Peripheral Neuropathy Clinical Trials, Diagnosis, and Treatment

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Peripheral Neuropathy

Peripheral Neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of the nerve or from the side-effects of systemic illness. Peripheral neuropathies vary in their presentation and origin, and may affect the nerve or the neuromuscular junction.

Current Research

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Causes

The causes are broadly grouped as follows:

Genetic diseases: Friedreich's ataxia, Charcot-Marie-Tooth syndrome
Metabolic/Endocrine: diabetes mellitus, Chronic renal failure, porphyria, amyloidosis, liver failure, hypothyroidism
Toxic causes: alcoholism, drugs (vincristine, phenytoin, isoniazid), organic metals, heavy metals
Inflammatory diseases: Guillain-Barré syndrome, systemic lupus erythematosis, leprosy, Sjögren's syndrome
Vitamin deficiency states: vitamin B12, vitamin A, vitamin E, thiamin
Others: malignant disease, HIV, radiation, chemotherapy

Many of the diseases of the peripheral nervous system may present similarly to muscle problems (myopathies), and so it is important to develop approaches for assessing sensory and motor disturbances in patients so that a physician may make an accurate diagnosis.

Types

Peripheral neuropathies may either be symmetrical and generalized or focal and multifocal, which is usually a good indicator of the cause of the peripheral nerve disease.

Generalized Peripheral Neuropathy

Generalized peripheral neuropathies are symmetrical, and usually due to various systematic illnesses and disease processes that affect the peripheral nervous system in its entirety. They are further subdivided into several categories:

Distal axonopathies are the result of some metabolic or toxic derangement of neurons. They may be caused by metabolic diseases such as diabetes, renal failure, deficiency syndromes such as malnutrition and alcoholism, or the effects of toxins or drugs.
Myelinopathies are due to a primary attack on myelin causing an acute failure of impulse conduction. The most common cause is acute inflammatory demyelinating polyneuropathy (AIDP; aka Guillain-Barré syndrome), though other causes include chronic inflammatory demyelinating polyneuropathy (CIDP), genetic metabolic disorders (e.g., leukodystrophy), or toxins.
Neuronopathies are the result of destruction of peripheral nervous system (PNS) neurons. They may be caused by motor neurone diseases, sensory neuronopathies (e.g., Herpes zoster), toxins or autonomic dysfunction. Neurotoxins may cause neuronopathies, such as the chemotherapy agent vincristine.

Signs and Symptoms

Those with diseases or dysfunctions of their peripheral nerves can present with problems in any of the normal peripheral nerve functions.

In terms of sensory function, there are commonly loss of function (negative) symptoms, which include numbness, tremor, and gait imbalance.

Gain of function (positive) symptoms include tingling, pain, itching, crawling, and pins and needles. Pain can become intense enough to require use of opiate drugs (i.e., morphine, oxycodone).

Skin can become so hypersensitive that patients are prohibited from having anything touch certain parts of their body, especially the feet. People with this degree of sensitivity cannot have a bedsheet touch their feet or wear socks or shoes, and eventually become housebound.

Motor symptoms include loss of function (negative) symptoms of weakness, tiredness, heaviness, and gait abnormalities; and gain of function (positive) symptoms of cramps, tremor, and fasciculations.

There is also pain in the muscles (myalgia), cramps, etc., and there may also be autonomic dysfunction.

During physical examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, though those with a pathology (problem) of the peripheral nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies like Guillain-Barré syndrome); or may show focal sensory disturbance or weakness, such as in mononeuropathies, radiculopathies and plexopathies.

Common disorders of the peripheral nerves include focal entrapment neuropathies (e.g., carpal tunnel syndrome), generalized peripheral neuropathies (e.g., diabetic neuropathy), plexopathies (e.g., brachial neuritis) and radiculopathies (e.g., of cranial nerve VII; Facial nerve).

Treatment

Many treatment strategies for peripheral neuropathy are symptomatic. Some current research in animal models has shown that neurotrophin-3 can oppose the demyelination present in some peripheral neuropathies.

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Peripheral_neuropathy)

Findings From Current Research

Neuropathy Progression in Charcot-Marie-Tooth Disease Type 1A

Authors: Shy ME, Chen L, Swan ER, Taube R, Krajewski KM, Herrmann D, Lewis RA, McDermott MP.

Wayne State University, Department of Neurology, Center for Molecular Medicine and Genetics, 421 Ea Canfield, Detroit, MI 48201, USA. m.shy@wayne.edu

OBJECTIVE: To determine the rate of disease progression in Charcot-Marie-Tooth disease type 1A (CMT1A). BACKGROUND: CMT1A is the most common inherited peripheral neuropathy, affecting approximately 1:5,000 people irrespective of ethnic background or gender. There is no cure for CMT1A. Clinical trials are being initiated that use the CMT Neuropathy Score (CMTNS), a composite score based on patient symptoms, signs, and neurophysiologic abnormalities, as the primary outcome variable. The sensitivity of the CMTNS or any other score to change over time, as a measure of CMT1A progression, has yet to be determined. METHODS: We determined the CMTNS as well as the Neuropathy Impairment Score (NIS) on 72 patients followed for up to 8 years. The rate of disease progression was evaluated for the CMTNS and NIS using mixed effects linear regression models, adjusting for age and gender. RESULTS: Both CMTNS and NIS showed changes over time. The CMTNS increased an average of 0.686 points per year (95% CI 0.461 to 0.911, p <or= 0.0001). The NIS increased 1.368 points per year on average (95% CI 0.616 to 2.121, p = 0.0005). There was a suggestion that the rate of progression increased with age. CONCLUSION: Progression of CMT1A can be detected by both the CMT Neuropathy Score (CMTNS) and the Neuropathy Impairment Score (NIS). This supports the feasibility of clinical trials to detect a slowing of disease progression using either or both of these scales as outcome measures. Since the CMTNS combines symptoms, signs, and electrophysiology and the NIS is based solely on the neurologic examination, the two scales may be complementary.

Journal: Neurology. 2008 Jan 29;70(5):378-83
Adapted from PubMed; click here to access full journal article.

Peripheral Neuropathy is an Early Complication of Type 2 Diabetes in Adolescence

Authors: Karabouta Z, Barnett S, Shield JP, Ryan FJ, Crowne EC.

Department of Paediatric Endocrinology & Diabetes, Directorate of Children’s Services, Bristol Royal Hospital for Children, Bristol, UK.

Objective: To screen for microvascular complications in adolescents with type 2 diabetes mellitus (T2DM). Subjects and methods: Seven adolescents with T2DM were assessed for early secondary complications. Median duration of diabetes was 1.8 (0.8-3.0) yr. All were assessed as follows: blood pressure, ophthalmologic examination for diabetic retinopathy, renal function, full blood count and vitamin B12 levels (to exclude B12 malabsorption - a side effect of metformin), random urine for microalbuminuria, an electrocardiogram (ECG) rhythm strip and podiatry performed by an experienced podiatrist. Testing for peripheral neuropathy included foot pulse palpation, tendo-Achilles reflexes, plantar callus test, large nerve fibre function (vibration and threshold for light touch/pressure) assessed by a 128-Hz tuning fork, and by the standard 10-g Semmes-Weinstein monofilament test, and small nerve fibre function (pain) assessed by pinprick neurotip. Results: Four adolescents had evidence of peripheral neuropathy on clinical examination, with abnormal large and small nerve fibre function. Six had plantar callus present, and four had weak but palpable posterior tibial pulses. All had normal tendo-Achilles reflex and normal response to vibration. None had diabetic retinopathy or hypertension. Renal function, full blood count (FBC), B12 levels and ECGs were normal. None of 120 adolescents with type 1 diabetes mellitus (T1DM) assessed by the same podiatrist had any signs of peripheral neuropathy. Conclusions: Unlike T1DM, peripheral neuropathy can be present soon after diagnosis in those with T2DM. Children with T2DM need surveillance for complications from the time of diagnosis.

Journal: Pediatr Diabetes. 2008 Jan 19
Adapted from PubMed; click here to access full journal article.

Impaired Glucose Tolerance and Neuropathy

Authors: Smith AG, Singleton JR.

From the *Department of Neurology and †Department of Pathology, University of Utah, Salt Lake City, Utah.

BACKGROUND:: Peripheral neuropathy is common. Diabetes is the most common cause, accounting for approximately half of cases, but up to 1/3rd of neuropathy patients have no identifiable etiology. Among this population, impaired glucose tolerance (IGT or "prediabetes") is observed in approximately 40%. The exact nature of the relationship between IGT and neuropathy is debated. REVIEW SUMMARY:: A variety of evidence suggests IGT causes neuropathy. Neuropathy may occur early in diabetes. The neuropathy associated with IGT is clinically similar to early diabetic neuropathy, with preferential injury to small nerve fibers resulting in pain and autonomic dysfunction. IGT and diabetic neuropathy patients share abnormal microvascular endothelial dysfunction. Treatment of IGT subjects with diet and exercise reduces risk of progression to diabetes, and those with neuropathy experience a short-term improvement in small fiber function with sustained benefit for pain. An evolving literature links other aspects of the metabolic syndrome to peripheral neuropathy. CONCLUSIONS:: IGT is common in peripheral neuropathy patients. The extent to which IGT directly causes nerve injury as opposed to being a covariant with other equally or more important features (eg, obesity, metabolic syndrome) remains to be determined. Preliminary data suggest diet and exercise counseling may be a useful treatment strategy.

Journal: Neurologist. 2008 Jan;14(1):23-29
Adapted from PubMed; click here to access full journal article.

The Total Neuropathy Score: A Tool for Measuring Chemotherapy-Induced Peripheral Neuropathy

Authors: Smith EM, Beck SL, Cohen J.

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center in Lebanon, NH, USA. ellen.l.smith@hitchcock.or

PURPOSE/OBJECTIVES: To describe the psychometric properties, clinical significance, and utility of the Total Neuropathy Score (TNS), a composite measurement tool used to assess chemotherapy-induced peripheral neuropathy (CIPN). DATA SOURCES: Published articles and abstracts and pertinent article references. DATA SYNTHESIS: CIPN has been quantified inadequately because of the lack of an optimal measurement tool. The TNS is the most comprehensive composite tool to have been tested in oncology settings. The tool assesses neuropathy signs and symptoms and incorporates nerve conduction study results but inadequately assesses neuropathy-related pain severity. Seven studies have reported on the TNS's psychometric properties. CONCLUSIONS: Initial but limited evidence supports the TNS's psychometric properties. The tool is too burdensome and inadequately assesses pain severity. Further revision and testing of the tool are recommended. IMPLICATIONS FOR NURSING: TNS simplification and further psychometric testing could lead to future use by oncology nurses.

Journal: Oncol Nurs Forum. 2008 Jan;35(1):96-102
Adapted from PubMed; click here to access full journal article.

Peripheral Neuropathy and Statins

(1) Statins are cholesterol-lowering drugs extensively used in cardiovascular prevention. Their most well-known adverse effect is muscle damage, including rhabdomyolysis. (2) Several cases of peripheral polyneuropathy attributed to a statin have been published or reported by pharmacovigilance centres. (3) They included sensory or sensorimotor polyneuropathy with signs of sensory impairment, and a decrease or sometimes a suppression of osteotendinous reflexes. Some patients also had a marked reduction in muscle strength in the affected limb(s). Renal failure and diabetes appear to increase the risk of this adverse effect. (4) Epidemiological studies and clinical trials have shown that this adverse effect is rare, affecting only about one patient in 10 000 treated for one year. (5) After ruling out other possible causes of peripheral neuropathy, statin withdrawal often leads to clinical improvement.

Journal: Prescrire Int. 2007 Dec;16(92):247-8.
Adapted from PubMed; click here to access full journal article.

Assessment of Epidermal Nerve Fibers: A New Diagnostic and Predictive Tool for Peripheral Neuropathies

Authors: Ebenezer GJ, Hauer P, Gibbons C, McArthur JC, Polydefkis M.

Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287-7609, USA.

Today, skin biopsies can play an important role in the diagnosis of peripheral nerve disorders and have yielded another diagnostic tool for the neurologist. One of the commonly reported neuropathologic abnormalities observed in skin biopsies is a reduction of epidermal nerve density. Analyzing the changes in the morphology and density of epidermal nerves is of immense diagnostic and prognostic value in peripheral neuropathies. These changes also provide an assessment of disease progression and of tissue responses to regenerative treatments. Combined with immunohistochemical studies, newly evolved skin biopsy and epidermal count techniques have the potential to provide significant information about the pathogenesis of many peripheral nervous system diseases. They have great potential for impacts on both research and clinical approaches to treatment. Evolution of a standardized and validated counting methodology and significant advances in procuring skin biopsies have opened up a wide spectrum of applications that make the technology easy to apply in practice. The application of this technology may lead to early detection of many common peripheral nerve diseases and an enhanced understanding of disease onset and progression. In this article we review the state of current research and clinical practice in the use of skin biopsies and epidermal nerve densities.

Journal: J Neuropathol Exp Neurol. 2007 Dec;66(12):1059-73.
Adapted from PubMed; click here to access full journal article.

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