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Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).
ABSTRACT
Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.
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Objective: Hypokinetic movement disorder and parkinsonian picture has been well described in literature following covid-19 but hyperkinetic MDS are very in global literatures. To investigate the epidemiology,clinical picture,the diagnostic and therapeutic challenges in patients hyperkinetic MDS in this context and to know the time schedule of the onset of the MDS with exploring the possible pathogenesis Background: Infections are up to 20% of movement disorders.The most frequent agents are beta-hemolytic streptococcus,and flavivirus causing Japanese encephalitisThe role of the viral stimulation of microglial activation in neuroinflammation has regained attention in the context of covid19 Methods: Patients of MDS attended the clinic from 31st march 2020 to March 2022,with recent onset of hyperkinetic movements were screened. Subjects had medical history either prior to the study or medical history reviewed by physicians suggestive of covid.PCR +VE or Presence of covid antibody in blood or csf in patients with recent onset hyperkinetic MDS within 6-12 weeks of onset of symptoms except.Ventilatory cases Other markers were used to rule out other viral infections causing MDS.MRI brain and EEG as a routine in all Immune markers in very selected cases in suspected immuomediated MDSThe attempted treatment were symptomatic and immunotherapy Results: In last 2 years 50 cases of new onset Hyperkinetic MDS are recorded, out of which only 9 cases were directly or indirectly linked to Covid,Nystagmus, orofacial dyskinesia and segmental or generalized myoclonus and ataxic gait associated delirium,tremors and ocular movement disorders along with epileptic seizures are also seen.Positive EEG findings are in the form of diffused bihemispheric slowing or periodic complexes with polyspikes at irregular interval and delta brush in few cases .MRI findings varied between non-specific changes to bitemporoparietal hyperintensities in flair and T2 both cortical and subcortical or bilateral basal ganglia. Treatment response in all the cases are statisfactory Conclusion(s): observational study revealed MDS in covid do happen Myoclonus is the most Frequent movement disorder associated with COVID-19 followed by dystonia and tremors .pathophysiology included neuro inflammation, autoimmune mechanisms and small vessels thrombosis hence not be co-incidental , response to steroid also s/o immune mediated.
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Background: There have been reports of demyelinating syndromes in association with COVID-19 and to a much lesser extent COVID 19 vaccines. The association between demyelination and vaccines, in general, remains controversial. We review a presentation of fulminant demyelination, and discuss antecedent COVID-19 vaccination, the formulation of a broader differential diagnosis and ultimately the pathologic diagnosis. Case presentation: An 80-year-old woman presented with seizure, encephalopathy, quadriparesis and ultimately expired. She received a SARS-CoV-2 vaccine one day prior. Imaging revealed contrast enhancing cerebral lesions, longitudinally extensive transverse myelitis. CSF was markedly inflammatory. Pathologic examination of the CNS lesions revealed demyelination and inflammation beyond white matter, not restricted to a perivenular distribution. Conclusion(s): This case depicts a seemingly fulminant course of a diffuse demyelinating syndrome characterized clinicopathologically as Marburg's variant of multiple sclerosis. There are several unique aspects of this case including the extremely rapid course, the unusual evolution of CSF abnormalities, with hypoglycorrhachia and markedly elevated protein. The proximity to vaccination is a pertinent association to document, though we cannot unequivocally prove causation.Copyright © 2022 The Authors
ABSTRACT
It has been proven that mRNA vaccines are highly effective against the COVID-19 outbreak, and low prevalence of side effects has been shown. However, there are still many gaps in our understanding of the biology and biosafety of nucleic acids as components of lipid nanoparticles (LNPs) most often used as a system for inctracellular delivery of mRNA-based vaccines. It is known that LNPs cause severe injection site inflammation, have broad biodistribution profiles, and are found in multiple tissues of the body, including the brain, after administration. The role of new medications with such pharmacokinetics in inflammation developing in inaccessible organs is poorly understood. The study was aimed to assess the effects of various doses of mRNA-LNP expressing the reporter protein (0, 5, 10, and 20 microg of mRNA encoding the firefly luciferase) on the expression of neuroinflammation markers (Tnfalpha, Il1beta, Gfap, Aif1) in the prefrontal cortex and hypothalamus of laboratory animals 4, 8, and 30 h after the intramuscular injection of LNP nanoemulsion. It was shown that mRNA-LNP vaccines in a dose of 10-20 microg of mRNA could enhance Aif1 expression in the hypothalamus 8 h after vaccination, however, no such differences were observed after 30 h. It was found that the Gfap, l11beta, Tnfalpha expression levels in the hypothalamus observed at different times in the experimental groups were different. According to the results, mRNA-LNPs administered by the parenteral route can stimulate temporary activation of microglia in certain time intervals in the dose-dependent and site specific manner.Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection has been associated with the development and persistence of various neurological symptoms in some patients. There have been few prior case reports of small fiber neuropathy (SFN) associated with this infection. However, literature is limited, and the etiology of these symptoms is unclear. Some reports suggested neuroinflammation. Objective(s): To present case series of 3 patients who developed small fiber neuropathy after SARS-COV2 infection. Method(s): We identified patients with SFN after SARSCOV2 infection from our neuromuscular database. We performed chart review and obtained clinical, demographic and, outcomes information of these patients. Result(s): The age of patients was 46, 56 and 71 years. Two female and one male. Time to neuropathy symptom evaluation in clinic from positive COVID19 test was 4 months, 6 months, and 10 months, respectively. None of the patients were hospitalized or given additional medications for COVID treatment. Patients 1& 3 had mild respiratory symptoms. Patient 2 had no symptoms, just a routine pre-op test was positive. All patients had numbness, tingling and painful paresthesias as the main symptoms. The second patient reported autonomic symptoms of heart racing and temperature dysregulation. Nerve conduction studies did not show large fiber peripheral neuropathy in any of the patients. Skin biopsy was performed at 7 months, 8 months and 13 months respectively post COVID infection and was positive in all 3 patients. There was no other etiology identified for the neuropathy Treatment included gabapentin for the first patient, the second patient received narcotic medication for a surgery and continued this for her neuropathic symptomsand the third patient is not on any medications for SFN. Conclusion(s): SFN can be associated with prior SARSCOV infection. There is need for further research to determine possible underlying neuropathological mechanisms and find effective treatments in COVID-related SFN.
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Aim/Introduction: Persisting cerebral symptoms such as fatigue and cognitive dysfunction after Sars-CoV-2 infection are typical for post COVID-19. Positron emission tomography (PET) can contribute to the understanding of post COVID-19 related brain disorders. The aim of this study was to investigate cerebral blood flow (CBF) and neuroinflammation with PET in post COVID-19 patients. Material(s) and Method(s): Data from eight healthy controls (HC) and four subjects with post COVID-19 symptoms were included. At the time of the PET investigation, three subjects had remaining post COVID-19 symptoms, of which one had severe headache. All subjects underwent a 6 min dynamic 15O-water PET scan to measure CBF and a 60 min dynamic 11CPK11195 PET scan to measure neuroinflammation. In addition, all subjects received a T1weighted MRI that was co-registered to the PET images. Parametric images, showing 15O-water CBF and 11CPK11195 binding potential (BPND) at the voxel level, were calculated. Mean total grey matter CBF and BPND values were calculated for all subjects. The co-registered MRI images were normalized to MNI standard space using statistical parametric mapping (SPM12) and the transformation matrices were applied to the respective parametric images. A voxel-wise z-test was performed in SPM12 to compare each 15Owater CBF and 11CPK11195 BPND image from the post COVID-19 patients to the HC CBF and BPND images, respectively. A statistical threshold of p<0.05 was applied. Result(s): Two of the subjects with remaining post COVID-19 symptoms demonstrated a significantly increased CBF in the whole brain compared to the HC. Total grey matter CBF values were 1.27 and 1.41 mL/cm3/min in these two subjects, compared to a mean +/- SD of 0.65 +/- 0.19 mL/cm3/min in the HC group. The subject with persisting headache also showed large clusters of significant increased 11C-PK11195 BPND in the meninges. Mean total grey matter 11CPK11195 BPND values in post COVID-19 subjects were within the range of values in the HC group. The other two subjects did not show increased CBF and no significant increase of 11C-PK11195 BPND. Conclusion(s): Neurological symptoms from post COVID-19 may be due to increased CBF and inflammation. However, further investigations are needed with larger study cohort to better understand the relation between post COVID-19 symptoms and neurological dysfunctions investigated with PET.
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In December of 2019, SARS-CoV-2 surfaced and the global COVID-19 pandemic began. The pandemic has had far-reaching effects, socially, economically, and especially for healthcare, presenting challenges to patients with neuroinflammatory disorders. Apart from the well-known respiratory, pulmonary, and cardiovascular symptoms that COVID-19 is responsible for, studies continue to show its role in generating neuroinflammation and the different neurological effects that can arise. This review summarizes the relationship between the COVID-19 pandemic and neuroinflammatory diseases, with an emphasis on the effects on patients with neuroinflammatory disorders. Copyright © 2022, Biolife s.a.s.. All rights reserved.
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In December of 2019, SARS-CoV-2 surfaced and the global COVID-19 pandemic began. The pandemic has had far-reaching effects, socially, economically, and especially for healthcare, presenting challenges to patients with neuroinflammatory disorders. Apart from the well-known respiratory, pulmonary, and cardiovascular symptoms that COVID-19 is responsible for, studies continue to show its role in generating neuroinflammation and the different neurological effects that can arise. This review summarizes the relationship between the COVID-19 pandemic and neuroinflammatory diseases, with an emphasis on the effects on patients with neuroinflammatory disorders. Copyright © 2022, Biolife s.a.s.. All rights reserved.
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Background: The main trigger for Parkinson's disease is a mutated version of a protein called alpha-synuclein.This protein accumulates in dopamine-producing neurons. COVID-19 can increase the risk of Parkinson's and other neurological diseases. Methods:This review study was conducted by the library method. Results: The results showed that the virus can cause neuroinflammation, which, as a predisposing event, predisposes the brain to overreaction to subsequent neurological events. This secondary neurological event can be anything from another viral infection to poisoning and even aging. A secondary neurological event triggers an abnormal brain response that leads to nerve degeneration and eventually Parkinson's disease. The results show that the SARS-CoV-2 virus as a neurotropic virus can enter brain tissue. Conclusion: Therefore, the virus certainly has the potential to act as a predisposing event in increasing the risk of Parkinson's disease.
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Background and aims: The COVID-19 pandemic has broadened the use of teleneurology, how this compares to face-to-face (F2F) clinics is unclear. This study compared virtual with F2F new neurological consultations. Methods: We retrospectively evaluated new outpatient consultations in neurology clinics in Aberdeen Royal Infirmary. We compared sociodemographic data, time to consultation, time to diagnosis, the need for reassessment and re-investigation between traditional F2F and virtual clinics using the web-based video platform (Near Me) or telephone into patients own homes (or chosen location) without a trained assistant. We calculated the relative risk of the need for reassessment and re-investigation over sixmonth periods by the suspected neurological diagnosis. Results: 73% of consultations were virtual (Near Me or telephone) between June and October 2020, this was almost non-existent (<0.1%) in June-October 2019. We analysed 352 F2F (June-July 2019) and 225 virtual consultations (June-July 2020). Compared to F2F clinics, virtual clinics had a longer time to diagnosis (p=0.019), were more likely to be re-assessed (RR: 2.2, 95% CI: 1.5-3.2;p<0.0001) and re-investigated (RR: 1.50, 95% CI: 0.88-2.54;p=0.133), this was likelier in those aged ≥60 years. Patients with headaches and suspected seizures were less likely to need reassessment or re-investigation following virtual clinics than multiple sclerosis & neuroinflammatory disorders, spinal cord disorders and functional neurological disorders. Conclusion: This study demonstrates that virtual clinics have higher rates of reassessment and re-investigation than F2F clinics. As virtual clinics become a potential consultation alternative, this study should instruct the selection of patients for either consultation type.
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Background and aims: COVID-19 infections are reported in numerous case-reports as a trigger for development of Parkinson's disease (PD). We report 4 patients with symptoms of PD developed or exagerated after SARSCoV2 infection. Methods: Patients were retrospectively recruited in an outpatient clinic of Department of Neurology, Faculty of Health Science, Medical University of Warsaw. Patients were independently assessed by 2 neurologists experienced in movement disorders. Results: We identified 4 patients with rapid onset of PD symptoms following COVID-19. All patients were female. Symptoms of COVID-19 included headache in 4/4 cases and anosmia in 3/4 cases. PCR test confirmed SARS-CoV2 infection in all cases. The age of onset was between 28 and 62 years old. The rest tremor was present in all patients, ridgidity in 3/4 patients. Non-motor symptoms included RBD in 2/4 patients. Two patients were treated with levodopa with good response. MRI findings were nonsignificant. The SPECT-DatScan was performed in one patient and was typical for parkinsonian disorders. The positive family history was present in two patients. Conclusion: We conclude that COVID-19 may trigger development of parkinsonian motor symptoms or exaggerate the slight disease progression. The cause is unknown. Involvement of olfactory bulb could trigger neuroinflammation in line with Braak's hypothesis. COVID-19 may also induce parkinsonism in patients with genetic predisposition.
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Since the description of the first clinical cases of the most common neurodegenerative diseases, numerous hypotheses have been proposed for their development. At the same time, the failure of therapeutic strategies in various directions of clinical research indicates the fallacy of most theories. In this regard, in recent years, various infectious agents are increasingly considered as a trigger of neuronal inflammation and a factor inducing the onset of the neurodegenerative process. Infectious agents differ in their mechanisms of invasion into the central nervous system and can even enter the brain perineurally. Reactivation of latent viral infection induces the production of viral proteins and the accumulation of abnormal proteins that are markers of Alzheimer's disease and Parkinson's disease. Both bacterial (chlamydia, causative agents of chronic periodontitis, E. coli) and viral (herpes viruses, noroviruses) infectious agents are considered. However, for the development of neurodegeneration, it is not enough just a simple invasion and reactivation of the infectious process: the genetic characteristics of the main histocompatibility complex also play a huge role. Currently, several studies have been initiated on the possible efficacy of antibacterial and antiviral drugs in Alzheimer's disease. Data obtained over the past year suggests that the brain may act as a target for SARS-CoV-2. Neurological manifestations of COVID-19 can occur as a result of both the direct cytopathic action of the pathogen and the activation of neuroinflammation, accompanied by a violation of the integrity of the blood-brain barrier. Further study of the molecular and cellular mechanisms of neuroinflammation and neurodegeneration in COVID-19 will form the basis for the development of treatments for neurological complications.
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Background: The neurobiology of depression can be heterogeneous with multiple hypotheses proposed, including serotonin and neuroinflammatory pathways, each falling short of explaining the complete picture. Several reports describe the increased frequency of depression in the community following the COVID-19 pandemic and reports about neuropsychiatric sequela of the virus are emerging and the possible role of neuroinflammation. We present a patient who developed severe depression with psychotic features subsequent to his COVID-19 infection and was treated successfully with ECT following several failed medication trials. Case: A 49-year-old male with a past medical history of type II diabetes, hyperlipidemia, hypertension, chronic kidney disease, and gastroesophageal reflux disease was diagnosed with COVID-19 in January 2021. Upon initial diagnosis, neither admission nor treatment with steroids was required. He presented to the emergency department four days later with sepsis, pneumonia, and AKI secondary to COVID-19 along with the new onset of suicidal ideations with plans to cut himself and significant psychomotor features despite no previous history of mental illness or treatment. His EEG showed diffuse slow waves, consistent with encephalopathy, but no delirium was noted. He exhibited irritability, anger, anhedonia, negativism, and isolated himself in his room. He demonstrated delusional fear about his apartment exploding due to electricity disconnected for not paying his bills. He misinterpreted the blood draws as someone suspecting he has HIV. Treatment started on the medical floor and he was later transferred to the psychiatric floor. Several psychotropic medications were tried separately including citalopram 20mg, escitalopram 20mg, and bupropion (titrated to 300mg) with the addition of aripiprazole 5 mg without improvement. ECT was considered and his depression and psychosis improved following 6 treatments of bilateral ECT. He was discharged following completion of 10 ECT treatments on 300 mg of bupropion daily and 5mg olanzapine at night. Discussion: Viral infections such as HIV, Hepatitis C, and Influenza are associated with neuropsychiatric sequelae, including depression. COVID-19 infection is occasionally associated with ‘cytokine storm’ which may exacerbate neuroinflammation via increases in cytokines and possible activation of mast cells and microglia.[1] The role of elevated pro-inflammatory cytokines and glucocorticoid receptor resistance is widely studied. Interleukin-6 and CRP are the most strongly linked to depression with a high correlation for anhedonia and psychomotor retardation, prominent features of depression in our case, hinting at a possible role of neuroinflammation. [2] Psychotic features and psychomotor retardation are predictors of ECT response which matched the response to ECT in this case. References: 1. Kempuraj, Duraisamy, et al. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation. The Neuroscientist 2020: 402-414. 2. Tiemeier, Henning, et al. Inflammatory proteins and depression in the elderly. Epidemiology 2003: 103-107.
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Despite the introduction of vaccines and drugs for SARS-CoV-2, the COVID-19 pandemic continues to spread throughout the world. In severe COVID-19 patients, elevated levels of proinflammatory cytokines have been detected in the blood, lung cells, and bronchoalveolar lavage, which is referred to as a cytokine storm, a consequence of overactivation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome and resultant excessive cytokine production. The hyperinflammatory response and cytokine storm cause multiorgan impairment including the central nervous system, in addition to a detriment to the respiratory system. Hyperactive NLRP3 inflammasome, due to dysregulated immune response, is the primary cause of COVID-19 severity. The severity could be enhanced due to viral evolution leading to the emergence of mutated variants of concern, such as delta and omicron. In this review, we elaborate on the inflammatory responses associated with the NLRP3 inflammasome activation in COVID-19 pathogenesis, the mechanisms for the NLRP3 inflammasome activation and pathway involved, cytokine storm, and neurological complications as long-term consequences of SARS-CoV-2 infection. Also discussed is the therapeutic potential of NLRP3 inflammasome inhibitors for the treatment of COVID-19.
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Objective: To evaluate clinical, laboratory, and epidemiological features of acute neuroinflammatory disorders (ANIDs) that followed the 2016 Zika epidemic in Colombia. Background: The outbreak of Zika virus infection in Colombia in 2015-2016, produced an increased incidence of Guillain-Barré Syndrome (GBS) and other ANID cases. The Neuroviruses Emerging in the Americas Study (NEAS) network was established in 2016 as a multicenter-based observatory of ANIDs to investigate the role of emerging pathogens in neuroinflammatory diseases. Design/Methods: NEAS serves as a multi-center study based on 13 hospitals in 7 cities in Colombia which study all newly diagnosed patients who fulfill established criteria for GBS, encephalitis, myelitis, meningoencephalitis, or cranial nerve disorders as part of an observational cohort. We analyzed the clinical and epidemiological features of all cases evaluated between January 2016 and September 2021. Results: An observational cohort of 825 patients with ANIDs were recruited during the study period. 58.8% of cases were male with a median age of 43 (IQR 25-58) years. The most frequent ANIDs were GBS (46.1%) and facial nerve palsy (28.7%). The diagnosis of encephalitis (9.5%), myelitis (6.5%), and optic neuritis (5.9%) were less frequent. Patients with GBS were predominantly male (70.6%) and had a median age of 49 (IQR 32-60) years. Interestingly, there was an increase incidence of GBS in 2019. Conclusions: The outbreak of Zika in Colombia produced a marked increase in the incidence of GBS in 2016. Although cases of GBS and other ANIDs continued to emerge after the incidence of Zika infection decreased in July 2016, the recent SARS-CoV-2 pandemic has not produced any significant increase in the incidence of GBS in Colombia.