Short-term recovery of insulin secretion in response to a meal is associated with future glycemic control in type 2 diabetes patients.

AIMS/INTRODUCTION: Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes. This study aimed to investigate the association between short-term recovery of insulin secretion during hospitalization and clinical background or future glycemic control in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 127 patients with type 2 diabetes were included. The recovery of endogenous insulin secretion was determined using the following indices: index A: fasting C-peptide index (CPI) at discharge - fasting CPI on admission; index B: postprandial CPI at discharge - postprandial CPI on admission; and index C: Δ C-peptide immunoreactivity (CPR) (postprandial CPR - fasting CPR) at discharge - ΔCPR on admission. We examined the associations of each index with clinical background and future glycemic control measured by glycosylated hemoglobin and continuous glucose monitoring. RESULTS: Using index A and B, the age was significantly younger, whereas BMI and visceral fat area were significantly higher in the high-recovery group than in the low-recovery group. Changes in glycosylated hemoglobin levels were significantly greater at 6 and 12 months in the high-recovery group in the analysis of index C. The receiver operating characteristic curve analysis identified the index B and index C as indicators to predict glycosylated hemoglobin <7.0% at 6 months after discharge. Furthermore, index C was positively correlated with the time in the target glucose range, and inversely correlated with the standard deviation of glucose at 3 and 12 months after discharge. CONCLUSIONS: Short-term recovery of insulin secretion in response to a meal during hospitalization, evaluated with the index-C, might predict future glycemic control.

Memory B cell resurgence requires repeated rituximab in myasthenia gravis.

The immunologic effects of rituximab (RTX) in myasthenia gravis (MG) remain to be explored. We aimed to clarify immunologic reactions and their association with response to RTX in MG. Regulatory T cell and B cell profiles of MG patients were monitored. Two patients presenting with generalized MG with anti-acetylcholine receptor antibodies were treated with RTX. The treatment led to sustained clinical improvement, discontinuation of intravenous immunoglobulin or plasma exchange, and reduction of prednisolone and other drugs. One patient was in remission for more than one year, whereas the other patient exhibited deterioration of symptoms within one year. Disease activity was associated with the repopulation of IgD-CD27- and IgD-CD27+ memory B cells. Clinicians should be aware of the possibility that MG ranges in the duration of B cell depletion and additional RTX should be prescribed upon resurgence of memory B cells.

The Cross-Sectional Area of Paraspinal Muscles Predicts the Efficacy of Deep Drain Stimulation for Camptocormia.

BACKGROUND: Camptocormia, a disturbance of posture, is a well-described clinical feature of PD and other parkinsonian syndromes. Previous reports have shown that DBS of the subthalamic nucleus (STN) or globus pallidus internus is effective in treating camptocormia. However, the efficacy of DBS for camptocormia varies. OBJECTIVE: To determine a clinical marker for selecting an appropriate therapy for camptocormia, a disabling manifestation of Parkinson's disease (PD) that has a variable response to systemic and local therapies. METHODS: We obtained pre-operative lumbar magnetic resonance imaging of 14 consecutive PD patients with camptocormia who underwent subthalamic nucleus deep brain stimulation (STN-DBS) in this retrospective-designed study. Lumbar MRI was performed three to six months prior to the operation. We measured the cross-sectional area (CSA) and width of each participant's paraspinal muscles. RESULTS: Four (28.6%) patients were effective (EF), five (35.7%) were partially effective (PE), and five (35.7%) were non-effective (NE) to STN-DBS. The lumbar paraspinal CSA and width were significantly larger in the EF group than in the PE and NE groups. CONCLUSIONS: The CSA of paraspinal muscles and erector spinae width can be good predictive markers for improving camptocormia in patients with PD after deep brain stimulation.

MR Spectroscopy in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids and Asymptomatic Carriers of Colony-stimulating Factor 1 Receptor Mutation.

PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare neurodegenerative disorder with various clinical presentations. Mutation of the colony-stimulating factor 1 receptor (CSF1R) gene is considered to be a cause of this autosomal dominant disorder. The purpose of this study was to report magnetic resonance spectroscopy (MRS) findings in patients with HDLS and asymptomatic carriers and to clarify the use of MRS in this disease. MATERIALS AND METHODS: In this retrospective, institutional review board-approved study, we included four consecutive patients, genetically diagnosed with HDLS, and two asymptomatic carriers after acquiring informed consent. We performed single-voxel MRS of the left centrum semiovale on a 3-T clinical scanner. We also included a sex-matched normal dataset. We quantified N-acetylaspartate (NAA), creatine, choline-containing compounds (Cho), glutamine, glutamate (Glu), myo-inositol (Ins), glutathione, lactate (Lac), and gamma-amino butyric acid using LCModel. We performed statistical analysis, and P value <0.05 was considered significant. RESULTS: In HDLS cases, MRS revealed decreased NAA and Glu concentrations, which probably reflected neuronal damage and/or loss, and a subsequent reduction of neurotransmitters. A patient with HDLS also had increased Cho and Ins concentrations, indicating gliosis, and increased Cho concentration was also observed in an asymptomatic carrier. This suggests that metabolic changes had already occurred in an asymptomatic state. CONCLUSION: We demonstrated changes in metabolite concentrations not only in patients with HDLS but also in asymptomatic CSF1R mutation carriers. Our study indicates that MRS is a potentially useful tool for the analysis of metabolic and pathophysiological findings of HDLS, even during the early stages of disease.

Ganglionic acetylcholine receptor autoantibodies in patients with autoimmune diseases including primary biliary cirrhosis.

OBJECTIVES: Autonomic dysfunction is closely associated with autoimmune diseases (AID) including primary biliary cirrhosis (PBC). The objective of this study was to determine the prevalence of anti-ganglionic (nicotinic) acetylcholine receptor (gAChR) antibodies in patients with AID. METHODS: We determined the presence of gAChR antibodies in serum samples from 146 patients (systemic lupus erythematosus [SLE] = 32; rheumatoid arthritis [RA] = 43; systemic sclerosis [SSc] = 38; PBC= 33) without information regarding autonomic symptoms, as well as 34 patients with other neurological diseases [OND], and 73 healthy controls [HC]. We specifically analyzed sera for anti-gAChRα3 and -ß4 antibodies using the luciferase immunoprecipitation system (LIPS) assay. RESULTS: LIPS assay detected anti-gAChRα3 and -ß4 antibodies in the sera from patients with SLE (12.5%, 4/32), RA (18.6%, 8/43), SSc (13.2%, 5/38), PBC (9.1%, 3/33), OND (2.9%, 1/34), and HC (0.0%, 1/73). There were no significant correlations between the levels of anti-gAChRα3 and -ß4 antibodies, and the total titers of autoantibodies in AID. CONCLUSIONS: The results demonstrated a significant prevalence of anti-gAChR antibodies in patients with AID, which is independent of the production of other autoantibodies in patients with autoimmune diseases. These anti-gAChR antibodies could mediate the autonomic dysfunction involved in the autoimmune mechanisms of AID.

Lack of KIR4.1 autoantibodies in Japanese patients with MS and NMO.

OBJECTIVES: To examine anti-KIR4.1 antibodies by 2 different assays in Japanese patients with multiple sclerosis (MS) or neuromyelitis optica (NMO). METHODS: One hundred sixty serum samples from 57 patients with MS, 40 patients with NMO/NMO spectrum disorder (NMOSD), and 50 healthy controls (all were Japanese) were tested with ELISA using a synthetic peptide of the first extracellular portion of human KIR4.1. In addition, we attempted to detect anti-KIR4.1 immunoglobulin G in the serum by the luciferase immunoprecipitation systems (LIPS) with the full length of human KIR4.1 produced in a human cell line, which is highly sensitive to single or multiple epitopes. RESULTS: We failed to detect antibodies to the peptide fragment KIR4.1(83-120) in any case of MS and NMO/NMOSD using ELISA. Antibodies to the recombinant full length of KIR4.1 protein were detected in only 2 patients with MS and none in the patients with NMO/NMOSD by the LIPS assay. CONCLUSIONS: We developed 2 different methods (ELISA and LIPS) to measure autoantibodies to KIR4.1 in serum. We detected anti-KIR4.1 immunoglobulin G at a very low frequency in Japanese patients with MS or NMO/NMOSD. Serologic testing for human KIR4.1-specific antibodies is unlikely to improve the diagnosis of MS or NMO/NMOSD in Japanese patients.

Ganglionic acetylcholine receptor autoantibodies in patients with Guillain-Barré syndrome.

OBJECTIVES: Although standardized autonomic tests are useful for diagnosing autonomic failure in patients with Guillain-Barré syndrome (GBS), they cannot be used as predictive markers. Thus, serological markers may correctly identify patients with GBS who are at risk for autonomic dysfunction. METHODS: We validated a luciferase immunoprecipitation system that detects IgG antibodies in patient serum that specifically bind to the α3 or ß4 subunits of ganglionic neuronal nicotinic acetylcholine receptors (gAChR). We then used luciferase-conjugated ligands specific to antibodies against two gAChR subunits to test 79 sera samples from patients with GBS, 34 from subjects with other neurological diseases (OND), and 73 from healthy controls (HC). 1) In the first analysis, patients were classified into two groups according to the presence or absence of autonomic symptoms (AS). We compared the frequency of the anti-gAChR antibodies between these two groups (AS+ and AS-). 2) In the second analysis, furthermore, patients were classified depending on the presence or absence of anti-glycolipid antibodies (AGA). We compared the frequency of the anti-gAChR antibodies between the four categories of GBS (AS+/AGA+, AS+/AGA-, AS-/AGA+, and AS-/AGA-), OND, and HC. RESULTS: Eight subjects with GBS were positive for α3 subunits, while one was positive for ß4 subunits. Anti-α3 and -ß4 gAChR antibodies were also detected in 13.6% of AS+ GBS group in the first analysis. Two of 35 patients in AS-GBS group were seropositive for the anti-gAChR antibodies and AGA in the second analysis. Patients with GBS that were positive for serum antibodies to the α3 and/or ß4 subunits of gAChRs showed a range of clinical features including AS and AGA. CONCLUSIONS: Patients with GBS may have circulating antibodies against gAChR, which may contribute to the autonomic dysfunction associated with this disease.

Insights from the ganglionic acetylcholine receptor autoantibodies in patients with Sjögren's syndrome.

OBJECTIVE: It is not known whether autonomic neuropathy is a feature of Sjögren's syndrome (SS) or whether it is related to circulating antiganglionic acetylcholine receptor (gAChR) antibodies. The goal of the present study was to investigate the autonomic dysfunction in patients with SS and the associations between autonomic dysfunction, anti-gAChR antibodies, and clinical features of SS. METHODS: (1) The first observational study tested for the presence of gAChR antibodies in the serum samples from 39 patients with SS (absent information regarding autonomic symptoms) and healthy volunteers. (2) In the second study, serological and clinical data from 10 Japanese patients diagnosed with SS were reviewed. These patients showed autonomic dysfunction, and luciferase immunoprecipitation systems (LIPS) test was conducted to detect anti-α3 and anti-ß4 gAChR antibodies. (3) In the final analysis, we combined the data of seropositive SS patients with autonomic symptom from the first study with all of the patients from the second study, and analyzed the clinical features. RESULTS: (1) The LIPS assay revealed that anti-gAChRα3 and anti-gAChRß4 antibodies were detected in the sera from patients with SS (23.1%, 9/39). Five of nine SS patients had autonomic symptoms. (2) Anti-α3 and anti-ß4 gAChR antibodies were also detected in 80.0% (8/10) of patients with SS with autonomic symptoms. Six of the ten patients were diagnosed as having SS after neurological symptoms developed. These seropositive patients had predominant and severe autonomic symptoms and were diagnosed with autonomic neuropathy. (3) Thirteen of fifteen SS patients with autonomic symptoms (86.7%) were seropositive for anti-gAChR antibodies, and we confirmed sicca complex, orthostatic hypotension, upper and lower gastrointestinal (GI) symptoms, and bladder dysfunction at high rates. CONCLUSION: The present results suggest the possibility of anti-gAChR antibodies aiding the diagnostics of SS with autonomic dysfunction.

Late-onset myasthenia gravis is predisposed to become generalized in the elderly.

OBJECTIVE: The continuous increase in the number of patients presenting with late-onset myasthenia gravis (LOMG) underscores the need for a better understanding of the clinical course and the establishment of an optimal therapeutic strategy. We aimed to clarify factors associated with clinical outcomes in LOMG. METHODS: We retrospectively reviewed the clinical profiles of 40 patients with early-onset MG (EOMG) (onset age: 49 years or younger), 30 patients with non-elderly LOMG (onset age: 50-64 years), and 28 patients with elderly LOMG (onset age: 65 years or older) and compared the subgroups according to onset age and thymus status. The evaluated parameters were MGFA classification before treatment, MG-ADL score, complicating diseases, antibody titer, treatment, and MGFA post-intervention status. RESULTS: Elderly LOMG patients showed transition to generalized symptoms at a higher frequency and underwent thymectomy less frequently than EOMG and non-elderly LOMG patients (p < 0.001). The frequencies of crisis and plasmapheresis were significantly lower in thymectomized LOMG patients without thymoma than in thymectomized LOMG patients with thymoma or non-thymectomized LOMG patients (p < 0.01, P < 0.05, respectively). However, the outcome was not significantly different. All of the thymectomized LOMG patients without thymoma presenting with hyperplasia or thymic cyst had a favorable clinical course. CONCLUSIONS: Our study showed that elderly LOMG patients are more prone to severity, suggesting that they require aggressive immunomodulatory therapy.

The Effectiveness of the Stereotactic Burr Hole Technique for Deep Brain Stimulation.

Deep brain stimulation (DBS) is performed by burr hole surgery. In microelectrode recording by multi-channel parallel probe, because all microelectrodes do not always fit in the burr hole, additional drilling to enlarge the hole is occasionally required, which is time consuming and more invasive. We report a stereotactic burr hole technique to avoid additional drilling, and the efficacy of this novel technique compared with the conventional procedure. Ten patients (20 burr holes) that received DBS were retrospectively analyzed (5 in the conventional burr hole group and 5 in the stereotactic burr hole group). In the stereotactic burr hole technique, the combination of the instrument stop slide of a Leksell frame and the Midas Rex perforator with a 14-mm perforator bit was attached to the instrument carrier slide of the arc in order to trephine under stereoguidance. The efficacy of this technique was assessed by the number of additional drillings. Factors associated with additional drilling were investigated including the angle and skull thickness around the entry points. Four of the 10 burr holes required additional drilling in the conventional burr hole group, whereas no additional drilling was required in the stereotactic burr hole group (p = 0.043). The thicknesses in the additional drilling group were 10.9 ± 0.9 mm compared to 9.1 ± 1.2 mm (p = 0.029) in the non-additional drilling group. There were no differences in the angles between the two groups. The stereotactic burr hole technique contributes to safe and exact DBS, particularly in patients with thick skulls.

Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients.

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and ß4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -ß4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG.

Predictors of neurologic deterioration in patients with small-vessel occlusion and infarcts in the territory of perforating arteries.

BACKGROUND: It is difficult to predict neurologic deterioration in patients with small-vessel occlusion (SVO), that is, small infarcts in the territory of cerebral perforating arteries. METHODS: We reviewed 110 patients with SVO who were admitted to our hospital. We divided them into groups with (n = 32, group 1) and without deterioration (n = 78, group 2) and evaluated their medical records, risk factors, magnetic resonance imaging findings, grade of periventricular hyperintensity (PVH), maximum diameter of the infarct area, and the number of slices showing infarcts on diffusion-weighted images (DWI). RESULTS: Our study population consisted of 110 patients (71 males and 39 females; mean age 69.2 years): 32 (29%) did and 78 (71%) did not suffer deterioration. By univariate analysis, the age, current smoking, history of stroke, maximum diameter of the infarcted area, number of DWI slices with infarcts, frequency of PVH, and PVH grade based on Fazekas classification differed significantly between the 2 groups. By multivariate analysis, conventional risk factors other than PVH and history of stroke were not associated with neurologic deterioration (PVH grade ≥ 2 versus PVH grade ≤ 1, odds ratio 6.72, P = .006; with stroke versus without stroke, odds ratio .21, P = .049). We also found that higher the PVH grade, the worse the National Institutes of Health Stroke Scale score at the time of discharge. CONCLUSIONS: PVH and without history of stroke are independently associated with neurologic deterioration in patients with SVO.

[Case of neuromyelitis optica spectrum disorder associated with central pontine and extrapontine myelinolysis preceded by syndrome of inappropriate antidiuretic hormone secretion].

A 36-year-old woman complained of general malaise. She presented with hyponatremia and plasma osmotic pressure was lower than urinary osmotic pressure. In addition, serum antidiuretic hormone level was higher than the measurement sensitivity. She was diagnosed with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). She fell into a coma despite correction of serum sodium level. Brain magnetic resonance imaging (MRI) revealed high signal intensities in the cerebral cortex, striatum, thalamus, hypothalamus, midbrain, and pons in fluid-attenuated inversion recovery images. Spinal MRI revealed a longitudinally extending lesion in the cervical cord. Serum sample was positive for anti-aquaporin-4 antibody, supporting the diagnosis of neuromyelitis optica spectrum disorder (NMOSD) combined with central pontine and extrapontine myelinolysis. In patients with NMOSD, the immune reaction can gradually cause destructive changes of the hypothalamus and lead to unstable ADH secretion in the absence of immunomodulatory treatment.

[Novel autoantibodies in myasthenia gravis].

Patients with myasthenia gravis(MG) are divided into three groups: (1) acetylcholine receptor antibody positive MG: 80%, (2) muscle-specific receptor tyrosine kinase (MuSK) antibody positive MG: 5-10%, and (3) double seronegative MG. In 2011, autoantibodies (Abs) against low-density lipoprotein receptor-related protein 4(Lrp4) were identified in Japanese MG patients and thereafter have been reported in Germany and USA. In other Lrp4 Ab papers, Lrp4 Ab positive sera inhibited agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. Anti-MuSK autoantibodies were revealed to block binding of collagen Q (ColQ) to MuSK. Anti-Kv1.4 antibodies targeting alpha-subunits(Kv1.4) of the voltage-gated potassium channel occurs frequently among MG patients with thymoma. Further understandings of neuromuscular junction structure and functions through newly discovered autoantibodies may provide more specific clinical information and treatments in MG.

[Autoantibody against the presynaptic P/Q-type voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome].

Antibodies against the muscle acetylcholine receptor (AChR) were recognized as the cause of myasthenia gravis in the 1970s'. Since then, other neurological disorders associated with autoantibodies have been identified, each associated with an antibody against a ligand- or voltage-gated ion channel. Autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs) are detected in patients with Lambert-Eaton myasthenic syndrome (LEMS). These antibodies interfere with the calcium-dependent release of acetylcholine from the presynaptic membrane. LEMS is an autoimmune disorder affecting the neuromuscular junction, and is characterized by proximal muscle weakness, reduction of tendon reflex, and autonomic dysfunction. Electrophysiological examinations show small-amplitude compound muscle action potentials and increments on rapid repetitive nerve stimulation. Fifty to sixty percent of LEMS patients present with tumors, mostly small cell lung carcinoma (SCLC), as a paraneoplastic syndrome. SCLC is a neuroendocrine tumor, which expresses neuronal VGCCs. Some patients present cerebellar ataxia, which is always accompanied by SCLC. These patients tend to show higher titers of VGCC antibodies than that by LEMS patients with no ataxia. The diagnosis can be confirmed by finding reduced compound muscle action potential amplitudes at rest that shows increments greater than 100% with repetitive nerve stimulation and antibody detection by using radioimmunoprecipitation assays. The treatment options are generally categorized as anti-tumor, immunomodulating, immunosuppressing, and symptomatic treatments. In cases with SCLC, effective treatment against the tumor can improve LEMS. Plasmapheresis and intravenous administration of high-dose immunoglobulins have a short effect. Prednisone, alone or in combination with immunosuppressants can achieve long-term control of the disorder.

Basal ganglia hyperintensity on T1-weighted imaging of a patient with central nervous system metastasis producing carcinoembryonic antigens.

We herein report unusual basal ganglia hyperintense lesions on noncontrast T1-weighted magnetic resonance imaging in a patient with central nervous system metastasis from lung adenocarcinoma that was treated with gefitinib. T2*-weighted magnetic resonance imaging showed no hypointense lesions, thereby excluding the possibility of calcification or haemorrhage. A stereotactic brain biopsy of the left basal ganglia lesions revealed atypical cells, some of which formed a glandular lumen with a micropapillary pattern. These cells were immunopositive for markers of lung adenocarcinoma, thereby confirming the diagnosis of metastasis. We speculate that proteins, including carcinoembryonic antigens from the adenocarcinoma cells in the basal ganglia, may have contributed to the hyperintensity observed on noncontrast T1-weighted magnetic resonance imaging.

Gait and posture assessments of a patient treated with deep brain stimulation in dystonia using three-dimensional motion analysis systems.

Kinesiologic analysis of gait disorders, postural instabilities and abnormal movements is quite difficult to assess objectively by clinical observation, such as by specific scale and video recordings. In this study, we reported one of the aspects of the usefulness of three-dimensional motion analysis (Vicon Systems, Oxford, United Kingdom), which can measure inclusive data of movement disorders and substitute for conventional assessments. A 49-year-old man who had various dystonic symptoms, mainly on his left side of the body, responded well to deep brain stimulation (DBS). The examination quantified how the involuntary movements or other symptoms with dystonia changed before and after treatments.