Yoshiko Shibuta

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.

Peripheral Nerve Excitability Measures at Different Target Levels: The Effects of Aging and Diabetic Neuropathy

Threshold tracking testing has provided novel insights of peripheral nerve excitability in normal and pathologic conditions. However, little has been known on the nerve excitability properties of axons with different stimulation thresholds and the effects of aging and peripheral neuropathy to those. We performed multiple nerve excitability tests in normal controls divided into three age groups and in patients with diabetic neuropathy, which were recorded at three target levels (10%, 40%, and 60% of the maximum motor response amplitudes). In all the control groups, tracking at low target level shows smaller threshold change by hyperpolarizing stimuli and greater threshold change by depolarizing stimuli, suggestive of greater transient Na+ current. Normal elderly showed greater threshold change by hyperpolarizing pulse than younger subjects at high target level, likely reflecting decrease of axon diameters. Patients with diabetic neuropathy showed smaller threshold changes by both depolarizing and hyperpolarizing pulses (“fanning-in”), more noticeably at the lower target level, suggestive of the combined effects of membrane depolarization and greater decrease of axonal diameters in smaller fibers. Given the reported unpredictable electrical recruitment order in the diseased conditions and difference of nerve excitability measures in threshold electrotonus at different target levels, comparing threshold electrotonus values between normal and diseased axons may be problematic by comparing axons with different nerve excitability characteristics.

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.

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.

Utility of recovery cycle with two conditioning pulses for detection of impaired axonal slow potassium current in ALS

OBJECTIVE Slow potassium current (I(Ks)) is important in controlling nerve excitability and its impairment is known in various neurological diseases, including amyotrophic lateral sclerosis (ALS). I(Ks) gives rise to the late subexcitability phase of the recovery cycle, which can be amplified by the use of multiple conditioning pulses. The clinical utility of this technique has not previously been explored. METHODS Nerve excitability tests, including recovery cycles with single and double conditioning pulses 4ms apart (RC and RC2, respectively) were performed in patients with ALS and control subjects. Late subexcitability values obtained by RC and RC2 were compared in both groups. RESULTS RC2 was well tolerated in all the subjects. The threshold changes in late subexcitability by RC2 were greater than those by RC in both groups (mean (%): RC, 16.0/13.3; RC2, 34.9/29.4 (Control/ALS)). The ALS group showed lower threshold changes than controls by both methods. Statistical analysis between the ALS and control groups provided smaller P value by RC2 (P=0.018) than by RC (P=0.046). Also, RC2 provided non-significant, but slightly more distinguishing non-parametric rank analysis and greater Area Under the Curve (AUC) by Receiver Operating Characteristic (ROC). RC2 produced more identifiable single peak for late subexcitability than RC in an ALS patient whose late subexcitability was decreased. CONCLUSIONS Two conditioning stimuli provide greater threshold change for late subexcitability and possibly clearer identification of a peak threshold change than conventional recovery cycle. The findings obtained by this new protocol reinforce the previously reported impairment of I(Ks) in ALS. SIGNIFICANCE Amplification of I(Ks) by double conditioning pulses is applicable in humans and may help elucidating its clinical significance in pathophysiology in neurological diseases.

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.

Successful treatment of stiff person syndrome with sequential use of tacrolimus

Stiff person syndrome (SPS) is a rare neurological disease with features of an autoimmune disease. SPS is characterised by severe progressive muscle stiffness of the spine and lower extremities with superimposed muscle spasms triggered by external stimuli such as noise, touch and emotional distress.1 Patients with SPS respond to high doses of muscle relaxants, such as diazepam and baclofen, several anticonvulsants, and gabapentin. Previous studies have reported that several causal treatments with corticosteroids, plasmapheresis, intravenous immunoglobulin (Ig) and new immunomodulating agents can reduce stiffness and lower sensitivity to stimuli and stress in patients with SPS.2 ,3 Because SPS is a chronic disease, patients generally require long-term treatments, which may be effective but difficult to take for long periods. Tacrolimus (Prograf, FK506) is a macrolide molecule belonging to the same immunosuppressant class as cyclosporine. Tacrolimus has a lower molecular weight and is 100-fold more potent in inhibiting T cell proliferation than cyclosporine. It acts through inhibition of the calcium-calcineurin (CaN) pathway and exerts its immunosuppressive effect by reducing the proliferation of activated T cells.4 We now report the successful treatment of patients with SPS using tacrolimus as the immunosuppressive agent. ### Patients We assigned two patients with SPS who had incomplete responses to conventional therapies and fulfilled the defined clinical criteria (online supplementary table 1).3 ### Clinical evaluations At baseline and each month thereafter, a neurologist used the distribution of stiffness index, the most consistent indicator of stiffness among patients and within patients, to evaluate the patients with SPS.3 Scores on this index range from 0 to 6 and reflect the extent of stiffness. The same neurologist also assessed the patients for changes in frequency of spasms with use of the heightened-sensitivity scale, which has been a reproducible and consistent means of assessing the number of factors triggering spasms.3 …