Covid-19 and encephalitis research papers during 2021

Neuropathophysiology of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Pilotto et al. (2021) investigated the cerebrospinal fluid (CSF) abnormalities in SARS-CoV-2-related encephalitis to answer the question whether SARS‐CoV‐2 may cause neurological manifestations through a direct neuropathic effect or by promoting a hyperinflammatory reaction in the host’s immune system in the form of cytokine release syndrome. Overall, the study included 13 patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), 21 patients with encephalitis only (ENC), and 18 healthy controls. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM2, YKL-40) levels like ENC but normal CXCL13 levels. Neuronal markers NfL and T-tau were abnormal only in severe cases. The authors concluded that their study proved that SARS-CoV-2 encephalitis are associated with early IL-8 increases and glial alterations, whereas neuronal damage markers were elevated in severe cases. Moreover, the pattern of neuroinflammatory markers assessed is highly suggestive for a cytokine-release syndrome as driver of SARS-CoV-2-related encephalitis.

Thakur et al. (2021) presented the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2
infections who died and underwent autopsy. Neuropathological examination revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem; sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. The PCR analysis of multiple fresh frozen and fixed tissues from 28 brains revealed low to very low, but detectable, viral RNA levels in most brains, although they were far lower than those in the nasal epithelia. As their study only detected very low levels of virus in the brains, the authors suggested that microglial activation, microglial nodules and neuronophagia, observed in most brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ ischaemia.

Pilotto A., Masciocchi S., Volonghi I., et al. (2021) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encephalitis is
a cytokine release syndrome: evidences from cerebrospinal fluid analyses. Clin Infect Dis; 73(9): e3019-e3026.

Thakur K.T., Miller E.H., Glendinning M.D., et al. (2021) COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain; 144(9):2696-2708.

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related encephalitis

Pilotto et al. (2021) reported clinical presentations, clinical course, response to treatment, and outcomes of 25 patients with encephalitis positive for SARS-CoV-2 infection included in the SARS-CoV-2 related encephalopaties (ENCOVID) multicentre
study. The incidence of encephalitis in this study was 50/100,000 patients with Covid-19. In 11 patients, neurological symptoms were concomitant with COVID-19 symptomatology; in 12 cases neurological onset followed COVID-19 symptoms with a median
of eight days and, in two cases, neurological symptoms preceded the onset of COVID-19 symptoms after three and five days.
Neurological manifestations included headache, delirum/altered mental status, aphasia/dysarthria, seizures, status epilepticus, focal
motor deficits. One patient developed a parkinsonian syndrome. Electroencephalography was abnormal in all patients. The
cerebrospinal fluid findings included pleocytosis in 68% of cases; however, SARS-CoV-2 RNA by reverse-transcription polymerase
chain reaction was negative. Based on magnetic resonance imaging (MRI) findings, cases were classified as acute demyelinating encephalomyelitis (ADEM) in three patients, limbic encephalitis (LE) in two patients, encephalitis with normal imaging in 13 patients and encephalitis with MRI alterations in seven patients. Patients with ADEM and LE had a delayed onset compared with the other patients with encephalitis,and were associated with more severe COVID-19 respiratory involvement. Six patients experienced a spontaneous recovery, five patients improved with immunotherapy and four patients died. Worse outcomes were observed in patients with encephalitis with MRI alterations.

Vasilevska et al. (2021) identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis in a systematic review study. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status,
or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimise neurological impairments.

Valencia Sanchez et al. (2021) aimed to determine the frequency and diagnostic features of coronavirus disease 2019 (COVID-19)-related autoimmune encephalitis (AE) in a cohort study of 556 consecutive Mayo Clinic Rochester patients who underwent
autoimmune encephalopathy neural immunoglobulin G (IgG) evaluation. Five patients met diagnostic criteria for AE, representing
0.05% of all patients with COVID-19 illnesses at their institution.  Neural IgG testing was negative in all patients. Three patients had
a “possible” AE diagnosis only and had spontaneous resolution of symptoms. One patient with definite limbic encephalitis responded
to immunotherapy but had residual mood and memory difficulties. One patient with probable autoimmune rhombencephalitis died
despite immune therapy. The authors emphasised that application of diagnostic criteria assists in differentiation of AE from toxicmetabolic causes arising in the setting of systemic infection.

Ray et al. (2021) investigated the spectrum of neurological and psychiatric complications associated with paediatric SARS CoV-
2 infection in hospitalised children and adolescents. For ten months, 52/1334 children and adolescents with Covid-19 were
identified, of which 27 were included in a Covid-19 neurology group and 25 in a paediatric inflammatory multisystem syndrome
temporally associated with SARS-CoV-2. In the neurology group, seven patients had status epilepticus, five patients had
encephalitis, five had Guillain-Barré syndrome, three had acute demyelinating syndromes, two chorea, two psychosis, two isolated
encephalopathy and one had transient ischaemic attack. At discharge, 37% of patients from neurology group had a disability.
The authors conclude that although COVID-19 requiring hospital treatment is very rare in children and young people overall, among
hospitalised children and adolescents, neurological or psychiatric manifestations are common (3·8 cases per 100 hospitalised patients). The authors also noted that these neurological or psychiatric manifestations disproportionately affected children from minority ethnic groups.

Fragiel et al. (2021) investigated the incidence, clinical characteristics, risk factors and outcome of meningoencephalitis (ME) in patients with COVID-19 attending 61 Spanish emergency departments (ED) during the Covid-pandemic. They identified 29 patients with ME in 71,904 patients with COVID-19 attending Eds, making an incidence of 0.40‰, which was higher than in non- Covid patients (150/1,358,134; 0.11‰). Characteristic for patients with Covid-ME were dyspnea and chest X-ray abnormalities. Neck stiffness was more frequent in patients with non-Covid ME. Risk factors for developing ME in Covid-19 patients included vomiting, headache and altered mental status. Patients with COVID-ME had a higher in-hospital mortality than non-COVID-ME patients and a higher need for hospitalisation and intensive care admission. The authors concluded that, although ME is an unusual form of COVID presentation, it is more than 4-fold more frequent than in non-COVID patients attending the ED.

Cleret de Langavant et al. (2021) reviewed the records of patients presented with neurological disorders associated with SARSCoV- 2 infection in a single centre. Their study included 26 patients diagnosed with SARS-CoV-2 infection. Neurological manifestations included encephalitis in eight patients, encephalopathy in six, cerebrovascular events in six, other central nervous system (CNS) disorders in four and Guillain-Barré syndrome in two. Remarkably the diagnosis of SARS-CoV-2 was delayed on average 1.6 days after the onset of neurological disorder, especially in case of encephalitis 3.9 days, encephalopathy 1.0 day, and cerebrovascular event 2.7 days. The authors noted that anti-SARS-CoV2 antibody detection in RT-PCR SARS CoV-2 negative suspected cases is useful to confirm a
posteriori the diagnosis of atypical COVID-19 presentations.

Guilmot et al. (2021) reported 15 patients (4.3%) with neurological manifestation out of 349 patients with Covid-19. CSF PCR for SARSCoV-2 was negative in all patients. Two patients presented CSF pleocytosis: one patient with anti-contactin-associated protein 2
(anti-Caspr2) antibody encephalitis and one patient with parainfectious polyradiculitis. In a study in Egypt of neurological complications of Covid-19, from 439 patients confirmed/probable COVID-19, neurological manifestations occurred in 222. The central nervous system was affected in 75 patients, encephalitis reported in six patients and meningoencephalitis in one patient (Khedr et al., 2021).

Cleret de Langavant L., Petit A., et al. (2021) Clinical description of the broad range of neurological presentations of COVID-19: A retrospective case series. Rev Neurol (Paris); 177(3): 275-282.

Fragiel M., Miró Ò., Llorens P., et al. (2021) Incidence, clinical characteristics, risk factors and outcomes of meningoencephalitis in patients with COVID-19. Eur J Clin Microbiol Infect Dis; 40(8):1645-1656.

Guilmot A. Maldonado Slootjes S., Sellimi A. et al. (2021) Immunemediated neurological syndromes in SARS-CoV-2-infected patients.
J Neurol; 268(3): 751-757.

Khedr E.M., Abo-Elfetoh N., Deaf E., et al. (2021) Surveillance study of acute neurological manifestations among 439 Egyptian
patients with COVID-19 in Assiut and Aswan University Hospitals. Neuroepidemiology; 55(2): 109-118.

Pilotto A., Masciocchi S., Volonghi I., et al. (2021) Clinical presentation and outcomes of severe acute respiratory syndrome
coronavirus 2-related encephalitis: The ENCOVID Multicenter Study. J Infect Dis; 223(1): 28-37.

Ray S.T.J., Mannan O., Sa M., et al. (2021) Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study. Lancet Child Adolesc Health; 5(9): 631-641.

Valencia Sanchez C., Theel E., Binnicker M., et al. (2021) Autoimmune Encephalitis After SARS-CoV-2 Infection: Case
Frequency, Findings, and Outcomes. Neurology; 97(23): e2262-e2268.

Vasilevska V., Guest P.C., Bernstein H.G. et al. (2021) Molecular mimicry of NMDA receptors may contribute to neuropsychiatric
symptoms in severe COVID-19 cases. J Neuroinflammation; 18(1): 245.

Covid-19 and encephalitis research papers during 2020

Coronavirus, or COVID-19, has dominated world news since first reports of the respiratory disease in late 2019 and the World Health Organization, as of writing (June 2021), currently reports there has been over 164 million confirmed COVID-19 cases worldwide. Besides the respiratory-related afflictions caused by COVID-19, there have been several case studies that report encephalitis, alongside other neurological disorders, to also be associated with COVID-19.

Pilotto et al. (2020) completed a multicentre study of encephalitis cases within healthcare centres of northern Italy between February and May of 2020. In total, 25 encephalitis cases (15 males and 10 females; mean age 65.9 ± 9.6 years, range 50-84) positive for COVID-19 infection via reverse transcription-polymerase chain reaction analysis were analysed. Magnetic resonance imaging (MRI) results classified the encephalitis cases as acute disseminated encephalomyelitis (ADEM) (n = 1), acute necrotizing encephalitis (ANE) (n = 2), limbic encephalitis (LE) (n = 2), encephalitis with normal imaging (n = 13) and encephalitis with MRI alterations (n = 7). Electroencephalography (EEG) was abnormal in all cases with most cases showing a generalised slowing deriving from the frontal lobe (64%), while focal epileptic alteration was observed in 24% of cases. Cerebrospinal fluid (CSF) analysis was abnormal in 68% of patients. Cases of ADEM and LE showed significantly delayed onset compared to other forms of encephalitis but were associated, alongside ANE, with greater severity of COVID-19 respiratory effects. Blood and CSF analyses also showed higher LDH levels within these subtypes of encephalitis. Common symptoms at the onset of encephalitis were delirium (64%), aphasia/dysarthria (24%) and seizures (24%). Headaches were reported at onset by 24% of patients, which increased to 40% of patients following disease progression. Spontaneous recovery was observed in 24% of patients. A positive response to methylprednisolone, was observed in one case of ADEM, one case of LE and three cases of encephalitis featuring MRI alterations. Four encephalitis cases resulted in death, three featuring MRI alterations and one featuring typical MRI. The authors proposed that, considering the 43,139 COVID-19 cases reported within the same period in this geographic region, the incidence of encephalitis following COVID-19 is 58 per 100,000 cases.

Varatharaj et al. (2020) investigated neurological and neuropsychiatric complications from COVID-19 via a multicentre analysis of the UK COVID-19 cases in April 2020. Case report platforms provided 153 (median age 71 years, range 23-94) unique cases of neurological impairments associated with COVID-19, of which 125 complete clinical datasets were available for analysis. Of the 125 cases, 31% presented with altered mental status, with 18% of these cases resulting in encephalitis diagnoses and 23% resulting in diagnoses of unspecified encephalopathy. Within the cases of altered mental status, 49% were younger than 60 years. All encephalitis cases were confirmed to have evidence of CNS inflammation that adequately met clinical definitions of encephalitis and confirmed to be positive for COVID-19 infection. Efficacy of treatment or clinical outcomes were not reported by the authors.

Koh et al. (2020) studied all confirmed cases of COVID-19 in Singapore that had been referred with a neurological complaint within three months of COVID-19 onset. Of 47,572 confirmed cases between March and July 2020, 90 cases (98.9% male, median age 38, range 22-75) were identified as featuring neurological disorders. Within these cases, four patients developed encephalitis (100% male, range 40-73 years). In terms of neurological deficit, Case 1 featured spastic quadriparesis and transient ocular flutter and Case 3 suffered two episodes of right and left hemiplegia. Cases 2 and 4 featured no focal neurological deficit. Case 1 displayed mild pleocytosis upon CSF analysis whilst Case 2’s CSF analysis remained normal. Cases 3 and 4 did not undergo CSF examination. MRI scans showed that in Cases 1-3, there were multifocal abnormalities in the cerebral white matter with varying impact on grey matter, brainstem and spinal cord. MRI of Case 4 showed multifocal haemorrhagic lesions predominantly within white matter. Cases 1, 3 and 4 did not respond significantly to intravenous immunoglobulin and corticosteroids. Case 2 eventually recovered after three months with mild neuropsychiatric deficits in working memory, visuospatial perception and planning abilities following physical therapy. Case 3 died three months into illness. No outcomes were reported for Cases 1 and 4.

Rifino et al. (2020) conducted a retrospective analysis of all COVID-19 cases from February 23rd to April 30th that were referred for neurological assessment at the Papa Giovanni XIII hospital in Bergamo, Italy. Of 1,760 COVID-19 positive patients, 137 showed evidence of neurological impairments following COVID-19 onset, of which 49 (35.8%) displayed altered mental status. Following brain MRI and CSF analyses of the patients with altered mental state, five patients were diagnosed with encephalitis. Of these five (mean age 66), one case was reported to be HSV1-related encephalitis, one necrotising encephalitis and two confirmed to be encephalitis cases with positive COVID-19 infection following RT-PCR of CSF. Efficacy of treatment or clinical outcomes were not reported by the authors.

Meppiel et al. (2021) performed a study of COVID-19 cases with neurological manifestation from March-April 2020 through data from 46 hospitals in France. The study comprised 222 COVID-19 patients with neurological manifestations (61% male and 39% female, median age 65 years, range 53-72) with neurological manifestations confirmed by MRI and CSF examination, and COVID-19 infection confirmed via RT-PCR in most cases. COVID- 19-associated encephalopathy was observed in 30.2% cases and diagnosed encephalitis was observed in 9.5% of cases. The authors reported that the onset of encephalitis typically occurred seven (range 5-10) days after the onset of COVID-19 symptoms. Brain MRI was abnormal in 14 of the 21 encephalitis cases and showed heterogeneous acute nonvascular lesions. EEG was also abnormal in 14 of the 15 encephalitis patients assessed this way. CSF examination showed pleocytosis in 14 of the 21 encephalitis patients. Concerning clinical outcomes, ten patients with encephalitis fully recovered, of which three received corticosteroids, and the mortality rate was 4.8%.

Cao et al. (2020) reported on five patients (range 37-77 years) with severe COVID-19-related encephalitis presenting with altered mental state and impaired consciousness. Brain MRIs showed punctiform and slightly diffuse bilateral hyperintense lesions in both deep and periventricular supratentorial white matter for Cases 1-3 and lesions in the pons for Cases 1-2. In Cases 4-5, these supratentorial lesions were diffuse and confluent. CSF examinations were reported to be unremarkable, besides in Case 3, which featured albuminocytologic dissociation, and in Case 4, which featured mild pleocytosis. EEGs showed unspecific slow- wave activity. All patients received immunotherapy combined with corticosteroids (methylprednisolone) for 5-10 days and therapeutic plasma exchanges with albumin for 5-10 sessions. Cases 1-3 showed neurological improvement and improvement to consciousness following this therapy. Cases 4-5, however, showed no signs of improvement and ultimately died. The authors proposed that differences in response to immunotherapy and therapeutic plasma exchange treatment was due to differences in lesion intensity, as shown by MRIs.

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Cao A., Rohaut B., Le Guennec L., et al. (2020) Neurosciences study group. Severe COVID-19-related encephalitis can respond to immunotherapy. Brain;143(12):102.

Koh J. S., De Silva D. A., Quek A. M. L.,et al. (2020). Neurology of COVID-19 in Singapore. Journal of the Neurological Sciences; 418:117-118.

Meppiel E., Peiffer-Smadja N., Maury A., et al. (2021). Neurologic manifestations associated with COVID-19: a multicentre registry. Clinical Microbiology and Infection; 27(3): 458-466.

Pilotto A., Masciocchi, S., Volonghi I. et al. (2020). The clinical spectrum of encephalitis in COVID-19 disease: the ENCOVID multicentre study. Medrxiv.

Rifino N., Censori B., Agazzi E., et al. (2020). Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy. Journal of neurology;1-8.

Varatharaj A., Thomas N., Ellul, M. A., et al. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. The Lancet Psychiatry ; 7(10) : 875-882.

Guasp M., Modena Y., Armangue T., et al. (2020) Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm; 7:e659. OPEN ACCESS. https://creativecommons.org/licenses/by-nc-nd/4.0/

Kerik-Rotenberg N., Diaz-Meneses I., Hernandez-Ramirez R., et al. (2020) A metabolic brain pattern associated with anti-N-Methyl-D- Aspartate receptor encephalitis. Psychosomatics: 61:39–48.

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Page taken from Advances in Encephalitis. Research Summary 2020

Thank you to our Research Volunteer - Oliver Milner (Student, Department of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London) for his help with producing this information.