Mild Peripheral Neuropathy Research Articles

Peripheral neuropathy: detection with diffusion-tensor imaging.

To investigate the ability of diffusion-tensor imaging (DTI) and T2 to help detect the mildest nerve lesion conceivable, that is, subclinical ulnar neuropathy at the elbow. This prospective study was approved by the institutional ethics board. Written informed consent was obtained from all participants. Magnetic resonance neurography was performed at 3.0 T by using proton density- and T2-weighted relaxometry and DTI on elbows in 30 healthy subjects without clinical evidence of neuropathy. Quantitative analysis of ulnar nerve T2 and fractional anisotropy (FA) was performed, and T2 and FA values were correlated to electrical nerve conduction velocities (NCVs) with Pearson correlation analysis. Additional qualitative assessment of T2-weighted and FA images was performed by two readers, and sensitivity and specificity were calculated. Ten of the 30 subjects (33%) had NCV slowing across the elbow segment. Compared with subjects without NCV slowing, subjects with slowing had decreased FA values (0.51 ± 0.09 vs 0.41 ± 0.07, respectively; P = .006) and increased T2 values (64.2 msec ± 10.9 vs 76.2 msec ± 13.7, respectively; P = .01) in the proximal ulnar sulcus. FA values showed a significant correlation (P = .01) with NCV slowing over the sulcus as an electrophysiologic indicator of myelin sheath damage. Qualitative assessment of FA maps and T2-weighted images helped identify subjects with conduction slowing with a sensitivity of 80% and 55%, respectively, and a specificity of 83% and 63%. FA maps can accurately depict even mild peripheral neuropathy and perform better than the current standard of reference, T2-weighted images. DTI may therefore add diagnostic value as a highly sensitive technique for the detection of peripheral neuropathy.

Small-cell lung cancer: a case report on the manifestation of paraneoplastic motor neuron disease after effective tumor shrinkage during chemotherapy

A 72-year-old Japanese man with locally advanced small-cell lung cancer presented with gait disturbance, caused by weakness in both lower extremities; this occurred during chemotherapy that effectively reduced the size of his tumor. Muscle weakness was severe in the bilateral proximal upper extremities, and moderate in the bilateral distal upper extremities and the bilateral lower limbs. Numbness and mild hypoesthesia were also present in the right upper and lower extremities. Involvement of brain and spinal lesions were an unlikely cause of these symptoms. Findings from a nerve conduction study suggested a mild peripheral sensory neuropathy complication. The patient died of respiratory failure and CO2 narcosis at 9 months after the diagnosis of malignancy and at 4 months after the first manifestation of muscular weakness. Anti-Hu antibody was reported to be positive after his death. Thus, paraneoplastic motor neuron disease (MND) was definitely confirmed. In conclusion, this was a rare case of paraneoplastic MND; the clinical course was uncommon in that the MND occurred when chemotherapy had successfully reduced the size of the tumor.

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.

Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

BackgroundPomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. MethodsOne hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. ResultsOne hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. ConclusionsClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures:Mark:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Orthostatic Tremor, Progressive External Ophthalmoplegia, and Twinkle

Orthostatic tremor (OT) is a high-frequency (13-18 Hz) leg tremor occurring in standing position. Orthostatic tremor has an unknown pathophysiologic mechanism. It is thought to be sporadic but siblings with OT from 3 unrelated families were reported. No mutations have been reported in OT. We describe a patient with OT carrying a C10orf2 TWINKLE mutation to highlight the possible association of OT with mitochondrial dysfunction and mutations in the mitochondrial replicative helicase Twinkle. A man in his late 60s had ptosis and tremor on standing for 30 years, followed by development of progressive external ophthalmoplegia. Polygraphic recordings revealed an orthostatic synchronic tremor with 17.5-Hz frequency. Electromyography/nerve conduction studies showed evidence for a mild myopathy and associated mild axonal sensorimotor peripheral neuropathy. Muscle biopsy revealed ragged red fibers; mild cerebral atrophy was evident by magnetic resonance imaging. Molecular analysis revealed a novel heterozygous missense mutation at an evolutionarily conserved residue of the C10orf2 TWINKLE gene. Although the incidental association of OT and C10orf2 TWINKLE mutation is possible, the simultaneous onset of OT and eyelid ptosis at a much younger age than usually observed for OT raises the possibility of mitochondrial dysfunction and loss of mitochondrial DNA integrity in the pathogenesis of OT.

Mitochondrial trifunctional protein deficiency: A rare cause of adult‐onset rhabdomyolysis

Mitochondrial trifunctional protein deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid β-oxidation that may be due to mutations in 2 different nuclear genes, HADHA and HADHB. Perturbation of this multienzyme complex compromises the oxidation of long-chain fatty acids, which leads to multiorgan dysfunction. Childhood- or adolescent-onset recurrent rhabdomyolysis is a common muscular manifestation and is preceded frequently by clinically overt peripheral neuropathy. In this report we describe a patient with late adult-onset recurrent rhabdomyolysis. Despite normal sensory examination, nerve conduction studies showed a mild axonal peripheral neuropathy. The acylcarnitine profile showed elevated long-chain and 3-hydroxy long-chain acylcarnitine species. HADHA sequencing revealed known compound heterozygous mutations c.180+3A>G (p.Thr37SerfsX6) and c.1528G>C (p.Glu510Gln). During a 10-month follow-up period, he had no further episodes of rhabdomyolysis after appropriate dietary modifications. Mitochondrial trifunctional protein deficiency should be considered in patients with adult-onset recurrent rhabdomyolysis, especially in those with either clinically overt or subclinical peripheral neuropathy.

Measurements of Anteroposterior and Intersidal Asymmetry in Patients with Diabetic Peripheral Neuropathy

The aim of this study was to investigate the anteroposterior and intersidal asymmetric weight bearing and plantar pressure in patients with mild diabetic peripheral neuropathy. A total of 102 subjects were enrolled in this study. Plantar pressure and anteroposterior and intersidal weight-bearing patterns on a foot plate were measured using Gaitview while standing and during dynamic walking. The subjects were evaluated with nerve conduction study, vibration sensory threshold (VST), and Diabetic Neuropathy Symptom (DNS) scores. The subjects were classified into normal nerve conduction study and mild diabetic peripheral neuropathy groups according to the results of the nerve conduction study tests. The two groups differed significantly in asymmetric weight-bearing pattern, DNS score, and VST. The sensitivities of anteroposterior and intersidal asymmetry were similar to those of DNS score and VST, with significant correlations between asymmetric weight bearing and VST and DNS scores. In contrast, highest plantar pressure did not differ significantly in the two groups and was not significantly correlated with nerve conduction study, VST, or DNS score. Measurements of asymmetric weight bearing may indicate the clinical significance of mild diabetic peripheral neuropathy similar as other screening tools. Asymmetric weight-bearing pattern may be useful for evaluating patients in the early period of diabetes mellitus because proper management would prevent further complications and improve quality-of-life.

Immediate Effects of Acute Postural Correction on Plantar Pressures and Gait Characteristics in an Individual with Diabetic Peripheral Neuropathy: A Case Report

Purpose: The purpose of this case report is to assess the immediate effects of acute postural changes on plantar pressure distribution and gait characteristics during comfortable walking speed in an individual with diabetic peripheral neuropathy. Case description/intervention: Subject is a 71 year old Caucasian male with a BMI of 31.3 and a medical diagnosis of Type II Diabetes given 8 years ago. The patient exhibits mild peripheral neuropathy as scored by the Michigan Neuropathy Screening Instrument (MNSI; 7/23) as well as callous formation over the 2nd and 3rd metatarsal heads. The patient performed 3 separate walking conditions at a comfortable walking speed. The 3 conditions were: (1) Normal walking (NW), (2) Forward bending walking (FBW), and (3) Upright walking (UW). Measurements were recorded and averaged from these 3 conditions. NW condition was used as a control for comparing gait characteristics and plantar pressure parameters with the other gait conditions. Results: UW may be the most mechanically efficient condition for distributing plantar pressure with increased gait speed (1.441 m/s), largest contact surface area of the foot, and increased hip range of motion; however, for this individual the increased plantar pressure in the forefoot (FF) area may contribute to the risk of ulceration. The FBW condition showed the limited medial to lateral excursion of the center of forceand lowest pressure in the FF area; therefore, FBW may be the most beneficial for this patient in decreasing the risk of ulceration in the area of greatest concern. Conclusion: Variations in gait characteristics during UW and FBW indicate that alterations in posture may serve as another method to reduce the risk of plantar ulcer formation; however, further research is needed to examine the long term effects of such an intervention.

073 Hereditary spastic paraplegia caused by spastin (SPAST, SPG4) mutations is found more often in males: report of novel mutations from one centre, and review of published literature

BackgroundHereditary spastic paraplegia (HSP) is characterised predominantly by slowly progressive spastic paraparesis. Early reports yielded conflicting results concerning sex differences in severity and prevalence of HSP in general. Around 40%...

Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin ( SPAST) mutations is found more often in males

Background Hereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encoding spastin. Patients and methods The clinical and investigation details of all patients with a SPAST mutation identified through our centre were reviewed. All published reports of SPAST mutations where the sex of patients was given were subsequently analysed in order to determine whether there is evidence of one sex being preferentially affected. Results In total 22 probable pathogenic changes were detected, including 11 novel ones. One patient carried two adjacent missense mutations. The pathogenicity of a further novel missense mutation is uncertain. Most patients had a pure phenotype, although mild peripheral neuropathy was sometimes present. The total number of patients with SPAST mutations was 27, as three of the previously known mutations were present in more than one person. The excess of males over females in our population (17:10) prompted us to review all published studies where the sex of the patients was given (n = 31). A significant excess of males was identified (ratio 1.29, p = 0.0007). Conclusions Our results are consistent with data suggesting that SPAST mutations mostly cause a pure HSP phenotype. The excess of males in our sample and in published reports suggests that penetrance or severity may be sex-dependent, and merits further investigation as it may have important implications for counselling.

Rapidly progressive polyneuropathy due to dry beriberi in a man: a case report

IntroductionWe describe a case of rapidly progressive and severely debilitating polyneuropathy in a patient with confirmed hypovitaminosis B1, consistent with dry beriberi. Crucially, this is a treatable condition, although sometimes with incomplete recovery, but it is probably under-recognized yet increasingly common given increasing levels of alcohol abuse in the western world.Case presentationA 49-year-old Caucasian British man presented with progressive weakness of both lower limbs of approximately seven months' duration. He noted difficulty climbing stairs. He also complained of lethargy, and loss of muscle bulk, including his thighs. He had a history of type 2 diabetes mellitus and admitted prior alcohol abuse but denied excessive alcohol intake in the five years prior to presentation. Initial clinical and neurophysiological examinations were consistent with a mild peripheral neuropathy and probable proximal myopathy. However, over the subsequent four months he evolved a marked tetraparesis, with profound sensory disturbance of all limbs. Repeat neurophysiology revealed a widespread polyneuropathy with extensive acute and sub-acute denervation changes in all four limbs, and reduced or absent sensory nerve action potentials. Hypovitaminosis B1 was confirmed (45 nmol/L, reference range 66-200 nmol/L). His rapid clinical deterioration was in keeping with dry beriberi. He was treated with thiamine. Subsequent follow-up revealed slow but significant improvement, such that by 15-16 months from the initial onset of symptoms, and approximately six months after the onset of his marked tetraparesis, he was able to stand independently and was gradually gaining confidence in walking pending a period of in-patient neurorehabilitation.ConclusionA potentially wide differential diagnosis exists for this type of presentation. Confirming hypovitaminosis B1 by requesting the assay prior to vitamin replacement ensures accurate diagnosis and appropriate ongoing treatment. An increasingly high index of suspicion is likely to be required in the context of increasing levels of alcohol abuse in the western world and the possible increasing prevalence of dry beriberi.

An asymptomatic 61‐year‐old man with BCR‐ABL‐positive bone marrow following autologous transplantation for multiple myeloma

An asymptomatic 61‐year‐old man with <i>BCR‐ABL</i>‐positive bone marrow following autologous transplantation for multiple myeloma

Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A report from the therapeutic advances in childhood leukemia (TACL) consortium

Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies. This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L-asparaginase, and doxorubicin (VXLD) in children with relapsed ALL. Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1 mg/m(2)). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3 mg/m(2)). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia. The combination of bortezomib (1.3 mg/m(2)) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3 mg/m(2) cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726).

Clinical neurophysiology in GJA12 -related hypomyelination vs Pelizaeus-Merzbacher disease

Among the hypomyelinating leukoencephalopathies with onset in childhood, Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) constitute a large subgroup with almost indistinguishable clinical and neuroradiologic features. Whereas PMD is due to X-linked PLP1 mutations, PMLD is genetically heterogeneous, with about 8% of patients carrying autosomal recessive GJA12/GJC2 mutations. The aim of this study was to evaluate whether neurophysiologic testing may separate PMD from GJA12/GJC2-associated PMLD. Retrospective data collection study with reevaluation of evoked potentials (EP) and nerve conduction studies (NCS) in 10 patients from 7 families with PMLD due to various GJA12/GJC2 mutations and 8 boys from 7 families with classic PMD caused by a PLP1 duplication or missense mutation. In brainstem auditory EP, waves III-V were absent in all patients with PMD, but clearly recordable in 11 of 13 investigations in 8 patients with PMLD. Visual evoked potentials and somatosensory evoked potentials revealed conduction delay in both PMD and PMLD, without significant difference. NCS were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD. In a patient with clinical and neuroradiologic features of Pelizaeus-Merzbacher disease/Pelizaeus-Merzbacher-like disease and a pedigree consistent with both conditions, brainstem auditory evoked potentials provide good selectivity between these disorders and point in the right direction for identifying the primary genetic defect.

Bortezomib and Thalidomide, a Steroid Free Regimen in Newly Diagnosed Patients with Multiple Myeloma.

Abstract 2867Poster Board II-843Corticosteroids have historically been the backbone of most myeloma targeted therapies. However, they are often the major cause of toxicities, especially in elderly patients. In recent years, novel agents such as bortezomib and thalidomide have demonstrated significant anti-myeloma activity with increased overall response rates. We thus designed a study combining these two agents in a steroid-free regimen. Bortezomib (B) and thalidomide (T) were examined as first line treatment in 27 patients with symptomatic multiple myeloma between September 2004 and September 2006. Patients received B 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days and T 150 mg daily for a maximum of 8 cycles. The overall response rate was 81.5%, with a near CR or greater of 25.8% and a CR (immunofixation negative) of 11%. A major response identified by greater than 90% reduction in the paraprotein was seen in 33% of the patients. Responses were rapid: median time to first response was 36.5 days (range, 14-101 days) and median time to best response was 61 days (range, 16-171 days). The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%) and fatigue (7%). The only grade 3 hematologic toxicity was anemia (7%). No grade 4 toxicities were seen. 3 patients had mild peripheral neuropathy (PN) at baseline. PN was the most common reason for dose reduction with an average B dose of 1.1mg/m2 and T of 110mg daily. The major cause of discontinuation of treatment was PN. The PN completely resolved in 80% of the patients upon completion of therapy. No venous thromboembolic events (VTE) were observed even in the absence of prophylactic anticoagulation. It should be noted that upon completion of the study all patients received either B or T maintenance and no patients proceeded onto stem cell transplant immediately. The median progression free survival (PFS) was 16.8 months (95% CI 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3 year overall survival is 74%. This study demonstrates: 1) the excellent efficacy of a steroid-free regimen; 2) good PFS in the absence of stem cell transplantation; and 3) that most treatment-related PN resolves. Disclosures:Huff:Celgene: Consultancy. Borrello:Celgene: Speakers Bureau; Mellenium: Consultancy.

Intraepidermal nerve fibre density at wrist level in diabetic and non‐diabetic patients

Myelinated nerve fibre pathology has been demonstrated at wrist level in diabetic patients. We examined if quantification of intra-epidermal nerve fibre density (IENFD) in hairy and glabrous skin at wrist level could detect signs of subclinical small nerve fibre neuropathy. In 35 diabetic patients who were age and gender matched with 31 non-diabetic patients, punch biopsies were obtained in conjunction with surgical carpal tunnel release. Biopsies were immunostained with anti-protein gene product (PGP) 9.5. The IENFD was quantified using manual counting by light microscopy. We could not demonstrate significant differences in IENFD between diabetic or non-diabetic patients. Additionally, no differences were found between patients with Type 1 and Type 2 diabetes or in diabetic patients with and without neurophysiologic signs of mild peripheral neuropathy. However, the IENFD was significantly higher in hairy skin compared with glabrous skin. Furthermore, the IENFD was significantly higher in females than in males and correlated with age, but not with duration of diabetes or glycated haemoglobin (HbA(1c)). In mild neuropathy no difference in IENFD at the wrist level could be detected between diabetic and non-diabetic patients. Independent of diabetes, we found IENFD to be higher in hairy skin compared with glabrous skin and higher in females than in males. These results must be taken into consideration when assessing small nerve fibre pathology in the upper extremity.

LOWER LIMB JOINT POSITION SENSE IN PATIENTS WITH TYPE II DIABETES MELLITUS

Diabetes mellitus (DM), of which type II has been described as an international epidemic, is a major cause of death. Diabetic peripheral neuropathy (PN) is a condition secondary to hyperglycemia, where progressive loss of peripheral nerve function, including sensory and motor functions, occurs over time. Early detection of PN-related impairments may be helpful for the management of patients with DM. Among the methods for the evaluation of these impairments, only that for joint position sense (JPS) requires both motor and sensory involvement. The purpose of the current study was to compare the JPS of the lower limb joints in patients with no or mild diabetic PN to those of normal controls both during weight-bearing (WB) and non-weight-bearing (NWB) conditions using 3D motion analysis methods. The results supported the hypothesis that in well controlled diabetic patients with no or mild PN, JPS deficits can be found only at the ankle joint during WB conditions, resulting in overestimation of dorsiflexion angles. This suggests that at the very early stage of development of diabetic PN, distal joint involvement precedes that of proximal joints. Early detection of these changes, through the assessment of the JPS for all the lower limb joints under both NWB and WB conditions, will be helpful for the development of clinical preventive and treatment programs for patients with DM, even if their glucose level are well controlled. Gait and balance training in these patients should emphasize proprioception training exercises during WB conditions.

Electromyographic sensitivity of peroneus tertius relative to abductor hallucis in assessment of peripheral neuropathy

The objective of this study was to compare the sensitivity of needle electromyography of the abductor hallucis and peroneus tertius muscles in the diagnosis of mild length-dependent peripheral neuropathy (PN). Nerve conduction studies and needle examination were performed on 50 patients with clinical evidence of mild PN. Results demonstrated that the peroneus tertius is as sensitive and is more specific than the abductor hallucis. It is particularly useful when more proximal muscles, such as the tibialis anterior and medial gastrocnemius, are not yet involved.

Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy.

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.

Remarkable Activity of Bortezomib Combined with Chemotherapy in a Phase I Study of Relapsed Childhood Acute Lymphoblastic Leukemia (ALL). A Report from the Therapeutic Advances in Childhood Leukemia (TACL) Consortium.

The outcome of relapsed ALL remains very poor, and many re-induction regimens are highly toxic. We report here the Phase I component of a Phase I/II study of bortezomib added to 4-drug induction with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin in children with relapsed ALL. A total of 10 patients were enrolled, 5 in 1st marrow relapse (2 early and 3 late relapses) and 5 in 2nd or subsequent relapse. Four patients were enrolled at dose level 1 (1 mg/m2) to obtain 3 evaluable patients. One patient was inevaluable for toxicity because of an error in dexamethasone doses and was removed after 8 days. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (1.3 mg/m2), the standard single agent dose. One patient had a DLT (hypophosphatemia and rhabdomyolysis) after1 dose of bortezomib, and that patient died from diffuse zygomyces infection by day 17. Five additional patients were enrolled with no further DLT's. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Only 2 patients had mild peripheral neuropathy (grades 1 and 2). Seven of the10 patients (70%) achieved a CR, and 1/10 had bone marrow CR with persistent central nervous system (CNS) leukemia despite weekly intrathecal (IT) methotrexate, for a total of 80% bone marrow CR rate. In conclusion: the combination of bortezomib with 4 standard drugs is highly active with acceptable toxicity in heavily pretreated relapsed pediatric ALL patients. We are expanding the MTD cohort for a phase II estimate, and intend to report updated results at the ASH meeting.Day1248111415182229 - 35Bortezomib (1 or 1.3 mg/m2)BBBBEvaluateVincristine (1.5 mg/m2)VVVVDoxorubicin (60 mg/m2)DoxDexamethasone (10 mg/m2) x 14 days———————————>PEG-Asparaginase (2500 U/ m2)PEGPEGPEGPEGIT Ara-CITACNS Negative: IT MethotrexateITMCNS Positive: IT TriplesITTITTITT