key: cord-1032378-rwm7rjxh authors: Negrini, Francesco; Ferrario, Irene; Mazziotti, Daniele; Berchicci, Marzia; Bonazzi, Maurizio; de Sire, Alessandro; Negrini, Stefano; Zapparoli, Laura title: Neuropsychological features of severe hospitalized COVID-19 patients at clinical stability and clues for post-acute rehabilitation date: 2020-09-28 journal: Arch Phys Med Rehabil DOI: 10.1016/j.apmr.2020.09.376 sha: 0d647af6facc0e4ca4f3637aa068c2981965e8cd doc_id: 1032378 cord_uid: rwm7rjxh Objective To report the cognitive features of severe COVID-19 patients entering in the post-acute phase, to understand whether COVID-19 acute respiratory distress syndrome itself could result in long-term cognitive deficits and whether neuropsychological treatment after the acute stage might represent a specific rehabilitation need. Design Case series. Setting Rehabilitation hospital. Participants We assessed the general cognitive functioning, through tablet-supported video-call, in 9 of 12 consecutive patients admitted to the hospital at least 30 days earlier for acute respiratory distress syndrome due to COVID-19. None of these patients presented cognitive symptoms before the hospitalization. Main Outcome Measures General Cognitive functioning, measured using the Mini-Mental State Examination Test. Results A general cognitive decay was observed in three patients (33.3%), who had a pathological score at the Mini-Mental State Examination (MMSE), with a specific decline in attention, memory, language and praxis abilities. The cognitive (mal)functioning seems to be linearly associated with the length of stay (in days) in the intensive care unit (ICU): the higher the number of days spent in the ICU, the lower the MMSE score (indicating a lower global cognitive functioning). Conclusions Our results indicate that some COVID-19 patients might also benefit from a neuropsychological rehabilitation, given their possible global cognitive decay. The link between the neuropsychological functioning and the length of stay in the ICU suggests that neurocognitive rehabilitative treatments should be directed explicitly towards patients who are treated in the ICU care, rather than towards every patient who suffered from acute respiratory distress syndrome due to COVID-19. However, given the limitation of a case series study, those hypotheses should be tested with future studies with larger samples and a longer follow-up. cognitive functioning). 23 Our results indicate that some COVID-19 patients might also benefit from a 24 neuropsychological rehabilitation, given their possible global cognitive decay. 25 The link between the neuropsychological functioning and the length of stay in the ICU suggests 26 that neurocognitive rehabilitative treatments should be directed explicitly towards patients who 27 are treated in the ICU care, rather than towards every patient who suffered from acute 28 respiratory distress syndrome due to COVID-19. However, given the limitation of a case series 29 study, those hypotheses should be tested with future studies with larger samples and a longer it is thought to be itself neuroinvasive 1 . In particular, previous studies highlighted brain 53 abnormalities in the medial temporal lobe, with multifocal white matter hyperintense lesions 2 . 54 In line with these observations, 84% of COVID-19 patients exhibited neurological signs, with 55 33% of them also showing inattention, disorientation, or poorly organized movements 3 . 56 However, at time of writing, it is not clear whether the COVID-19 acute respiratory distress 57 syndrome (ARDS) itself could result in long-term cognitive deficits, and whether 58 neuropsychological treatment after the acute phase is a specific rehabilitation need 4 . 59 The aim of this paper is to report the cognitive and psychological features of the first 60 consecutive severe COVID-19 patients entering in the post-acute phase, defined as clinical 61 stability and complete weaning from sedative and antipsychotic drugs. We measured the cognitive and psychological functioning in 9 of 12 consecutive patients 66 admitted to the hospital at least 30 days earlier for ARDS due to COVID-19. One patient was 67 excluded due to his/her non-compliance to the testing, two patients were excluded because 68 affected by ischemic-stroke during acute phase of COVID-19. 69 Patients were hospitalized between March 3 rd and April 8 th , 2020; respiratory symptoms started 70 on average 12.3 days before hospitalization (range: 3-26 days); mean age was 60 years old 71 (range: 21-77 years) and mean education was 10 years (range: 5-18 years). wave complexes, thus requiring therapy with antiepileptic drug (levetiracetam). They were also 86 screened after extubation with cranial CT scan and all resulted negative for acute brain injury. 87 Written informed consent for the cognitive evaluation was obtained from all participants 91 according to the Helsinki Declaration (1964). All participants took part in the study after the 92 nature of the procedure had been fully explained and they could withdraw their participation in 93 any moment. 94 None of the patients showed cognitive or psychological symptoms before the hospitalization. 95 Their pre-morbid status was assessed through structured interviews to the patients' caregivers. 96 They were required to give an explicit judgment about the patients' mental functioning on a 5-97 point Likert scale, ranging between 1 (no symptoms) to 5 (symptoms always present), for the 98 following cognitive domains: spatial and temporal orientation (mean score: 1, range: 1-1 for 99 both measures), short and long-term memory (mean score: 1.29, range: 1-3 for both measures), 100 language comprehension and production (mean score: 1, range: 1-1 for all measures), attention 101 (mean score: 1.29, range: 1-3), disinhibition behaviour (mean score: 1, range: 1-1), self-care 102 skills (mean score: 1.14, range: 1-2). 103 Patients' cognitive and psychological evaluation was performed after two conditions were 104 achieved: (i) complete weaning from sedative and antipsychotic drugs, and (ii) clinical stability 105 defined by PaO2/FiO2 ratio > 250 and possibility to answer to an interview without a fall in 106 Oxygen Saturation (SpO2) below 90%. Interviews were conducted on average 44 days after the 107 admission (range: 29-61 days). 108 Cognitive and psychological data were collected via tablet-supported video-calls with a 109 neuropsychologist, with the aid of a clinician who was physically with the patient. Neuropsychological scores were adjusted for age, gender and education. This was done in order 118 to take into account the possible intervening role of age, gender and education on the raw 119 scores. 120 General cognitive decline was observed in three patients (33.3%), who had a pathological 123 MMSE score. An item-by-item analysis showed that all these patients had low scores in the 124 domain of attention and calculation (counting backwards task), short-term memory (recall of 125 three familiar words), constructional praxia (copy a drawing of two intersecting pentagons) and 126 written language (writing of a sentence). 127 Only one patient (11.1%) showed a decay of executive frontal functioning, as measured by the 128 pathological scores at the FAB test, with deficits in conceptualization, lexical fluency (an index 129 of mental flexibility) and motor programming. 130 Interestingly, the cognitive decay seems to be linearly associated with the LOS (in days) in the 131 ICU, as shown in Figure 1a . The relative small sample of the present paper however does not 132 permit to statistically test the significance of this association. On the other hand, the relationship 133 between cognitive functioning and clinical data seems to be less evident when considering the 134 PaO 2 /FiO 2 (see Figure 1b) . 135 Finally, six patients (66.7%) displayed anxiety symptoms; two of them (22.2%) had also mild 136 depressive symptoms. These however seemed not being associated with the cognitive 137 functioning (see Table 1 for further details). The present report provides some information for the post-acute rehabilitation management of 140 COVID-19 patients. Taken together, these preliminary results suggest the importance of testing 141 and eventually supporting cognitive functioning in COVID-19 patients after their discharge. 142 COVID-19 is a new virus with unknown long-term outcomes and cognitive functioning cannot 143 be left out when considering the rehabilitation of these patients. 144 Neurocognitive rehabilitative treatments should be specifically directed towards patients treated 145 in the ICU care, rather than towards every patient who suffered from ARDS due to Indeed, current results seem to link the neuropsychological decay more to the LOS in ICU 147 rather than a possible direct damage due to SARS-CoV-2 infection, similarly to what observed 148 in patients suffering from Post Intensive Care Syndrome (PICS) 10 . 149 It is worth mentioning that our neuropsychological evaluation was successfully conducted via 150 video-calls, which can be easily administered also by using a smartphone. Thus, tele-monitoring 151 and tele-rehabilitation might be considered as feasible options for the early study of COVID-19 152 patients, providing convenient access without the risk of exposure in a congested hospital or in 153 medical practice waiting rooms. In case of large scale assessments, other instruments (such as 154 the telephone, see for example 11 ) might be adopted, in order to reach a bigger number of 155 participants. 156 related behavioural differences, like more smoking and drinking, lower rates of handwashing, 166 and resistance to following social distancing requirements (see 12 ). 167 Furthermore, all the patients admitted in ICU were intubated, regardless of their length of stay: 168 being intubated or not might, alone, explain the decline in cognitive functions. However, the 169 binary nature of this variable does not allow us to further explore its potential association with 170 the cognitive functioning. Does SARS-Cov-2 invade the brain? 188 Translational lessons from animal models Brain MRI Findings in Severe COVID-19: A Retrospective Observational 190 Study Neurologic Features in Severe 193 SARS-CoV-2 Infection Systematic rapid "living" 195 review on rehabilitation needs due to COVID-19: update to March 31 st , 2020 Mini-mental state". A practical method for 198 grading the cognitive state of patients for the clinician The FAB: a Frontal Assessment Battery at 200 bedside The 202 Importance of Cognitive Executive Functions in Gait Recovery After Total Hip State-Trait anxiety inventory. The Corsini Encyclopedia of Psychology Beck depression inventory-II Post-210 intensive care syndrome: its pathophysiology, prevention, and future directions Telephone assessment of cognitive function in adulthood: The 213 brief test of adult cognition by telephone Gender Differences in Patients With COVID-19: Focus on 215 Severity and Mortality J o u r n a l P r e -p r o o f • The decline linearly associates with the length of stay in the ICU. • Some COVID-19 patients might benefit from a neuropsychological rehabilitation.