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.

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.

COVID-19 lockdown attack on headache emergency admissions: a multidisciplinary retrospective study.

BACKGROUND: During the first COVID-19 lockdown in Italy, it was observed a reduction in emergency department (ED) attendances due to non-SARS-COV-2-related acute/chronic conditions. OBJECTIVE: To analyze the impact of the COVID-19 lockdown on patients reporting headache as the principal presenting symptom on admission to the ED of the tertiary care University Hospital of Trieste over the relevant period. METHODS: We retrospectively evaluated the frequency, features, and management of ED attendances for headache during the COVID-19 lockdown from 8 March to 31 May 2020, comparing it with the pre-lockdown period (January-February 2020) and the first 5 months of 2019. RESULTS: A reduction in ED total attendances was observed in the first 5 months of 2020 compared to the same period in 2019 (21.574 and 30.364, respectively; - 29%), in particular with respect to headache-related attendances (174 and 339 respectively; - 49%). During the COVID-19 lockdown, it was recorded a minor reduction in the ED access rate of female patients (p = 0.03), while no significant variation was detected in repeaters' prevalence, diagnostic assessment, and acute treatment. The ratio of not otherwise specified, secondary, and primary headaches (48.4%, 30.6%, and 21.0% respectively) remained unchanged during the COVID-19 lockdown, in comparison to the control periods. CONCLUSION: The COVID-19 pandemic impacted the number of ED attendances for headache but not their management and setting. Despite a reduction of accesses for headache due to the pandemic emergency, the distribution of headache subtypes and the rate of repeaters did not change.

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.

Clinical neurophysiology and cerebrospinal liquor analysis to detect Guillain-Barré syndrome and polyneuritis cranialis in COVID-19 patients: A case series.

We report a case series of five patients affected by SARS-CoV-2 who developed neurological symptoms, mainly expressing as polyradiculoneuritis and cranial polyneuritis in the 2 months of COVID-19 pandemic in a city in the northeast of Italy. A diagnosis of Guillain-Barré syndrome was made on the basis of clinical presentation, cerebrospinal fluid analysis, and electroneurography. In four of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 g/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 compound muscle action potential (cMAP). Four patients presented a mild facial nerve involvement limited to the muscles of the lower face, with sparing of the forehead muscles associated to ageusia. In one patient, taste assessment showed right-sided ageusia of the tongue, ipsilateral to the mild facial palsy. In three patients we observed albuminocytological dissociation in the cerebrospinal fluid, and notably, we found an increase of inflammatory mediators such as the interleukin-8. Peripheral nervous system involvement after infection with COVID-19 is possible and may include several signs that may be successfully treated with immunoglobulin therapy.

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.

Smart technology for physical activity and health assessment during COVID-19 lockdown.

BACKGROUND: The worldwide lockdown in response to COVID-19 pandemics has often led to physical inactivity and social distancing. When combined, these factors may affect quality and life and increase the risk of different diseases. Therefore, assessment of physical activity levels should be encouraged to monitor and identify those at a higher risk of inactivity. Smart technology is a promising tool to assess physical activity and health and may be particularly useful during a period of general lockdown. METHODS: An online survey was developed and shared among the Italian general population to collect data about physical activity and daily routine changes between January 2020 and the lockdown period from March 23 to March 29. Participants were asked to provide data such as daily step count (Steps) or heart rate (HR) measured and collected by their smart technology devices. RESULTS: Four hundred participants were included in the final analysis. During the lockdown, the number of steps dropped from 8284±4390 to 3294±3994 steps (P<0.001), while mean peak HR decreased from 61.3±18.2% to 55.9±17.3% (P<0.001). CONCLUSIONS: These findings provide objective data about the effects of the COVID-19 lockdown on physical activity, thus encouraging the use of smart devices to monitor and promote healthy lifestyles while faced with a confinement condition.

Return to school in the COVID-19 era: considerations for temperature measurement.

COVID-19 pandemics required a reorganisation of social spaces to prevent the spread of the virus. Due to the common presence of fever in the symptomatic patients, temperature measurement is one of the most common screening protocols. Indeed, regulations in many countries require temperature measurements before entering shops, workplaces, and public buildings. Due to the necessity of providing rapid non-contact and non-invasive protocols to measure body temperature, infra-red thermometry is mostly used. Many countries are now facing the need to organise the return to school and universities in the COVID-19 era, which require solutions to prevent the risk of contagion between students and/or teachers and technical/administrative staff. This paper highlights and discusses some of the strengths and limitations of infra-red cameras, including the site of measurements and the influence of the environment, and recommends to be careful to consider such measurements as a single "safety rule" for a good return to normality.

Miller Fisher syndrome diagnosis and treatment in a patient with SARS-CoV-2.

This case report describes the clinical characteristics of a 50-year-old woman that developed SARS-CoV-2 pneumonia and was admitted at the COVID-19 dedicated unit where she developed neurological symptoms 10 days after admission. After neurological examination, including a panel of blood cerebrospinal fluid biomarkers, a diagnosis of Miller Fisher syndrome (MFS) was hypothesized and intravenous immunoglobulin therapy (IVIG) was initiated. Fourteen days after the start of IVIG treatment, the patient has been discharged at home with the resolution of respiratory symptoms and only minor hyporeflexia at the lower limbs, without any side effect.