Table 1.

Summary of the main clinical, biological and imaging findings in the patients with COVID-19-related encephalopathy

N°/age/sex	Past medical history	Acute phase (delay after COVID-19 onset)				Treatment and follow-up (FU) (delay after COVID-19 onset)
		COVID-19 presentation	Main biological findings	Neurological symptoms & EEG findings	Imaging findings	Evolution 1 month later	Long-term evolution
1/50/M	IgA vasculitis complicated by renal failure, kidney transplantation, HCV infection	Myalgia, asthenia, anorexia, fever, dyspnea. Respiratory distress requiring mechanical ventilation	Blood IL-6 : 8913 pg/ml (N < 6.5)	Delayed awakening after stopping sedation. Generalized myoclonus, pyramidal syndrome with left hemiparesis, internuclear ophthalmoplegia. Attentional and executive deficit (MMSE 12/30, FAB 9/16), apathy, anxio-depressive syndrome (29 days). EEG: slow fronto-temporal bilateral activity.	MRI: white matter bilateral small pseudonodular lesions in high FLAIR and diffusion signal with contrast enhancement; splenium of corpus callosum microbleedings. PET: hypometabolism of bilateral prefrontal cortex, ACC, insula (− 8%) and cerebellum. Visual cortex hypermetabolism (89 days)	Corticosteroids and plasma exchanges. Improvement of cognition and myoclonus within a few days after plasma exchange PET: moderate, residual hypometabolism in the right insula, prefrontal cortex and cerebellum (145 days)	Physical and cognitive fatigue due to the loss of the kidney transplant and repeated dialysis. Normal neurological examination. MMSE 26/30; FAB 16/18. Executive and attention disorders, with mild difficulties in visual episodic memory and recognition of facial emotion. No significant difficulties in language. Anxio-depressive syndrome under escitalopram 10 mg/day, alprazolam 0.5 mg/day (6.4 months). PET: moderate hypometabolism in the right insula and orbitofrontal cortex, normal cerebellar metabolism (6.4 months)
2/53/M	Type 2 diabetes, hypertension, chronic renal failure, schizoaffective disorder	Fever, dyspnea. Respiratory distress requiring mechanical ventilation	Blood IL-6 1675 pg/ml CSF protein 1.07 g/L (N 0.15–0.45) CSF IL-6 9 pg/ml (N < 2.5 pg/ml)	ICU delirium (10 days) Oculomotor disturbances (nystagmus, bobbing) Pyramidal syndrome Left hemiparesis Dysarthria EEG: slow anterior delta waves, diphasic and sometimes triphasic, reactive	MRI: bilateral frontal, bilateral anterior cingulate, right insular hypoperfusion PET: hypometabolism of bilateral prefrontal cortex, insula (− 21%), ACC (− 20%), PT cortex, cerebellar hemispheres, caudate (− 57%), thalamus (− 30%) and pons (53 days)	No specific treatment. Improvement of delirium, oculomotor disturbances and hemiparesis PET: metabolism improvement in PT cortex; residual hypometabolism in the prefrontal cortex, ACC, insula, caudate and cerebellum. (104 days)	Complains about balance and walking difficulties, with normal physical neurological examination MMSE 28/30, FAB 17/30. Mild executive and attention difficulties. No significant difficulties in language assessment, severe dysarthria No psychiatric signs under mirtazapine 15 mg/day and alprazolam 0.5 mg/day (3.6 months) PET: residual, moderate hypometabolism in the prefrontal cortex, insula, ACC, caudate and cerebellum (6.5 months)
3/60/F	Temporal lobe epilepsy (right hippocampal sclerosis)	Fever, cough, diarrhoea	None	Psychomotor agitation, severe anxiety and depressed mood (secondarily requiring an hospitalization in psychiatric ward), dysexecutive syndrome (FAB 11/18) cerebellar syndrome with hypotonia, gait ataxia, dysmetria, dysarthria, nystagmus (no delay) Normal EEG	MRI: right mesial sclerosis PET: hypometabolism of bilateral prefrontal cortex with right predominance, moderate PT cortex, insula (− 17%), ACC (− 23%), PCC (− 17%), right hippocampus (− 28%), right amygdala (− 20%), right caudate nucleus (− 33%), left putamen (− 17%), right thalamus (− 20%) and cerebellum Hypermetabolism in the midbrain. (15 days)	Corticosteroids. Improvement of mood after admission in psychiatry for 5 days, cognition and cerebellar syndrome. PET: moderate improvement with persistent prefrontal, ACC, temporal and subcortical hypometabolism. Stable hypermetabolism in the midbrain (43 days)	No cognitive or emotional complaints. Normal neurological examination; MMSE 26/30, FAB 14/18. Mild executive dysfunction, mild disorders accessing the lexicon. Persistence of anxiety under venlafaxine 37.5 mg/day (4.9 months) PET: unchanged pattern with hypometabolism mainly affecting prefrontal cortex. Stable hypermetabolism in the midbrain (4.9 months)
4/63/F	Bipolar disorder, left parasagittal meningioma, migraine, breast cancer cured by radiotherapy	Fever, myalgia, asthenia, anorexia, rhinorrhea, headaches	Blood IL-6 28.8 pg/ml	Confusion with agitation (day 6) Frontal syndrome, spatio-temporal disorientation (MMSE 11/30, FAB 2/18) Right brachiofacial motor seizure, anxiety (day 30) EEG: slow anterior bilateral theta waves	MRI: cerebellar hyperperfusion PET: hypometabolism of bilateral prefrontal cortex, ACC (− 15%), insula (− 15%), PTO cortex and caudate nucleus (− 43%) Focal hypermetabolism in the left frontal cortex (seizure); metabolism increase in the cerebellum. (33 days)	No specific treatment Improvement of cognition, no recurrence of seizure PET: stable, prefrontal and posterior hypometabolism. No more hypermetabolic area (54 days)	Admitted in psychiatry (2.6 months) for decompensation of bipolar disorders. Despite therapeutic changes (tiapride, venlafaxine, lamotrigine) ECT was indicated. After 2 sessions, she presented with a focal status epilepticus (7.1 months), and ECT was stopped. PET at 5.9 months FU: major metabolism decrease in the occipital cortex, persistent prefrontal hypometabolism with focal prefrontal and cerebellar metabolism increase At 8.1 months clinical FU: always hospitalized in psychiatry department with anxiety, depression and psychotic symptoms (delusion, auditive and visual hallucination). Treatment: valproic acid 500 mg twice/day venlafaxine 75 mg/day. Axial extrapyramidal syndrome. MMSE 29/30, FAB 12/18; moderate dysexecutive syndrome with frontal behaviour (apathy), associated with attention difficulties (fluctuation). Denomination difficulties with semantic disorders associated with a reduction of fluency
5/72/M	None	Fever, cough, anosmia	CSF leukocytes 6/mm3 (N < 6)	Psychomotor agitation, cognitive and behavioural frontal lobe syndrome, upper limbs myoclonus, cerebellar ataxia (15 days) Normal EEG	Normal MRI PET: hypometabolism of bilateral prefrontal cortex, ACC (− 35%), insula (− 21%), PT associative cortex, cerebellum, thalamus (− 12%), amygdala (− 23%), caudate nucleus (− 25%) and hippocampus (− 25%) Hypermetabolism of cerebellar vermis and midbrain (23 days)	Intravenous immunoglobulins Improvement of cognition, myoclonus and ataxia PET: improvement with normal posterior cortical metabolism, mild prefrontal, insular, mesiotemporal, cerebellar hypometabolism. Midbrain hypermetabolism. (43 days)	At 5.1 months clinical FU: cognitive complaint with anterograde memory, attention difficulties and problem accessing the lexicon. Neurological examination was normal. MMSE 29/30, FAB 16/18, severe attention and vigilance disorders, severe visual recognition memory difficulties and moderate executive dysfunction associated with frontal behaviour. No difficulties in language assessment. Major impact on the emotion of the COVID-19 with compulsive disorders, anxiety and depression with elements for a post-traumatic stress disorders PET: unchanged with limited hypometabolism in the prefrontal cortex, hippocampus and cerebellum. Midbrain hypermetabolism (5.1 months)
6/66/F	None	Fever, fatigue, dyspnea	CSF IL-6 13 pg/ml	Psychomotor slowing, cognitive and behavioural frontal lobe syndrome with perseveration, and severe anxiety requiring specialist psychiatric advice (7 days) EEG: Generalized periodic discharges, slowed background activity, irregular anterior rhythms	MRI: bilateral frontal hypoperfusion, nonspecific white matter hyperintensities PET: widespread hypometabolism of bilateral prefrontal, insula and PTO cortices Hypermetabolism of cerebellar vermis (+ 20%), dentate nucleus, amygdala (+ 26%), hippocampus (+ 24%) (21 days)	Intravenous immunoglobulins and corticosteroids Cognitive improvement within a few days after corticosteroids and normalized within 2 weeks PET: less marked hypometabolism in prefrontal, insular, parietal areas. Stable hypermetabolism in the cerebellar vermis, dentate nucleus, right amygdala (+ 9%) and hippocampus (+ 11%) (45 days)	At 5.1 months clinical FU: complain about fatigue, attention disorders, words missing and anterograde memory difficulties. Normal neurological examination. MMSE 30/30, FAB: 16/18. Mild executive and attention difficulties and mild disorders in recognition of facial emotion. Normal speech therapy assessment. Mild anxiety under paroxetine 20 mg/day PET: huge improvement with mild and patchy hypometabolism in ACC, prefrontal cortex and cerebellum. No more hypermetabolism. (5.3 months)
7/69/M	Diabetes mellitus type 2, hypertension	Fever, fatigue, anosmia, agueusia	Blood IL-6 143.6 pg/ml CSF protein 0.66 g/L CSF IL-6 16 pg/ml	Generalized convulsive status epilepticus, frontal lobe syndrome (FAB 3/18) and agitation with messianic delusion requiring specialist psychiatric advice (7 days) EEG: Lateralized periodic discharges in the right frontal lobe	MRI: right T2-FLAIR and diffusion orbitofrontal, insular, cingulate and caudate nucleus hyperintensity Bilateral cerebellar and vermis hyperperfusion PET: widespread hypometabolism in bilateral prefrontal and PTO cortices, insula (− 20%), caudate nucleus (− 52%), thalamus (− 21%) and left amygdala (− 9%) Hypermetabolism of cerebellar vermis (+ 18%) (39 days)	Intravenous immunoglobulins and corticosteroids Improvement of psychomotor slowing, persisting dysexecutive syndrome, improvement of behavioural frontal disturbances and praxis PET: unchanged, widerspread cortical and subcortical hypometabolism (83 days)	At 8.3 months clinical FU: complain about cognitive fatigability. Normal neurological examination. MMSE 24/30; FAB 9/18 with a moderate executive disorder associated with attention, visual recognition memory difficulties and denomination problem PET: metabolism improvement in the posterior cortex; unchanged large, prefrontal hypometabolism (5.9 months)

CSF, cerebrospinal fluid; EEG, electroencephalogram; FAB, frontal assessment battery; ICU: intensive care unit; FU, follow-up; PET, positron emission tomography; IL-6, interleukin 6; MMSE, mini-mental state evaluation; N, normal; MRI, magnetic resonance imaging; NP, not performed; RT-PCR, real-time polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus; PTO cortex, parietotemporooccipital cortex; PT, parietotemporal cortex; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; ECT, electroconvulsive therapy; glucose metabolism change (expressed in percentage) is based on regions-of-interest analysis in comparison with healthy controls