Clinical description of the broad range of neurological presentations of COVID-19: A retrospective case series.

BACKGROUND: Neurological disorders associated with SARS-CoV-2 infection represent a clinical challenge because they encompass a broad neurological spectrum and may occur before the diagnosis of COVID-19. METHODS: In this monocentric retrospective case series, medical records from patients with acute neurological disorders associated with SARS-CoV-2 infection from medicine departments of an academic center in Paris area were collected between March 15th and May 15th 2020. Diagnosis of SARS-CoV-2 was ascertained through specific RT-PCR in nasopharyngeal swabs or based on circulating serum IgG antibodies. RESULTS: Twenty-six patients diagnosed with SARS-CoV-2 infection presented with neurological disorders: encephalitis (N=8), encephalopathy (N=6), cerebrovascular events (ischemic strokes N=4 and vein thromboses N=2), other central nervous system (CNS) disorders (N=4), and Guillain-Barré syndrome (N=2). The diagnosis of SARS-CoV-2 was delayed on average 1.6 days after the onset of neurological disorder, especially in case of encephalitis 3.9 days, encephalopathy 1.0 day, and cerebrovascular event 2.7 days. CONCLUSIONS: Our study confirms that COVID-19 can yield a broad spectrum of neurological disorders. Because neurological presentations of COVID-19 often occur a few days before the diagnosis of SARS-COV-2 infection, clinicians should take preventive measures such as patient isolation and masks for any new admission to avoid nosocomial infections. Anti-SARS-CoV2 antibody detection in RT-PCR SARS CoV-2 negative suspected cases is useful to confirm a posteriori the diagnosis of atypical COVID-19 presentations.

The evaluation of depression in multiple sclerosis using the newly proposed Multiple Sclerosis Depression Rating Scale.

Fatigue and depression are frequent symptoms in multiple sclerosis (MS). Both are overlapping and shadowing each other and may impair the quality of life. For detection of depression symptoms in MS, the Multiple Sclerosis Depression Rating Scale (MSDRS) has been proposed recently. Here, we compare the performance of MSDRS in MS patients with and without fatigue to that of established rating scales, i.e. Hospital Anxiety and Depression Scale and Beck Depression Inventory. Twenty-nine MS patients were screened for fatigue and depression symptoms. Patients with fatigue showed significantly higher depression scores compared to patients without fatigue, whereas the number of depressed patients did not differ between the two groups. MSDRS seems to have higher sensitivity to detect severe depression than established rating scales. However, one should keep in mind that such a finding might be due to an increase in false positive cases when using MSDRS. Implementing this scale in future studies might be of help to enhance the understanding of its potential utility.

Fatigue in multiple sclerosis: pathophysiology and emergent interventions.

Not available.

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) can relieve neuropathic pain when applied at high frequency (HF: 5-20 Hz) over the primary motor cortex (M1), contralateral to pain side. In most studies, rTMS is delivered over the hand motor hot spot (hMHS), whatever pain location. Navigation systems have been developed to guide rTMS targeting, but their value to improve rTMS efficacy remains to be demonstrated. OBJECTIVE: To compare the analgesic efficacy of HF-rTMS targeting the hMHS (non-navigated procedure) or the M1 representation of the pain region (navigated procedure). METHODS: The analgesic effect of a single session of 10 Hz-rTMS of M1 was assessed in 66 patients with neuropathic pain of various causes and locations, according to three conditions: sham or active non-navigated rTMS of the hMHS and active navigated rTMS of the pain region. RESULTS: Pain was relieved by both active rTMS conditions, and not by sham. Pain location influenced the results: upper or lower limb pain was significantly relieved, but not facial or hemibody pain. Pain relief lasted 1 week only after navigated rTMS, compared to sham. CONCLUSION: Navigation may improve HF-rTMS efficacy in patients with limb pain, whereas targeting remains to be optimized for more diffuse or facial pain. WHAT DOES THIS STUDY ADD?: To produce analgesic effects, HF-rTMS should be applied over the precentral cortex contralaterally to the painful side. Although the hMHS is the target normally chosen for stimulation, the optimal target has not been defined yet. Neuronavigational methods have been recently developed; they allow the integration of MRI data and are thought to improve rTMS efficacy.

[Transcranial direct current stimulation (tDCS) for depression: Results of nearly a decade of clinical research]. / La stimulation transcrânienne à courant continu (tDCS) dans la dépression : bilan de près d'une décennie de recherche clinique.

OBJECTIVE: Since 2006 transcranial direct current stimulation (tDCS) has been investigated in the treatment of depression. In this review, we discuss the implications and clinical perspectives that tDCS may have as a therapeutic tool in depression from the results reported in this domain. METHODS: A comprehensive literature review has found nearly thirty articles - all in English - on this topic, corresponding to clinical studies, placebo-controlled or not, case reports and reviews. RESULTS: Several meta-analyses showed that the antidepressant effects of active tDCS are significant against placebo, but variable, mainly due to the heterogeneity of the patients included in the studies, for example regarding the resistance to antidepressant treatment. CONCLUSIONS: Specific recommendations for the use of tDCS in treating depression may not yet be available, but some elements of good practice can be highlighted. Of particular note is that anodal tDCS of the left prefrontal cortex at 2mA for 20 minutes per day has a potential therapeutic value without risk of significant side effects: tDCS offers safe conditions for clinical use in the treatment of depression.

Somatosensory evoked potentials in the assessment of peripheral neuropathies: Commented results of a survey among French-speaking practitioners and recommendations for practice.

BACKGROUND: Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. STUDY AIM: To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. METHODS: A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. RESULTS: SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. CONCLUSIONS: Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. CLINICAL RELEVANCE: We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

Analysis of tremor in multiple sclerosis using Hilbert-Huang Transform.

Tremor is frequently described in patients with multiple sclerosis (MS) but remains poorly characterized using neurophysiological techniques. Accelerometric (ACC) and electromyographic (EMG) recordings were performed in 26 MS patients complaining of clumsiness, associated (n = 16) or not associated (n = 10) with visible tremor. Seventeen healthy subjects with physiological tremor (PT) and eight patients with essential tremor (ET) served as controls. Signals were analyzed using non-linear Empirical Mode Decomposition (EMD) and related Hilbert-Huang Transform (HHT), compared to the standard linear spectral analysis using Fast Fourier Transform (FFT). The presence of cerebellar signs and motor deficit was assessed on clinical examination. Using FFT, tremor was found in all patients with ET and 12% of subjects with PT, but in none of the MS patients, even in the presence of visible tremor. In contrast, EMD-HHT analysis of ACC-EMG coupling showed common frequency peaks characterizing tremor related to a central generator in 62.5% of MS patients with visible tremor, 40% of MS patients without visible tremor, 29% of subjects with PT, and all patients with ET. In EMD-HHT analysis, tremor characteristics were similar in subjects with PT and MS patients, regardless of the presence of a visible tremor, but these characteristics clearly differed in patients with ET. A visible tremor in MS patients was associated with more frequent cerebellar signs and less motor deficit at the upper limb. The low-frequency tremor observed in MS patients could therefore originate in lesions of the brainstem (midbrain) or cerebellothalamic circuits, or may correspond to an enhanced PT, partly favored by cerebellar dysfunction and being more visible during movement execution in the absence of concomitant motor deficit.

Distinction between essential and physiological tremor using Hilbert-Huang transform.

Neurophysiological investigation, based on accelerometric (ACC) and electromyographic (EMG) recordings, is an essential step in the diagnosis of tremor. Among various signal analysis methods, fast Fourier transform (FFT) is the most frequently used in this domain. However, FFT has several limitations: first, it assumes that tremor is a periodic and linear signal, which is not true; second, it cannot distinguish between different types of tremor, when their frequency overlap in similar range, such as essential tremor (ET) and physiological tremor (PT). Therefore, we decided to apply a non-linear method of signal analysis based on empirical mode decomposition (EMD) and Hilbert Huang transform (HHT), according to various procedures and compared to a more classical FFT approach. A first group of 8 healthy subjects with PT and a second group of 8 patients with ET were included in this study. At individual level, FFT was effective to highlight ET in the 8 patients, but PT in only 2 subjects. The EMD-HHT procedures performed better than FFT, revealing a common peak of PT in all subjects. Moreover, at group level, our EMD-HHT method allowed to clearly differentiate the two groups, especially by giving evidence for the existence of low frequency oscillations (around 4Hz) in subjects with PT. Although their physiological origin remains largely unknown, such slow oscillations seem to be of great importance to highlight PT and they have been much underestimated in the literature. Our original EMD-HHT approach is able to provide substantial improvement in the neurophysiological characterisation of the different types of tremor, especially for diagnostic application.

Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability.

BACKGROUND AND PURPOSE: High-dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry. METHODS: The functional cortical effects of high-dose steroids in 21 MS patients before and after 3 days of intravenous administration of methylprednisolone (1 g/day) for the treatment of MS relapse were studied. Investigations included various clinical scales [Kurtzke Functional System Scale (KFSS), Expanded Disability Status Scale and Fatigue Severity Scale, 10-m walk] and transcranial magnetic stimulation (TMS) tests of cortical excitability [resting motor threshold, recruitment curve of motor evoked potentials, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at various interstimuli intervals (ISIs), cortical silent period and interhemispheric inhibition]. RESULTS: Following steroid administration, clinical improvement was significant for the KFSS pyramidal (motor) and total scores, whilst TMS showed a reduction of SICI (mean and maximum values) and an increase of ICF at 10 ms ISI. CONCLUSIONS: Very rapid functional changes in the excitability of cortical circuits involved in motor control can be induced by steroids, before any process of remyelination or axonal regeneration has time to occur. The net effect of steroids on the balance between intracortical GABAergic inhibition and glutamatergic facilitation was in favour of weaker inhibition or stronger facilitation, which could lead to improving the motor performance in MS patients.

Definition of DLPFC and M1 according to anatomical landmarks for navigated brain stimulation: inter-rater reliability, accuracy, and influence of gender and age.

The optimization of the targeting of a defined cortical region is a challenge in the current practice of transcranial magnetic stimulation (TMS). The dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) are among the most usual TMS targets, particularly in its "therapeutic" application. This study describes a practical algorithm to determine the anatomical location of the DLPFC and M1 using a three-dimensional (3D) brain reconstruction provided by a TMS-dedicated navigation system from individual magnetic resonance imaging (MRI) data. The coordinates of the right and left DLPFC and M1 were determined in 50 normal brains (100 hemispheres) by five different investigators using a standardized procedure. Inter-rater reliability was good, with 95% limits of agreement ranging between 7 and 16 mm for the different coordinates. As expressed in the Talairach space and compared with anatomical or imaging data from the literature, the coordinates of the DLPFC defined by our algorithm corresponded to the junction between BA9 and BA46, while M1 coordinates corresponded to the posterior border of hand representation. Finally, we found an influence of gender and possibly of age on some coordinates on both rostrocaudal and dorsoventral axes. Our algorithm only requires a short training and can be used to provide a reliable targeting of DLPFC and M1 between various TMS investigators. This method, based on an image-guided navigation system using individual MRI data, should be helpful to a variety of TMS studies, especially to standardize the procedure of stimulation in multicenter "therapeutic" studies.

[Transcranial magnetic stimulation and motor cortex stimulation in neuropathic pain]. / Transkranielle Magnetstimulation und Motorkortexstimulation bei neuropathischen Schmerzen.

Non-invasive and invasive cortical stimulation allows the modulation of therapy-refractory neuropathic pain. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the contralateral motor cortex yields therapeutic effects at short-term and predicts the benefits of epidural motor cortex stimulation (MCS). The present article summarizes the findings on application, mechanisms and therapeutic effects of cortical stimulation in neuropathic pain.

Pain-related evoked potentials: a comparative study between electrical stimulation using a concentric planar electrode and laser stimulation using a CO2 laser.

OBJECTIVE: To compare the pain-related evoked potentials (PREPs) obtained by superficial electrical stimulation using a concentric planar electrode to those obtained by CO2 laser stimulation. METHODS: In 12 healthy subjects, PREPs, sympathetic skin reflexes (SSRs), motor reaction times (mRTs), and the conduction velocity (CV) of the recruited nerve fibres were assessed in response to electrical and laser stimulation. RESULTS: In response to superficial electrical stimulation, PREP latencies and mRTs were shorter, while PREP amplitude tended to be increased. By contrast, SSR amplitudes and latencies and estimated CVs of the stimulated nerve fibres did not differ between electrical and laser stimulation. Fifteen minutes after PREP recordings, the residual pain intensity and the degree of unpleasantness were higher for laser stimulation than for electrical stimulation. In addition, CO2 laser stimuli induced dyschromic spots on the skin. For these reasons, all subjects declared that they would prefer superficial electrical stimulation rather than CO2 laser stimulation if they had to perform PREPs again. CONCLUSIONS: The estimated CVs of the recruited nerve fibres and the localized pinprick sensation felt by the subjects suggest that small-diameter fibres in the A-delta range, conveying "first-pain" information, were stimulated in response to superficial electrical stimulation as for laser stimulation. Superficial electrical stimulation using a concentric planar electrode could be a valuable alternative to laser stimulation for assessing PREPs in the practice of clinical neurophysiology.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming.

BACKGROUND: 'Conventional' protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than 'conventional' protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of 'conventional' 10 Hz-rTMS. METHODS: In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10 Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. RESULTS: Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. CONCLUSIONS: The present results show that the analgesic effects of 'conventional' 10 Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

[French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. / Recommandations françaises sur l'utilisation de la stimulation magnétique transcrânienne répétitive (rTMS) : règles de sécurité et indications thérapeutiques.

During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.

Comparison of "standard" and "navigated" procedures of TMS coil positioning over motor, premotor and prefrontal targets in patients with chronic pain and depression.

Since about 15 years, transcranial magnetic stimulation (TMS) is used as a technique to investigate the function of specific cortical regions. Single pulse TMS studies have targeted the dorsolateral premotor cortex (dlPMC) to characterize premotor-motor interactions in movement disorders. Repetitive TMS (rTMS) trials have targeted the dorsolateral prefrontal cortex (dlPFC) to treat depression. In almost all previous studies, these targets have been defined according to a "standard" scalp distance to the site of stimulation evoking motor responses of maximal amplitude in the contralateral hand ("hand motor hotspot" corresponding to the primary motor cortex, M1). The "standard" procedure of coil positioning locates the dlPMC and dlPFC as 2-3 and 5cm, respectively, anterior to the "hand motor hotspot". The aim of our study was to compare the locations of M1, dlPMC and dlPFC targets provided by the "standard" procedure of coil positioning and those provided by using a neuronavigation system integrating individual brain magnetic resonance imaging (MRI). Twenty-two patients were enrolled, all being treated for depressive symptoms in the context of chronic pain syndrome. The centers of the dlPMC and dlPFC regions were accurately targeted by the "standard" procedure in 14 and eight patients (64 and 36% of the series), respectively. In the other patients, the "standard" procedure located the dlPMC target on the M1/dlPMC border and the dlPFC target on the dlPMC/dlPFC border. On average, the MRI-guided location of M1, dlPMC, and dlPFC was, respectively, 6.1mm posterior, 31.7mm anterior and 69.0mm anterior to the "hand motor hotspot". The "standard" procedure failed to accurately locate the dlPMC and dlPFC targets by about 1 and 2cm, respectively. A statistical analysis of the MRI coordinates (x, y, z) of the targets revealed that the M1 target was more posterior, the dlPMC target more superficial and the dlPFC target more anterior, lateral, and deeper, using neuronavigation compared to the "standard" procedure. This study confirms that the "standard" procedure of coil positioning is not accurate to target a desired cortical region. Target location can be improved by the use of a navigation system taking individual brain anatomy into account. The present results incline to be cautious on the pathophysiological interpretations of previous results reported in TMS studies based on "standard" targeting, e.g. regarding premotor-motor interactions. Similarly, the inaccuracy of the "standard" procedure of coil positioning could partly explain the between-study variability of the therapeutic effects produced by rTMS in patients with depression. Our results strongly support a more anterior and lateral placement of the TMS coil for dlPFC stimulation in the treatment of depression.

A reappraisal of the value of lateral spread response monitoring in the treatment of hemifacial spasm by microvascular decompression.

BACKGROUND: Lateral spread response (LSR) to the electrical stimulation of a facial nerve branch is a specific electrophysiological feature of primary hemifacial spasm (HFS). The curative treatment of HFS is based on surgical microvascular decompression (MVD). However, the outcome of this procedure is not always satisfactory. OBJECTIVE: To evaluate the correlation between intraoperative LSR changes and the short- and long-term postoperative clinical outcome following MVD. METHODS: Thirty-two consecutive patients with primary HFS treated by MVD performed with intraoperative LSR monitoring were retrospectively included. The patients were assessed for the presence of HFS and surgical complications at 1 day, 1 month and 6 months after surgery. The long-term clinical result was assessed between 1 and 10 years (mean 5.4 years) using a self-report questionnaire. RESULTS: Patients were divided into three groups based on intraoperative LSR changes: (1) in 15 patients, LSRs were present before incision and disappeared after MVD (47%); (2) in nine patients, LSRs were present before incision but persisted despite MVD (28%); (3) in eight patients, LSRs were absent before surgery and remained so after the procedure (25%). Intraoperative LSR abolition during the MVD procedure correlated with HFS relief in the long term (p<0.0001, Fisher exact test), but not on the first day after surgery (p = 0.3564). CONCLUSIONS: Monitoring MVD by recording LSRs intraoperatively could be of value not only to indicate the resolution of the vasculonervous conflict at the end of surgery, but also to predict a successful clinical outcome in the long term after the surgical intervention.