key: cord-0847491-vap9wm4b
authors: Umapathi, Thirugnanam; Jason, Quek Wei Ming; Min, Yen Jia; Wai, Khin Hnin Su; Yuan, Mah Yun; Yee, Joel Chan Chee; Min, Ling Li; Wai-Yung, Yu
title: Encephalopathy in COVID-19 patients; viral, parainfectious, or both?
date: 2020-09-21
journal: eNeurologicalSci
DOI: 10.1016/j.ensci.2020.100275
sha: 1391140cfd18bbcb9bc6806faf18b17e4c47fa43
doc_id: 847491
cord_uid: vap9wm4b

We describe the clinical, laboratory and radiological features of 3 critically ill patients with COVID-19 who developed severe encephalopathy. The first patient did not regain consciousness when sedation was removed at the end of 2 weeks of intensive care. He had received treatment with convalescent plasma. His clinical examination was remarkable for intact brainstem reflexes, roving eye movements, later transient ocular flutter; and then what appeared to be slow ocular dipping. He had no coherent volitional response to the environment. The second patient recovered with measurable cognitive deficits after a prolonged period of encephalopathy. He had received combination treatment with interferon beta 1b and lopinavir/ritonavir. The third patient remained in persistent, severe agitated delirium and died 3 months into his illness. The MRI of the 3 patients showed multifocal abnormalities predominantly in the cerebral white matter, with varying involvement of the grey matter, brainstem and spinal cord. Case 1's MRI changes were consistent with acute disseminated encephalomyelitis. The patients also displayed blood markers, to varying degree, of autoimmunity and hypercoagulability. We were not able to convincingly show, from microbiological as well as immunological evaluation, if the effects of COVID-19 on these patients' nervous system were a direct consequence of the virus, proinflammatory-thrombotic state or a combination. Patient 1 responded partially to empirical, albeit delayed, therapy with intravenous immunoglobulins. Patient 2 recovered with no specific treatment. These cases illustrate the need to understand the full spectrum of encephalopathy associated with COVID-19 so as to better guide its management.

Corona viruses have rarely been reported to cause encephalitis, most convincingly with the HCoV-OC43 virus [1] [2] [3] . There are rare reports of microbiologically proven central nervous system involvement by severe acute respiratory syndrome (SARS) virus, SARS-CoV-1 [4] [5] [6] . Viral genome sequences were detected in the brains of patients who died from SARS although it is unclear what neurological symptoms these patients had antemortem [7] . Most other neurological complications of SARS [5, 8] and the closely related Middle Eastern Respiratory Syndrome (MERS) [9, 10] appear to be indirect and consequential pathology rather than primary viral encephalitis.

We describe 3 patients with severe COVID-19, with what we believe is the spectrum of encephalopathy that can develop from SARS-CoV-2 infection. The definition of infective encephalitis as well as Acute Disseminated Encephalomyelitis (ADEM) was based on published criteria [11] [12] [13] . Likewise, the likelihood of these complications being related to COVID-19 was graded using guidelines from a recently published review by Ellul et al. [14] .

A 59-year old man, with a past history of chronic hypertension was diagnosed with COVID-19 by a positive nasopharyngeal swab for SARS-CoV-2 real-time polymerase chain reaction (RT-PCR). He was asymptomatic and was tested during routine screening of COVID-19 patient contacts. He only reported fever and malaise on day 8 of illness.

He had no neurological symptoms, including anosmia and dysgeusia. He rapidly declined from day 9 and developed severe acute respiratory distress syndrome (ARDS) and required inotropic support. Renal function worsened. Viraemia was documented on day 11 (cycle threshold value 32.22) . He received convalescent plasma on day 11 and 14.

Serum SARS-CoV-2 RT-PCR turned negative on day 14.. He remained drowsy in spite J o u r n a l P r e -p r o o f of withdrawal of sedation and adequate renal replacement therapy. The brain stem reflexes, namely pupillary, doll's and corneal reflexes were intact. He had no limb movements to pain. Deep tendon reflexes, jaw jerk and pout reflexes were brisk.

Babinski's reflex was absent. Initially slow conjugate ping-pong movements were noted.

Subsequently, the eyes drifted continuously and conjugately in vertical and horizontal directions; often remaining in right and downward positions for up to a minute. Spinal tap done twice on days 30 and 37 was remarkable for only borderline low glucose, slight pleocytosis, and raised protein (Table 1) . Spinal fluid SARS-CoV-2 RT-PCR, IgG and viral culture were negative. EEG showed continuous diffuse slow activity (1) (2) (3) intermixed with theta activity. Plain and contrasted CT brain did not reveal any abnormalities to explain his condition. MRI brain was only done on day 34 when endotracheal tube SARS-CoV-2 RT-PCR became negative (Fig 1a-d) . It showed multiple discrete hyperintense foci on T2 weighted (T2W) and FLAIR images in the periventricular and deep white matter bilaterally, with foci in the temporal region, subcortical white matter as well as the forceps minor. T2W and FLAIR hyperintense foci were also present bilaterally in the cerebral peduncles, pons, middle cerebellar peduncles and cerebellar white matter. These were hyperintense on diffusion weighted imaging (DWI) without corresponding restricted diffusion on the apparent diffusion coefficient (ADC) maps. The lesions in the cerebral white matter were centrally more T2W hyperintense, corresponding to low signal on T1 weighted images (T1WI), and were ill defined and fluffy peripherally. Susceptibility weighted images (SWI) showed 2 foci of microhaemorrhage in the left cerebellar white matter and left middle cerebellar peduncle.

Equivocal FLAIR signal was seen in the olfactory nerves and bulbs. Chronic lacunar infarcts in the right caudate head and right thalamus were attributed to background small vessel disease. Magnetic Resonance Angiogram (MRA) was unremarkable. There were several subtle foci of intramedullary hyperintense signal on T2W images (T2WI) within the spinal cord at C1, T9-T11 and the conus (Fig 1e) . Gadolinium could not be given because of his renal failure. The combination of white matter, brain stem and spinal cord changes were suggestive of ADEM [13] . His blood investigations (Table 1) indicated an inflammatory and prothrombotic state. He was given low molecular weight heparin prophylaxis on day 25 which was stopped subsequently because of unexplained decrease J o u r n a l P r e -p r o o f in hemoglobulin. At Day 40 he was weaned-off the ventilator. On day 43 ocular flutter was noted. As ocular flutter and its extension opsoclonus are associated with parainfectious autoimmunity, serum anti-Ri antibody was requested, and he was given a course of intravenous immunoglobulin (IVIg). Follow up MRI brain performed on day 44 showed no new lesions but some of the lesions, particularly on left side of the pons, became more discrete. Diffuse confluent background T2W and FLAIR hyperintensity in the cerebral white matter was also more apparent (Fig 1f) . By day 47 the ocular flutter was largely replaced by slow ocular dipping. Although the anti-Ri antibody returned negative, we extended the IVIg for a total of 7 days because of the suggestion of a positive response. At the end of the treatment, the ocular dipping and roving eye movements improved. Further 2 courses of 2g/kg of IVIg was given at 3 weekly 

He was eventually discharged after 103 days to a rehabilitation hospital. The Montreal Cognitive Assessment score on day 112 was 17/30. Formal neuropsychological assessment showed mild impairment in working memory, processing speed, visuospatialperceptual abilities and planning. This prompted a brain MRI on day 114 of illness. It showed bilateral symmetrical curvilinear non-enhancing lesions in the temporal and occipital deep-subcortical white matter that paralleled the ventricles, with intervening normal appearing periventricular white matter. They were hyperintense on T2W, suppressed on FLAIR and hypointense on T1WI with no restricted diffusion. Similar and smaller lesions were present in the inferior frontal white matter bilaterally (Fig 2a-c) .

Multiple discrete round-ovoid T2W hyperintense lesions, some corresponding to hypointensity in T1WI, were also present in the deep and subcortical white matter bilaterally. There was also a background of subtle diffuse T2 prolongation in the centrum semiovale (Fig 2d) . A few scattered microhemorrhages were present in the deep and subcortical white matter. Overall, the lesions were chronic and deemed to be possible sequelae of hypoxia-ischaemia, or alternatively inflammatory demyelination; and could explain the patient's cognitive deficits. (table 1) . Although the strokes could be attributed to his co-morbidities (hypertension, atrial fibrillation) the rest of the radiological pathology was believed to be related to para-infectious autoimmune coagulopathy. He could not receive anticoagulation or immunotherapy and remained in poor neurological state. The agitation and restlessness required constant sedation and restraints. He had no volitional response to external stimulus. After 93 days he was given an empirical trial of high dose steroids, with the intention of improving his mental state and quality of life. His condition did not change. On day 104 all curative therapy was withdrawn, and he passed away.

We describe the clinical, laboratory and radiological features of 3 critically ill patients with COVID-19 who developed severe encephalopathy. Case 1 satisfied criteria for ADEM while case 2 and 3 -possible encephalitis‖ [11] [12] [13] . Using case definition of Ellul et al. [14] , we graded the association with COVID-19 as -probable‖ for all 3 cases.

Although it was difficult to accurately date the onset of illness, the median interval from onset of respiratory symptoms to the point when encephalopathy was suspected was 23 days. All 3 patients were critically ill with multiple and severe organ dysfunction. They demonstrated to varying degrees, inflammatory and prothrombotic markers that COVID-19 has been associated with, the so-called -cytokine storm‖ [18] . We discuss the key clinical dilemmas we faced in the evaluation and management of these 3 patients.

Firstly, it was difficult to delineate the cause of the patients' altered mental state, considering the combined and interacting effects of their multiple co-morbidities. For instance in case 1, uremic encephalopathy and the prolonged sedative effects of midazolam and morphine, that are not efficiently removed via dialysis, were initially thought be the cause of his coma [15] [16] [17] These drugs had to be used because of the worldwide shortage of intensive care drugs . Further investigations were largely J o u r n a l P r e -p r o o f prompted by the patient's lack of recovery after adequate renal replacement and switching the sedatives to dexmedetomidine and remifentanil. Case 2 was initially not thought to have any central nervous system pathology. We found significant cognitive impairment when he was recuperating, which correspondeded with the changes seen on MRI brain. However, it was difficult to decide if these lesions were due to a direct viral effect, possible hypoxia-hypotension or inflammatory demyelination. This segues to our second dilemma.

We struggled to understand the underlying pathophysiology of our patients' encephalopathy. Were they suffering from direct viral infection of the central nervous system or from the spectrum of parainfectious and prothrombotic processes related to COVID-19? The experience with other infections such as tick-borne encephalitis suggests that there is no correlation between viral load, timing of viraemia and clinical severity. Not surprising diagnostic criteria for encephalitides do not mandate the demonstration of viral particles in spinal fluid or blood [11, 12, 19, 20] . We have summarized the pointers that led to our clinical equipoise, with regards to direct viral effect versus parainfectious pathology for cases 1 and 3 in table 2.

To date there have only been a few reports of COVID-19 patients with positive SARS-CoV-2 RT-PCR in CSF [23, 24] or post mortem evidence of viral antigens in CNS [25] .

In the latter report, the patient's primary neurological manifestation was agitation and delirium [25] . Most reports did not support a direct neurotropism of the virus. In a series describing of neurological complications associated with hospitalized COVID-19 patients, two were encephalopathic. Both had normal MRI. One case had normal spinal fluid including negative RT-PCR for SARS-CoV2; the other case did not have spinal fluid analysed [26] . In an autopsy series of 18 patients, all of whom were noted to be drowsy or confused antemortem, the main pathological findings were hypoxic changes, with no specific features of encephalitis. There were also no viral inclusions. SARS-CoV-2 RT-PCR were positive at low levels in only 5 patients [27] . Of the 578 spinal fluid samples from a cohort of 555 patients (neurological symptoms unclear) only two were positive for SARS-CoV-2 RT-PCR, at CT values of 32 and 35. Both were suspected to J o u r n a l P r e -p r o o f be contamination by blood as the brain biopsy samples were negative. This study suggested that although SARS-CoV-2 can replicate in neuronal cells in vitro, demonstration in CSF is uncommon [28] . On the other hand, most reports of COVID-19 related encephalopathy were a result of indirect CNS complications such as stroke [29] [30] [31] [32] [33] and para-infectious, inflammatory conditions such as acute hemorrhagic necrotizing encephalopathy [34] [35] [36] and ADEM. A 40-year-old lady with dysarthria, dysphagia, facial weakness and gaze presence had imaging consistent with ADEM. Her CSF was normal. She had some improvement with IVIG treatment [37] . Another patient with similar MRI findings but presenting with seizures and drowsiness responded well to high dose dexamethasone [38] . A 51-year-old with coma and ADEM-like MRI changes responded to high dose steroids and IVIg [39] . A 71-year-old man passed away from severe COVID-19 related respiratory failure and hyperinflammatory state. His postmortem showed brain findings consistent with, ischaemia, acute hemorrhagic leukoencephalitis and ADEM. The patient's antemortem neurological manifestations were however unclear [40] .

Finally, what was the best treatment for our patients, beyond what they received during the acute respiratory illness and the supportive intensive care? Remdesivir has shown some efficacy in COVID 19. In one case of Ebola virus related meningoencephalitis, intravenous remdesivir together with high dose dexamethasone was associated with reduction in viral load and the patient improved [21] . Did Remdesivir have a role in our patients, notwithstanding the renal failure, its poor spinal fluid penetration (brain:plasma ratio <5%, [22] ) and the relatively late presentation into illness when viral clearance was already demonstrated in a combination of sputum, serum, spinal fluid and stool? If the pathology was parainfectious and autoimmune, should they have received immunosuppressants? In our patients, the decision to start immunomodulators empirically was confounded by recurrent and severe nosocomial infections. For instance, case 1 had Pseudomonas aeruginosa and Enterococcus faecium when the ocular flutter was noted. Hence, the decision to try IVIg with appropriate antibiotic cover rather than corticosteroids. Without good evidence of its efficacy it was also difficult to justify the substantial undertaking of plasma exchange. Increasing reports of the efficacy of immune J o u r n a l P r e -p r o o f Journal Pre-proof therapy [25] [37] [38] [39] and the findings of the RECOVERY study [41] , showing lower mortality among critically ill COVID-19 patient receiving dexamethasone, have raised the possibility that earlier administration of corticosteroids, or gentler immunotherapy such as IVIg, would have improved the neurological outcome for Cases 1 and 3.

The medical ethos of nonmaleficence, otherwise known as the -Do No Harm‖ principle; and the recent experience with hydroyxchloroquine in treatment of COVID-19 should guard us against our bias to -try something‖ in the absence of evidence [42] . On the other hand, -absence of evidence‖ does not equate to -no evidence‖. A better understanding of the relationship between the effect of the SARS-CoV-2 and associated parainfectious autoimmunity is urgently needed [43, 44] . We hope our cases generate discussions and prompt other clinicians to report similar cases. We expect this will lead to derivation of best practices for the diagnosis and management of COVID-19 related encephalopathy. In this regard recent initiatives to set-up international databases of COVID-19 associated neurological complications is timely [45, 46] .

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