Efficacy and safety of mycophenolate mofetil for steroid reduction in neuromyelitis optica spectrum disorder: a prospective cohort study

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction. Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.</p

Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation

<div><p>Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFA_SEP(N20) and HFA_SEP(N80)) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFA_CCEP(N1) and HFA_CCEP(N2)). HFA_SEP(N20) showed the power peak in the frequency above 200 Hz, while HFA_CCEP(N1) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFA_CCEP(N1) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.</p></div

Patient profile.

<p>FLE = frontal lobe epilepsy, TLE = temporal lobe epilepsy, PLE = parietal lobe epilepsy, FCD = focal cortical dysplasia, HS = hippocampal sclerosis, DNT = dysembryoplastic neuroepithelial tumor</p><p>Patient profile.</p

The distributions of logarithmic power values in reference to the baseline in each frequency band.

<p>As for the 4 groups, HFA_{<b>SEP(N20)</b>} (a black solid line), HFA_{<b>CCEP(N1)</b>} (a grey solid line), HFA_{<b>SEP(N80)</b>} (a black dashed line) and HFA_{<b>CCEP(N2)</b>} (a grey dashed line), all the power values of 7 hemispheres are averaged (mean ± SE). RM-ANOVA showed statistically significant interactions between the 4 groups. An asterisk indicates significant interaction between the 2 groups in the post-hoc analysis. Other conventions are the same as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130461#pone.0130461.g003" target="_blank">Fig 3</a>.</p

SEPs and HFAs_SEP recorded from the peri-rolandic area and 3D-MRI (patient 1, left hemisphere).

<p>A: SEPs to right median nerve stimulation are plotted with subaverages (black and grey waveforms) across the CS identified on 3D-MRI (in a representative case). The vertical line corresponds to the time of median nerve stimulation (a white arrowhead). N20 component showing the maximum amplitude is identified on the primary somatosensory cortex (SI) (a black arrowhead). B: Time-frequency representation of SEP to right median nerve stimulation (HFA_<b>SEP</b>) by using the short-time Fourier Transform is shown across the CS. The frequency range is from 40 to 600 Hz. The vertical line corresponds to the time of median nerve stimulation (a white arrowhead). The averaged logarithmic power spectrum in reference to the baseline is calculated. Increase of power is indicated in red and decrease in blue. C: On 3D-MRI, subdural electrodes are plotted as white circles. A hand SI electrode is plotted as a white circle with a cross. Only electrodes at and around the hand SI and stimulus electrodes are shown in the figure. Since most of the induced high frequency activities were within 200 ms from the stimulus onset, we displayed the STFT results across the whole time points and frequencies in 3 dimensions (time, frequency, and power value) in a time window of 220 ms (from 20 ms before to 200 ms after the stimulus onset). SEP, somatosensory evoked potential; HFA, high frequency activity; CS, central sulcus.</p

CCEPs and HFAs_CCEP recorded from the peri-rolandic area and 3D-MRI (patient 1, left hemisphere).

<p>A: Single pulse stimulation was applied to the electrodes on the precentral gyrus and CCEPs were recorded time-locked to the stimuli (in a representative case). Two subaverages (black and grey waveforms) are shown. The vertical line corresponds to the time of single pulse stimulation (white arrowhead). B: Time-frequency representation of CCEP (HFA_<b>CCEP</b>) by using the short-time Fourier Transform. C: Electrodes on 3D-MRI. CCEP = cortico-cortical evoked potential. Other conventions are the same as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130461#pone.0130461.g001" target="_blank">Fig 1</a>.</p

DataSheet_1_Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy.docx

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.</p

SEP, CCEP, HFA_SEP, and HFA_CCEP at SI (patient 1, left hemisphere).

<p>A-D: SEP (A), CCEP (B), HFA_<b>SEP</b> (C), and HFA_<b>CCEP</b> (D) recorded from the same hand SI electrode are shown in a representative case. The STFT was performed by using the short analysis-window of 25 points (12.5 ms) in order to differentiate the stimulus artifact from the CCEP N1 potential. Since the sliding window is set at 5 ms, each time bin (5ms-width) displays the STFT results of the 12.5 ms analysis-window. For example, the 5 ms-time bin centered at 15 ms (highlighted by a black rectangle in C and D) corresponds to the results of 12.5 ms analysis-window (from 9 ms to 21.5 ms, centered at 15 ms; see shaded gray rectangle in A and B). The stimulus artifacts in CCEP last up to 3–4 ms from the stimulus onset. Therefore, the bins centered at -5, 0, 5, and 10 ms potentially include the stimulus artifacts and they are not analyzed. Because we put the transistor-transistor logic (TTL) pulse from the electric stimulator into the DC input of the EEG machine, and offline triggered the stimulus onset using a certain threshold with a Matlab-script, the trigger timing could have jitter within the sampling point, namely, 0.5 ms. This jitter is reflected in the representative CCEP waveform (B). As for the induced activities, the 5 ms time bins centered at -5 and 0 ms, which correspond to the results of 12.5 ms window centered at -5 and 0 ms, could include the stimulus artifact (D). E, F: The row traces (30 trials) of HFA_<b>SEP</b> (E) and HFA_<b>CCEP</b> (F) for the frequency bands centered at 80 and 320 Hz are shown. G-J: The power changes of HFA_{<b>SEP(N20)</b>}, HFA_{<b>CCEP(N1)</b>}, HFA_{<b>SEP(N80)</b>}, and HFA_{<b>CCEP(N2)</b>} in reference to the baseline activity for each frequency band (every 80 Hz, centered at 80, 160, 240, 320, 400, 480, and 560 Hz) are plotted (G, H, I, and J).</p

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new “Integrated Epilepsy Classification”?

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the “Four-dimensional epilepsy classification” (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the “Integrated Epilepsy Classification”. This consists of five categories derived to different degrees from both of the classification systems: 1) a “Headline” summarizing localization and etiology for the less specialized users, 2) “Seizure type(s)”, 3) “Epilepsy type” (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) “Etiology”, and 5) “Comorbidities & patient preferences”