Predicting neurological outcome after cardiac arrest by combining computational parameters extracted from standard and deviant responses from auditory evoked potentials.

Background: Despite multimodal assessment (clinical examination, biology, brain MRI, electroencephalography, somatosensory evoked potentials, mismatch negativity at auditory evoked potentials), coma prognostic evaluation remains challenging. Methods: We present here a method to predict the return to consciousness and good neurological outcome based on classification of auditory evoked potentials obtained during an oddball paradigm. Data from event-related potentials (ERPs) were recorded noninvasively using four surface electroencephalography (EEG) electrodes in a cohort of 29 post-cardiac arrest comatose patients (between day 3 and day 6 following admission). We extracted retrospectively several EEG features (standard deviation and similarity for standard auditory stimulations and number of extrema and oscillations for deviant auditory stimulations) from the time responses in a window of few hundreds of milliseconds. The responses to the standard and the deviant auditory stimulations were thus considered independently. By combining these features, based on machine learning, we built a two-dimensional map to evaluate possible group clustering. Results: Analysis in two-dimensions of the present data revealed two separated clusters of patients with good versus bad neurological outcome. When favoring the highest specificity of our mathematical algorithms (0.91), we found a sensitivity of 0.83 and an accuracy of 0.90, maintained when calculation was performed using data from only one central electrode. Using Gaussian, K-neighborhood and SVM classifiers, we could predict the neurological outcome of post-anoxic comatose patients, the validity of the method being tested by a cross-validation procedure. Moreover, the same results were obtained with one single electrode (Cz). Conclusion: statistics of standard and deviant responses considered separately provide complementary and confirmatory predictions of the outcome of anoxic comatose patients, better assessed when combining these features on a two-dimensional statistical map. The benefit of this method compared to classical EEG and ERP predictors should be tested in a large prospective cohort. If validated, this method could provide an alternative tool to intensivists, to better evaluate neurological outcome and improve patient management, without neurophysiologist assistance.

Somatic symptom disorder in patients with post-COVID-19 neurological symptoms: a preliminary report from the somatic study (Somatic Symptom Disorder Triggered by COVID-19).

OBJECTIVES: To assess the diagnosis of somatic symptom disorder (SSD) in patients with unexplained neurological symptoms occurring after SARS-CoV-2 infection, also referred to as long COVID. DESIGN: Single-centre observational study. PARTICIPANTS: Adult patients experiencing unexplained long-lasting neurological symptoms after mild COVID. Of the 58 consecutive patients referred in our centre, 50 were included. INTERVENTION: Patients were contacted for a standardised psychometric evaluation by phone, followed by a self-survey. MAIN OUTCOME: Positive diagnosis of SSD according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). RESULTS: Although the patients did not meet the DSM-5 criteria for a functional neurological symptom disorder specifically, SSD diagnosis based on DSM-5 criteria was positive in 32 (64%) patients. In the remaining 18 patients, SSD was considered possible given the high score on diagnostic scales. Physical examination were normal for all. Brain MRI showed unspecific minor white matter hyperintensities in 8/46 patients. Neuropsychological assessment showed exclusively mild impairment of attention in 14 out of 15 tested patients, in discrepancy with their major subjective complaint. Forty-five (90%) patients met criteria for Chronic Fatigue Syndrome. Seventeen (32%) patients were screened positive for mood-anxiety disorders, 19 (38%) had a history of prior SSD and 27 (54%) reported past trauma. Additional self-survey highlighted post-traumatic stress disorder in 12/43 (28%), high levels of alexithymia traits and perfectionism. Long-lasting symptoms had a major impact with a high rate of insomnia (29/43, 67%), psychiatric follow-up (28/50, 56%) and work or pay loss (25/50, 50%). CONCLUSION: A majority of patients with unexplained long-lasting neurological symptoms after mild COVID met diagnostic criteria for SSD and may require specific management. TRIAL REGISTRATION NUMBER: NCT04889313.

Contribution of intermittent photic stimulation to routine EEG.

OBJECTIVE: Intermittent photic stimulation (IPS) is an activation procedure performed during electroencephalography (EEG) to detect photosensitive patients. This procedure is recommended in routine EEGs but the benefit of IPS in the general population is not clearly ascertained. METHODS: We retrospectively analyzed 7683 EEGs of patients referred for a routine EEG to the Clinical Physiology Department of Lariboisière hospital, mainly from the emergency ward and the department of neurology, not specifically involved in epilepsy. All EEGs were performed with a standardized protocol. Photic driving response, photomyoclonic response and photoparoxysmal response (PPR) were specifically collected. A correlation analysis was performed between the response induced by IPS, demographical and clinical data, and current treatment or recreational drug use. RESULTS: Median age was 56.4 years (41.7-71.2); 3,042 (39.6%) of patients were female; 1,208 patients (15.7%) had a past medical history of epilepsy. Photic driving response occurred in 67 EEGs (0.9%), and PPR in 6 EEGs (0.1%), all with a known history of epilepsy. Thus 0.5% (6/1,208) of epilepsy patients had a PPR. Photomyoclonic responses were not observed. Juvenile myoclonic epilepsy was the only factor associated with the presence of PPR (RR=75.26 [11.82-479.21]). PPR was not associated with clinical symptoms or seizures. There was no correlation with the type of treatment or recreational drug use. CONCLUSIONS: Our results confirm that responses to IPS are rare in adult patients and especially PPR. Moreover, all patients with a PPR had a known previous history of epilepsy. These results question the benefit of IPS in adult patients with no history of epilepsy.

Clinical Outcome of Acute Ischemic Strokes in Patients with COVID-19.

INTRODUCTION: Acute ischemic stroke (AIS) and thrombotic events (TEs) were reported in patients with COVID-19. Clinical outcome of AIS in the course of COVID-19 remains unknown. We compared early clinical outcome and mortality of COVID-positive (+) patients admitted for AIS with COVID-negative (-) ones. We hypothesized that COVID+ patients would have poorer clinical outcomes and present a higher rate of TEs and mortality compared with COVID- ones. METHODS: In this multicentric observational retrospective study, we enrolled patients over 18 years old admitted for AIS in 3 stroke units of the Parisian region during lockdown from March 17, 2020, to May 2, 2020. COVID-19 status as well as demographic, clinical, biological, and imaging data was collected retrospectively from medical records. Poor outcome was defined as modified Rankin score (mRS) 3-6 (3-6) at discharge. We also compared TE frequency and mortality rate through a composite criterion in both groups. RESULTS: Two hundred and sixteen patients were enrolled; mean age was 68 years old, and 63% were male. Forty patients were CO-VID+ (18.5%) and 176 were COVID-. Obesity was statistically more frequent in the COVID+ group (36 vs. 13% p < 0.01). The percentage of patients with mRS (3-6) at discharge was higher in the COVID+ group compared with the COVID- group (60 vs. 41%, p = 0.034). The main predictor of presenting a mRS (3-6) at discharge was high NIHSS score at admission (OR, CI 95%: 1.325, 1.22-1.43). Mortality rate was higher in the COVID+ group (12 vs. 3.4%, p = 0.033) as well as TE frequency (15 vs. 2.8%, p < 0.01). CONCLUSION: In this study, patients with AIS infected by SARS-CoV-2 showed a poorer early outcome than COVID- ones. However, when compared to other factors, COVID-19 was not a significant predictor of poor outcome. Vascular morbidity and mortality rates were significantly higher in the COVID+ group compared with the COVID- group.

Neurologic manifestations associated with COVID-19: a multicentre registry.

OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Contribution of EEG in transient neurological deficits.

Identification of stroke mimics and 'chameleons' among transient neurological deficits (TND) is critical. Diagnostic workup consists of a brain imaging study, for a vascular disease or a brain tumour and EEG, for epileptiform discharges. The precise role of EEG in this diagnostic workup has, however, never been clearly delineated. However, this could be crucial in cases of atypical or incomplete presentation with consequences on disease management and treatment. We analysed the EEG patterns on 95 consecutive patients referred for an EEG within 7 days of a TND with diagnostic uncertainty. Patients were classified at the discharge or the 3-month follow-up visit as: 'ischemic origin', 'migraine aura', 'focal seizure', and 'other'. All patients had a brain imaging study. EEG characteristics were correlated to the TND symptoms, imaging study, and final diagnosis. Sixty four (67%) were of acute onset. Median symptom duration was 45 min. Thirty two % were 'ischemic', 14% 'migraine aura', 19% 'focal seizure', and 36% 'other' cause. EEGs were recorded with a median delay of 1.6 day after symptoms onset. Forty EEGs (42%) were abnormal. Focal slow waves were the most common finding (43%), also in the ischemic group (43%), whether patients had a typical presentation or not. Epileptiform discharges were found in three patients, one with focal seizure and two with migraine aura. Non-specific EEG focal slowing is commonly found in TND, and may last several days. We found no difference in EEG presentation between stroke mimics and stroke chameleons, and between other diagnoses.

Inhibitory rTMS applied on somatosensory cortex in Wilson's disease patients with hand dystonia.

Hand dystonia is a common complication of Wilson's disease (WD), responsible for handwriting difficulties and disability. Alteration of sensorimotor integration and overactivity of the somatosensory cortex have been demonstrated in dystonia. This study investigated the immediate after effect of an inhibitory repetitive transcranial magnetic stimulation (rTMS) applied over the somatosensory cortex on the writing function in WD patients with hand dystonia. We performed a pilot prospective randomized double-blind sham-controlled crossover rTMS study. A 20-min 1-Hz rTMS session, stereotaxically guided, was applied over the left somatosensory cortex in 13 WD patients with right dystonic writer's cramp. After 3 days, each patient was crossed-over to the alternative treatment. Patients were clinically evaluated before and immediately after each rTMS session with the Unified Wilson's Disease rating scale (UWDRS), the Writers' Cramp Rating Scale (WCRS), a specifically designed scale for handwriting difficulties in Wilson's disease patients (FAR, flow, accuracy, and rhythmicity evaluation), and a visual analog scale (VAS) for handwriting discomfort. No significant change in UWDRS, WCRS, VAS, or FAR scores was observed in patients treated with somatosensory inhibitory rTMS compared to the sham protocol. The FAR negatively correlated with UWDRS (r = -0.6; P = 0.02), but not with the WCRS score, disease duration, MRI diffusion lesions, or with atrophy scores. In our experimental conditions, a single inhibitory rTMS session applied over somatosensory cortex did not improve dystonic writer cramp in WD patients.

Contribution of TMS and rTMS in the Understanding of the Pathophysiology and in the Treatment of Dystonia.

Dystonias represent a heterogeneous group of movement disorders responsible for sustained muscle contraction, abnormal postures, and muscle twists. It can affect focal or segmental body parts or be generalized. Primary dystonia is the most common form of dystonia but it can also be secondary to metabolic or structural dysfunction, the consequence of a drug's side-effect or of genetic origin. The pathophysiology is still not elucidated. Based on lesion studies, dystonia has been regarded as a pure motor dysfunction of the basal ganglia loop. However, basal ganglia lesions do not consistently produce dystonia and lesions outside basal ganglia can lead to dystonia; mild sensory abnormalities have been reported in the dystonic limb and imaging studies have shown involvement of multiple other brain regions including the cerebellum and the cerebral motor, premotor and sensorimotor cortices. Transcranial magnetic stimulation (TMS) is a non-invasive technique of brain stimulation with a magnetic field applied over the cortex allowing investigation of cortical excitability. Hyperexcitability of contralateral motor cortex has been suggested to be the trigger of focal dystonia. High or low frequency repetitive TMS (rTMS) can induce excitatory or inhibitory lasting effects beyond the time of stimulation and protocols have been developed having either a positive or a negative effect on cortical excitability and associated with prevention of cell death, γ-aminobutyric acid (GABA) interneurons mediated inhibition and brain-derived neurotrophic factor modulation. rTMS studies as a therapeutic strategy of dystonia have been conducted to modulate the cerebral areas involved in the disease. Especially, when applied on the contralateral (pre)-motor cortex or supplementary motor area of brains of small cohorts of dystonic patients, rTMS has shown a beneficial transient clinical effect in association with restrained motor cortex excitability. TMS is currently a valuable tool to improve our understanding of the pathophysiology of dystonia but large controlled studies using sham stimulation are still necessary to delineate the place of rTMS in the therapeutic strategy of dystonia. In this review, we will focus successively on the use of TMS as a tool to better understand pathophysiology, and the use of rTMS as a therapeutic strategy.

Cerebral venous thrombosis in paroxysmal nocturnal hemoglobinuria: a series of 15 cases and review of the literature.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells characterized by hemolytic anemia, marrow failure, and a high incidence of life-threatening venous thrombosis. Cerebral venous system is the second most frequent location of thrombosis after hepatic veins. However, data about PNH-related cerebral venous thrombosis (CVT) are very scarce because of the rarity of both the disorders.We report a French study about PNH patients with CVT. Patients were recruited retrospectively, from the Société Française d'Hématologie (SFH) registry of 465 patients with PNH; the Lariboisière registry of 399 patients with CVT; and a direct contact with 26 French Hematology Units. We review cases reported since 1938 in the English and French language literature. We then compared patients of our series with cases from the literature, with non-PNH-related CVT cases from Lariboisière registry, and with PNH patients without CVT from SFH registry.Fifteen patients were included between 1990 and 2012. Most patients were women (12/15) and half of them presented associated hormonal venous thrombosis risk factors. Three patients had concomitant hepatic vein thrombosis. CVT was the first manifestation of PNH in 4 patients. No major difference in CVT characteristics was found compared with non-PNH-related CVT cases, except for a younger age at diagnosis in PNH patients (P < 0.001). All patients were treated with anticoagulation therapy. One death occurred in acute stage. All surviving patients were independent 1 year after. Median survival time was 9 years. Recurrent thrombosis rate was 50% at 6 years, occurring in patients that did not have bone marrow transplantation or eculizumab therapy. Cases of death were mainly related to hepatic vein thrombosis.Prognosis of CVT was good in our series. However, these patients have a poor long-term prognosis due to PNH disease by itself. PNH treatment should be proposed as soon as possible to avoid recurrent thrombosis. Besides, inaugural CVT events encourage investigating PNH in case of cytopenia, hemolysis, abdominal veins thrombosis, or aplastic anemia history associated with the neurological complication.

Early netrin-1 expression impairs central nervous system remyelination.

OBJECTIVE: Chronically demyelinated multiple sclerosis (MS) lesions are frequently characterized by scarce undifferentiated oligodendrocyte progenitor cells (OPCs), suggesting the exhaustion of a local OPC pool followed by failure of recruitment and differentiation. Stimulating prompt OPC recruitment following demyelination could improve myelin repair by providing sufficient numbers of remyelinating cells during the repair-permissive period. Understanding mechanisms that determine this process may have important therapeutic implications. We therefore investigated the role of the guidance molecule netrin-1 in OPC recruitment and central nervous system (CNS) remyelination. METHODS: Netrin-1 expression was analyzed immunohistochemically in different types of MS lesions and in the murine lysolecithin model of demyelination. The influence of netrin-1 on CNS remyelination was examined using gain and loss of function experiments. RESULTS: We show that in MS lesions, astrocytes upregulate netrin-1 expression early during demyelination and netrin-1 receptors are expressed by OPCs. In contrast, in the efficiently repairing lysolecithin model of demyelination (astrocyte-free), netrin-1 expression is absent during early phases and detected concomitant with completion of OPC recruitment. In vitro migration assays demonstrated that netrin-1 is a chemorepellent for migrating adult OPCs. In mouse lesions, antibody-mediated disruption of netrin-1 function at the peak phase of recruitment increased OPC numbers. Conversely, lentiviral-mediated induction of netrin-1 expression prior to OPC recruitment reduced the number of cells recruited and impaired remyelination. INTERPRETATION: Our findings support the conclusion that netrin-1 expression within demyelinating MS plaques blocks OPC recruitment, which with repeated demyelinating episodes contributes to permanent remyelination failure.

Portosystemic shunts: an underdiagnosed but treatable cause of neurological and psychiatric disorders.

Portosystemic shunts (PSS) remain an unrecognized cause of neurological or psychiatric disorders. Here we report 5 patients with neuropsychiatric presentations of PSS. Main presentations encompassed progressive Parkinsonism, organic psychosis, recurrent coma, recurrent delusion, cognitive decline and posterior cortical atrophy. None of our patients had a known history of liver disease and laboratory analyses of liver function were normal or only slightly perturbed. Only 16 similar cases of PSS revealed by neurological or psychiatric symptoms were found in the English literature. Clinical presentations were similar to our patients but asterixis, cerebellar symptoms and spastic paraparesis were noticed in some cases. EEG could be normal or could show non specific slow waves or even, rarely, triphasic slow waves. The most frequent and specific diagnostic features included hyperammonemia, abnormal brain magnetic resonance spectroscopy and visualization of the shunts by ultrasonography or abdominal imaging techniques. Therefore, in otherwise unexplained neuropsychiatric disturbances, ammonia should be routinely measured and, if elevated, a dedicated gastroenterologist or an expert radiologist should be consulted for potential PSS examination. Treatment of the shunts or of the hyperammonemia resulted in marked neurological or psychiatric improvement in all cases.