John C. Kincaid

Quantitative sensory testing Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Objective: This assessment evaluates the clinical utility, efficacy, and safety of quantitative sensory testing (QST). Methods: By searching MEDLINE, Current Contents, and their personal files, the authors identified 350 articles. Selected articles utilized computer operated threshold systems, manually operated threshold systems, and electrical threshold devices. The authors evaluated the use of normal values and the degree of reproducibility between the same and different systems. Articles were rated using a standard classification of evidence scheme. Results: Because of differences between systems, normal values from one system cannot be transposed to others. Reproducibility of results was also an important concern, and there is no consensus on how it should be defined. The authors identified no adequately powered class I studies demonstrating the effectiveness of QST in evaluating any particular disorder. A number of class II and III studies demonstrated that QST is probably or possibly useful in identifying small or large fiber sensory abnormalities in patients with diabetic neuropathy, small fiber neuropathies, uremic neuropathies, and demyelinating neuropathy. Conclusions: QST is a potentially useful tool for measuring sensory impairment for clinical and research studies. However, QST results should not be the sole criteria used to diagnose pathology. Because malingering and other nonorganic factors can influence the test results, QST is not currently useful for the purpose of resolving medicolegal matters. Well-designed studies comparing different QST devices and methodologies are needed and should include patients with abnormalities detected solely by QST.

The molecular biology and clinical features of amyloid neuropathy

Neuropathy is often a major manifestation of systemic amyloidosis. It is most frequently seen in patients with hereditary transthyretin (TTR) amyloidosis, but is also present in 20% of patients with systemic immunoglobulin light chain (primary) amyloidosis. Familial amyloid polyneuropathy (FAP) is the most common form of inherited amyloidotic polyneuropathy, with clinical and electrophysiologic findings similar to neuropathies with differing etiologies (e.g., diabetes mellitus). Hereditary amyloidosis is an adult‐onset autosomal‐dominant disease with varying degrees of penetrance. It is caused by specific gene mutations, but demonstration that a patient has one such mutation does not confirm the diagnosis of amyloidosis. Diagnosis requires tissue biopsy with demonstration of amyloid deposits either by special histochemical stains or electron microscopy. Transthyretin amyloidosis is treated by liver transplantation, which eliminates the mutated transthyretin from the blood, but for some patients continued amyloid deposition can occur from wild‐type (normal) transthyretin. Presently, a study is ongoing to determine whether amyloid deposition can be inhibited by small organic molecules that are hypothesized to affect the fibril‐forming ability of transthyretin. Proposed gene therapy with antisense oligonucleotides (ASOs) to suppress hepatic transthyretin synthesis is effective in a transgenic mouse model but has not yet been tested in humans. Muscle Nerve, 2007

Electrocardiographic Abnormalities and Sudden Death in Myotonic Dystrophy Type 1

BACKGROUND Sudden death can occur as a consequence of cardiac-conduction abnormalities in the neuromuscular disease myotonic dystrophy type 1. The determinants of the risk of sudden death remain imprecise. METHODS We assessed whether the electrocardiogram (ECG) was useful in predicting sudden death in 406 adult patients with genetically confirmed myotonic dystrophy type 1. A patient was characterized as having a severe abnormality if the ECG had at least one of the following features: rhythm other than sinus, PR interval of 240 msec or more, QRS duration of 120 msec or more, or second-degree or third-degree atrioventricular block. RESULTS Patients with severe abnormalities according to the entry ECG were older than patients without severe abnormalities, had more severe skeletal-muscle impairment, and were more likely to have heart failure, left ventricular systolic dysfunction, or atrial tachyarrhythmia. Such patients were more likely to receive a pacemaker or an implantable cardioverter-defibrillator during the follow-up period. During a mean follow-up period of 5.7 years, 81 patients died; there were 27 sudden deaths, 32 deaths from progressive neuromuscular respiratory failure, 5 nonsudden deaths from cardiac causes, and 17 deaths from other causes. Among the 17 patients who died suddenly in whom postcollapse rhythm was evaluated, a ventricular tachyarrhythmia was observed in 9. A severe ECG abnormality (relative risk, 3.30; 95% confidence interval [CI], 1.24 to 8.78) and a clinical diagnosis of atrial tachyarrhythmia (relative risk, 5.18; 95% CI, 2.28 to 11.77) were independent risk factors for sudden death. CONCLUSIONS Patients with adult myotonic dystrophy type 1 are at high risk for arrhythmias and sudden death. A severe abnormality on the ECG and a diagnosis of an atrial tachyarrhythmia predict sudden death. (ClinicalTrials.gov number, NCT00622453.)

Electrophysiologic evaluation of diaphragm by transcutaneous phrenic nerve stimulation

Phrenic nerve function was evaluated by transcutaneous stimulation in the neck and recording the diaphragmatic potential from surface electrodes placed at the ipsilateral seventh intercostal space (7CS) and the xiphoid process (XP). Simultaneous recordings from 7CS and XP electrodes connected together (XP-7CS) and each connected to a remote reference (knee-7CS and knee-XP) disclosed that the 7CS electrode was always more active and showed electropositive activity, whereas the XP electrode, which was only minimally active, showed electronegative response. Out-of-phase summation of opposite polarity activity at the two electrodes resulted in a higher amplitude response in XP-7CS derivation. Phrenic nerve studies are useful in establishing phrenic nerve injury following cardiothoracic operation. They may also provide evidence of phrenic nerve or diaphragmatic involvement in demyelinative neuropathies, motor neuron disease, and muscular dystrophies.

Practice Advisory: Utility of surgical decompression for treatment of diabetic neuropathy Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Surgical decompression at the site of anatomic narrowing has been promoted as an alternative treatment for patients with symptomatic diabetic neuropathy. Systematic review of the literature revealed only Class IV studies concerning the utility of this therapeutic approach. Given the current evidence available, this treatment alternative should be considered unproven (Level U). Prospective randomized controlled trials with standard definitions and outcome measures are necessary to determine the value of this therapeutic intervention.

Contribution of wild-type transthyretin to hereditary peripheral nerve amyloid

To elucidate the contribution of wild‐type transthyretin (TTR) to amyloid polyneuropathy in TTR amyloidosis, we biochemically investigated amyloid fibrils isolated from sciatic nerve of an autopsied patient with TTR Ala25Ser variant and compared the amount of wild‐type and variant TTR in the nerve to that in the heart. Amyloid subunit protein from isolated fibrils was solubilized in 6M guanidine HCl and purified by gel filtration chromatography. The relative amounts of variant and wild‐type TTR in the purified protein were estimated from the recovered amounts of tryptic peptides with Ser25 or Ala25. Approximately 60% variant and 40% wild‐type TTR were found in both the nerve and heart amyloid deposits. Our results indicate that wild‐type TTR co‐deposits in the peripheral nerves with variant TTR as amyloid fibril, and therefore that progression of amyloid deposition in the peripheral nerves from wild‐type TTR may occur after liver transplantation, as has been seen in the heart. Muscle Nerve 28: 438–442, 2003

Rate of Progression of Transthyretin Amyloidosis

Hereditary transthyretin (TTR) amyloidosis is an adult-onset disease characterized mainly by peripheral neuropathy and cardiomyopathy. Although disease progression is usually 5 to 15 years from time of diagnosis to death, no specific measurements of disease progression have been identified. The present study was designed to identify objective parameters to measure progression of hereditary TTR amyloidosis and determine if these parameters would show significant change within 1 year. Nine patients with biopsy-proved TTR amyloidosis and evidence of cardiac involvement were studied at baseline, 6 months, and 12 months by cardiac magnetic resonance imaging (MRI), electrocardiogram, and echocardiogram. Neurologic impairment score and electromyogram were determined at baseline and 12 months. Left ventricular mass determined by MRI and echocardiogram showed significant change at 12-month examination (p = 0.005 and p = 0.0009, respectively). Electrocardiogram and neurologic impairment score did not show significant change at 12 months. Measurement of left ventricular mass by MRI and echocardiographic techniques showed significant change in hereditary TTR cardiac amyloidosis within 1 year. In conclusion, these methods provide a means to clinically monitor progression of hereditary TTR amyloidosis and determine efficacy of therapeutic interventions.

The influence of the reference electrode on CMAP configuration: Leg nerve observations and an alternative reference site

Peroneal and tibial compound motor action potentials (CMAP) recorded using the standard belly‐tendon montage have different configurations. The peroneal CMAP is a smooth dome shape, while the tibial CMAP has a slow‐rising initial component followed by a higher amplitude negative peak. To evaluate possible causes of these differences, we investigated the individual activity recordable at the belly and tendon electrodes by using a referential montage with the opposite foot as the reference. This type recording shows that the peroneal belly site produces most of the nerve CMAP, whereas the tendon site generates most of the high tibial CMAP. Some features and technical problems of referential CMAP recording using an opposite limb reference are shown. An alternative method using an ipsilateral distal leg reference site is described. A montage which separately records the activity at the belly or tendon electrodes may provide new insight into mechanisms of commonly observed nerve conduction phenomena.

Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram

BACKGROUND Sympathetic nerve activity is important to cardiac arrhythmogenesis. OBJECTIVE The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. METHODS We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. RESULTS In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1-V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. CONCLUSION SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.

Late‐onset familial amyloid polyneuropathy in an American family of English origin

Recent advances permit biochemical and genetic classification of familial amyloidotic polyneuropathy. We report a family with the methio-nine-30 prealbumin variant, which is atypical in late age of onset and the appearance of proximal arm weakness before more typical generalized neuropathy.