Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment.

OBJECTIVE: Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single "paired-pulse" transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI). METHODS: We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex. RESULTS: MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients' performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001). CONCLUSIONS: Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found. SIGNIFICANCE: These findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with "brain fog".

Efficacy of intravenous immunoglobulin (IVIg) on COVID-19-related neurological disorders over the last 2 years: an up-to-date narrative review.

Introduction: Among the clinical manifestations of SARS-CoV-2 infection, neurological features have been commonly reported and the state-of-the-art technique suggests several mechanisms of action providing a pathophysiological rationale for central and peripheral neurological system involvement. However, during the 1st months of the pandemic, clinicians were challenged to find the best therapeutic options to treat COVID-19-related neurological conditions. Methods: We explored the indexed medical literature in order to answer the question of whether IVIg could be included as a valid weapon in the therapeutic arsenal against COVID-19-induced neurological disorders. Results: Virtually, all reviewed studies were in agreement of detecting an acceptable to great efficacy upon IVIg employment in neurological diseases, with no or mild adverse effects. In the first part of this narrative review, the interaction of SARS-CoV-2 with the nervous system has been discussed and the IVIg mechanisms of action were reviewed. In the second part, we collected scientific literature data over the last 2 years to discuss the use of IVIg therapy in different neuro-COVID conditions, thus providing a summary of the treatment strategies and key findings. Discussion: Intravenous immunoglobulin (IVIg) therapy is a versatile tool with multiple molecular targets and mechanisms of action that might respond to some of the suggested effects of infection through inflammatory and autoimmune responses. As such, IVIg therapy has been used in several COVID-19-related neurological diseases, including polyneuropathies, encephalitis, and status epilepticus, and results have often shown improvement of symptoms, thus suggesting IVIg treatment to be safe and effective.

Cerebral hypoperfusion in post-COVID-19 cognitively impaired subjects revealed by arterial spin labeling MRI.

Cognitive impairment is one of the most prevalent symptoms of post Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) state, which is known as Long COVID. Advanced neuroimaging techniques may contribute to a better understanding of the pathophysiological brain changes and the underlying mechanisms in post-COVID-19 subjects. We aimed at investigating regional cerebral perfusion alterations in post-COVID-19 subjects who reported a subjective cognitive impairment after a mild SARS-CoV-2 infection, using a non-invasive Arterial Spin Labeling (ASL) MRI technique and analysis. Using MRI-ASL image processing, we investigated the brain perfusion alterations in 24 patients (53.0 ± 14.5 years, 15F/9M) with persistent cognitive complaints in the post COVID-19 period. Voxelwise and region-of-interest analyses were performed to identify statistically significant differences in cerebral blood flow (CBF) maps between post-COVID-19 patients, and age and sex matched healthy controls (54.8 ± 9.1 years, 13F/9M). The results showed a significant hypoperfusion in a widespread cerebral network in the post-COVID-19 group, predominantly affecting the frontal cortex, as well as the parietal and temporal cortex, as identified by a non-parametric permutation testing (p < 0.05, FWE-corrected with TFCE). The hypoperfusion areas identified in the right hemisphere regions were more extensive. These findings support the hypothesis of a large network dysfunction in post-COVID subjects with cognitive complaints. The non-invasive nature of the ASL-MRI method may play an important role in the monitoring and prognosis of post-COVID-19 subjects.

Cognitive deficit in post-acute COVID-19: an opportunity for EEG evaluation?

BACKGROUND AND PURPOSE: Among the most common post-COVID symptoms, many patients experienced subjective cognitive deficit, commonly named "brain fog," that might be present also in those individuals without severe acute COVID-19 respiratory involvement. Some studies have investigated some of the mechanisms that might be associated with the brain fog with objective techniques including transcranial magnetic stimulation and neuroimaging. METHODS: The aim of this study was to investigate the presence of electroencephalographic (EEG) alterations in people with post-COVID self-reported cognitive deficit. RESULTS: Out of the 90 patients attending the post-COVID neurology ambulatory service, twenty patients presenting brain fog at least 4 weeks after acute non-severe COVID-19 infection, and without previous history of epilepsy, were investigated with 19-channel EEG, Montreal Cognitive Assessment (MoCA), and magnetic resonance imaging (MRI). EEG was found altered in 65% of the sample, among which 69% presented a slowing activity and 31% were characterized by epileptic discharges principally in the frontal areas. None of the patients showed DWI MRI lesions. CONCLUSIONS: These findings highlight the usefulness of EEG analysis to objectively describe possible neurophysiological abnormalities in post-COVID patients presenting subjective cognitive deficit.

Stuttering-Like Dysfluencies as a Consequence of Long COVID-19.

PURPOSE: We present two patients who developed neurogenic stuttering after long COVID-19 related to SARS-CoV-2 infection. METHODS AND RESULTS: Both patients experienced both physical (e.g., fatigue) and cognitive difficulties, which led to impaired function of attention, lexical retrieval, and memory consolidation. Both patients had new-onset stuttering-like speech dysfluencies: Blocks and repetitions were especially evident at the initial part of words and sentences, sometimes accompanied by effortful and associated movements (e.g., facial grimaces and oro-facial movements). Neuropsychological evaluations confirmed the presence of difficulties in cognitive tasks, while neurophysiological evaluations (i.e., electroencephalography) suggested the presence of "slowed" patterns of brain activity. Neurogenic stuttering and cognitive difficulties were evident for 4-5 months after negativization of SARS-CoV-2 nasopharyngeal swab, with gradual improvement and near-to-complete recovery. CONCLUSIONS: It is now evident that SARS-CoV-2 infection may significantly involve the central nervous system, also resulting in severe and long-term consequences, even if the precise mechanisms are still unknown. In the present report, long COVID-19 resulted in neurogenic stuttering, as the likely consequence of a "slowed" metabolism of (pre)frontal and sensorimotor brain regions (as suggested by the present and previous clinical evidence). As a consequence, the pathophysiological mechanisms related to the appearance of neurogenic stuttering have been hypothesized, which help to better understand the broader and possible neurological consequences of COVID-19.

Sex-dependent characteristics of Neuro-Long-COVID: Data from a dedicated neurology ambulatory service.

"Long-COVID" is a clinical entity that consists of persisting post-infectious symptoms that last for more than three months after the onset of the first acute COVID-19 symptoms. Among these, a cluster of neurological persisting symptoms defines Neuro-Long-COVID. While the debate about the pathogenesis of Long-COVID is still ongoing, sex differences have been individuated for both the acute and the chronic stage of the infection. We conducted a retrospective study describing sex differences in a large sample of patients with Neuro-Long-COVID. Demographic and clinical data were collected in a specifically designed Neuro-Long-Covid outpatient service. Our sample included 213 patients: 151 were females and 62 were males; the mean age was similar between females (53 y, standard deviation 14) and males (55 y, standard deviation 15); no significant differences was present between the demographic features across the two groups. Despite the prevalence of the specific chronic symptoms between male and females showed no significant differences, the total number of females accessing our service was higher than that of males, confirming the higher prevalence of Neuro-Long-COVID in female individuals. Conversely, a worse acute phase response in males rather than females was confirmed by a significant difference in the rates of acute respiratory symptoms (p = 0.008), dyspnea (p = 0.018), respiratory failure (p = 0.010) and the consequent need for ventilation (p = 0.015), together with other acute symptoms such as palpitations (p = 0.049), headache (p = 0.001) and joint pain (p = 0.049). Taken together, these findings offer a subgroup analysis based on sex-dependent characteristics, which can support a tailored-medicine approach.

Rapidly evolving Creutzfeldt-Jakob disease in COVID-19: from early status epilepticus to fatal outcome.

We report the case of a 70-year-old man coming to our attention for new onset refractory status epilepticus (NORSE) in a rapidly evolving CJD during SARS-CoV-2 co-infection. Our case report describes a fulminant CJD evolution associated with SARS-CoV-2 infection, which led to patient death after 15 days from admission. First EEG presented continuous diffuse spikes, sharp waves and sharp-and-slow wave complexes, pattern consistent with a non-convulsive status epilepticus (NORSE). Our case supports how CJD with SARS-CoV-2 co-infection could be characterized by an accelerated evolution, as already hypothesize for others microorganism infections, and how the diagnosis might be more challenging due to its uncommon presentations, such as NORSE.

A Novel Non-Invasive Thermometer for Continuous Core Body Temperature: Comparison with Tympanic Temperature in an Acute Stroke Clinical Setting.

There is a growing research interest in wireless non-invasive solutions for core temperature estimation and their application in clinical settings. This study aimed to investigate the use of a novel wireless non-invasive heat flux-based thermometer in acute stroke patients admitted to a stroke unit and compare the measurements with the currently used infrared (IR) tympanic temperature readings. The study encompassed 30 acute ischemic stroke patients who underwent continuous measurement (Tcore) with the novel wearable non-invasive CORE device. Paired measurements of Tcore and tympanic temperature (Ttym) by using a standard IR-device were performed 3-5 times/day, yielding a total of 305 measurements. The predicted core temperatures (Tcore) were significantly correlated with Ttym (r = 0.89, p < 0.001). The comparison of the Tcore and Ttym measurements by Bland-Altman analysis showed a good agreement between them, with a low mean difference of 0.11 ± 0.34 °C, and no proportional bias was observed (B = -0.003, p = 0.923). The Tcore measurements correctly predicted the presence or absence of Ttym hyperthermia or fever in 94.1% and 97.4% of cases, respectively. Temperature monitoring with a novel wireless non-invasive heat flux-based thermometer could be a reliable alternative to the Ttym method for assessing core temperature in acute ischemic stroke patients.

Comprehensive telemedicine solution for remote monitoring of Parkinson's disease patients with orthostatic hypotension during COVID-19 pandemic.

OBJECTIVE: Orthostatic hypotension (OH) represents a frequent but under-recognized phenomenon in Parkinson's disease (PD). During COVID-19 pandemic, Information and Communication Technologies (ICT) have become pivotal in the management of chronic diseases like PD, not only to assess motor impairment, but also for vital signs monitoring. This pilot study aimed to propose a real-time remote home-monitoring system and protocol for PD patients with OH. METHODS: Vital parameters were acquired by wireless devices and transmitted to an ICT platform, providing data and smart notifications to the healthcare provider through an interactive web portal. Eight patients with idiopathic PD and OH underwent 5-day monitoring. Data about OH episodes, therapeutic interventions, impact on daily activities, and patient satisfaction were collected and analyzed. RESULTS: The proposed solution allowed the identification of 65 OH episodes and subsequent medical interventions. Thirty-five episodes were asymptomatic, especially in the postprandial and in the afternoon recordings. Systolic-blood-pressure (SBP) and diastolic-blood-pressure (DBP) were significantly lower in symptomatic episodes, while the pressure drops resulted significantly higher in presence of symptoms. High usability and patient satisfaction scores were observed. CONCLUSION: The proposed home-monitoring system and protocol have proved to provide useful information and to allow prompt interventions in the management of PD patients with OH during COVID-19 pandemic.

Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID-19 neuropathy patients.

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.

Autonomic dysfunction in post-COVID patients with and witfhout neurological symptoms: a prospective multidomain observational study.

The autonomic nervous system (ANS) can be affected by COVID-19, and dysautonomia may be a possible complication in post-COVID individuals. Orthostatic hypotension (OH) and postural tachycardia syndrome (POTS) have been suggested to be common after SARS-CoV-2 infection, but other components of ANS function may be also impaired. The Composite Autonomic Symptom Scale 31 (COMPASS-31) questionnaire is a simple and validated tool to assess dysautonomic symptoms. The aim of the present study was to administer the COMPASS-31 questionnaire to a sample of post-COVID patients with and without neurological complaints. Participants were recruited among the post-COVID ambulatory services for follow-up evaluation between 4 weeks and 9 months from COVID-19 symptoms onset. Participants were asked to complete the COMPASS-31 questionnaire referring to the period after COVID-19 disease. Heart rate and blood pressure were manually taken during an active stand test for OH and POTS diagnosis. One-hundred and eighty participants were included in the analysis (70.6% females, 51 ± 13 years), and OH was found in 13.8% of the subjects. Median COMPASS-31 score was 17.6 (6.9-31.4), with the most affected domains being orthostatic intolerance, sudomotor, gastrointestinal and pupillomotor dysfunction. A higher COMPASS-31 score was found in those with neurological symptoms (p < 0.01), due to more severe orthostatic intolerance symptoms (p < 0.01), although gastrointestinal (p < 0.01), urinary (p < 0.01), and pupillomotor (p < 0.01) domains were more represented in the non-neurological symptoms group. This study confirms the importance of monitoring ANS symptoms as a possible complication of COVID-19 disease that may persist in the post-acute period.

e-Health solution for home patient telemonitoring in early post-acute TIA/Minor stroke during COVID-19 pandemic.

BACKGROUND: When it comes to critical early post-acute TIA/stroke phase, there is a lack of a comprehensive multi-parametric telemonitoring system. The COVID-19 emergency, its related global mobility restrictions and fear of hospitalization further highlighted the need of a comprehensive solution. OBJECTIVE: We aimed to design and test a pragmatic e-Health system based on multiparametric telemonitoring to support of TIA/stroke patients in sub-acute phase during the COVID-19 pandemic. METHODS: We proposed a telemonitoring system and protocol for TIA/minor stroke patients during COVID-19 pandemic for patients at risk of stroke recurrence. This system involves the use of portable devices for BP/HR/SpO2/temperature sensing, panic-button, gateway, and a dedicated ICT platform. The protocol is a 14-day multiparametric telemonitoring, therapy, and emergency intervention based on vital sign alteration notifications. We conducted a proof-of-concept validation test on 8 TIA/minor stroke patients in the early post-acute phase (< 14 days from ischemic event). RESULTS: The proposed solution allowed to promptly and remotely identify vital sign alterations at home during the early post-acute phase, allowing therapy and behavioral intervention adjustments. Also, we observed a significant improvement of quality of life, as well as a significant reduction of anxiety and depression status. TUQ showed ease of use, good interface quality and high user satisfaction of the proposed solution. The 3-month follow-up showed total adherence of prescribed therapy and no stroke/TIA recurrence or other emergency department admissions. CONCLUSION: The proposed e-Health solution and telemonitoring protocol may be highly useful for early post-acute remote patient management, thus supporting constant monitoring and patient adherence to the treatment pathway, especially during the COVID-19 emergency.

Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.

Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.

CT perfusion in hyper-acute ischemic stroke: the acid test for COVID-19 fear.

PURPOSE: The fear of COVID-19 infection may discourage patients from going to the hospital even in case of sudden onset of disabling symptoms. There is growing evidence of the reduction of stroke admissions and higher prevalence of severe clinical presentation. Yet, no studies have investigated the perfusion pattern of acute strokes admitted during the lockdown. We aimed to evaluate the effects of the COVID-19 pandemic on hyper-acute stroke CT perfusion (CTP) pattern during the first months of the pandemic in Italy. METHODS: In this retrospective observational study, we analyzed CTP images and clinical data of ischemic stroke patients admitted between 9 March and 2 June 2020 that underwent CTP (n = 30), to compare ischemic volumes and clinical features with stroke patients admitted during the same period in 2019 (n = 51). In particular, CTP images were processed to calculate total hypoperfused volumes, core volumes, and mismatch. The final infarct volumes were calculated on follow-up CT. RESULTS: Significantly higher total CTP hypoperfused volume (83.3 vs 18.5 ml, p = 0.003), core volume (27.8 vs 1.0 ml, p < 0.001), and unfavorable mismatch (0.51 vs 0.91, p < 0.001) were found during the COVID-19 period compared to no-COVID-19 one. The more unfavorable perfusion pattern at admission resulted in higher infarct volume on follow-up CT during COVID-19 (35.5 vs 3.0 ml, p < 0.001). During lockdown, a reduction of stroke admissions (- 37%) and a higher prevalence of severe clinical presentation (NIHSS ≥ 10; 53% vs 36%, p = 0.029) were observed. CONCLUSION: The results of CTP analysis provided a better insight in the higher prevalence of major severity stroke patients during the COVID-19 period.

Heat risk exacerbation potential for neurology patients during the COVID-19 pandemic and related isolation.

COVID-19 may increase the risk of heat-related symptoms during hot weather since vulnerable populations, including the elderly and those with neurological disabilities, must continue to self-isolate, often indoors. Within the chronic neurological patient population, indoor conditions in summer months present a hazard because of impaired and/or altered thermoregulation, including poor hydration status due to both autonomic and behavioral dysfunction(s). To address this increased risk, telemedicine protocols should include an assessment of the patient's environmental parameters, and when combined with physiological data from wearable devices, identify those with neurological diseases who are at higher risk of heat illness. Personalized medicine during times of self-isolation must be encouraged, and using smart technology in ambient assisted living solutions, including e-health to monitor physiological parameters are highly recommended, not only during extreme weather conditions but also during times of increased isolation and vulnerability.