COVID-19 is primarily an acute respiratory syndrome, but it can also cause dysfunction of multiple organs and body systems, including the brain and peripheral nervous system.
COVID-19 can be classified as
Acute COVID-19: The first 4 weeks after onset of illness
Subacute COVID-19: Symptoms and abnormalities present from 4 to 12 weeks after onset of acute COVID-19
Chronic COVID-19 (post–COVID-19): Symptoms and abnormalities that persist ≥ 12 weeks after onset of acute COVID-19 and not accounted for by an alternative diagnosis
Long COVID is a commonly used term broadly defined as symptoms, signs, and conditions that continue or develop ≥ 4 weeks after the initial, usually mild phase of infection.
Neurologic and neuropsychiatric manifestations of COVID-19 have been widely reported and can occur during the acute phase and/or during the recovery period, which can be prolonged.
Pathophysiology of COVID-Related Neuropsychiatric Manifestations
Acute phase
SARS-CoV-2, the coronavirus that causes COVID-19, invades the olfactory bulbs. This invasion may be the cause of alterations in smell and taste; however, it is not clear that the virus directly infects other parts of the central nervous system (CNS).
Neuropsychiatric manifestations of COVID-19 may be a secondary phenomenon rather than the result of direct brain infection; possible mechanisms include
Encephalopathy secondary to factors common in severe illness and to complications that occur during intensive care (eg, hypoxia, electrolyte abnormalities, liver and renal dysfunction)
A viral-induced immune reaction and autoimmunity
Possibly certain COVID-specific complications, such as vascular endothelial damage, a hyperinflammatory state, and/or coagulopathy
Acute, severe COVID-19 often causes systemic hypoxemia and sometimes hypoxic encephalopathy, which has numerous well-known neuropsychiatric manifestations and sequelae, including deficits in cognition and memory, personality changes, and motor impairment. Sometimes residual encephalopathy persists, and sometimes manifestations never fully resolve.
Regardless of the cause, critical illness puts patients at risk of neuropsychiatric complications, including delirium and agitation. Particularly at risk are older patients who are in an intensive care unit (ICU) and who have underlying cerebrovascular disease, heart failure, or hypertension. The risk is due to factors common to critical illness and management in an ICU rather than factors specific to the illness, including COVID-19. These factors include systemic hypoperfusion, prolonged use of sedatives and other drugs, disruption of circadian rhythm and sleep-wake cycles, metabolic derangements (eg, electrolyte abnormalities), and sepsis. When removed from their typical environment and the support of family and friends, older patients, with or without overt dementia, are particularly vulnerable.
A viral-induced immune reaction and autoimmunity may also play a role in COVID-19 pathogenesis. Many patients with severe COVID-19 experience a hyperinflammatory state with a surge of proinflammatory cytokines (a cytokine storm). Molecular mimicry, in which a foreign antigen can resemble a self-antigen, can trigger the autoimmune reaction, a potential mechanism for COVID-19–associated neuropsychiatric complications.
COVID-19–specific complications may be related to a number of factors, including the following:
Interaction between angiotensin-converting enzyme 2 (ACE-2) receptors and SARS-CoV-2: SARS-CoV-2 enters cells through this interaction; this interaction is thought to possibly damage vascular endothelial cells, leading to microvascular problems that may affect the brain. ACE-2 receptors are also widespread in peripheral and CNS neurons.
Changes in brain parenchyma and vessels by SARS-CoV-2: These changes may damage blood–brain and blood–cerebrospinal fluid barriers, resulting in inflammation of neurons, supportive cells, and brain vasculature.
A severe, generalized inflammatory state that affects multiple organs, including the brain: This state often results from severe COVID-19.
Thrombogenic effects of COVID-19: These effects can lead to thrombosis of the brain vasculature and cause acute ischemic stroke.
Chronic phase
After recovery from the acute illness, some patients report a wide range of neuropsychiatric symptoms that persist or first manifest months after initial infection. Problems with thinking, memory, and concentration (so-called brain fog) after critical illness in patients with COVID-19 may result from hypoxia, deconditioning, or posttraumatic stress disorder (PTSD). However, brain fog has also been reported after mild COVID-19, suggesting that other factors may also contribute (1).
Pathophysiology reference
1. Graham EL, Clark JR, Orban ZS, et al: Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers.” Ann Clin Transl Neurol 8 (5): 1073–1085, 2021. doi: 10.1002/acn3.51350
Symptoms and Signs of COVID-Related Neuropsychiatric Manifestations
Neurologic manifestations have been reported in about 80% of hospitalized patients with COVID-19 (1). A large retrospective cohort study reported a substantial incidence of neurologic and psychiatric morbidity during the 6 months after hospitalization for COVID-19, especially in patients with severe disease (2). Autonomic dysregulation (dysautonomia, such as postural orthostatic hypotension) can also develop in COVID-19, more commonly in the chronic phase.
Acute neuropsychiatric symptoms
Acute neurologic complications of COVID-19 can manifest as nonspecific neurologic symptoms such as headache, dizziness, myalgia, and fatigue. Symptoms more specific to COVID-19 include loss of smell (anosmia) and taste (ageusia). In critically ill patients, delirium is common, causing fluctuations in attention, cognition, and level of consciousness; agitation or somnolence may predominate.
Infrequent but more severe neurologic complications of COVID-19 may include acute ischemic stroke, intracranial hemorrhage, meningitis, encephalitis, and seizures. Neuromuscular disorders such as Guillain-Barré syndrome (GBS) have been reported, but the overall incidence of GBS during the COVID-19 pandemic appears to be no different from the baseline rate. However, the number of other infections that can trigger these disorders (eg, influenza) has decreased during the pandemic, so COVID-19 may be increasing risk more than other infections are.
More severe complications of acute COVID-19, such as ischemic or hemorrhagic stroke, hypoxic-anoxic damage, posterior reversible encephalopathy syndrome (PRES), and acute disseminated myelitis, may lead to lingering or permanent neurologic deficits requiring extensive rehabilitation (1). (PRES is an acute or subacute clinical-radiologic syndrome characterized by varied neurologic symptoms, including headache, altered mental status, seizures, and visual disturbances and by a distinctive pattern of signal change in the parieto-occipital area that reflects vasogenic edema [shown on MRI].) Also, acute critical illness myopathy and peripheral neuropathies resulting from acute COVID-19 or from the use of neuromuscular blockers can cause residual symptoms that persist for weeks to months.
Post-recovery and chronic neuropsychiatric symptoms
During recovery and as part of post-COVID syndrome, many patients (eg, 80% in some series, even among patients not hospitalized) report more than one persistent neuropsychiatric symptom, including chronic malaise, diffuse myalgia, and nonrestorative sleep (3). Cognitive impairment occurs with or without fluctuations, including brain fog, which may manifest as problems with concentration, memory, receptive language, and/or executive function. These neurologic and cognitive symptoms are major features of long COVID and often significantly affect activities of daily living.
Migraine-like headaches (often refractory to traditional analgesics) and numbness and tingling are also common. Loss of taste and smell may persist after other symptoms resolve.
Symptoms of mood disorders, mainly anxiety and depression, are common and are more likely in patients recovering from COVID-19 than in those recovering from influenza or other serious respiratory tract infections (2).
Patients are also at increased risk of PTSD, with recurrent, intrusive memories replaying the event and often nightmares; when present, PTSD complicates the diagnosis of any co-existing mood and anxiety disorders (4).
In a recent systematic review and meta-analysis, the pooled prevalence of persistent neuropsychiatric symptoms in patients with long COVID-19 was as follows (5):
Sleep disturbances: 27.4%
Fatigue: 24.4%
Objective cognitive impairment: 20.2%
Anxiety, 19.1%
PTSD: 15.7%
Subjective cognitive impairment:15.3%
Depression: 12.9%
Dysosmia: 11.4%
Dysgeusia: 7.4%
Headache: 6.6%
Sensorimotor disturbances: 5.5%
Dizziness: 2.9% (5)
Symptoms and signs references
1. Liotta EM, Batra A, Clark JR, et al; Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients. Ann Clin Transl Neurol 7 (11):2221–2230, 2020. doi: 10.1002/acn3.51210
2. Taquet M, Geddes JR, Husain M, et al: 6-Month neurological and psychiatric outcomes in 236379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry 8:416–427, 2021. doi: 10.1016/S2215-0366(21)00084-5
3. Graham EL, Clark JR, Orban ZS, et al: Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers.” Ann Clin Transl Neurol 8 (5): 1073–1085, 2021. doi: 10.1002/acn3.51350
4. Kubota T, Kuroda N, Sone D. Neuropsychiatric aspects of long COVID: A comprehensive review. Psychiatry Clin Neurosci 77 (2):84–93, 2023. doi: 10.1111/pcn.13508 Epub 2022 Dec 12.
5. Badenoch JB, Rengasamy ER, Watson C et al Persistent neuropsychiatric symptoms after COVID-19: A systematic review and meta-analysis. Brain Commun 4(1):fcab297, 2021. doi: 10.1093/braincomms/fcab297
Diagnosis of COVID-Related Neuropsychiatric Manifestations
Clinical evaluation
Testing for other causative disorders
MRI of the brain is indicated if patients have focal neurologic deficits and probably if clinicians suspect that neuropsychiatric symptoms are due to acute COVID.
If patients have neuropsychiatric symptoms during or after acute COVID, appropriate laboratory testing must also be done to exclude alternative diagnoses (eg, metabolic disorders, CNS infections and structural disorders, psychiatric disorders).
The criteria for diagnosis of specific mood disorders (eg, major depressive disorder) and anxiety disorders in patients with COVID are the same as those for other people. If patients have cognitive impairment after acute COVID, neuropsychologic testing may help define cognitive deficits and measure their severity. Standard screening tools should be used to identify patients with anxiety, depression, sleep disturbances, PTSD, dysautonomia, and fatigue.
Treatment of COVID-Related Neuropsychiatric Manifestations
Supportive care
Sometimes antidepressants
For most neuropsychiatric sequelae of COVID-19, supportive care is the main intervention. A comprehensive multidisciplinary approach aimed at the optimal management of comorbid conditions in patients with long COVID is important.
Prognosis for COVID-Related Neuropsychiatric Manifestations
The duration and degree of recovery from neuropsychiatric sequelae of COVID-19 are unclear. Prospective studies with longer follow-up are needed.
Key Points
Patients hospitalized with COVID-19 are likely to have neuropsychiatric symptoms during the acute phase and the recovery period.
During the acute phase of COVID-19, critically ill patients may have delirium and agitation or somnolence.
After recovery from COVID-19, many patients report persistent neuropsychiatric symptoms (long COVID); these symptoms may include sleep disturbances, fatigue, impaired memory and cognition, headache, numbness and tingling, or anosmia.
Neuropsychologic testing may be useful in defining cognitive deficits and measuring their severity.
In patients who have acute neuropsychiatric symptoms or who have recovered from COVID-19, exclude alternative diagnoses with appropriate imaging and laboratory testing.
Treat patients with supportive care and antidepressants as needed, and use a comprehensive, multidisciplinary approach to manage comorbid conditions in patients with long COVID.
