Yoshimitsu Shimatani

Can Awaji ALS criteria provide earlier diagnosis than the revised El Escorial criteria

BACKGROUND Recently, new electrophysiological ALS criteria incorporating fasciculation potentials (FPs) as evidence for lower motor neuron signs (Awaji Criteria (AC)) was proposed to provide earlier detection of early-stage ALS than revised El Escorial electrophysiological criteria (REEC). However, serial electrophysiological analysis is lacking to ascertain the original intention. The objective for this study was to elucidate whether electrophysiological criteria set for AC detects ALS earlier than REECs counterpart in patients with ALS. METHODS Of the 51 patients who were clinically suspected of ALS, 35 patients prospectively received serial electrophysiological studies every 3 months until (1) both electrophysiological AC and REEC criteria were met in more than two muscles representing both of the cervical and lumbosacral segments or (2) either clinically definite or clinically probable REEC criteria was met. The intervals were determined between the initial disease onset and when the respective electrophysiological criteria were met. RESULTS Electrophysiological diagnostic criteria were met in 94.3% by AC and 40% by REEC at the initial visits. The intervals between the disease onset and the time of meeting the electrophysiological criteria were shorter in AC (mean: 9.0 months) than in REEC (mean: 15.2 months) (P<0.01). Eleven patients who met only AC electrophysiological criteria on the initial study subsequently met REEC electrophysiological criteria with the mean interval of 3.8 months. A higher percentage of bulbar-type ALS (83.3%) met AC than limb-onset ALS (43.4%) (P<0.05). FPs tended to be more frequently observed than fib/psw in the muscles outside the region of initial clinical onset. CONCLUSION Electrophysiological criteria of AC were met earlier than that of REEC in ALS patients, especially in patients with bulbar onset. Early recognition of ALS by AC may allow effective therapeutic intervention in the early disease stage.

Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography.

OBJECTIVE Progressive atrophy and loss of motor axons is a hallmark of amyotrophic lateral sclerosis (ALS). Limited sonographic data are available on potential detection of atrophy of peripheral nerves and nerve roots in ALS. METHODS Patients with either definite or probable ALS and control subjects underwent sonographic evaluation of the cervical roots (C5, C6, and C7) and peripheral nerves (median and ulnar nerves) on the right. These diameters and cross-sectional areas (C6, median, and ulnar nerves) were compared. RESULTS The diameters and cross-sectional areas were consistently smaller in ALS than in controls. No correlation was present between the sonographic parameters and the disease severity, disease duration, age, or gender. The overall sensitivity and specificity tended to be greater in the cervical nerve roots than in the peripheral nerves. CONCLUSIONS This study shows atrophy of cervical nerve roots and peripheral nerves in ALS detected by sonography. Cervical nerve roots might be more appropriate to detect motor axon loss than peripheral nerves. SIGNIFICANCE Sonographic evaluation of nerve roots and peripheral nerves may be a useful disease marker in ALS to confirm the diagnosis and to potentially monitor the disease progression.

Comparison between botulinum neurotoxin type A2 and type A1 by electrophysiological study in healthy individuals.

Botulinum neurotoxin type A1 (BoNTs/A1) and type B (BoNT/B) have been used for treating hyperactive muscle contractions. In the present study, we compared the effect of botulinum neurotoxin subtype A2 (6.5 mouse LD50 units A2 neurotoxin, A2NTX) and onabotulinumtoxinA (10 mouse LD50 units BoNT/A1 product) by measuring the compound muscle action potentials (CMAPs) before and after administration. In total, 8 healthy subjects were examined in the present study. A2NTX was injected into the extensor digitorum brevis (EDB) muscle, followed by onabotulinumtoxinA injection into the contralateral EDB muscle after 16 weeks. The CMAP amplitudes from the EDB, abductor hallucis (AH), and abductor digiti minimi pedis (ADM) muscles were measured after each BoNT injection on days 1, 3, 7, 14, 28, 56, 84, and 112 to assess the effect of the toxin. On day 14, both A2NTX and onabotulinumtoxinA produced an approximately 70% decline in EDB CMAP amplitude compared to the baseline values; significant reduction of the CMAP continued through day 112. The CMAP amplitudes from neighboring muscles (AH and ADM) remained intact throughout the study period, except for a slight but significant drop at day 28 after onabotulinumtoxinA injection compared to A2NTX. The current findings indicate that small doses (6.5 units and 10 units) of A2NTX and onabotulinumtoxinA have at least comparable onset and duration of action, although similar clinical effects were obtained with lower dose using A2NTX.

Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan.

Introduction: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. Results: The ratio of MMN to ALS patients (0–0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers. Muscle Nerve 49:357–361, 2014

Neurogenic and Myogenic Diseases: Quantitative Texture Analysis of Muscle US Data for Differentiation

Purpose To assess the multiple texture features of skeletal muscles in neurogenic and myogenic diseases by using ultrasonography (US). Materials and Methods After institutional review board approval, muscle US studies of the medial head of the gastrocnemius were performed prospectively in patients with neurogenic diseases (n = 25 [18 men]; mean age, 66.0 years ± 12.3 [standard deviation]), in patients with myogenic diseases (n = 21 [12 men]; mean age, 68.3 years ± 11.5), and in healthy control subjects (n = 21 [11 men]; mean age, 70.5 years ± 8.4) between January 2013 and May 2016. Written informed consent was obtained. Muscle texture parameters were obtained, and five algorithms were used to classify the groups. Results The neurogenic and myogenic disease groups showed higher echo intensities than the control subjects. The histogram-derived texture parameters had overlaps between the neurogenic and myogenic groups and thus had a low discrimination rate. With assessment of more classes of texture parameters, three groups were correctly classified (100% correct, according to four of five classification algorithms). Tenfold cross validation showed 93.5%-95.7% correct classification between the neurogenic and myogenic groups. The run-length matrix, autoregressive model, and co-occurrence matrix were particularly useful in distinguishing the neurogenic and myogenic groups. Conclusion Texture analysis of muscle US data can enable differentiation between neurogenic and myogenic diseases and is useful in noninvasively assessing underlying disease mechanisms.

Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome

OBJECTIVE Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K(+) channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. METHODS Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. RESULTS Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K(+) current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. CONCLUSIONS This study showed that patients with CFS might have abnormal kinetics in a slow K(+) current. SIGNIFICANCE Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K(+) channel openers.

Intramuscular dissociation of echogenicity in the triceps surae characterizes sporadic inclusion body myositis

Differential diagnosis of sporadic inclusion body myositis (s‐IBM) and polymyositis (PM)/dermatomyositis (DM) is difficult and can affect proper disease management. Detection of heterogeneous muscular involvement in s‐IBM by muscle sonography could be a unique diagnostic feature.

Increased variability of axonal excitability in amyotrophic lateral sclerosis

OBJECTIVE Amyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS. METHODS Multiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes). RESULTS In normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength-duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability. CONCLUSIONS Some of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels. SIGNIFICANCE Variable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels.

Which muscle shows fasciculations by ultrasound in patients with ALS

The purpose of the present study was to elucidate the relative frequencies of fasciculations assessed by sonography in a large number of muscles in patients with amyotrophic lateral sclerosis (ALS). The patients diagnosed as having ALS were retrospectively assessed by muscle sonography. The frequencies of having fasciculations were compared among the 15 muscles and the subtypes according to the initially affected body region. Overall, approximately half of the muscles had fasciculations (48.8%), in the average of 11.4 muscles per patient. The frequency of fasciculations tended to be lower in the patients with longer disease durations upon testing. Biceps brachii had the highest frequency, followed by extensor digitorum communis, whereas sternocleidomastoid and rectus abdominis had the lowest frequencies. The frequencies of fasciculations were similar among the clinical subtypes. In conclusion, in patients with ALS, fasciculations were detected most frequently in proximal arm muscles by sonography, whereas truncal muscles had lower frequencies. Fasciculations tended to be less evident in the advanced disease stage, possibly reflecting muscle degeneration. Appropriate selection of muscles to observe fasciculations is important for diagnosis of ALS.

Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy

OBJECTIVE To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy. METHODS (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling. RESULTS In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes. CONCLUSION Ih was upregulated after MGO administration in normal mice. SIGNIFICANCE MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.