon caliber and the decrease in a motor nerve conduction velocity (MCV) following burn. iNOS knockout mice prevented MCV decrease in the first 3 days post-burn, but iNOS knockout MCV was significantly reduced at 7-14 days post-burn. These results suggest that an increase in NO production generated by systemic inflammatory response pathways after burn injury contributes to the development of structural and functional deficits in peripheral motor axons.
TL;DR: Linezolid is the first of a new class of oxazolidinone antibiotics, which was approved in Germany in 2002, and has high activity against methicillinand vancomycin-resistant gram-positive pathogens, is 100% bioavailable, and can be given orally.
Abstract: Dear Editor, Linezolid is the first of a new class of oxazolidinone antibiotics, which was approved in Germany in 2002. Linezolid has high activity against methicillinand vancomycin-resistant gram-positive pathogens, is 100% bioavailable, and can be given orally (Moellering, 2003). Its profile of adverse events is considered to be acceptable and mainly concerns diarrhea, headache, nausea and vomiting, and taste disorder (Halle et al., 2002). Optic and peripheral neuropathies have been reported with long-term use of linezolid (Bressler et al., 2004; Zivkovic and Lacomis, 2005). The cases of linezolid-associated peripheral neuropathy were sensory-motor axonal, mainly large fiber, and variably recovered after discontinuation of linezolid. Recently, Chao et al. (2008) reported a painful small-fiber neuropathy after prolonged use of linezolid. They demonstrated in skin biopsy denervation and signs of reinnervation. We wish to emphasize this clinical observation by reporting a further case. A 54-year-old, otherwise healthy,woman had undergone left knee replacement, which was complicated by severe wound infection and beginning sepsis with methicillin-resistant Staphylococcus aureus. A total of five surgical wound revisions were necessary. Linezolid was given for 16 weeks in a dosage of 600 mg twice daily. The knee wound healed with this antibiotic regimen. After the 15th week of linezolid therapy, the patient reported numbness and continuing burning pain in both feet. She had allodynia. Sleep was greatly disturbed due to pain. At this time, linezolid was discontinued. However, symptoms persisted and prompted neurological consultation. Examination showed sensory loss in a stocking distribution. Differentiation of cold and warm stimuli was severely impaired using the tip therm probe on both feet. Vibration at toes and ankles was significantly diminished. The remainder of the neurological examination was normal except an absent left knee reflex. Nerve conduction studies in the lower limbs were normal. The following tests were normal or negative: oral glucose tolerance test; D-xylose test; vitamins B1, B6, B12, and E; folic acid; methylmalonic acid; liver and renal function; serum electrophoresis and quantitative measurement of immunoglobulins, carbohydrate deficient transferrin, hemoglobin, leucocytes, thrombocytes, thyroid stimulating hormone, and thyroxin; Bence Jones proteins in urine; analysis of cerebrospinal fluid; tests for borreliosis, lues, varicella zoster, HIV, and hepatitis C; and tests for the immunologic parameters antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antibodies in Sjögren disease (Neundörfer, 1993). Treatment with gabapentin resulted in moderate pain relief. At 3-month follow-up, clinical signs were unchanged. Based on the clinical findings, we diagnosed smallfiber neuropathy in our patient. There was no evidence of dysfunction of the large-diameter motor and sensory nerves based on clinical and electrodiagnostic findings. In our patient, we strongly assume an association between the neuropathy and the intake of linezolid for two reasons. First, signs and symptoms of small-fiber neuropathy began after the 15th week of linezolid use, i.e., there was a close temporal relation between linezolid administration and onset of symptoms. This is in keeping with other published cases of neuropathy that occurred after prolonged use of linezolid (Corallo and Paull, 2002; Bressler et al., 2004). Second, we did not find an alternative explanation for the occurrence of polyneuropathy. In their patient, Chao et al. (2008) demonstrated histological signs of reinnervation with concomitant clinical improvement after discontinuation of linezolid. However, in our patient, we could not detect a substantial clinical improvement after discontinuation of linezolid, as reported in the majority of other cases. The cause of nerve injury by linezolid is unclear (Zivkovic and Lacomis, 2005). It is speculated that linezolid may cause mitochondrial dysfunction and thus damage optic and peripheral nerves (Lee et al., 2003).
TL;DR: An African man with hereditary amyloid neuropathy from a TTR Val107 mutation with an atypical clinical presentation is reported, including sensorimotor polyneuropathy, sensory ataxia, carpal tunnel syndrome, asthenia, cardiomyopathy, and cognitive disorders.
Abstract: Dear Editor, Amyloid neuropathies are characterized by endoneurial deposits of amyloid substance. Familial amyloid polyneuropathies (FAP) are inherited disorders often caused by transthyretin (TTR) mutations with an autosomal dominant transmission. We report an African man with hereditary amyloid neuropathy from a TTR Val107 mutation with an atypical clinical presentation, including sensorimotor polyneuropathy, sensory ataxia, carpal tunnel syndrome, asthenia, cardiomyopathy, and cognitive disorders. A 70-year-old native from Benin was first seen in September 2004 for gait disturbance. For 6 months, he noted progressive asthenia, weight loss, and paresthesias affecting the right lower limb and the mouth. His mental statuswas notable for joviality, disinhibition, and disordered executive functions. He had moderate sensory ataxia, weakness in the distalmuscles of the upper limbs, and areflexia but with normal sensation. His history included arterial hypertension treated by angiotensin-converting enzyme inhibitor, surgery 20 years ago for left subdural hematoma, and moderate alcohol consumption. The patient did not know his parents. Laboratory tests were normal aside from an elevated cerebrospinal fluid (CSF) protein (0.6 g/l). Tumor markers, onconeuronal antibodies, immunological assays [antinuclear, anti-Ro (SSA) and anti-La (SSB) antibodies, and cryoglobulin], thyroid hormones, serologies (hepatitis B and C, HIV, and Lyme disease), hepatic biology, and serum vitamin B-12 levels were normal. Thoraco-abdomino-pelvic computed tomography scan was normal. Electroneuromyogram confirmed the presence of sensorimotor polyneuropathy with predominant distal involvement of lower limbs, marked reduction of compound muscle action potentials and prolonged distal motor latencies in median nerves, and complete disappearance of sensory potentials of all studied nerves (Table 1). Salivary glands biopsy showed chronic sialadenitis of grade 3 without amyloid deposits. Prednisone was started at a dose of 1 mg/kg/day. Gait worsened with progressive alteration in cognitive functions associated with sphincter disorders such as urinary dribbling and itchy lesions on the left upper limb. Physical examination in July 2005 found temporospatial disorientation, sensory ataxia, glove and socks hypoesthesia, motor deficit in median nerves territories in both hands, and areflexia. There were no palpable masses on lymph node examination. Orthostatic hypotension was found. Lumbar puncture showed elevated protein (1.48 g/l) with a normal cell count. Echocardiography showed hypertrophic cardiomyopathy and a granular sparkling appearance of the septum. The nerve conduction studies worsened compared with the prior study with prolonged distal latencies, decreased compound muscle action potentials, and reduction in conduction velocity in some nerves (Table 1). The nerve biopsy showed a massive loss of large-diameter myelinated fibers (90%), few regeneration clusters, and no modification in the myelin. Endoneurial amyloid deposits were rarely featured (Fig. 1). Amyloid deposits were also shown in osteomedullary biopsy. Cerebral magnetic resonance imaging (MRI) revealed multiple lacunar infarctions associated with hemorrhagic lesions (Fig. 2). The molecular study of the TTR gene identified the Val107 mutation. Over 80 distinct mutations of the TTR gene have been reported. The Portuguese form, the most frequent, was initially described by Andrade (1952). The substitution of a methionine for a valine at position 30 was the first pathogenic TTR variant identified by Saraiva et al. (1984) responsible for FAP. A rarer form related to a substitution of a valine for isoleucine at position 107 was described for the first time in 1994, associating polyneuropathy with cardiomyopathy, carpal tunnel syndrome, and bulbar affection (Jacobson et al., 1994). Our case is unusual in several aspects. First, we report a TTR Val107 mutation in an African patient. Address correspondence to: Julien Cassereau, MD, Département de Neurologie, CHU Angers, 4 rue Larrey, 49033 Angers, France. Tel:þ33 2 41 35 46 18; Fax:þ33 2 41 35 51 18; E-mail: juliencassereau@ hotmail.com Journal of the Peripheral Nervous System 13:251–254 (2008)