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.

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.

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.

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.