Kotaro Asanuma

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.

Comparison of monophasic versus biphasic stimulation in rTMS over premotor cortex: SEP and SPECT studies

OBJECTIVE To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. METHODS In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. RESULTS Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. CONCLUSIONS Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. SIGNIFICANCE Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.

Efficacy of zolpidem for dystonia: a study among different subtypes

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor.

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.

Modulation of the onset age in primary dystonia by APOE genotype.

APOE polymorphisms were studied in 200 unrelated patients with primary dystonia as well as 300 age-matched control subjects. Although no difference was found in APOE genotype between the patients with dystonia and the controls, APOE-ε4 carriers developed the disease on average approximately 10 years earlier than APOE-ε4 noncarriers (p = 0.0012). This suggests that APOE-ε4 genotype affects the clinical presentation of primary dystonia.

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.

Generalized dystonia in a patient with a novel mutation in the GLUD1 gene

Hyperinsulinism-hyperammonemia syndrome (HHS; MIM 606762) is a form of congenital hyperinsulinism caused by mutations in the glutamate dehydrogenase 1 gene (GLUD1). This gene encodes glutamate dehydrogenase (GDH), which catalyzes the oxidation of glutamate to ammonia. Mutations in GLUD1 cause GDH hyperactivity by lowering the enzyme’s sensitivity to guanosine-50-triphosphate (GTP), an allosteric inhibitor of GDH, resulting in persistent hyperammonemia and hyperinsulinism. Although GLUD1-related HHS is frequently associated with epilepsy and mental retardation, generalized dystonia has only been reported in 1 case. Here, we confirm this association and describe a fulminant clinical progression of dystonia to dystonic storm, as well as significant improvement with bilateral globus pallidus internus deep brain stimulation (GPi-DBS). The female patient grew normally until 6 months of age, when she had an episode of generalized tonic–clonic seizures that responded poorly to antiepileptic drugs. Laboratory tests at age 33 months revealed hypoglycemia and hyperinsulinemia followed by persistent hyperammonemia. She also had moderate mental retardation, although her EEG and brain MRI appeared normal. A diagnosis of HHS was made, and we began treatment with diazoxide, which controlled her blood glucose levels and stopped the seizures. At age 11, she developed stereotyped repetitive neck rotation and upper arm contraction. The dystonic movements spread to whole areas of the body within a few months and were refractory to pharmacotherapy that included trihexyphenidyl, risperidone, clonazepam, baclofen, and L-3,4-dihydroxyphenylalanine. The patient eventually developed a life-threatening dystonic storm at age 16, and bilateral GPi-DBS was performed. GPi-DBS had a striking impact on her symptoms; her preoperative Burke-Fahn-Marsden Dystonia Rating Scale score of 112 decreased to 11.5 after GPi-DBS (Video). This improvement was essentially stable on examination 1 year after surgery. The genetic study was approved by the ethics committee, and participants provided written informed consent. We analyzed GLUD1 gene exons by PCR sequencing and confirmed the presence of a heterozygous sequence variation in exon 7: c.943C>T (Fig. 1A). Basal GDH activity was 35 nmol/min/mg of protein (control, 29), and allosteric inhibition by GTP (IC50) was 1819 nM (control, 135). These results are consistent with HHS caused by GLUD1 gene mutations. The patient underwent magnetic resonance spectroscopy (H-MRS) at age 14 (Fig. 1B–D), according to a previously reported method. Coding exons of the TOR1A and THAP1 genes did not contain mutations. Bahi-Buisson et al previously described generalized dystonia with prominent cranial-cervical features in a patient affected with the major GTP-binding site mutation. The mutation in the presented case lies in the same region. Further parallels include the age of dystonia onset, repeated hypoglycemic seizures, and moderate learning disability. Although epilepsy is reported frequently with the major mutation in the GTP-binding site, clonazepam may have masked the patient’s EEG aberrations. This case further supports that mutations in the GLUD1 gene could be a potential cause of dystonia and also suggests that GLUD1-related dystonia occurs through unique GLUD1 gene mutation– induced disruption of metabolic pathways. GLUD1 mutations can induce GDH overactivity that chronically depletes glutamate, which serves as the precursor of GABA. Loss of GABAergic inhibition is critical in dystonia development. Indeed, an MRS study showed that this patient had reduced levels of GABA and glutamate in the basal ganglia. Moreover, our patient showed decreased GABA levels in CSF and plasma (96 pmol/mL [normal controls, 239 6 76] and 74 pmol/mL [normal controls, 120–210], respectively). These data suggest that HHS-associated dystonia may be caused by altered GABAergic neurotransmission from GDH overactivity following direct mutation of the major GTP-binding site.

Incidence and clinical correlation of intracranial hemorrhages observed by 3-tesla gradient echo T(2)*-weighted images following intravenous thrombolysis with recombinant tissue plasminogen activator.

Background: The purpose of this study was to determine the incidence and clinical correlation of intracranial hemorrhages (ICHs) detected by 3-tesla gradient echo T2*-weighted images after intravenous recombinant tissue plasminogen activator (rt-PA) administration. Methods: We included 43 consecutive patients with anterior-circulation ischemia who underwent MRI studies before and after thrombolysis. Each hemorrhage was classified as a hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) according to the European Cooperative Acute Stroke Study definition. The clinical outcome was defined as an improvement (≧4-point reduction) or deterioration (≧4-point increase) based on a comparison between the initial and the 30-day NIHSS scores. Results: The incidence of ICHs was 58%, and the HI rate was 52%; both were higher than the rates reported in the literature. Most of the patients with HI improved clinically, and these patients had second MRAs that showed recanalization. None of the patients with PH demonstrated improvement. Conclusions: Three-tesla MRI may reveal a higher frequency of HI type hemorrhages than lower-field MRIs, and HI may be a predictor of good recovery by reflecting the presence of recanalization. The rate of PH in our study was low compared to other studies, probably due to the lower dosage of rt-PA.

136. Long-term effect of repetitive transcranial magnetic stimulation (rTMS) over the premotor cortex for upper limb dystonia

Subclinical rhythmic electrographic discharges of adults (SREDA) is a rare pattern reported in fewer than 0.05% of patients. We documented SREDA-like discharges in a patient with Parkinson’s disease (PD). A 59-year-old woman was admitted to our hospital due to slowly progressive motor disturbance of her left arm. On examination, she had left-dominant rigidity without autonomic and cognitive dysfunctions. Brain MRI showed a mild diffuse cerebral atrophy and SPECT revealed the hypoperfusion in the right thalamus and bifrontal areas. Her symptoms improved by L-DOPA, and thus we diagnosed her with PD. She underwent EEGs twice. In both tests, we found the repetitive discharges characterized by an abrupt onset during hyperventilation: occipital dominant theta waves preceded by delta waves appeared and evolved repeatedly, lasting 4–5 min. While these discharges were observed, her consciousness was alert and she had no symptoms. These discharges seemed to be SREDA, however, they lasted for long time and showed slower frequencies.