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Objective To determine limb differences in motor axon excitability properties in stroke survivors and their relation to maximal electromyographic (EMG) activity. Methods The median nerve was stimulated to record compound muscle action potentials (CMAP) from the abductor pollicis brevis (APB) in 28 stroke subjects (57.3 ± 7.5 y) and 24 controls (56.7 ± 9.3 y). Results Paretic limb axons differed significantly from non-paretic limb axons including (1) smaller superexcitability and subexcitability, (2) higher threshold during subthreshold depolarizing currents, (3) greater accommodation (S3) to hyperpolarization, and (4) a larger stimulus-response slope. There were smaller differences between the paretic and control limbs. Responses in the paretic limb were reproduced in a model by a 5.6 mV hyperpolarizing shift in the activation voltage of Ih (the current activated by hyperpolarization), together with an 11.8% decrease in nodal Na+ conductance or a 0.9 mV depolarizing shift in the Na+ activation voltage. Subjects with larger deficits in APB maximal voluntary EMG had larger limb differences in excitability properties. Conclusions Stroke leads to altered modulation of Ih and altered Na+ channel properties that may be partially attributed to a reduction in neuromuscular activation. Significance Plastic changes occur in the axon node and internode that likely influence axon excitability.

Falls are common in the elderly, especially in those with cognitive impairment. The elderly are often treated with several medications, which may have both beneficial and deleterious effects. The use and type of medication in Alzheimer’s disease (AD) patients and association with falls is limited. We examined the association between falls and medication use in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Diagnosis, demographics, medication use, apolipoprotein E4 allele status and functional activity level at baseline were gathered for 810 participants enrolled in the ADNI, including healthy controls and subjects with mild cognitive impairment or Alzheimer’s. Reports detailing adverse event falls were tabulated. Baseline characteristics were compared between subjects with and without one or more falls. Cox proportional hazards models were conducted to evaluate the association between subject characteristics and hazard of the first fall. Age (p

Introduction: The differential diagnosis of patients presenting with multiple cranial neuropathies, ataxia, and altered mentation is broad and includes immunologic, infectious, vasculitic and metabolic conditions. Primary considerations are Bickerstaff’s brainstem encephalitis (BBE), the Miller Fisher syndrome (MFS), Wernicke’s encephalopathy and botulism. The initial workup may be unrevealing. Timely treatment is imperative and unnecessary treatment can be associated with serious adverse reactions. Sensitivity to the decisions needed in such patients is therefore important. Case report: A 58-year-old male presented with symptoms of altered mental status, blurred vision, dysphagia and dysarthria, impaired pupillary responses to light, facial diplegia, ataxia, and decreased tendon reflexes after an episode of a self resolving diarrheal disease. Primary initial diagnostic concerns were Bickerstaff’s brainstem encephalitis (BBE), Miller Fisher syndrome (MFS), Wernicke’s encephalopathy and botulism. Initial work-up including cerebrospinal fluid analyses, imaging studies, and an electrodiagnostic examination did not provide information helpful for narrowing this differential. The patient was treated with botulinum antitoxin, thiamine and intravenous immune globulin (IVIG) before the results of specialized tests were available. The patient’s clinical condition improved. Retrospectively, the patient was diagnosed as BBE. Conclusion: This case emphasizes the difficulties in distinguishing between BBE, MFS, and botulism as well as demonstrating the complexities of treating such patients.

Background Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP. Methods A literature review using MEDLINE, EMBASE, Science Citation Index and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. Results and Conclusions 1. Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine) and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2. Genetic testing is established as useful for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic (EDX) features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1 ), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).

Background: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy.Methods: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence.Results and Recommendations: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.AAN = American Academy of Neurology; AANEM = American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R = American Academy of Physical Medicine and Rehabilitation; ART = autonomic reflex testing; BRSI = baroreflex sensitivity index; CASS = composite autonomic scoring scale; CIDP = chronic inflammatory demyelinating polyneuropathy; DSFN = distal small fiber neuropathy; DSP = distal symmetric polyneuropathy; EDx = electrodiagnosis; EFNS = European Federation of Neurological Societies; HRV = heart rate variability; IAN = idiopathic autonomic neuropathy; IENF = intraepidermal nerve fibers; MSNA = muscle sympathetic nerve activity; NCSs = nerve conduction studies; PGP 9.5 = protein-gene-product 9.5; PN = peripheral neuropathy; PRT = blood pressure recovery time; QAE = quantitative autonomic examination; QSART = quantitative sudomotor axon reflex test; QSS = Quality Standards Subcommittee; QST = quantitative sensory testing; SFSN = small fiber sensory polyneuropathy; TST = thermoregulatory sweat testing.

Electrodiagnostic (EDX) patterns of neuropathic dysfunction have been based on axonal/demyelinating criteria requiring prior assumptions. This has not produced classifications of desired sensitivity or specificity. Furthermore, standard nerve conduction studies have limited reproducibility. New methodologies in EDX seem important. Recurrent Quantification Analysis (RQA) is a nonlinear method for examining patterns of recurrence. RQA might provide a unique method for the EDX evaluation of neuropathies. RQA was used to analyze F-wave recordings from the abductor hallucis muscle in 61 patients with neuropathies. Twenty-nine of these patients had diabetes as the sole cause of their neuropathies. In the other 32 patients, the etiologies of the neuropathies were diverse. Commonly used EDX variables were also recorded. RQA data could separate the 29 patients with diabetic neuropathies from the other 32 patients (P<0.009). Statistically significant differences in two EDX variables were also present: compound muscle action potential amplitudes (P<0.007) and F-wave persistence (P<0.001). RQA analysis of F-waves seemed able to distinguish diabetic neuropathies from the other neuropathies studied, and this separation was associated with specific physiological abnormalities. This study would therefore support the idea that RQA of F-waves can distinguish between types of neuropathic dysfunction based on EDX data alone without prior assumptions.

Objective To evaluate the F-wave dilution hypothesis; which implies that absolute F-wave latencies obscure the much smaller delay associated with slow intra-lesion conduction, such is caused by nerve root compression in lumbosacral radiculopathy. A corollary objective is to determine how F-wave measurement and pathological factors influence diagnostic accuracy. Methods An analytical model is developed based on signal detection theory and a number of simplifying assumptions. Diagnostic accuracy, quantified by the area under the receiver operating characteristic (ROC) curve, is determined for various model realizations derived from the clinical and experimental neurophysiology literature. A preliminary experimental validation of model predictions is also performed. Results Absolute F-wave latency does not influence the accuracy of focal lesion detection. F-wave latency variance and lesion pathology are the determinant factors. F-wave latencies and distal latencies are estimated to have qualitatively similar detection characteristics, although distal latencies have quantitatively better diagnostic efficacy for comparable focal pathology. Preliminary experimental results support the modeled dependence of diagnostic accuracy on latency variance and lesion severity. Conclusions Absolute F-wave latency does not dilute slow conduction within focal lesions, such as in lumbosacral radiculopathy. The dominant measurement factor is F-wave latency variance. Significance To maximize the diagnostic utility of F-wave latencies, focus must be placed on reducing latency variance, such as through correction for demographic covariates. This model calls into question the F-wave dilution hypothesis.

The chronic autoimmune neuropathies are a diverse group of disorders, whose diagnosis and classification is based on the clinical presentations and results of ancillary tests. In chronic inflammatory demyelinating polyneuropathy, controlled therapeutic trials demonstrated efficacy for intravenous gamma-globulins, corticosteroids, and plasmaphereis. In multifocal motor neuropathy, intravenous gamma-globulins have been shown to be effective. In the other immune-mediated neuropathies, there are no reported controlled therapeutic trials, but efficacy has been reported for some treatments in non-controlled trials on case studies. Choice of therapy in individual cases is based on reported efficacy, as well as severity, progression, coexisting illness, predisposition to developing complications, and potential drug interactions.

The pharmaceutical industry is one of the largest and most profitable industries in the world, and in the United States, the industry has a particularly privileged economic position. Yet the cost of drugs in the United States is higher than anywhere else, due largely to the fact that the industry is focusing increasingly on marketing rather than on the development of meaningful new medications: available evidence does not support claims of great expense for the development of new drugs. Because of its vast resources, the pharmaceutical industry has assumed an increasing influence in medicine, which, given the differences in values and priorities between medicine and the drug companies, is a cause for concern. The pharmaceutical industry has acted to maximize its profits in ways that frequently conflict with medicine's need for truth and full disclosure. Indeed, the industry has arguably worked to compromise physicians' judgments, as well as academic standards. As a result, despite government regulation there have been unnecessary adverse effects from drugs. The experience with butorphanol (Stadol) exemplifies problems in the current system and the harm that can result. Changes are suggested to make the pharmaceutical industry more responsive to the needs of patients and physicians.

L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p < 0.005, n = 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS- or diabetes-associated peripheral neuropathy, may elicit sensory nerve conduction deficits.

The anatomy, pathophysiology, and clinical evaluation of radiculopathies are discussed. Defining whether root injury is present and which roots are involved can be difficult but critical for patient management. In conjunction with clinical and radiological information, studies that establish physiological abnormalities of roots should be helpful and important. Clinical neurophysiological studies for radiculopathies are performed frequently but have yet to achieve a universally accepted role in the evaluation of these patients. Electrophysiological techniques for the evaluation of radiculopathies are reviewed. Needle electromyography is the best established of these procedures but has the disadvantage of requiring injury to motor fibers of both a certain degree and distribution. Nerve conduction studies may rarely be abnormal in radiculopathies but are needed to be certain other conditions that may produce similar symptoms and signs are not present. H reflexes and F waves probably have roles in the evaluation of radiculopathies but published reports about F waves in radiculopathies have been marred by inadequate methodology. There is evidence based on large series of patients that somatosensory evoked potentials can be helpful for evaluating patients with multilevel injury such as spinal stenosis, patients where electrophysiological studies may have their greatest clinical utility. Further work using either electrical stimulation with needles or magnetic stimulation of roots seems warranted. The demonstration of meaningful electrophysiological changes with activities that reproduce radicular symptoms may be a promising experimental approach. Available information does not necessarily answer critical questions about the role of electrophysiology in patients with radiculopathies. This cannot be done using analyses based on current ideas about evidence based medicine given the absence of a 'gold standard' for defining radiculopathies as well the absence of blinded studies. The available information provides strong arguments for further investigations evaluating different clinical neurophysiological techniques in the same patient, and for evaluating the value of these techniques by concentrating on their clinical import.

H-reflexes are commonly elicited electrophysiological responses that are produced by submaximal stimulation of large afferent fibers and subsequent activation of motoneurons in the anterior horn of the spinal cord, possibly monosynaptically. In adults, H-reflexes are consistently elicited in calf muscles and the homologous forearm flexor muscles. H-reflexes are inhibited by increasing stimulus intensity primarily due to patterns of central inhibition. H-reflexes can be useful in the clinical and research evaluation of disorders of peripheral nerves, roots, and the central nervous system.

Reflexes are involuntary activity arising from an afferent input and a subsequent efferent response. These can be proprioceptive arising from receptors within muscles, tendons, and joints or exteroceptive arising from skin and subcutaneous tissues. Proprioceptive spinal cord reflexes may produce monosynaptic activation (group Ia fibers), disynaptic inhibition (group Ib afferents) of motoneurons, or polysynaptic flexion withdrawal (group II afferents). The blink reflex is the most commonly used exteroceptive reflex – afferent Vth cranial nerve and efferent VIIth. Such reflexes are characterized by a simple short-latency (R1) component followed by a longer latency, more complex second component (R2).

Monoclonal gammopathy of unknown significance (MGUS) is a monoclonal B cell expansion characterized by high levels of circulating monoclonal antibody that affects 3% of individuals over the age of 70. Although this is considered benign, a high percentage of MGUS patients develop a debilitating peripheral autoimmune neuropathy and have a significantly increased risk for progression to multiple myeloma. Here we show that the relative numbers of the CD30(+) T cell subset and levels of CD30 expression are elevated in activated lymphocytes from normal aged individuals (or =60 years) and in MGUS patients, when compared to younger controls. PBL from MGUS patients and age-matched controls produced comparable levels of IL-6 when activated with anti-CD3 plus IL-2, and costimulation with a soluble form of CD30 ligand (sCD30L/CD8alpha) augmented anti-CD3 inducible IL-6 production similarly in both groups. However, MGUS PBL also produced measurable IL-6 when activated with sCD30L/CD8alpha alone. This capability was associated with the unique presence of CD30(+) T cells in the peripheral blood of MGUS patients. Furthermore, a higher percentage of activated MGUS T cells express CD30 when activated by incubation with idiotype-expressing autologous serum (68 +/- 13) than those activated by anti-CD3 plus IL-2 (43 +/- 7). These results indicate that quantitative alterations in CD30(+) T cells accompany aging and MGUS and that these cells may contribute to the chronic activation of B cells though the production of IL-6.

An emerging body of evidence from in vitro studies and in vivo animal models supports a pathogenic role of antibodies in the development of peripheral neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS). Although the assessment of motor and sensory nerve fiber function is of clinical importance, it is seldom applied experimentally. We describe the application of an electrophysiologic method for the evaluation of motor and sensory nerve fiber function using an experimental model of MGUS neuropathy. Supramaximal stimulation of the tibial nerve elicited an early motor response (M-wave, 1.7 ± 0.1 ms, n = 10) and a late sensory (H-reflex, 7.8 ± 0.1 ms, n = 10) response that was recorded from the hind foot of anesthetized rats. Intraneural injection of serum antibodies from a MGUS patient with sensorimotor polyneuropathy, but not from an age-matched control subject, produced a marked attenuation of the H-reflex (P < 0.01, n = 10) without affecting the M-wave. Light and electron microscopy of affected nerve showed myelinoaxonal degeneration with sparing of the smaller unmyelinated nerve fibers. The combined electrophysiologic and morphologic findings presented in this study are consistent with a selective sensory conduction deficit in MGUS neuropathy. Selective injury of afferent nerve fibers by this patient's serum antibodies may result from reactivity to neural antigens uniquely expressed by sensory neurons. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 809–816, 2001

A 43-year-old woman was admitted with progressive leg pains and weakness and was found to have rhabdomyolysis. Prior to this admission the patient had hypercalcemia, but this returned to normal following treatment with calcitonin. During the hospitalization, she developed the syndrome of calciphylaxis consisting of necrotic skin and muscle associated with vascular calcification. This is the first case report of rhabdomyolysis caused by calciphylaxis in a patient without chronic renal failure.

Keywords: F waves; peripheral neuropathies; radiculopathies; nerve injury; F-wave utility

Intravenous immunoglobulin (IVIg) is a useful tool in the treatment of a variety of neuromuscular disorders. Though IVIg therapy is generally safe, hemolytic anemia is a potentially serious complication that is often overlooked, and is currently not listed in product inserts. We analyzed 45 patients who received IVIg therapy, including 38 consecutive patients who received IVIg over a 13-month period. On 42 patients, direct antiglobulin testing was performed, searching for antibodies to the patients' own blood type. Of these 42 patients, 12 developed passive sensitization with antibodies to their own blood group antigens after receiving IVIg. Of these 12 patients, 11 patients developed hemolysis severe enough to lower the hemoglobin level by at least 1 g/dL. Of these patients, 3 required blood transfusion, and 1 had IVIg therapy truncated because of the hemolysis. Antibodies to blood group antigens are found in all commercial preparations of IVIg. Though most patients do not have clinically significant hemolysis, clinicians should be aware of this potentially serious complication. Careful monitoring of hemoglobin levels during IVIg therapy is recommended.

This study evaluates the sensitivity of root mean square voltage (Vrms)/turns (T) ratios in neuropathies. Data were recorded with concentric needle electrodes from the biceps brachii, first dorsal interosseous, tibialis anterior, and calf muscles. Recordings were analyzed from 35 normal subjects as well as 24 consecutive patients referred for evaluation of neuropathic disorders. Direct tension measurements were not required. Reasoning from studies in normal subjects in which Vrms/T values were related to measurements of relative tension, the data were recorded during strong muscle contractions of less than 80% of maximum tension as monitored by mean amplitude values. For all 5 muscles, mean Vrms/T values ≥1.0 claculated from four separate needle sites were significantly more frequent in the patients than controls (p < 0.012–0.0001). There were 13 muscles in which relevant conduction studies were abnormal and Vrms/T ≥1.0 were the only abnormality of the needle EMG examination. In addition, a Vrms/T of ≥1.0 was present in 10/14 muscles in which abnormalities might have been expected but where other needle EMG parameters were unremarkable and relevant nerve conductions normal. This study indicates that Vrms/T measurements can add meaningfully to the electrodiagnostic evaluation of neurogenic dysfunction. © 1995 John Wiley & Sons, Inc.

Introduction Amyotrophic lateral sclerosis is a rapidly progressive, fatal neurodegenerative disorder for which there is no effective treatment. The diagnosis is dependent on the clinical presentation and consistent electrodiagnostic studies. Typically, there is a combination of upper and lower motor neuron signs as well as electrodiagnostic studies indicative of diffuse motor axonal injury. The presentation of amyotrophic lateral sclerosis, however, may be variable. At the same time, the diagnosis is essential for patient prognosis and management. It is therefore important to appreciate the range of possible presentations of amyotrophic lateral sclerosis. Case presentation We present the case of a 57-year-old Caucasian man with pathological findings on postmortem examination consistent with amyotrophic lateral sclerosis but atypical clinical and electrodiagnostic features. He died after a rapid course of progressive weakness. The patient did not respond to immunosuppressive therapy. Conclusion Amyotrophic lateral sclerosis should be considered in patients with a rapidly progressive, unexplained neuropathic process. This should be true even if there are atypical clinical and electrodiagnostic findings. Absence of response to therapy and the development of upper motor neuron signs should reinforce the possibility that amyotrophic lateral sclerosis may be present. Since amyotrophic lateral sclerosis is a fatal illness, however, the possibility of this disease in patients with atypical clinical features should not diminish the need for a thorough diagnostic evaluation and treatment trials.

Somatosensory evoked potentials are used to monitor the integrity of the of the spinal cord during surgical procedures where the spinal cord is at risk. Changes in somatosensory evoked potential latencies and amplitudes can indicate impending structural damage. This use of somatosensory evoked potentials is complicated by the effects of nonsurgical factors, including anesthetics. Fifty patients were studied during surgery to determine the effects of coadministered isoflurane and nitrous oxide on cortical and subcortical somatosensory evoked potentials potentials following stimulation of the tibial and median nerves. Analysis revealed statistically significant correlations between expired isoflurane concentrations and prolongation of scalp and cervical latencies, and a negative correlation between nitrous oxide concentrations and scalp amplitudes. Scalp somatosensory evoked potential latencies were also positively correlated with procedure duration, unexplained by other variables. These data emphasize the complexity of interpreting somatosensory evoked potential changes during surgical monitoring, and indicate that separate, defined physiologic effects of an anesthetic can be manifest even when more than one anesthetic is administered.

F waves were recorded from the abductor pollicis brevis stimulating the median nerve at the wrist. These data were compared to responses obtained after preceding supramaximal stimulation of digital fibers of the second (II) finger or the median nerve at the wrist. The time between conditioning and test stimuli were 50 msec. Following conditioning stimuli, F wave latencies were significantly increased while F amplitudes, durations, and persistences were all decreased. Chronodispersion was not significantly affected. These changes were associated with increased repetition of individual F responses. The most prominent changes were found after stimulation of fibers of digit II but only at levels of stimulation supramaximal for the sensory nerve action potential. Some, but relatively limited, changes were present after stimulation of digital fibers of the fifth finger. The results are consistrent with afferent fiber, probably A delta, inhibition of antidromic motoneuron activation with associated decrease in central motor neuron pool excitability. The study also demonstrates that, except for chronodispersion, changes in F waves found with peripheral nerve injury may also occur due to physiological changes in the central nervous system.

Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. A literature review using MEDLINE, EMBASE, Science Citation Index, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. (1) Autonomic testing may be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). (2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). (3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber (IENF) density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy.

Background:Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of DSP.Methods:A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence.Results and Recommendations:1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2) Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).AAN= American Academy of Neurology;AANEM= American Academy of Neuromuscular and Electrodiagnostic Medicine;AAPM&R= American Academy of Physical Medicine and Rehabilitation;CMT= Charcot-Marie-Tooth;DSP= distal symmetric polyneuropathy;EDX= electrodiagnostic;GTT= glucose tolerance testing;IFE= immunofixation electrophoresis;QSS= Quality Standards Subcommittee;SPEP= serum protein electrophoresis.

Background: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. Methods: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. Results and Recommendations: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy. Neurology ® 2009;72:177–184

Purpose This study evaluates the effect of submaximal stimulation and varying stimulus rates on F-wave parameters. Methods F-waves were recorded from the abductor pollicis brevis muscle from 3 normal subjects stimulating at 25%, 50%, and 75% intensity in comparison with supramaximal stimulation based on peak-to-peak compound muscle action potential amplitude. The effect of varying stimulus intensity (0.5, 1.0, and 2.0 Hz) at 30% stimulus intensity was also evaluated. Data were evaluated based on "true" values obtained after 100 stimuli. F-wave parameters studied included latencies (minimal and mean), amplitudes, persistences, durations, chronodispersions, and mean F amplitudes/maximum compound muscle action potential amplitudes. Results For varying stimulus intensities and rates, the following results were obtained: (1) no meaningful change in F latencies or durations; (2) mean latency values were more reproducible than minimum; (3) amplitudes, persistence, and mean F amplitudes/maximum M-wave amplitude ratios increase linearly with increase in stimulus intensities; (4) chronodispersion increases with increase in stimulus intensity; (5) 20 stimuli appear adequate for true values at supramaximal stimulation but more are needed at submaximal levels; (6) varying stimulus frequency at submaximal stimulation did not meaningfully affect the results. Conclusions F-parameters require more stimuli at submaximal stimulation and, except for latencies and durations, would require different normal values than at supramaximal stimulation.

This study evaluates the importance of varying electrodiagnostic (EDX) parameters abnormalities in patients with possible lumbosacral radiculopathies (LSR).34 patients referred for EDX studies with clinical findings consistent with a LSR without other causes for their symptoms were evaluated. Studies included not only standard (Routine EDX) nerve conduction studies (NCS) including F-waves and needle electromyography (nEMG) but also a multiparameter automated analysis system using prefabricated nerve conduction electrodes without nEMG (NC-stat EDX).Abnormal Routine EDX was present in 24 of the patients. Abnormal nEMG was present in only 14 of these patients, all of whom also had other relevant NCS abnormalities. Abnormal NC-stat EDX was found in 29 of the patients. In all but one patient there was agreement in the radicular localization between Routine and NC-stat EDX. In 30 patients, there was recent computed tomography or magnetic resonance imaging of the lumbosacral region. Comparable statistical agreements with the radiographic information were obtained for Routine EDX and NC-stat data. This was true including when the analyses were based on the neuroradiological evaluation of likely root injury.This study emphasizes the importance of EDX studies other than nEMG in the evaluation of patients with possible LSR and supports the value of a computerized mutliparameter methodology in these patients.

Medicine and industry are bound together by mutual needs. The development and utilization of new drugs and medical devices requires both the scientific and clinical expertise of physicians, and the resources and entrepreneurial ethos of business. The medicine-industry partnership has contributed to dramatic improvements in medical care. The increasing influence of the pharmaceutical and medical equipment industry in medicine has, however, raised concerns about costs and regulation, as well as about medicine's traditional independence and objectivity. Some critics feel that the fundamental obligation of business to provide profit for shareholders conflicts with physicians' traditional role as disinterested advocates of patients' interests. Nonetheless, with about 15% of the U.S. economy now devoted to health care, an ongoing and ro-bust relation between business and medicine seems inevitable. A mutually productive relationship between medicine and industry is essential for continued innovation and improvement in health care. Continuous and open dialogue, such as that in the following articles, is necessary to resolve conflicts and achieve this goal.

Motor conduction velocities (CVs) were correlated with distal compound muscle action potential (CMAP) amplitudes for tibial, peroneal, and median nerves in patients with biopsy-proven chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic neuropathy, and amyotrophic lateral sclerosis. Only in the diabetic patients did CV significantly correlate with CMAP amplitude. The data show that diabetic neuropathy produces conduction velocity slowing that cannot be explained by axon loss alone, and that differentiation between diabetic neuropathy and CIDP in an individual nerve is difficult.

The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, Cohen JA, Fisher MA, Howard JF, Kinsella LJ, Latov N, Lewis RA, Low PA, Sumner AJ. Distal symmetrical polyneuropathy: a definition for clinical research. A report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. The objective of this report was to develop a case definition of "distal symmetrical polyneuropathy" to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetrical polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetrical polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

Objective: F-waves are well-established clinical neurophysiological studies. F-wave analysis is now cumbersome limiting the usefulness of F-waves. This study evaluates the accuracy and reliability of an automated analysis method for F-wave latencies. Methods: F-waves following 20 supramaximal stimuli recorded from the extensor digitorum brevis muscle of 80 limbs (55 subjects) were analyzed. F-wave latencies were determined using a computer program developed by NEUROMetrix (Waltham, MA). These results were compared in a blinded fashion with manual measurements of the same datasets by a clinical neurophysiologist with established expertise in F-waves. The manual measurements were repeated once. Results: The yield rate of automated median F-wave latencies was 100% with a correlation coefficient (CC) of 0.996 when compared with manual assignment results. For individual F-wave latency measurements, comparable values were 90% and 0.977, respectively. The repeated manual measurements revealed a yield rate and CC for median latencies of 100% and 0.998, respectively, with comparable values for individual latency measurements of 95% and 0.992. Conclusions: These results indicate the feasibility of a reliable computerized automated analysis of F-wave latencies. Significance: A reliable automated analysis of F-waves should add meaningfully to the value of these responses in clinical neurophysiology.

L-Periaxin is a PDZ-domain protein localized to the plasma membrane of myelinating Schwann cells and plays a key role in the stabilization of mature myelin in peripheral nerves. Mutations in L-periaxin have recently been described in some patients with demyelinating peripheral neuropathy, suggesting that disruption of L-periaxin function may result in nerve injury. In this study, we report the presence of autoantibodies to L-periaxin in sera from two of 12 patients with diabetes mellitus (type 2)-associated neuropathy and three of 17 patients with IgG monoclonal gammopathy of undetermined significance (MGUS) neuropathy, an autoimmune peripheral nerve disorder. By comparison, anti-L-periaxin antibodies were not present in sera from nine patients with IgM MGUS neuropathy or in sera from 10 healthy control subjects. The effect of anti-L-periaxin serum antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-L-periaxin antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly (p0.005, n = 3) attenuated sensory-evoked compound muscle action potential (CMAP) amplitudes in the absence of temporal dispersion. In contrast, motor-evoked CMAP amplitudes and latencies were not affected by intraneural injection of sera containing anti-L-periaxin antibody. Light and electron microscopy of anti-L-periaxin serum-injected nerves showed morphologic evidence of demyelination and axon enlargement. Depleting sera of anti-L-periaxin antibodies neutralized the serum-mediated effects on nerve function and nerve morphology. Together, these data support anti-L-periaxin antibody as the pathologic agent in these serum samples. We suggest that anti-L-periaxin antibodies, when present in sera of patients with IgG MGUS- or diabetes-associated peripheral neuropathy, may elicit sensory nerve conduction deficits.

H reflexes and F waves have become integral parts of the electrodiagnostic examination in general, and nerve conduction studies in particular. They supplement the sensory and motor conduction studies by assessing the entire nerve segments including proximal portions of the motor and sensory axons. H reflexes and F waves have their own advantages and limitations, similarities and differences. These "late" responses are useful in patients with radiculopathies, plexopathies, and peripheral polyneuropathies, including the Guillain-Barre syndrome. They are also helpful in spinal cord disorders.

Elevated levels of serum antibodies to neurofilament proteins have been associated with a variety of neurological diseases, including autoimmune disorders such as neuropathy with monoclonal gammopathy of undetermined significance (MGUS). The pathological significance of anti-neurofilament antibodies in sera of affected patients, however, remains unclear. In this study, we report our findings of polyclonal antibodies in sera from 4 of 16 IgG MGUS neuropathy patients that react strongly on immunoblot with a high molecular weight neurofilament protein (NFH). The effect of anti-NFH polyclonal antibody on peripheral nerve function was tested in vivo by intraneural injection. Sera containing anti-NFH antibody, but not sera from age-matched control subjects, injected into the endoneurium of rat sciatic nerve significantly attenuated proximal-evoked motor nerve compound muscle action potential (CMAP) amplitudes in a complement-dependent manner. In contrast, ankle-evoked CMAP amplitudes were unaffected by intraneural injection of sera containing anti-NFH antibody. Anti-NFH serum-injected nerves showed changes in both axon caliber (shrinkage) and myelin ultrastructure (vesiculation and ovoid formation), suggestive of intramyelinic edema. Preincubation of sera containing anti-NFH antibody with purified NFH protein abolished immunoreactivity to NFH protein and neutralized the serum-mediated toxicity. The data suggest that anti-NFH polyclonal antibodies occurring in sera of some patients with IgG MGUS neuropathy may elicit peripheral nerve conduction block independent of the patients' IgG paraprotein. Anti-neural polyclonal antibodies in sera of IgG MGUS neuropathy patients may have a greater pathological significance than previously anticipated.