Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS. METHODS: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. RESULTS: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. CONCLUSION: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

The use of the 25 Sprotte needle markedly reduces post-dural puncture headache in routine neurological practice.

OBJECTIVES: The objectives of this article are to test the feasibility of lumbar puncture (LP) using 25-gauge (G) needles in daily neurological practice and to compare the risk of post-dural puncture headache (PDPH) with four types of needles. METHODS: In a prospective rater-blind study, pros and cons of four different LP needles, the 20G Quincke (20Q), 22G Sprotte (22S), 25G Whitacre (25W) and 25G Sprotte (25S), were evaluated in 394 LPs performed by seven neurologists. The neurologist performing the LP recorded the type and size of needle, intensity of pain, safety, time of the procedure and failure or success. Between five and 15 days later another neurologist, blind to the type of needle used, completed an ad-hoc questionnaire for PDPH. RESULTS: PDPH developed in 35.9% patients when using a 20Q needle, and in 12.9%, 6.8% and 1.6%, respectively, when using a 22S, 25W or 25S needle. The difference in incidence of PDPH following LP performed with the 20Q needle and the 25S or 22S was statistically significant (p < 0.001 and p = 0.008, respectively) and it approached significance when comparing the 25S and 25W (p = 0.06). As 25W and 25S needles need CSF aspiration, LP requires more time and skill. Pain caused by LP was similar with the four needles. CONCLUSION: The use of the 25S needle in diagnostic LP reduces the frequency and severity of PDPH.

Tailoring Rituximab According to CD27-Positive B-Cell versus CD19-Positive B-Cell Monitoring in Neuromyelitis Optica Spectrum Disorder and MOG-Associated Disease: Results from a Single-Center Study.

INTRODUCTION: B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates. METHODS: This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs). RESULTS: A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09-16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78-14.23) before CD27 monitoring and 15.93 months (range 8.56-35.37) after CD27 monitoring (p < 0.001). We observed no AEs. CONCLUSION: Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy.

Sleep-wake cycle and effects of cabergoline monotherapy in de novo Parkinson's disease patients. An ambulatory polysomnographic study.

OBJECTIVE: To investigate the sleep-wake cycle and the effects of cabergoline monotherapy in a homogenous group of de novo Parkinson's Disease (PD) patients without confounding comorbid factors. DESIGN AND PARTICIPANTS: Twelve de novo patients affected by idiopathic PD underwent two ambulatory polysomnographic (APSG)monitoring sessions. The first was performed at baseline, and the second recording one-month after stable treatment with cabergoline monotherapy. Subjective daytime sleepiness was evaluated by means of the Epworth Sleepiness Scale.Data obtained in PD patients at baseline were compared with those obtained in 12 age- and sex-matched healthy subjects. RESULTS: Diurnal sleep parameters did not show significant differences between controls and PD patients at baseline. In PD patients, no significant changes in diurnal sleep were observed between baseline and cabergoline treatment. Regarding nocturnal sleep, patients at baseline showed a significantly lower sleep efficiency and a significantly higher Wakefulness After Sleep Onset than controls. With respect to baseline, a significant increase in REM latency and a significant reduction in REM sleep were observed during cabergoline treatment. CONCLUSIONS: In the early stage of PD, the neurodegenerative process does not seem to be directly responsible for daytime somnolence, but it may be directly involved in the alteration of nocturnal sleep. Cabergoline monotherapy does not affect daytime sleep propensity and, despite clinical improvement, it may have negative effects on REM sleep.

High-Risk PML Patients Switching from Natalizumab to Alemtuzumab: an Observational Study.

INTRODUCTION: The choice of therapy in patients withdrawing from natalizumab treatment is still an open question and neurologists need strategies to manage this group of patients. The aim of this study is to evaluate if alemtuzumab is able to control the disease when used in patient who have stopped natalizumab. METHODS: 16 patients stopped natalizumab treatment after a median number of 20 infusions (range 12-114); all the patients were responders to natalizumab (neither clinical nor radiological activity during natalizumab therapy) and the reason for stopping was the risk of PML for all of them. Patients were switched to alemtuzumab after a median wash-out period of 70 days (range 41-99 days); patients underwent brain MRI every three months during natalizumab treatment and then just before starting alemtuzumab in order to exclude signs suggestive of PML; then, contrast-enhanced brain MRI was planned 6 and 12 months after alemtuzumab infusion. RESULTS: At present, 8 out of 16 patients have a follow-up >6 months and 2 out of 8 reached 1-year follow-up; 5 have a follow-up of 3-6 months and 3 have a follow-up <3 months. Brain MRI at 6 months after alemtuzumab is available for 8 out of 16 patients and in all of them, neither signs of disease activity nor new lesions are present; in 2 out of 8 patients, brain MRI at 12 months is also available, showing no sign of disease activity. Clinical evaluation performed at 6 and at 12 months (when available) showed stability, in particular neither relapses nor increase in EDSS were observed. CONCLUSIONS: Alemtuzumab was able to control the disease course in patients who stopped natalizumab; of course, as this is a single-centre study and the number of patients is small, these findings are very preliminary and need further confirmation.

Normative Values for Intertrial Variability of Motor Responses to Nerve Root and Transcranial Stimulation: A Condition for Follow-Up Studies in Individual Subjects.

OBJECTIVE: Intertrial variability (ITV) of motor responses to peripheral (CMAP) and transcranial (MEP) stimulation prevents their use in follow-up studies. Our purpose was to develop strategies to reduce and measure CMAP and MEP ITV to guide long-term monitoring of conduction slowing and conduction failure of peripheral and central motor pathway in the individual patient. METHODS: Maximal compound muscle action potentials to High Voltage Electrical Stimulation (HVES) of lumbo-sacral nerve roots (r-CMAP) and activated, averaged motor evoked potentials (MEPs) to Transcranial Magnetic Stimulation (TMS) using double cone coil were recorded from 10 proximal and distal muscle districts of lower limbs. The procedure was repeated twice, 1-2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients, using constant stimulating and recording sites and adopting a standardized procedure of voluntary activation. ITV for latency and area indexes and for the ratio between MEP and r-CMAP areas (a-Ratio) was expressed as Relative Intertrial Variation (RIV, 5th-95th percentile). As an inverse correlation between the size of area and ITV was found, raw ITV values were normalized as a function of area to make them comparable with one another. RESULTS: All RIV values for latencies were significantly below the optimum threshold of ± 10%, with the exception of r-CMAP latencies recorded from Vastus Lateralis muscle. RIVs for a-Ratio, the most important index of central conduction failure, ranged from a maximum of -25.3% to +32.2% (Vastus Medialis) to a minimum of -15.0% to + 17.4% (Flexor Hallucis Brevis). CONCLUSIONS: The described procedure represents an effort to lower as much as possible variability of motor responses in serial recording; the reported ITV normative values are the necessary premise to detect significant changes of motor conduction slowing and failure in the individual patient in follow-up studies.

Quantitative EEG and dynamic susceptibility contrast MRI in Alzheimer's disease: a correlative study.

OBJECTIVE: To investigate the relationship between the electroencephalographic (EEG) power spectra features obtained by quantitative EEG (qEEG) and the hemodynamic parameters detected by dynamic susceptibility contrast-enhanced MR imaging (DSC MRI) in patients with Alzheimer's disease (AD). METHODS: Fourteen patients with probable AD and 15 elderly healthy controls were included in the study. All subjects underwent both EEG recording in a rest condition and perfusion MRI. Three EEG scalp areas were defined (anterior, central and posterior) and power spectra values were obtained from each scalp area. Relative values of temporoparietal and sensorimotor regional cerebral blood volume (rCBV) were measured bilaterally and successively averaged to obtain a total perfusion index. The brain atrophy index was calculated and used as a covariate to rCBV. Correlation analysis was performed between EEG variables and hemodynamic-morphological parameters. RESULTS: qEEG power spectra of AD patients were characterized by an increase in mean relative power of theta (4-7.75 Hz) associated with a decrease in alpha (8-12.75 Hz) frequency bands with a topographic distribution over the central and posterior EEG scalp regions, when compared with controls; beta (13-31 Hz) frequency band also displayed a significant decrease over the anterior and posterior EEG scalp regions of AD patients with respect to controls. The DSC MRI revealed a bilateral reduction in the temporoparietal and sensorimotor rCBV with respect to controls. Correlation analysis showed that the total level of hypoperfusion selectively correlates with the EEG power spectra in theta and alpha frequency bands distributed over anterior/central and central region, respectively. Within AD patients, the lower the level of hypoperfusion, the higher the content of EEG power spectra in theta frequency band, and the lower the level of hypoperfusion, the lower the content of EEG power spectra in alpha band. CONCLUSIONS: The combined qEEG and DSC MRI technology unveiled a selective correlation between neurophysiological and hemodynamical patterns in AD patients. Further investigations will ascertain the relevance of this multi-modal approach in the heterogeneous clinical context of AD.

Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy.

PURPOSE: To evaluate the effects of topiramate (TPM) on interictal epileptiform abnormalities (IEA) and background activity by means of a computerized EEG analysis, in adult patients affected by focal epilepsy, with or without secondarily generalization, treated with TPM as adjunctive therapy or monotherapy. METHODS: Twenty-four patients affected by symptomatic or cryptogenic focal epilepsy underwent long-term video-EEG recording before and after TPM addition (mean dose 175+/-25 mg per day). RESULTS: TPM addition induced a significant reduction of both partial and secondarily generalized tonic-clonic (SGTC) seizures; treatment responder patients (seizure reduction > or = 50%) were 19 out of 24 patients (79.1%), of whom 5 were seizure-free. Quantitative analysis of IEA showed a significant decrease in the mean number of spikes/10 min during TPM therapy ( 4.2+/-4.2 versus 2.2+/-4.4; P<0.003 ). The analysis of spatial distribution of interictal spikes showed that such reduction was more evident at the level of the epileptogenic area rather than on the spreading component. Statistical analysis revealed only a significant decrease of mean relative power of alpha band in the EEG spectral content, recorded at rest in a group of 18 out of 24 epileptic patients during TPM therapy. In addition, during TPM treatment we observed a significant reduction in alpha reactivity without any important changes of alpha indexes (peak frequency and median frequency). CONCLUSION: These findings suggest that TPM has a strong inhibitory effect on IEA, probably acting on the generating processes, and, if used at low dosage and gradually titrated, seems to have only mild interferences with EEG background activity.

A new neurophysiological approach to assess central motor conduction damage to proximal and distal muscles of lower limbs.

OBJECTIVE: To develop a neurophysiological method to explore central motor pathways to proximal and distal muscles of lower limbs. METHODS: MEPs to transcranial magnetic stimulation using the double cone coil were bilaterally and simultaneously recorded from vastus medialis, tibialis anterior and flexor hallucis brevis. Voluntary facilitation was controlled using a predefined sequence of movements of constant amplitude. Compound motor action potentials elicited by maximal high voltage electrical stimulation of lumbosacral roots (root-CMAPs) were recorded from the same muscles to obtain the corresponding peripheral conduction times. We studied 28 healthy subjects and 28 multiple sclerosis (MS) patients with no or mild motor impairment. RESULTS: The described facilitation procedure and the averaging of 5 MEPs reduced area variability to about 10%. In MS patients conduction slowing and/or MEP area reduction in at least one muscle was found in 91.7% of cases, with significant correlation with individual motor impairment. CONCLUSIONS: Combined use of stable MEPs and maximal root-CMAPs was able to detect both conduction slowing and conduction failure in central motor pathways to proximal and distal districts of lower limbs in MS patients. SIGNIFICANCE: The proposed method provides an extensive electrophysiological mapping of central motor impairment of lower limbs in clinical application.

A methodological reappraisal of non invasive high voltage electrical stimulation of lumbosacral nerve roots.

OBJECTIVE: To describe a neurophysiological method to locate the optimal stimulation site (OSS) over the vertebral column, customized to the individual subject, to achieve maximal activation of lumbosacral roots by means of non-invasive high voltage electrical stimulation (HVES). METHODS: OSS was located in 30 volunteers by testing different stimulation points of a surface multi-electrode array placed over the dorso-lumbar junction of the vertebral column. The dorso-ventral stimulating montage was used (Troni et al., 1996). Motor responses to root stimulation (rCMAPs) were bilaterally recorded from Vastus Medialis (VM), Tibialis Anterior (TA), Soleus (SL) and Flexor Hallucis Brevis (FHB) muscles. The direct nature of rCMAPs was tested by delivering two maximal stimuli 50 ms apart. RESULTS: Except for a few subjects with large girth, maximal rCMAPs could be obtained from all muscles with a stimulating current intensity up to 550 V (1050 mA). Maximal double HVES excluded any reflex component in the recorded rCMAPs. The procedure was well tolerated and no side effects were observed. CONCLUSIONS: A single maximal electric shock delivered at the proper vertebral level by means of the dorso-ventral montage is able to safely achieve synchronous, bilateral maximal activation of several roots, from L3 to S1. SIGNIFICANCE: Maximal activation of lumbosacral roots at their origin, unattainable with magnetic stimulation, is the essential requirement for direct detection of proximal nerve conduction slowing and block in lower limbs.

Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis.

BACKGROUND: Pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood. METHODOLOGY: We conducted a genome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls) followed during their pregnancy. Samples were obtained before, during (i.e. at the third, sixth, and ninth month of gestation) and after pregnancy. A validation of the expression profiles has been conducted by using the same samples and an independent group of 25 MS patients and 11 healthy controls. Finally, considering the total group of 32 MS patients, we compared expression profiles of patients relapsing during pregnancy (n = 6) with those of relapse-free patients (n = 26). PRINCIPAL FINDINGS: Results showed an altered expression of 347 transcripts in non-pregnant MS patients with respect to non-pregnant healthy controls. Complementary changes in expression, occurring during pregnancy, reverted the previous imbalance particularly for seven inflammation-related transcripts, i.e. SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Longitudinal analysis showed that the overall deregulation of gene expression reverted to "normal" already within the third month of gestation, while in the post-partum gene expressions rebounded to pre-pregnancy levels. Six (18.7%) of the 32 MS patients had a relapse during pregnancy, mostly in the first trimester. The latter showed delayed expression profiles when compared to relapse-free patients: in these patients expression imbalance was reverted later in the pregnancy, i.e. at sixth month. CONCLUSIONS: Specific changes in expression during pregnancy were associated with a decrease in disease activity assessed by occurrence of relapses during pregnancy. Findings might help in understanding the pathogenesis of MS and may provide basis for the development of novel therapeutic strategies.

Glatiramer acetate is a treatment option in neutralising antibodies to interferon-beta-positive patients.

Neutralising antibodies develop in 15% of interferon-beta (IFNbeta)-treated patients, causing the reduction of the clinical effects of the treatment. This is the first study that shows that switching patients from IFNbeta to glatiramer acetate (GA) in case of neutralising antibodies (NAb) positivity is effective in reducing relapse rate and in delaying the time to first relapse. In conclusion, our data suggest the use of GA in NAb-positive patients.

Contralateral smile and laughter, but no mirth, induced by electrical stimulation of the cingulate cortex.

The cerebral representation of laughter is dissociated. The emotional aspects seem to be processed in the temporal lobe; whereas the motor features apparently rely on the frontal cortex. In a few prior studies of patients in whom laughter was elicited by electrical stimulation (ES), it always was associated with mirth. We report a patient in whom ES in the right cingulate gyrus elicited smile and laughter, but no mirth. At low voltages, smiling was seen first contralaterally and became bilateral with increasing currents. Our observation supports the concept of the motor representation of laughter in the mesial frontal cortex.

EEG source imaging in pediatric epilepsy surgery: a new perspective in presurgical workup.

PURPOSE: Epilepsy is a relatively frequent disease in children, with considerable impact on cognitive and social life. Successful epilepsy surgery depends on unambiguous focus identification and requires a comprehensive presurgical workup, including several neuroimaging techniques [magnetic resonance imaging, positron emission tomography (PET), and single-photon emission computed tomography (SPECT)]. These may be difficult to apply in younger or developmentally delayed children or both, requiring sedation, and hence, a significant workforce. Modern electric source imaging (ESI) provides accurate epileptic source-localization information in most patients, with minimal patient discomfort or need for cooperation. The purpose of the present study was to determine the usefulness of ESI in pediatric EEG recordings performed with routine electrode arrays. METHODS: Preoperative EEGs recorded from 19 to 29 scalp electrodes were reviewed, and interictal epileptiform activity was analyzed by using a linear source-imaging procedure (depth-weighted minimum norm) in combination with statistical parametric mapping. RESULTS: In 27 (90%) of 30 patients, the ESI correctly localized the epileptogenic region. These numbers compare favorably with the results from other imaging techniques in the same patients (PET, 82%; ictal SPECT, 70%). In extratemporal epilepsy, ESI was correct in all cases, and in temporal lobe epilepsy, in 10 of 13 cases. In two temporal lobe patients showing less-accurate ESI results, 128-electrode data could be analyzed, and in both cases, the 128-electrode ESI was correct. CONCLUSIONS: ESI with standard clinical EEG recordings provides excellent localizing information in pediatric patients, in particular in extratemporal lobe epilepsy. The lower yield in temporal lobe epilepsy seems to be due to undersampling of basal temporal areas with routine scalp recordings.

Dynamic susceptibility contrast (DSC) MRI and interictal epileptiform activity in cryptogenic partial epilepsy.

PURPOSE: To study the possible correlation between interictal EEG patterns and neuroradiologic data obtained by dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) in patients with partial epilepsy. METHODS: Seventeen subjects with cryptogenic partial epilepsy underwent long-term video-EEG monitoring and DSC-MRI in the same session. Ten patients had temporal lobe epilepsy (TLE) and seven, epilepsy of extratemporal origin (ExTE). MRI data were compared with EEG findings, and the accuracy of DSC-MRI was analyzed considering spiking rate (number of interictal epileptiform abnormalities, IEA/min) and type of epilepsy. RESULTS: DSC-MRI showed a relevant asymmetry in the frontal, temporal, and occipital regions in eight (47%) of 17 patients, consisting of a relative regional cerebral blood volume (rCBV) increase in these areas. Because this region corresponded to the interictal EEG focus (IEF) or to the hemisphere involved in the genesis of epileptic discharges in most patients showing a higher spiking rate, patients were classified in two groups: patients with high spiking rate (HSR, n = 9) and with low spiking rate (LSR, n = 8); the cutoff corresponded to the median value of IEA/min. The rCBV increase corresponded to the IEF or to the hemisphere involved in the genesis of epileptic discharges in seven (77.7%) of nine HSR patients. No patients with LSR showed significant asymmetries in rCBV pattern. In five of six patients with TLE-HSR (83.3%), DSC-MRI showed a relative rCBV increase concordant with IEF or hemisphere involved in the genesis of epileptic discharges; in patients with ExTE-HSR, the concordance was 66%. CONCLUSIONS: DSC-MRI is a noninvasive procedure that may provide useful additional information to lateralize and/or localize the IEF when interictal epileptiform activity is sufficiently elevated.