Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin (IVIg) is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005, 2008 and 2011. OBJECTIVES: To assess the effects of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH METHODS: On 22 September 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE and LILACS for trials of MMN. We also searched two trials registers for ongoing studies. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs. We considered prospective and retrospective case series and case reports in the Discussion. DATA COLLECTION AND ANALYSIS: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. MAIN RESULTS: Only one RCT of an immunosuppressive or immunomodulatory agent has been performed in MMN. This study randomised 28 participants and showed that mycophenolate mofetil, when used with IVIg, did not significantly improve strength, function or reduce the need for IVIg. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion. AUTHORS' CONCLUSIONS: According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for IVIg or improving muscle strength in MMN. Trials of other immunosuppressants should be undertaken.

Chinese medicine NeuroAiD efficacy stroke recovery-extension study (CHIMES-E study): an observational multicenter study to investigate the longer-term efficacy of NeuroAiD in stroke recovery.

BACKGROUND: Stroke carries a poor long-term prognosis for death and disability. There are few acute treatments that reduce death and disability after stroke. The ongoing international, multicenter, randomized, placebo-controlled, double-blind CHIMES trial is currently testing the hypothesis that a 3-month course of the traditional Chinese medicine MLC601 (NeuroAiD) is superior to placebo in reducing neurological deficit and improving functional outcome after acute ischemic stroke in patients receiving standard stroke care. This extension study tests the hypothesis that at 2 years, an initial 3-month administration of NeuroAiD is superior to placebo in reducing neurological deficit and improving functional outcome in patients with cerebral infarction of an intermediate range of severity. METHODS: Study subjects will be those who are already participants in CHIMES - aged above 21 years, had signs and symptoms of acute stroke, 6 ≤ NIHSS ≤ 14, neuroimaging consistent with ischemic stroke, and received study medication within 72 h of stroke onset. A subject will not be eligible for inclusion in CHIMES-E if they have withdrawn consent from all participation and follow-up for CHIMES. Subjects will be contacted at 6, 12, 18 and 24 months after CHIMES enrollment. After verbal consent is obtained, subjects will be assessed for functional state by the modified Rankin scale (mRS) and Barthel Index (BI), and a history of recurrent vascular events as well as medical events. The primary outcome measure will be the mRS at month 24. Secondary outcome measures will be mRS and BI at 6, 12 and 18 months, and BI at 24 months. Analysis will be based on the intention-to-treat principle. If the number of patients lost to follow-up is substantial, a sensitivity analysis based on the last observation carried forward method will be carried out, to compare the results with those from the main analysis without imputation. Based on a cumulative odds ratio of 1.5 for the NeuroAiD group, a two-sided test of 5% type I error and an expected 30% dropout rate after 2 years of follow-up for the 1,100 patients recruited into CHIMES, the 770 subjects with mRS data expected to be available at year 2 yields an 89% power to detect a difference in efficacy between NeuroAiD and placebo. CONCLUSIONS: This study will provide evidence for the longer-term efficacy of an initial course of a neurorestorative therapy after acute ischemic stroke of intermediate severity.

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005 and 2008. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3 in The Cochrane Library), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), and LILACS (January 1982 to September 2011) for trials of multifocal motor neuropathy. SELECTION CRITERIA: We planned to include randomised and quasi-randomised controlled trials. We considered prospective and retrospective case series and case reports in the Discussion. DATA COLLECTION AND ANALYSIS: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. MAIN RESULTS: Only one randomised controlled trial of an immunosuppressive or immunomodulatory agent has been performed in multifocal motor neuropathy. This study randomised 28 participants and showed that mycophenolate mofetil, when used with intravenous immunoglobulin, did not significantly improve strength, function or reduce the need for intravenous immunoglobulin. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion. AUTHORS' CONCLUSIONS: According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for intravenous immunoglobulin or improving muscle strength. Trials of other immunosuppressants should be undertaken.

Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore.

BACKGROUND AND AIMS: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. METHODS: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007-2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. RESULTS: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). CONCLUSION: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin is beneficial but the role of immunosuppressive agents is uncertain. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH STRATEGY: For this update, we searched the Cochrane Neuromuscular Disease Group Trials Register (October 8 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 4), MEDLINE (from January 1966 to October 8 2008), and EMBASE (from January 1980 to October 8 2008), for trials of multifocal motor neuropathy. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials were to be included and one was found. Prospective and retrospective case series and case reports were considered in the Discussion. DATA COLLECTION AND ANALYSIS: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. MAIN RESULTS: In this update, we found the first randomised controlled trial of multifocal motor neuropathy. This study, which randomised 28 patients, showed that mycophenolate mofetil did not significantly improve strength or function or reduce the need for intravenous immunoglobulin. We summarised the results of retrospective and prospective case series in the discussion. AUTHORS' CONCLUSIONS: In the only randomised placebo-controlled trial of any immunosuppressive agent, mycophenolate mofetil did not produce significant benefit. Trials of other immunosuppressants should be undertaken.

Partial ulnar nerve transfer to the nerve to the biceps for the treatment of brachial plexopathy in metastatic breast carcinoma: case report.

Brachial plexus neuropathy can cause progressive pain and disability in patients with breast cancer. Metastatic spread and radiation injury are the most common causes in these patients. We report a case of partial ulnar nerve transfer to the nerve to the biceps muscle to restore elbow flexion in a patient with combined radiation-induced and metastatic brachial plexopathy.

Diagnostic lumbar puncture: minimizing complications.

Diagnostic lumbar puncture (LP) is essential to the diagnosis of central nervous system infections and subarachnoid haemorrhage. Life or limb-threatening adverse events due to the procedure are rare, but less severe complications may be common. Clinical practice in diagnostic LP is often not evidenced based. The aim of the study was to use best available published evidence to address questions on minimizing complications associated with diagnostic LP. We searched PubMed for studies in the English language using key words relevant to the complications of diagnostic LP. We emphasized randomized controlled trials and systematic reviews enrolling adult patients undergoing diagnostic LP. Uncontrolled studies and studies involving children or spinal anaesthesia were considered when no other evidence was available. There were nine prospective studies and three systematic reviews on reducing complications from LP. Recommendations on interventions to minimize complications of LP are graded based on the quality and strength of evidence.

Diffusion-weighted MR imaging in early diagnosis and prognosis of hypoglycemia.

SUMMARY: We describe 2 cases of diffusion-weighted (DW) MR imaging in hypoglycemic coma. One patient, with diffuse cortical lesions, had a poor outcome, but the other, with transient white matter abnormalities, made a complete recovery. The distinctive patterns of DW MR imaging abnormalities in hypoglycemic patients should be recognized and may be a predictor of clinical outcome.

Finger flexion resembling focal dystonia in Isaacs' syndrome.

We describe a patient with a 5-month history of gradually progressive painless flexion of the left ring finger associated with cramps in both thighs. She has severe chronic obstructive pulmonary disease and was on salbutamol. Serum anti-voltage-gated potassium channel antibodies was positive. Electromyography showed generalized neuromyotonia and myokymic discharges. The cramps were partially relieved by phenytoin. We would like to highlight that finger flexion resembling dystonia can be a presenting sign of Isaacs' syndrome.

A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy.

To investigate the aetiology of chronic idiopathic axonal polyneuropathy (CIAP), 50 consecutive patients were compared with 50 control subjects from the same region. There were 22 patients with painful neuropathy and 28 without pain, 26 with sensory neuropathy and 24 with sensory and motor neuropathy. The typical picture was a gradually progressive sensory or sensory and motor neuropathy. It caused mild or sometimes moderate disability, and reduced the quality of life. There was no evidence that alcohol, venous insufficiency, arterial disease or antibodies to peripheral nerve antigens played a significant part. There was a possible history of peripheral neuropathy in the first or second-degree relatives of six patients and no controls (P = 0.01), and claw toes were present in 12 patients and four controls (P = 0.03). Thirty-two per cent of the patients and 14% of the controls had impaired glucose tolerance or fasting hyperglycaemia but, after adjusting for age and sex, the difference was not significant (P = 0.45), even in the painful neuropathy subgroup. The mean (SD) fasting insulin concentrations were significantly (P = 0.01) higher in the patients [75.9 (44.4) mmol/l] than the controls [47.3 (37.9) mmol/l], and the mean was higher still in the painful neuropathy subgroup [92.2 (37.1) mmol/l] (P < 0.0001). However, insulin resistance as assessed using the homeostasis model assessment formula was not significantly greater in the patients, even in those with pain, than the controls. After adjustment for body mass index as well as age and sex, there was no significant difference in the serum cholesterol concentrations, but there were significantly higher triglyceride concentrations in the patients [mean 1.90 (1.41) mmol/l] than the controls [mean 1.25 (0.79] mmol/l) (P = 0.02). In the patients with painful peripheral neuropathy, the mean triglyceride concentration was 2.37 (1.72), which was even more significantly greater compared with the controls (P = 0.003). In conclusion, CIAP is a heterogeneous condition. A logistic regression analysis identified environmental toxin exposure and hypertriglyceridaemia, but not glucose intolerance or alcohol overuse as significant risk factors that deserve further investigation as possible causes of CIAP.

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy is a distinct clinical entity characterised by progressive, predominantly distal, asymmetrical limb weakness and minimal sensory abnormality. The diagnostic feature of this condition is the presence of multiple partial motor nerve conduction blocks. Controlled trials have demonstrated the efficacy of regular intravenous immunoglobulin infusions. Immunosuppressive agents have been used as primary, second-line or adjunctive agents for its treatment. This review was undertaken to identify and review systematically randomised controlled trials of immunosuppressive agents. The use of intravenous immunoglobulin will be the subject of a separate review. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register for all trials of multifocal motor neuropathy published, using 'multifocal motor neuropathy' OR 'chronic inflammatory demyelinating polyradiculoneuropathy' OR ' conduction block' OR ' motor neuropathy' AND 'immunosuppressive agents', 'immunosuppressants', 'corticosteroids', 'plasma exchange', 'azathioprine', 'cyclophosphamide', 'cyclosporin', 'ciclosporin', 'methotrexate', and 'mycophenolate', 'immunomodulatory agents', 'interferon', 'total lymphoid irradiation' or 'bone marrow transplantation' as search terms. In addition we searched MEDLINE, EMBASE for 2000 and 2001 and CINAHL, LILACS for all years. We updated the register search in February 2004 and searched MEDLINE (January 1966 to end May 2004) and EMBASE (January 1980 to end May 2004). SELECTION CRITERIA: All randomised controlled trials and quasi-randomised clinical trials in which allocation was not random but was intended to be unbiased (e.g. alternate allocation) were to have been selected. Since no such trials were discovered, all prospective and retrospective case series were included in the 'background' or 'discussion' sections of the review. DATA COLLECTION AND ANALYSIS: All studies on multifocal motor neuropathy or lower motor neuron weakness with conduction block and no sensory abnormality were scrutinised for data on patients treated with any form of immunosuppressive agents besides intravenous immunoglobulin. The information on the outcome of treatment was then collated and summarised. MAIN RESULTS: We found no randomised controlled trials of any immunosuppressive agents for multifocal motor neuropathy. We summarised the results of retrospective and prospective case series in the discussion of the review. AUTHORS' CONCLUSIONS: There are no randomised controlled trials to indicate whether immunosuppressive agents are beneficial in multifocal motor neuropathy.

Field application of Lepto lateral flow for rapid diagnosis of leptospirosis.

The Lepto lateral flow assay for leptospirosis was evaluated at a primary health centre in the Andaman Islands, where leptospirosis is endemic. One hundred and seventeen suspected patients were included in the study; acute serum samples were collected from all of them and convalescent samples from 104. The standard criteria for diagnosis of leptospirosis were: (i) isolation of leptospires from blood, (ii) seroconversion in microscopic agglutination test (MAT) with a minimum titre of 100, (iii) a fourfold rise in titre in MAT or (iv) a MAT titre of 400 or more if only a single sample was available. The results of the lateral flow test were compared with these criteria. Lepto lateral flow had sensitivity of 52.9 % (37/70) in the first week of illness and 86 % (49/57) during weeks 2-4. The corresponding specificities were respectively 93.6 % (44/47) and 89.4 % (42/47). The sensitivity was 34.3 % (12/35) on days 2-3 of the illness, 63.3 % (14/22) on days 4-5 and 84.6 % (11/13) at the end of the first week. The test had a positive predictive value of 92.5 % (37/40) during the first week and 90.7 % (49/54) subsequently. Corresponding negative predictive values were respectively 57.1 % (44/77) and 84 % (42/50). Agreement of the results with the standard criteria was low during the first week, but high during weeks 2-4, with a kappa value of 0.7491. The positivity rates of the tests showed a logarithmic relationship with the MAT titres of samples (r(2) = 0.9271). All indices of validity and utility of lateral flow were similar to those of IgM ELISA and Lepto dipstick. The test can be performed at the bedside of the patient, as whole blood can also be used for testing.

Large artery ischaemic stroke in severe acute respiratory syndrome (SARS).

Of the 206 patients who contracted Severe Acute Respiratory Syndrome (SARS) in Singapore five developed large artery cerebral infarctions. Four patients were critically-ill and three died. Intravenous immunoglobulin was given to three patients. An increased incidence of deep venous thrombosis and pulmonary embolism was also observed among the critically-ill patients. We believe our experience warrants an increased vigilance against stroke and other thrombotic complications among critically-ill SARS patients in future outbreaks, especially if treatment such as intravenous immunoglobulin, that increases pro-thrombotic tendency, is contemplated.

Susac syndrome: serial diffusion-weighted MR imaging.

Susac syndrome (SS) is a clinical triad of hearing loss, retinal artery occlusion and encephalopathy. The typical MR imaging findings of multiple focal lesions in the corpus callosum and subcortical white matter can be easily misdiagnosed as multiple sclerosis. On diffusion-weighted (DW) MR imaging, new lesions were hyperintense, with reduced apparent diffusion coefficient (ADC). These lesions later became less prominent or hypointense on subsequent DW MR imaging. Serial DW imaging and ADC maps may be useful in differentiating SS from demyelinating diseases.

Immunosuppressive treatment for multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy is a distinct clinical entity characterised by progressive, predominantly distal, asymmetrical limb weakness and minimal sensory abnormality. The pathognomonic feature of this condition is the presence of multiple partial motor nerve conduction blocks. Controlled trials have demonstrated the efficacy of regular intravenous immunoglobulin infusions. Immunosuppressive agents have been used as primary, second-line or adjunctive agents for its treatment. This review was undertaken to identify and review systematically randomised controlled trials of immunosuppressive agents. The use of intravenous immunoglobulin will be the subject of a separate review. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH STRATEGY: The Cochrane Neuromuscular Disease Group register was searched for all trials of multifocal motor neuropathy published, using 'multifocal motor neuropathy' OR 'chronic inflammatory demyelinating polyradiculoneuropathy' OR ' conduction block' OR ' motor neuropathy' AND 'immunosuppressive agents', 'immunosuppressants', 'corticosteroids', 'plasma exchange', 'azathioprine', 'cyclophosphamide', 'cyclosporin', 'methotrexate', and 'mycophenolate', 'immunomodulatory agents', 'interferon', 'total lymphoid irradiation' or 'bone marrow transplantation' as search terms. In addition we searched MEDLINE, EMBASE for 2000 and 2001 and CINAHL, LILACS for all years. SELECTION CRITERIA: All randomised controlled trials and quasi-randomised clinical trials in which allocation was not random but was intended to be unbiased (e.g. alternate allocation) were to have been selected. Since no such trials were discovered, all prospective and retrospective case series were included in 'background' or 'discussion' sections of the review. DATA COLLECTION AND ANALYSIS: All studies on multifocal motor neuropathy or lower motor neuron weakness with conduction block and no sensory abnormality were scrutinized for data on patients treated with any form of immunosuppressive agents besides intravenous immunoglobulin. The information on the outcome of treatment was then collated and summarised. MAIN RESULTS: We found no randomised controlled trials of any immunosuppressive agents for multifocal motor neuropathy. We summarised the results of retrospective and prospective case series in the discussion of the review. REVIEWER'S CONCLUSIONS: There are no randomised controlled trials to indicate whether immunosuppressive agents are beneficial in multifocal motor neuropathy.

Evaluation of darkground microscopy as a rapid diagnostic procedure in leptospirosis.

BACKGROUND & OBJECTIVES: Although darkground microscopy (DGM) is the method employed for examining the growth of leptospires in culture, it is not useful for diagnosis when used directly on body fluids. However, it continues to be used as a method for diagnosing leptospirosis in many centres in India. The present study was undertaken to evaluate the diagnostic accuracy of DGM by comparing it with established tests like culture, microscopic agglutination test (MAT), IgM ELISA and Lepto-Dipstick. METHODS: A total of 170 patients clinically suspected to have leptospirosis were included in the study. The gold standard for diagnosis was positive blood culture, or seroconversion, or a four-fold rise in titre in MAT. DGM was done on plasma after centrifugation at 1000 g and 3000 g and on serum. Indices of accuracy including sensitivity, specificity, predictive values and kappa value of agreement with the gold standard diagnostic criteria were calculated. RESULTS: DGM had a sensitivity of 40.2 per cent, specificity of 61.5 per cent, a positive predictive value of 55.2 per cent and a negative predictive value of 46.6 per cent. It had agreement with the gold standard in only 50 per cent cases the kappa value being 0.017141. INTERPRETATION & CONCLUSION: DGM has low indices of accuracy. The results obtained in patients who met the gold standard criteria for diagnosis and those who did not were identical indicating that the test results are not determined by the presence of leptospiral infection in the patient. DGM, therefore, is not recommended as a sole diagnostic procedure for early diagnosis of leptospirosis.

The value of comparing mortality of Guillain-Barré syndrome across different regions.

OBJECTIVE: To study the clinical profile of Guillain-Barré syndrome (GBS) patients who died in 4 Asian countries in order to understand factors underlying any variation in mortality. METHODS: Retrospectively reviewed medical records of GBS patients who died in 7 hospitals from 4 Asian countries between 2001 and 2012. Baseline characteristics, timing and causes of death were recorded. RESULTS: A total of 16 out of 261 GBS patients died. The overall mortality rate was 6%, with a range of 0 to 13%. The leading causes of death were respiratory infections, followed by myocardial infarction. The median age of our patients was 77 years. Half of the patients required mechanical ventilation and almost all had significant concomitant illnesses. A disproportionate number of patients in the Hong Kong cohort died (13%). Patients with advanced age, fewer antecedent respiratory infections and need for mechanical ventilation were at most risk. Most deaths occurred during the plateau phase of GBS and on the general ward after having initially received intensive care. CONCLUSIONS: There is considerable variability in mortality of GBS among different Asian cohorts. Although the risks factors for mortality were similar to Western cohorts, the timing and site of death differed. This allows specific measures to be implemented to improve GBS care in countries with higher mortality.

Intraepidermal nerve fiber density as a marker of early diabetic neuropathy.

The purpose of the study was to reliably identify an early stage of diabetic polyneuropathy (DPN) by measuring injury to epidermal nerve fibers. We compared intraepidermal nerve fiber density (IENFD) at the ankle and thigh of 29 diabetic subjects who had no clinical or electrophysiological evidence of small- or large-fiber neuropathy to that of 84 healthy controls. The mean ankle IENFD of diabetic subjects was 9.1+/-5.0 mm and that of controls, 13.0+/-4.8 mm (P<0.001). The thigh IENFD did not differ significantly. The IENFD ratio (thigh IENFD divided by ankle IENFD) was 2.39+/-1.30 in diabetic subjects and 1.77+/-0.58 in controls (P<0.001), indicating a length-dependent reduction of IENFD in diabetics. Ankle IENFD remained significantly lower and the IENFD ratio higher in diabetic subjects after adjusting for age. Two subjects had parasympathetic dysfunction, two had retinopathy, and two early nephropathy. Age, height, weight, duration of diabetes, and average HbA1c did not influence IENFD among diabetic subjects. We used receiver operating characteristic (ROC) curves to describe and compare the utility of various threshold values of ankle IENFD and IENFD ratio for the diagnosis of early DPN. The sensitivity and specificity of diagnosing DPN using ankle IENFD of less than 10 mm were 72.4% and 76.2%, respectively. Thus, asymptomatic diabetics have a measurable, length-dependent reduction of distal epidermal nerves. Analogous to microalbuminuria in diabetic nephropathy, reliable identification and quantitation of nascent diabetic neuropathy may have potential therapeutic implications.