key: cord-1033360-oh4v3gtt
authors: Helbok, Raimund; Chou, Sherry Hsiang-Yi; Beghi, Ettore; Mainali, Shraddha; Frontera, Jennifer; Robertson, Courtney; Fink, Ericka; Schober, Michelle; Moro, Elena; McNett, Molly; Bassetti, Claudio L
title: NeuroCOVID: it's time to join forces globally
date: 2020-09-16
journal: Lancet Neurol
DOI: 10.1016/s1474-4422(20)30322-7
sha: 9609bc0d040a6aa692ad454281f0056d2680b50f
doc_id: 1033360
cord_uid: oh4v3gtt

nan

side. He was empirically treated with a course of 5 days intravenous high dose methylprednisolone, without any consistent effect. Because of the worsening of tremor in his right extremities, in a followup visit on June 29, biperiden was added at a dose of 2 mg daily, and increased to 4 mg daily after 1 week, which resulted in improvement of the tremor.

The mechanism that led to the presumed degeneration of nigro stria tal dopaminergic nerve terminals is unclear. Perhaps a susceptible genetic makeup made our patient vulner able to immunologically mediated mitochondrial injury and neuronal oxidative stress. Another hypothesis could be that the virus causes inflam mation via microglial activation, contributing to protein aggregation and neurodegenera tion. 3 However, the short time inter val between the acute infection and the parkinsonian symptoms makes this hypothesis unlikely. Other researchers have pro posed the socalled multiple hit hypothesis, by which the com bination of toxic stress and an inhibition of neuroprotective responses can lead to neuronal death. 4 Parkinson's disease is often preceded by anosmia, which is a common feature of SARSCoV2 infection. 5 Immune activation in the olfactory system might eventually lead to the misfolding of αsynuclein and the development of Parkinson's disease. 6 This mechanism is supported by postmortem studies, showing increased levels of TNF, 7 IL1, and IL6. 8 Moreover, patients with Parkinson's disease had an elevated CSF antibody response to seasonal coronaviruses, compared with age matched healthy controls. 9 In AshkenaziJewish people with Parkinson's disease, about a third are carriers of either a GBA or a LRRK2 mutation. 10 A genetic analysis for these mutations and 62 other muta tions associated with the disease was negative and our patient had no previous family history of Parkinson's disease. However, we cannot exclude an interaction between other, less frequent mutations and SARSCoV2. The temporal association between the episode of SARSCoV2 infection and parkinsonian symptoms, which appeared during the acute infection, is intriguing. Before his admission to the Department of Neurology, the patient had tested negative for SARSCoV2 on realtime RTPCR on two occasions; however, he was then found positive for antiSARSCoV2 IgG antibodies in serum, but negative for these anti bodies in CSF. Nonetheless, we cannot exclude the possibility that SARSCoV2 entered the CNS, particularly in view of the olfactory involvement and borderline pleocytosis.

We declare no competing interests. 

Since the recognition of the severe acute respiratory syndrome coron avirus 2 out break in December, 2019, there are now over 22·1 million COVID19 cases worldwide, with more than 780 220 deaths. Reports of neurologi cal manifestations associated with COVID19 range from mild (head ache, hyposmia, ageusia, myalgia, and fatigue or sleepiness) to severe (encepha lopathy, ischemic and haem or rhagic strokes, seizures, hypoxicischaemic brain injury, and GuillainBarré and other autoimmune syn dromes), 1-3 with prevalence rates rang ing from 6% to 84%. [1] [2] [3] The true prevalence, underlying mechanisms (infectious, autoimmune, secondary to systemic complications), and outcomes of COVID19 neurological mani festations remain a key knowledge gap. Many global initiatives have emerged to address these critical questions. 4 The rapid and parallel implementation of these initiatives in a pandemic has resulted in discrepant data ele ments and definitions of neurological symptoms and signs. Furthermore, fragmented scientific approaches and over lapping consortia, in which centres can contribute data to multiple registries, raise the possibility of double counting in future metaanalysis. All of these factors threaten the scientific rigour and yield of these combined global efforts. To address this issue, the European Academy of Neurology (EAN) and the Neurocritical Care Society (NCS)endorsed Global Consortium Studies of Neurological Dysfunction in www.thelancet.com/neurology Vol 19 October 2020 COVID19 (GCSNeuroCOVID) estab lished a formal collaboration, thus forming the largest global network to date. An important research priority is to develop consensus and harmonisa tion of data elements with uniform definitions, which was emphasised in a recent Editorial in The Lancet Neurology. 4 The design and principals of the GCSNeuroCOVID consortium studies were previously reported. 5 The GCS NeuroCOVID group, in close partnership with the Pediatrics Neurocritical Care Research Group, formed and rapidly developed a paediatrics arm of the consortium to investigate the effects of COVID19 in children and ado l es cents. Currently, the GCSNeuroCOVID consort ium includes 123 sites registered for adults and 96 sites registered for paediatrics across all continents (appendix).

In parallel, the EAN created a pro spec tive registry (The EAN Neuro COVID Registry Consortium [ENERGY]) to evaluate the prevalence of neuro logical manifestations in con firmed COVID19 cases and their outcomes at 6 months and 12 months. So far, over 254 sites have registered to ENERGY from 69 countries and three continents. This initiative was preceded by a survey of 2343 clinicians on neurological mani festa tions, com pleted on April 27, 2020, by the EAN core COVID19 task force. 1 Together, this new global collabora tive effort has extensive global outreach, with 473 sites representing all continents (appendix). In addition to global data elements and the harmonisation of definitions, this collaborative brings together comple mentary neurological expertise from acute resuscitation and critical care to outpatient clinic and rehabilitation settings, encompassing all ages of the population. This strong global collaborative infrastructure will serve as a crucial framework for current and future pandemics that threaten global neurological health. From April 6 to May 29, 2020, the Yale NeuroCOVID team reviewed 100 cases, unburdening the primary neurology consult service, identified trends in disease presentations and demographics, and provided diag nostic and treatment recommendations based on emerging scientific litera ture (appendix p 2). In reviewing our NeuroCOVID patients, it was striking to observe that 25 (25%) were Hispanic and 25 (25%) were Black, while Connecticut is demograph ically 17% Hispanic and 12% Black. 3 This disproportionate representation of nonwhite patients requiring NeuroCOVID consultation parallels racial and ethnic disparities in COVID19 disease presentations noted in the USA and Europe. 4 Hispanic NeuroCOVID patients were younger (median age 55 years, IQR 45-68) and had lower inhospital mortality (16%) compared with white or Black patients (median ages 72 years, IQR 64-81 and See Online for appendix

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS

Division of Neurology

The international EAN survey on neurological symptoms in patients with COVID19 infection

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

Neurologic features in severe SARSCoV2 infection

The Lancet. The neurological impact of COVID19

Global Consortium Study of neurological dysfunction in COVID19 (GCSNeuroCOVID): study design and rationale