Tomotaka Yamamoto

Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis.

To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

RESPONSE OF ANTI-NMDA RECEPTOR ENCEPHALITIS WITHOUT TUMOR TO IMMUNOTHERAPY INCLUDING RITUXIMAB

Paraneoplastic encephalitis with antibodies against NR1/NR2 heteromers of the NMDA receptor associates frequently with ovarian teratoma and has recently been established as a distinct clinical entity.1 Most patients are young women who develop a syndrome with prodromal cold-like illness, intractable seizures, psychosis, dyskinesia, and hypoventilation.1,2 However, about 40% of patients do not have a detectable tumor,3 and the treatment of these patients remains unclear. We report a patient with anti-NR1/NR2 encephalitis without teratoma who showed a nearly complete recovery after intensive immunotherapy including rituximab. ### Case report. A 42-year-old woman had cough and headache for 3 weeks. On the day before admission, she was found to be unresponsive for several minutes, and subsequently developed generalized seizures. On admission, her temperature was 38.2°C, and she had meningeal signs. CSF revealed mild pleocytosis (10/mm3) and slightly elevated protein concentration (45 mg/dL) with normal glucose concentration and IgG index. MRI (figure, A) and EEG were unremarkable. After the seizures were controlled, minimal disorientation was observed. Acyclovir and ceftriaxone were started. Figure MRI and FDG-PET studies of the brain (A) On day 2, the FLAIR MRI was normal. (B) On day 18, the FLAIR image revealed new high-intensity areas in the right temporal cortex, insula, parts of the frontal, parietal, and occipital cortices, and hippocampus. These findings were accompanied by mild edema. High-intensity areas were also observed in the left inferior temporal cortex and hippocampus

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis

Objective: To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. Methods: Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. Results: Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. Conclusions: In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy.

Primary face motor area as the motor representation of articulation

No clinical data have yet been presented to show that a lesion localized to the primary motor area (M1) can cause severe transient impairment of articulation, although a motor representation for articulation has been suggested to exist within M1. Here we describe three cases of patients who developed severe dysarthria, temporarily mimicking speech arrest or aphemia, due to a localized brain lesion near the left face representation of the human primary motor cortex (face-M1). Speech was slow, effortful, lacking normal prosody, and more affected than expected from the degree of facial or tongue palsy. There was a mild deficit in tongue movements in the sagittal plane that impaired palatolingual contact and rapid tongue movements. The speech disturbance was limited to verbal output, without aphasia or orofacial apraxia. Overlay of magnetic resonance images revealed a localized cortical region near face-M1, which displayed high intensity on diffusion weighted images, while the main portion of the corticobulbar fibers arising from the lower third of the motor cortex was preserved. The cases suggest the existence of a localized brain region specialized for articulation near face-M1. Cortico-cortical fibers connecting face-M1 with the lower premotor areas including Brocas area may also be important for articulatory control.

Severe Hypokinesis Caused by Paraneoplastic Anti-Ma2 Encephalitis Associated with Bilateral Intratubular Germ-Cell Neoplasm of the Testes

We report a 40‐year‐old man with severe hypokinesis as paraneoplastic manifestation of a microscopic “carcinoma in situ” of the testis. The young age of the patient, along with progressive neurologic deterioration, detection of anti‐Ma2 antibodies, and ultrasound findings of bilateral microcalcifications, led to bilateral orchiectomy, revealing the tumor in both testes. After orchiectomy, neurological symptoms stabilized, but the patient eventually died of systemic complications caused by his severe neurological deficits. Anti‐Ma2 paraneoplastic encephalitis should be considered in patients with severe hypokinesis, and intensive investigation and aggressive approach to treatment is encouraged to prevent progression of the neurological deficits.

Postural tremor in X-linked spinal and bulbar muscular atrophy†

Postural tremor is a common initial symptom in spinal and bulbar muscular atrophy (SBMA), but its pathophysiological mechanisms remain to be studied. This study was undertaken to examine the physiological mechanisms underlying postural tremor in SBMA. For eight patients (36–63 years old) with genetically confirmed SBMA, we recorded surface electromyograms (EMGs) from the forearm muscles and hand movements with an accelerometer (ACC) while maintaining a posture with and without a weight load. We then analyzed their power spectra and coherence. The peak tremor frequency was 6–9 Hz in seven patients and 2–3 Hz in one patient. Oscillatory movements were associated with EMG activity in five patients, but not in three patients. Weight loads and postural changes affected the tremor frequency in all patients. Tremor was classified as “reflex tremor” in five patients and “mechanical tremor” in three patients. These results suggest that peripheral factors play important roles in tremor genesis in SBMA, although its clinical features resemble essential tremor. Subclinical sensory disturbance or a decrease of motor unit numbers might be candidates for such peripheral factors contributing to tremor genesis in SBMA.

Identification of Human Limb Viscoelasticity using Robotics Methods to Support the Diagnosis of Neuromuscular Diseases

In this paper we present an original method to estimate in vivo the joint dynamics of the human limbs. The method is based on a non-invasive and painless technology making use of an optical motion capture system and an associated skeletal model to record the human motion and compute its kinematics and its dynamics. The formalism that is used for the identification is commonly used in robotics. The passive limb joints properties are modeled by enhanced spring-damper systems. The inverse dynamics is sampled along a movement to give an over-determined system. The obtained system is solved by the linear least-squares method. To perform the estimation, we place emphasis on giving indicators and requirements to interpret the obtained results, and on using painless, passive constraint-free movements that are usually performed during the clinical diagnosis of neuromuscular diseases. Finally the method is experimentally applied to two healthy subjects and five patients of neuromuscular diseases in order to estimate the upper-limb viscoelastic properties. The obtained results are discussed.

Evaluation of spinal and bulbar muscular atrophy by the clustering index method

Introduction: A reliable electrophysiological marker for clinical trials is increasingly needed in spinal and bulbar muscular atrophy (SBMA). We previously developed a quantitative analysis method for surface electromyography (SEMG), the clustering index (CI) method. Our purpose was to test the utility of the CI method for evaluating lower motor neuron involvement in SBMA patients. Methods: Subjects included 29 SBMA patients and 27 healthy controls. The recording electrode was placed over the abductor digiti minimi (ADM) muscle with a proximal reference. The Z‐score, based on the CI method, was compared with compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE), with regard to sensitivity. Results: The Z‐scores of the CI method, CMAP amplitude, and MUNE were abnormal in 100%, 72%, and 93% of the patients, respectively. Interrater reliability of the CI method was sufficiently high. Conclusion: The CI method is promising as a non‐invasive electrophysiological marker in SBMA. Muscle Nerve, 2011

Autotaxin enzyme immunoassay in human cerebrospinal fluid samples

Lysophosphatidic acid (LPA), a simple glycerophospholipid, is attracting attention as an important lysophospholipid mediator [1]. In spite of its simple structure, LPA mediates various cellular responses through interaction with G protein-coupled cell surface receptors, namely, LPA1/Edg2, LPA2/Edg4, LPA3/Edg7, LPA4/p2y9/GPR23 and LPA5/GPR92 [1,2]. Mediated by these receptors, LPA activates GTPases, Ras, Rac and Rho, resulting in multiple (patho)physiological actions [1]. It has been shown that plasma LPA is produced by autotoxin/ lysophospholipase D (ATX/lysoPLD), which hydrolyzes lysophospholipids (mainly lysophosphatidylcholine (LPC)) [3]. Numerous studies have indicated that ATX/lysoPLD is a key enzyme in LPA synthesis and is responsible for the bulk of the LPA present in the plasma [4]. In human, the serum ATX antigen concentration has been shown to be significantly correlated with the serum lysoPLD activity [5,6]. Furthermore, the ATX/lysoPLD antigen concentration and activity were shown to be correlated with the plasma LPA concentration [5,6]. Emerging roles of LPA in the (patho)physiology of the nervous system have been indicated in previous studies. LPA has been shown to be involved in various neural cell functions, such as neurite remodeling, demyelination, survival, and inhibition of axonal growth [7]. A broad range of cell types related to the function of the nervous system respond to LPA, including oligodendrocytes, Schwann cells, astrocytes, microglia, and brain endothelial cells [7]. LPA has been shown to mediate transmembrane Ca influx in cultured oligodendrocytes. In astrocytes also, LPA stimulates dynamic calcium fluctuations and morphological rearrangements. This bioactive lysophospholipid has also been shown to regulate the morphology and adhesiveness of cultured Schwann cells. On the other hand, various neural cells have been shown to express LPA receptors [7]. LPA1 and LPA2 are expressed in the embryonic cerebral cortex, and exert effects on brain formation during embryonic development. These data suggest receptor-mediated LPA signaling as a potentially important process in nervous system development and function. In addition, Northern blot analysis showed that steady-state autotaxin mRNA expression is most abundant in the brain [8]. Furthermore, it has been reported that ATX is detected in the cerebrospinal fluid (CSF) and that it regulates the production of LPA from LPC through its lysoPLD activity [9]. Considering the importance of ATX/lysoPLD as an enzyme that produces LPA, it was assumed that measurement of ATX in the CSF may provide information on the (patho) physiological state of the nervous system. The CSF and serum samples used in this study were residual samples of those obtained for routine laboratory analyses (for clinical purposes) at the University of Tokyo Hospital. Informed consent was obtained from the subjects for the use of the residual samples, and the study was approved by the Institutional Research Ethics Committee of the Faculty of Medicine, the University of Tokyo. Whole blood specimens were put into glass tubes allowed to clot then centrifuged