Table 1.
Neurological and psychiatric sequelae of long COVID.
| Study design | Time of assessment | Number of patients | Age (years) | Neurological and psychiatric complication | Location | Reference |
|---|---|---|---|---|---|---|
| CFQ-11 | Median interval between study assessment and discharge from hospital or a timepoint 14 days following diagnosis if managed as an outpatient: 72 days (IQR: 62–87) | 128; 53.9% women | Mean (SD): 49.5 ± 15 | Fatigue: <56 days (20.3%) 56–69 days (24.2%) 69–83 days (25.8%) >84 days (29.7%) |
St. James's Hospital, Dublin, Ireland | Townsend et al. (2020) |
| Ambidirectional cohort study Face-to-face interview with filling up questionaries: self-reported symptom questionnaire, mMRC dyspnea scale, EQ-5D-5L, EQ-VAS, ischemic stroke/cardiovascular event registration form |
Six months (Median = 186.0 days; IQR = 175.0–199.0) after acute infection (between symptom onset and hospital discharge) | 1,733, 48% women |
Median: 57.0; IQR: 47.0–65.0 |
Fatigue or muscle weakness (63%) Sleep difficulties (26%) Anxiety or depression (23%) Smell disorder (11%) Taste disorder (7%) Dizziness (6%) Myalgia (2%) Headache (2%) |
Jin Yin-tan Hospital and its outpatient clinic, Wuhan, China) | Huang et al. (2021) |
| Prospective cohort study BDI-13, IES-R, OCI, PCL-5, STAI-Y, WHIIRS, ZSDS |
One-three months (90.1 ± 13.4 days) after hospitalization | 226; 34% women | Mean (SD): 58.5 ± 12.8 Range: 26-87 |
Depression (persistent) PTSD, anxiety and insomnia (decreased during follow-up) |
IRCCS San Raffaele Hospital, Milan, Italy | Mazza et al. (2021) |
| GAD-7, IES-6, PHQ-9 | One month after hospitalization | 114; 46,5% women | Median: 40 IQR: 31.75–50.25 |
Provisional PTSD diagnosis (36%) | First Hospital of Changsha, Hunan, China | Ju et al. (2021) |
| CAPS-5 | 30–120 days after recovery from COVID-19 | 381; 43.6% women | Mean (SD): 55.26 ± 14.86 | PTSD (30.2%) | Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy | Janiri et al. (2021) |
| Online survey | Four-twelve weeks | 3,290; 78% women | Range: 45-54 | Fatigue (83.3%) Muscle weakness or joint stiffness (50.6%) Sleep disturbances (46.2%) Problems with mental abilities (45.9%) Changes in mood, anxiety and depression (43.1%) |
United Kingdom | Buttery et al. (2021) |
| Prospective observational study Questionnaire |
Patients were followed-up either at the institute's post COVID-19 clinic or by phone 91 (IQR: 45–181) days post discharged/post-end of isolation | 1,234; 30.6% women | Mean (SD): 41.4 ± 14.2 Range: 18-97 |
Myalgia (10.9%) Fatigue (5.5%) Insomnia (1.4%) Mood disturbances (0.48%) Anxiety (0.6%) |
Tertiary healthcare center, New Delhi, India | Naik et al. (2021) |
| Prospective observational study The primary outcome: mRS Secondary outcomes: ADL, Telephone MoCA, Neuro-QoL |
Six months (±1 month) from the onset of neurological symptoms among cases, or from the onset of COVID-19 symptoms among controls | 382; 65% women | Neurologic COVID-19 Median: 68 Range: 55-77 COVID-19 Control: Median = 69 Range: 57-78 |
Limited activities of daily living (56%) Abnormal cognition (50%) Worsen than average anxiety, depression, fatigue or sleep scores (62%) |
Four New York City area hospitals, USA | Frontera et al. (2021) |
| Prospective study Neurological examination, PROMIS. Evaluation of cognitive function was done with the National Institutes of Health (NIH) Toolbox (in-person visit) |
Mean (SD): 5.27 ± 1.83 months after infection | 100 [50 SARS-CoV-2 laboratory-positive; 50 laboratory-negative (suspected COVID-19)]; 70% women | Mean (SD): 43.2 ± 11.3 | Fatigue (85%) Non-specific cognitive complaints – “brain fog” (81%) Headache (68%) Numbness/tingling (60%) Dysgeusia (59%) Anosmia (55%) Myalgia (55%) Depression/Anxiety (47%) Dizziness (47%) Pain (43%) Insomnia (33%, Short-term memory deficit (32%) Blurred vision (30%) Tinnitus (29%) Attention deficit (27%) |
Neuro-Covid-19 Clinic of Northwestern Memorial Hospital, Chicago, USA | Graham et al. (2021) |
| Online survey | Seven months after COVID-19 onset | 3,762 (1020; antibody positive; 2,742 suspected – antibody negative or untested); 78.9% women |
≥18 |
Frequency of symptoms ≥ 60%: “Brain fog”, poor attention, difficulty thinking, anxiety, short-term memory loss, dizziness/vertigo, insomnia Frequency of symptoms ≥ 50%: Irritability, difficulty in executive functioning, difficulty in problem solving Frequency of symptoms ≥ 40%: Depression, mood liability, tearfulness, tingling/pins and needles, tremors, sleep problems, slowed thoughts, difficulty finding right words |
56 countries | Davis et al. (2021) |
| Neurological examination MoCA |
Six months after hospitalization | 165; 30.3% women | Mean (SD): 64.8 ± 12.6 | Fatigue (33.9%) Memory complains/attention deficits (31.5%) Insomnia (31.5%) Myalgia (30.3%) Depressive symptoms/anxiety (26.7%) Blurring/loss of vision (19.5%) Paresthesia (18.8%) Hyposmia/hypogeusia (16.4%) Confusion (13.3%) Headache (9.7%) |
COVID-19 Unit of the ASST Spedali Civili Hospital, Brescia, Italy | Pilotto et al. (2021) |
| Single-center study Interview, SF-12 MCS |
Five and twelve months after confirmed diagnosis of COVID-19 | 96; 55.2% women | Median: 57; IQR: 50–63 |
Five months: Fatigue (42%) Sleep problems (32%) Concentration problems (32%) Headache (20%) Twelve months: Fatigue (53%) Sleeping problems (25%) Concentration problems (39%) Headache (17%) |
University Hospital, Heidelberg, Germany | Seeβle et al. (2021) |
| Nationwide retrospective cohort study Data from the TriNetX electronic health records network |
Six months after confirmed diagnosis of COVID-19 | All patients: 236,379; 55.6% women | Mean (SD): 46.0 ± 19.7 |
Anxiety disorder (17.39%) Ischemic stroke (2.10%) Psychotic disorder (1.40%) Dementia (0.67%) Intracranial hemorrhage (0.56%) Parkinsonism (0.11%) Nerve, nerve root, or plexus disorders (2.85%) Guillain-Barré syndrome (0.08%) |
USA | Taquet et al. (2021) |
| Patients with ITU admission: 8,945; 46.7% women |
Mean (SD): 59.1 ± 17.3 | Anxiety disorder (19.15%) Ischemic stroke (6.92%) Psychotic disorder (2.77%) Dementia (1.74%), Intracranial hemorrhage (2.66%) Parkinsonism (0.26%) Nerve, nerve root, or plexus disorders (4.24%) Guillain-Barré syndrome (0.33%) |
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| Mental health examination QoL questionnaire EQ-5D-5L, PCFS, HADS-A, HADS-D |
Four-twelve weeks after mild/moderate COVID-19 infection | 64 inpatients; 51,56% women | Median: 46 | Depression (46.87%) Anxiety (34.37%) |
Romania | Giurgi-Oncu et al. (2021) |
| 79 outpatients; 56.96% women |
Median: 42 | Depression (27.84%) Anxiety (40.5%) |
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| Prospective online survey EQ5D index score |
Six and twelve months after recovery (Median: 454 days; IQR: 451–458) |
All: 1,141 12 months: 241; 68% women |
Median: 37; IQR: 26.0–51.0 |
Concentration difficulties (most frequent among 18–49 years old) Cognitive disfunction (most frequent among 50–59 years old) Amnesia, depression, fatigue (most frequent among ≥60 years old) Anxiety. |
Kyungpook National University Hospital, Korea | Kim et al. (2022) |
| Prospective monocentric cohort study SAS, SDS |
Six and twelve months after hospitalization | 64; 36% women | Median: 68; (1st-3rd quartiles: 56.5–75) |
Six months: Anxiety (48.5%), depression (56.4%), persistent fatigue (37.5%), memory and attention deficits (11%) Twelve months: Anxiety (50%), depression (61%), persistent fatigue (12.5%), memory and attention deficits (4.7%) |
Hospital of Fermo, Marche, Italy | Martino et al. (2022) |
| Prospective monocentric observational study MMSE, COWA S, COWA Ph, CVLT Immediate, CVLT Delayed, TOL, Rey figure copy, Rey figure recall |
IUC patients Mean (SD): 141 ± 4.22 after COVID-19 diagnosis |
52; 23% women |
Mean (SD): 60 ± 9.9 | Scores of tests, median (range) MMSE: 29 (26–30) COWA S: 48 (29–70) COWA Ph: 39 (15–59) CVLT Immediate: 55 (24–100) CVLT Delayed: 60 (20–100) TOL: 15 (0–22) Rey figure copy: Rey figure recall: 34 (18–36) |
University Hospital, Brescia, Italy | Mattioli et al., 2021 |
| Non-IUC patients Mean (SD): 121 ± 41.2 days after COVID-19 diagnosis |
163; 75% women |
Mean (SD): 49.6 ± 9.4 | Scores of tests - median (range) MMSE: 29 (27–30) COWA S: 46 (19–61) COWA Ph: 37 (3–58) CVLT Immediate: 70 (0–95) CVLT Delayed: 86 (0–107) TOL: 16 (1–22) Rey figure copy: 34 (18–36) Rey figure recall: 18 (2–31) |
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| Multicenter cohort study HADS-D, HADS-A, PSQI |
Mean (SD): 8.4 ± 1.5 months after onset of infection | 1,969; 46.4% women | Mean (SD): 61 ± 16 | Fatigue (61.3%) Pain, headache (45.1%) Poor sleep quality (34.2%) Depression (18.9%) Memory loss (17.3%) Anxiety (15.6%) Cognitive blurring “brain fog” (9.6%) Concentration loss (7.1%) Anosmia (4.05%) Ageusia (2.7%) |
Five public hospitals in Madrid, Spain | Fernández-de-Las-Peñas et al. (2022) |
| Retrospective observational study Surveys containing patient-reported outcomes: FSS, EQ-5D-5L, GAD-7, PHQ-2, Neuro-QoL test, VAFS |
Median: 351 (range 82–457) days after onset of COVID-19 | 156; 69% women | Median: 44; Range:13-79 |
Fatigue (82%) “Brain fog” (67%) Headache (60%) Sleep disturbances (59%) Dizziness (54%) At least mild cognitive impairment (63%) |
Mount Sinai's Post-acute COVID-19 Syndrome Clinic, New York, USA | Tabacof et al. (2022) |
| Prospective observational study Neuropsychological evaluation COMPASS-31, MoCA |
Four weeks – nine months (median: 59; range: 31–175 days) after onset of infection | 180; 70.6% women | Mean (SD): 51 ± 13 | “Brain fog”/cognitive deficit (42.3%) Hyposmia/hypogeusia (37.1%) Myalgia/asthenia (22.7%) Headache (13.4%) Sleep disturbances (10.3%) Dizziness (7.2%) |
University Hospital and Health Services, Trieste, Italy | Buoite Stella et al. (2022) |
| Multi-center observational study | Six months after acute neurological symptoms | 60 | NP | Impaired cognition (68.9%) Residual disability (51.7%) Smell/taste disorder (45%) Memory complaints (34%) Anxiety or depression (32%) |
NeuroCOVID hospital-based registry, France | Chaumont et al., 2022 |
| Follow-up cognitive assessment by phone MoCA-BLIND 7.1 |
Median: 270 days; range: 258–300 | 95; 42% women) | Median: 50 Range: 28-86 |
Easy fatigability (51.04%) Anxiety (38.54%) New-onset headache (38.54%) |
Large tertiary hospital, Tehran, Iran | Mirfazeli et al. (2022) |
| Prospective cohort study PHQ, EST-Q2 Depression subscale, EST-Q2 Anxiety subscale; The Primary Care PTSD Screen for DSM-5, the PTSD checklist for DSM-5, EST-Q2 Insomnia subscale, PSQI |
Mean (SD): 5.65 ± 4.26 months after diagnosis of COVID-19 | 247,249 COVID-19 diagnosis during the study period: 9,979 (67.9% women) No COVID-9 diagnosis: 237,270 (61.7% women) |
COVID-19 diagnosis - mean (SD): 46.6 ± 12.9; Non COVID-19 diagnosis – mean (SD): 48.9 ± 11.9 |
COVID-19 diagnosis vs. no Covid diagnosis, prevalence ratio: Depression – 1.18 Poorer sleep quality – 1.13 Anxiety – 0.97 COVID-19-related distress – 1.05 |
Denmark, Estonia, Iceland, Norway, Sweden, United Kingdom | Magnúsdóttir et al. (2022) |
| PHQ-9-D | Ten months after hospitalization | 101; 42% women | Median: 60.0 IQR: 50.8–66.0 Range: 28-69 |
Fatigue (49%) Cognitive impairment (39%) Signs of major depression (28%) |
RoMed hospital, Rosenheim, Germany | Staudt et al. (2022) |
| Observational study - online survey TSQ |
Three and six months after onset of COVID-19 symptoms | 239; 82.8% women | Median: 50 IQR: 39-56 |
Three months: PTSD (37.2%), anxiety (35.6%), depression (46.9%) Six months: PTSD (26.8%), anxiety (34.7%), depression (40.6%) |
The Netherland and Flanders | Houben-Wilke et al. (2022) |
| Structured questionnaire filled up during phone calls GAD-2 |
Five-eight months after confirmation of SARS-CoV-2 infection | 236; 61% women | Mean: 41.2 Range: 19-81 |
Sleep problems (45.8%) Feeling depressed (44.9%) Memory complaints (39.8%) Anxiety (36.9%) Fatigue (21.6%) Headache (19.1%) Myalgia (16.1%) |
Two public hospitals in the Federal District, Brazil | Titze-de-Almeida et al. (2022) |
| Self administered questionnaires: BDI-II, FACIT-F, IES-R, ISI, RS-14, SF-12, ZSAS | Mean (SD): 88.67 ± 12.62; range: 63–108 days after COVID-19 recovery | 21; 38,09% women | Mean (SD): 57.05 ± 11.02 Range: 39-83 | PTSD (28.6%) Moderate anxiety (14.3%) Moderate depressive symptoms (9.5%) Clinical insomnia (9.5%) |
Pulmonary Outpatient Clinic of Volterra Azienda USL, Pisa, Italy |
Vagheggini et al. (2022) |
| Single-center study Interview, questionaries/tests: DSB, DSF, FAB, HADS, K10, MFTC, MMSE, PSQI, RAVLT, TMT |
Days since first symptoms, mean (SD): 96.5 ± 45.3; since hospital discharge, 62.1 ± 39.7 |
100; 35% women | Mean (SD): 73.4 ± 6.1 | Fatigue (49%) Sleep problems (33%) Attention disorders (30%) Memory disorders (30%) Myalgias (17%) Anosmia (16%) Dysgeusia (12%) Language disorders (12%) Headache (5%) Vertigo (5%) |
Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy | Lauria et al. (2022) |
| Systematic review, meta-analysis of 15 publications Database search (LitCOVID and Embase) |
14–110 days post-viral infection | 47,910 | Range: 17-87 | Fatigue (58%) Headache (44%) Attention disorder (27%) Ageusia (23%) Anosmia (21%) Memory loss (16%) Anxiety (13%) Depression (12%) Sleep disorder (11%) Stroke (3%) PTSD (1%) |
UK/Europe (9), US (3), Australia (1), China (1), Egypt (1), Mexico (1) | Lopez-Leon et al. (2021) |
| Meta-analysis of 18 studies: 3 case-control, 6 cross-sectional, 8 prospective cohort, and 1 retrospective cohort study | Symptoms reported ≥ three months post onset of COVID-19 (mid-term: 3–6 months and long-term: > 6 months) | 10,530; 59% women | Mean (SD): 52 ± 10 | Fatigue (37%) “Brain fog” (32%) Sleep disturbances (31%) Memory problems (28%) Anxiety (23%) Attention disorder (22%) Depression (27%) Myalgia (17%) Headache (15%) Anosmia (12%) Dysgeusia (10%) |
Premraj et al. (2022) | |
| Systemic review and meta-analysis | 257,348 |
Three to < six months: Fatigue (32%), sleep disorder (24%), difficulty concentrating (22%) Six to < nine months: Fatigue (36%), sleep disorder (29%) Nine to 12< months Fatigue (37%) >12 months Fatigue (41%), sleep disorder (30%), myalgia (22%) |
North America (6), East Asia (12), Europe (37), North Africa, the Middle East or South Asia (8) |
Alkodaymi et al. (2022) |
Acronyms: ADL, Barthel Index for Activities of Daily Living; BDI-II, Beck Depression Inventory-II; BDI-13, 13-item Beck's Depression Inventory; CAPS-5, Clinician-Administered PTSD Scale for DSM-5; CFQ-11, Chalder Fatigue Scale; COMPASS-31, Composite Autonomic Symptom Scale 31 questionnaire; COWA, Controlled Oral Word Association (S - Semantic, Ph – phonemic); CVLT, California Verbal Learning Test; DSB, Digit Span Backward; DSF, Digit Span Forward; EQ-5D-5L, EuroQol five-dimension five-level questionnaire; EQ5D, EuroQol-5 dimension index score; EQ-VAS, EuroQol Visual Analog Scale; EST-Q2, Emotional State Questionnaire; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue subscale; FAB, Frontal Assessment Battery; FSS, Fatigue Severity Scale; GAD-2, Generalized Anxiety Disorder 2-item questionnaire; GAD-7, Generalized Anxiety Disorder 7-item questionnaire; HADS, Hospital Anxiety and Depression Scale or Hamilton Anxiety and Depression Scale; HADS-A, Hospital Anxiety and Depression Scale with subscale for anxiety symptoms; HADS-D, Hospital Anxiety and Depression Scale with subscale for depressive symptoms; IES-6, Impact of Event Scale-6; IES-R, Impact of Event Scale–Revised; IQR, Interquartile Range; ISI, Insomnia Severity Index; ITU, Intensive Therapy Unit; K10, Kessler Psychological Distress Scale; MCS, Mental Component Scale; MMSE, Mini Mental State Examination; MFTC, Multiple Features Target Cancellation Test; MoCA, Montreal Cognitive Assessment; mMRC, the modified Medical Research Council; mRS, modified Rankin Scale; Neuro-QoL, Quality of Life in Neurological Disorders; NP, Not provided; OCI, Obsessive-Compulsive Inventory; PCFS, Post-COVID-19 Functional Status Scale; PCL-5, PTSD Checklist for DSM-5; PHQ-2, Patient Health Questionnaire-2; PHQ-9-D (PHQ-9), Patient Health Questionnaire for Depression; PROMIS, Patient Reported Outcome Measurement Information System; PSQI, Pittsburgh Sleep Quality Index; PTSD, Post Traumatic Stress Disorder; RAVLT, Rey Auditory Verbal Learning Test; RS-14, 14-Item Resilience Scale; SAS, Self-Rating Anxiety Scale; SD, Standard Deviation; SF-12, 12-Item Short-Form Health Survey; STAI-Y, State-Trait Anxiety Inventory form Y; TMT, Trial Making Test; TOL, Tower of London; TSQ, Trauma Screening Questionnaire; VAFS, Visual Analog Fatigue Scale; WHIIRS, Women's Health Initiative Insomnia Rating Scale; ZSDS (SDS), Zung's Self-Rating Depression Scale.