Amanda C. Peltier

Recent advances in drug-induced neuropathies.

Purpose of reviewPeripheral neuropathy is a common neurotoxic effect of medications. When medications are used to treat life-threatening illnesses, balancing the toxic effects of peripheral neuropathy with the therapeutic benefits of the drug can be difficult. This article examines recent research into the cellular mechanisms associated with neuropathy after treatment with medications to treat cancer, and HIV, and to prevent transplant rejection. Recent findingsCisplatin and suramin induce a length, dose, and time-dependent axonal sensorimotor polyneuropathy. Cisplatin and suramin both result in apoptosis in dorsal root ganglion neurons that may partially explain the neuropathy that develops with treatment. In contrast, nerve growth factor prevents initiation of the programmed cell death associated with cisplatin neurotoxicity. Suramin causes accumulation of lamellar inclusion bodies in dorsal root ganglion neurons related to dose of administration and severity of the neuropathy. Nucleoside reverse transcriptase inhibitors affect mitochondrial function and lead to depletion of the nerves mitochondrial DNA and inhibition of DNA polymerase. These effects on the mitochondrion may be related to the polyneuropathy that develops in these patients. In contrast to the axonal neuropathies, tacrolimus and rarely suramin can result in a demyelinating neuropathy that may mimic Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Many of these neuropathies can be reversed by early recognition of the symptoms or by using sensitive electrophysiological testing. In certain instances, specific therapies may ameliorate the neuropathy. Glutamine may reduce paclitaxel-induced toxicity, while some patients with tacrolimus or suramin-induced demyelinating neuropathy may respond to intravenous immunoglobulin or plasmapheresis. SummaryImproved understanding of neurotoxic mechanisms in the peripheral nervous system associated with chemotherapeutic and anti-HIV medications, coupled with early improved diagnosis, promises to help limit neurotoxicity associated with these medications.

The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant 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.

Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin II. The denture cream is a primary source of excessive zinc

Neurodegeneration of the central and peripheral nervous system associated with hypocupremia and hyperzincinemia has been widely recognized but the origin of high zinc remained unknown. Denture cream has been recently suggested as one possible source of zinc, but the frequency with which denture fixative alone accounts for this syndrome is unknown. We analyzed the origin of excessive zinc in eleven patients with a progressive myelopolyneuropathy and unexplained hypocupremia with hyperzincinemia. These patients had a detailed clinical assessment, determination of zinc and copper levels, and analyzed use of denture cream with the estimates of daily zinc exposure. We identified denture cream as a source of excessive zinc in 100% patients in our cohort. They all had a history of ill-fitting dentures requiring large amounts of denture cream, resulting in significant zinc exposure. Their copper and zinc normalized after stopping denture cream, further confirming that this is the source of high zinc. Inappropriate use of denture cream appears to be the sole source of excessive zinc in these patients.

Painful diabetic neuropathy

Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 1 diabetes than in those with type 2 disease. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined.

Reliability of Quantitative Sudomotor Axon Reflex Testing and Quantitative Sensory Testing in Neuropathy of Impaired Glucose Regulation

Reproducible neurophysiologic testing paradigms are critical for multicenter studies of neuropathy associated with impaired glucose regulation (IGR), yet the best methodologies and endpoints remain to be established. This study evaluates the reproducibility of neurophysiologic tests within a multicenter research setting. Twenty‐three participants with neuropathy and IGR were recruited from two study sites. The reproducibility of quantitative sudomotor axon reflex test (QSART) and quantitative sensory test (QST) (using the CASE IV system) was determined in a subset of patients at two sessions, and it was calculated from intraclass correlation coefficients (ICCs). QST (cold detection threshold: ICC = 0.80; vibration detection threshold: ICC = 0.75) was more reproducible than QSART (ICC foot = 0.52). The performance of multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in our IGR patients was similar to reports of other studies. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for use as a secondary endpoint measure in clinical research trials. Muscle Nerve, 2008

Advances in understanding drug-induced neuropathies

Many commonly used medications have neurotoxic adverse effects; the most common of these is peripheral neuropathy. Neuropathy can be a dose-limiting adverse effect for many medications used in life-threatening conditions, such as malignancy and HIV-related disease. Epidemiological evidence supports previous case reports of HMG-CoA reductase inhibitors (or ‘statins’) causing an axonal sensorimotor neuropathy or a purely small-fibre neuropathy in some patients. The neuropathy improves when the medication is withdrawn. Despite the association between HMG-CoA reductase inhibitors and neuropathy, the risk is low compared with the significant vascular protective benefits. Oxaliplatin, a new platinum chemotherapy agent designed to have fewer adverse effects than other such agents, has been shown to cause a transient initial dysaesthesia in addition to an axonal polyneuropathy. Thalidomide, an old therapy currently being utilised for new therapeutic indications (e.g. treatment of haematological malignancies), is associated with a painful, axonal sensorimotor neuropathy that does not improve on withdrawal of the drug. Nucleoside reverse transcriptase inhibitors are important components of highly active antiretroviral therapy, but are associated with a sensory neuropathy that is likely to be due to a direct effect of these drugs on mitochondrial DNA replication. New research demonstrates that lactate levels may help discriminate between neuropathy caused by nucleoside analogues and HlV-induced neuropathy. Understanding the mechanism of drug-induced neuropathy has led to advances in preventing this disabling condition.

Natural history of pure autonomic failure: A United States prospective cohort

To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.

Assessing autonomic dysfunction in early diabetic neuropathy The Survey of Autonomic Symptoms

Objective: Autonomic symptoms may occur frequently in diabetic and other neuropathies. There is a need to develop a simple instrument to measure autonomic symptoms in subjects with neuropathy and to test the validity of the instrument. Methods: The Survey of Autonomic Symptoms (SAS) consists of 11 items in women and 12 in men. Each item is rated by an impact score ranging from 1 (least severe) to 5 (most severe). The SAS was tested in observational studies and compared to a previously validated autonomic scale, the Autonomic Symptom Profile (ASP), and to a series of autonomic tests. Results: The SAS was tested in 30 healthy controls and 62 subjects with neuropathy and impaired glucose tolerance or newly diagnosed diabetes. An increased SAS score was associated with the previously validated ASP (rank order correlation = 0.68; p < 0.0001) and with quantitative measures of autonomic function: a reduced quantitative sudomotor axon reflex test sweat volume (0.31; p < 0.05) and an abnormal 30:15 ratio (0.53; p < 0.01). The SAS shows a high sensitivity and specificity (area under the receiver operating characteristic curve 0.828) that compares favorably with the ASP. The SAS scale domains had a good internal consistency and reliability (Cronbach α = 0.76). The SAS symptom score was increased in neuropathy (95% confidence interval [CI] 2.99–4.14) compared to control (95% CI 0.58–1.69; p < 0.0001) subjects. Conclusions: The SAS is a new, valid, easily administered instrument to measure autonomic symptoms in early diabetic neuropathy and would be of value in assessing neuropathic autonomic symptoms in clinical trials and epidemiologic studies.

Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes

Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS–POTS) to those without CFS (non-CFS–POTS), to determine whether CFS–POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS–POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS–POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS–POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS–POTS patients had greater orthostatic tachycardia than the non-CFS–POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS–POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.

The Natural History of Pure Autonomic Failure: a U.S. Prospective Cohort

To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.