key: cord-0953447-dz02mm09
authors: Fusunyan, Mark; Praschan, Nathan; Beach, Scott; Fricchione, Gregory
title: Akinetic Mutism and COVID-19: A Narrative Review
date: 2021-08-27
journal: J Acad Consult Liaison Psychiatry
DOI: 10.1016/j.jaclp.2021.08.009
sha: 0d1cacced1d311a86b2b034970f2efae38eb650a
doc_id: 953447
cord_uid: dz02mm09

BACKGROUND: Coronavirus Disease 2019 (COVID-19) has been associated with neuropsychiatric complications ranging from new-onset psychosis to delirium, dysexecutive syndromes, catatonia and akinetic mutism (AM). AM can be conceptualized as a disorder of motivation wherein patients exhibit a loss of speech and spontaneous movement, owing to disruption of underlying frontal-subcortical circuits. OBJECTIVES: Review the concept and differential diagnosis of AM, as well as the clinical literature on AM in COVID-19. Discuss potential implications for underlying functional neuroanatomy and mechanistic pathways, as well as clinical management. METHODS: A narrative literature review was performed using PubMed querying published articles for topics associated with AM and its occurrence in COVID-19. RESULTS: AM has been described in case reports and a prospective cohort study of COVID patients with neurological complaints. Three COVID-19 AM subgroups can be distinguished, including individuals with severe respiratory illness, those with meningoencephalitis, and those with delirium and pre-existing neuropsychiatric illness. Electrophysiology and functional imaging suggest COVID-19 AM may result from underlying frontal lobe dysfunction and disruption of associated distributed circuits subserving goal-directed behavior. Distinctive combinations of pathophysiological mechanisms may be at play in the different subgroups of COVID-19 AM cases. CONCLUSION: AM has been described in association with COVID-19 and may manifest in clinically heterogenous subgroups with distinct underlying mechanisms. The diagnosis of AM and evaluation of potential etiologies can be complex. The occurrence of AM contributes evidence to the hypothesis of frontal lobe dysfunction in COVID-19.

Coronavirus Disease 2019 (COVID-19) is increasingly recognized as a potent cause of encephalopathy, which is the presenting symptom in a substantial proportion of patients (1) (2) (3) (4) (5) . COVID-associated encephalopathy is not a unitary phenomenon; however, the literature on COVID-19 and delirium has identified unusual characteristics such as pyramidal and extrapyramidal signs, myoclonus, and both severe agitation and hypoactivity (6) .

Among presentations of extreme hypoactivity are cases of akinetic mutism (AM), where patients are awake but mute with minimal spontaneous goal-directed movement due to a profound motivational deficit. AM patients are vulnerable to complications of immobility and often require total care, straining acute care and post-acute rehabilitation settings, and can trigger psychiatric consultation for diagnostic and management assistance.

COVID-associated AM is significant as it may represent the extreme end of a spectrum of motivational deficits in a larger number of patients. Further, AM can be more precisely localized with regards to underlying circuitry than delirium. Its occurrence may signal specific network dysfunction in a substantial subset of COVID-associated encephalopathy cases.

Thus far, the literature on AM in COVID-19 is derived from case reports and a single cohort study that does not provide detailed clinical descriptions (4, (6) (7) (8) (9) (10) (11) (12) . In the following review, we will discuss the concept of AM, review the literature on AM in COVID and offer hypotheses regarding the underlying functional neuroanatomy and potential etiological mechanisms. Implications for management are also discussed. The aim is to raise awareness of severe abulic states in COVID-19 encephalopathy and gauge their potential significance for our understanding of the disease.

Cairns et al. introduced the term akinetic mutism in 1941 to describe a state of wakeful unresponsiveness in a patient with a third ventricle cyst (13) . His definition of AM depicted the striking co-occurrence of alertness as evinced by visual tracking with physical inertness characterized by lack of spontaneous movement, speech, and emotional expression. Importantly, akinesis and mutism were not total; command-following and short, appropriate answers could be elicited with sufficient prompting some of the time.

Cairns' initial definition was essentially preserved in subsequent diagnostic criteria for AM published by the Aspen Neurobehavioral Workgroup, a multidisciplinary collaboration that has set terminology for disorders of consciousness since the mid-1990s (14) . Therein, AM was considered a subtype of the minimally responsive state, later re-characterized as the minimally conscious state (MCS) (15) . The four criteria of AM included 1) akinesis and mutism, 2) preserved visual tracking, 3) brief interaction with vigorous and persistent prompting, and 4) lack of elementary sensorimotor dysfunction (such as quadriparesis) (14) . The most recent Aspen guidelines in 2018 did not make mention of AM (16) , though leading contributors have continued to describe AM as a subset of MCS in other published work (17) .

The intact but dormant capacity for complex behavior in AM has led a number of authors to implicate frontal-subcortical circuits subserving goal-directed behavior. According to this view, AM is conceptualized as an especially severe form of abulia or apathy. C. Miller-Fisher wrote that while AM itself was uncommon, partial presentations, or "abulia minor," were present in a wide range of neurological conditions (18) , anticipating the current interest in apathy as a pervasive clinical issue in neuropsychiatry. However, while AM patients would appear to meet recent consensus criteria for apathy (19) , other authors have questioned the relationship of AM to apathy/abulia, in part due to issues of diagnostic reliability which have not been systemically assessed (20, 21) . We will proceed from the conceptualization of AM as a disorder of diminished motivation, while acknowledging these considerations.

The association between AM and structural brain injury has obscured cases reported in relation to toxic-metabolic as well as immunologic/infectious etiologies. While AM can be a chronic state, particularly in the setting of bilateral lesions, the prognosis differs based on etiology. Unsurprisingly, resolution of the underlying cause such as infection or toxic exposure typically leads to clinical improvement (22, 23) . Moreover, certain important AM etiologies, including delayed post-hypoxic leukoencephalopathy, tend to exhibit substantial improvement as a feature of their natural history (24) .

Like delirium or catatonia, AM is a syndrome rather than a disease and must be fully characterized to guide differential diagnosis. AM has been conceptualized as a profound deficit in motivation due to damage to the mesocorticolimbic dopamine tracts or global dopamine depletion (25) . Consequently, AM patients exhibit minimal goal-directed behavior despite wakefulness and intact sensorimotor capacity. Isolating the motivational deficit in AM requires careful behavioral observation and examination to rule out dysfunction at other levels of the nervous system (Table 1) .

First, the examiner must consider the patient's level of arousal. In AM, patients have intact arousal but diminished motivation with lack of goal-directed behavior. Due to diminished arousal, persistent vegetative states (PVS) also exhibit an absence of goal-directed behavior. Clinically, AM can be distinguished from PVS by the presence of eye tracking (26) .

The relationship between AM and MCS is more complex as AM has been categorized as a subtype of MCS (1). The most recent international guidelines defined the category of MCS plus, which refers to preservation of language function that is a positive prognostic indicator (27) .

Similarly, AM patients may demonstrate transient restoration of speech or action in response to environmental stimuli, classically when speaking on the phone, known as the "telephone sign" (28) . These awakenings reflect the intact but dormant capacity for integrated behavior AM, which is otherwise devastated in many cases of MCS. The absence of goal-directed behavior is typically more extreme in AM, MCS, and PVS than typical delirium. As such, the absence of goal-directed behavior outside of MCS/PVS should raise concern for conative disorders including AM and catatonia. Non-convulsive status epilepticus (NCSE) has been reported in COVID-19 and can also precipitate mutism and stupor (29) .

The next distinction is whether lack of spontaneous movement is due to encephalopathy at all. In critically ill COVID-19 patients, polyneuropathy/myopathy needs consideration as this condition can occur after prolonged sedation and paralysis. In addition, ischemic and hemorrhagic stroke can damage upper motor neuron tracts and curtail movement, with the locked-in syndrome being the most dramatic manifestation (30) . The presence of these insults can obscure co-occurring motivational deficits, such as in the patient that not only "won't" but "can't" (31) . The same may be true to a lesser extent in Parkinsonian states, where there is marked slowness of motor initiation and performance (noting that Parkinsonism may also result in motivational deficits related to mesocorticolimbic hypodopaminergia) (32) .

The final consideration is that of akinetic catatonia, wherein patients can present as immobile and mute with an apparent lack of voluntary movement (28) . Indeed, AM may represent a pure "motor catatonia" with overlapping pathophysiology, but lacking the subjective experience of intense fear or anxiety, which is common in patients with catatonia and may represent a human equivalent of the mammalian fear response (i.e., "playing possum") (28, 33, 34) . Catatonic patients are more likely to exhibit hyperkinetic features such as automatisms (stereotypies, mannerisms) and echophenomena. Interestingly, both AM and catatonic patients may exhibit abnormal tone in the form of gegenhalten, though waxy flexibility and catalepsy are typically absent in AM (28) . Medications such as amantadine or zolpidem may have therapeutic benefit in catatonia and AM (25) , but AM does not typically respond to benzodiazepines (35) . As such, the lorazepam challenge may also have a role for distinguishing catatonia and AM.

AM has been described in case reports of COVID-associated encephalopathy as well as a recent cohort study (7) (8) (9) (10) (11) (12) 36, 37) . While there is no single clinical profile associated with AM in COVID-19, there do appear to be three main subgroups, including patients with 1) severe respiratory illness, 2) meningoencephalitis, or 3) pre-existing neuropsychiatric vulnerability.

Most reported cases have occurred in patients with severe respiratory illness requiring intubation in the absence of meningoencephalitis. In a recent prospective cohort study, Nersesjan et al. reported the development of AM in 8 out of 61 (13%) COVID-positive patients enrolled on admission (11) . In 7 of 8 cases, AM also emerged after extubation and persisted for a median of four days prior to spontaneous recovery. Clinical data was otherwise reported at group rather than case level. In another case report, AM also emerged after extubation in severe COVID-19, lasting for a duration of 5-7 days (7). Imaging and CSF were normal, and the patient's mental status ultimately improved after the administration of high-dose steroids and IVIg.

Another subset of cases involved patients with meningoencephalitis and mild respiratory disease, where AM occurred within a week of symptom onset. For example, two cases of AM were reported after several days of progressive behavioral change with mild respiratory symptoms. Both patients met criteria for meningoencephalitis based on clinical exam and elevated CSF protein and pleocytosis, though severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR was negative. In another case, a healthy 16-year-old girl developed fever, tachycardia, and acute-onset paranoia which progressed to AM over five days with normal CSF studies, serum CRP, and imaging (38) .The patient was also treated with IVIg for presumed parainfectious autoimmune encephalitis, with equivocal response.

In our own COVID-associated delirium case series, three patients aged 68 to 76 with pre-existing neuropsychiatric vulnerability and signs of systemic hyperinflammation presented with acuteonset behavioral changes and progressed from hyperactive delirium to abulia and mutism within the course of a week (5).

Importantly, AM may be underreported in COVID-19, obscured under the label of encephalopathy or dysexecutive syndromes (39) . Moreover, AM may represent the "tip of the iceberg" of more common but subtle abulic presentations in COVID-19. Indeed, a recent survey of "long-haulers" after severe COVID-19 demonstrated significant elevations in apathy on standardized psychometrics (40) . As the literature on AM in COVID-19 develops, we may be better able to characterize prevalence, epidemiology, and clinical course, as well as potential interventions.

The functional neuroanatomy of AM and related states has been clarified by clinical correlation and neuroimaging. Frontal-subcortical circuitry involved in AM may be vulnerable to COVID-19 by a range of putative mechanisms.

Functional Neuroanatomy of AM Early studies on the functional neuroanatomy of AM proceeded from clinical correlation with focal brain lesions, which typically involved anteromedial frontal lobes or centromedian mesodiencephalic regions (28) . Culprit insults were highly varied, ranging from cerebrovascular accident, hypoxia, or neoplasm to neurodegenerative and inflammatory or infectious disease (25) . C. Miller-Fisher attempted to unify these heterogenous findings by positing common disruption to the mesodiencephalofrontal activating system subserving reward and motivationbased goal-directed behavior, identifying mesocorticolimbic dopamine projections as a particular site of vulnerability (18) .

Advances in neuroimaging and functional neuroanatomy have confirmed the general thrust of Miller-Fisher's early observations (25) . Investigators have identified the anterior cingulate cortex (ACC) as the overlapping hub of functional networks affected by diverse lesions in patients with AM (25) . Indeed, AM often results from bilateral anterior circulation infarcts that damage the ACC (41) . Accordingly, the ACC is reciprocally connected to the cingulate motor areas and participates in cortico-striato-thalamo-cortical (CSTC) loops, explaining its involvement in motor and salience networks subserving motivational decision-making (42) . Thus, lesions in the J o u r n a l P r e -p r o o f basal ganglia, thalamus, or midbrain can generate AM phenotypes similar to those precipitated by the frontal lesions described by C. Miller Fisher (43) .

Evidence of Frontal Lobe Dysfunction in COVID-associated Encephalopathy AM may be conceptualized as a frontal lobe syndrome due to disruption of CSTC circuits originating in the ACC. Interestingly, neuroimaging and neurophysiological studies in COVID-19 patients have yielded evidence of frontal lobe dysfunction in COVID-associated encephalopathy, including but not limited to patients with AM.

While diffuse EEG slowing is typically observed in delirium, frontal-predominant theta-delta slowing was reported in up to 33% of cases in a systematic review of 617 COVIDencephalopathy patients (44) . AM has also been reported to be associated with frontal EEG slowing and frontal hypometabolism on perfusion imaging in COVID-19 patients. For example, Nersesjan et al. found frontal intermittent rhythmic delta activity (FIRDA) in 75% cases where EEG was obtained (11). Cani et al. report a case of likely parainfectious immune-mediated AM in COVID-19 associated with frontal EEG slowing and hypoperfusion on fluorodeoxyglucose positron emission tomography (FDG-PET) (12) .

Investigators have also described specific functional networks involved in COVID-associated encephalopathy. Kas et al. report on seven consecutive COVID-19 patients who received FDG-PET imaging during the acute phase and at one-and six-months post-recovery (8) . Frontal behavioral syndromes were the most common clinical feature in the sample, though AM was not specifically investigated. Notably, perfusion imaging showed bilateral frontal hypoperfusion most consistent in the ACC and caudate nucleus. Mild perfusion abnormalities persisted in these regions through six-month follow-up, which may reflect a shared substrate between AM and longer-lasting executive dysfunction observed in many post-COVID patients (45) .

Early clinical reports suggest AM is a heterogenous phenomenon in COVID-19 occurring in the context of 1) severe respiratory illness, 2) CSF-negative encephalitis, and 3) patients with preexisting neuropsychiatric vulnerability following hyperactive delirium. Distinct combinations of etiological mechanisms likely contribute to these respective presentations. See Table 2 for a summary of these etiological mechanisms and Figure 1 for a graphical depiction.

Severe Respiratory Illness Compared to those with mild respiratory illness, mechanically ventilated COVID-19 patients are more likely to develop systemic inflammation (48) , hypoxic-ischemic injury, coagulopathy, and metabolic disturbances (49) , which could all conceivably contribute to AM.

Several authors have compared COVID-associated encephalopathy to neurotoxicity associated with chimeric-antigen receptor T-cell (CAR-T) therapy for hematologic malignancy (50) (51) (52) (53) (54) . CAR-T therapy triggers massive systemic cytokine release thought to disrupt blood-brain-barrier (BBB) function, leading to a distinctive encephalopathy characterized by mutism, loss of spontaneous movement, and aphasia (50) . Cases of AM have also been reported in tacrolimus toxicity, suggesting that a systemically distributed agent can affect particular circuits, perhaps via selective vulnerability of specific regions of the BBB (55) . Regarding SARS-CoV-2 infection, a fenestrated endothelial region like the ACC abutting organum vasculosum, which contains angiotensin II receptors, may be a particularly important candidate zone of AM vulnerability (56) . In this way, intense peripheral inflammation in COVID-19 may produce AM among patients with severe respiratory illness.

Furthermore, hypoxemic-ischemic insult is also a possibility in mechanically ventilated patients and comprises the most common neuropathological finding in patients with severe COVID-19 (2) . AM has been associated with damage to the basal ganglia after acute hypoxia (57, 58) as well as post-hypoxic leukoencephalopathy (DPHL) occurring weeks to months after the initial insult (59) . DPHL following severe COVID-19 hypoxemia has been reported in the literature (60) . Another study of brain magnetic resonance spectroscopy in COVID-19 patients has revealed a molecular signature consistent with DPHL, which may cause AM through damage to white matter tracts involved in motivational functions (61) .

Given the association of AM with cerebrovascular accidents (CVA) (43), COVID-associated vascular disease is another consideration. Although large-scale cerebrovascular disease has not been reported in COVID-associated AM, the contribution of microvascular coagulopathy to neurologic morbidity has yet to be fully elucidated (61) . It is conceivable that strategic infarcts disrupting frontal neurocircuitry in the setting of COVID-19 may contribute to some AM cases.

In the reported cases of AM in meningoencephalitis, symptoms correlated with elevated inflammatory cytokines in the CSF despite normal serum studies; concordantly, improvement in AM coincided with immunosuppressive therapy. These findings lend further support to an immune-mediated mechanism of AM.

Similar to AM in severe respiratory COVID-19, authors have drawn comparisons between CAR-T neurotoxicity and CSF-negative meningoencephalitis. However, massive systemic inflammation was absent in reported cases of CSF-negative meningoencephalitis. Nonetheless, more subtle forms of immune dysregulation could conceivably disrupt BBB integrity, precipitating the movement of inflammatory cells into the CNS.

Other proposed hypotheses implicate immune responses against non-viral antigens in the CSF. For example, evidence of intrathecal antibody synthesis has been reported in CSF studies (62) , and cases of limbic encephalitis have presented in association COVID-19 (9). The proinflammatory effects of COVID-19 may disrupt immune tolerance (63) , leading to autoimmunity against CNS antigens. Alternatively, CSF-negative meningoencephalitis may reflect an immune response to transient, low-grade CNS involvement by SARS-CoV-2 difficult to detect on CSF studies. Indeed, it has been proposed that SARS-CoV-2 may enter the frontotemporal regions at modest levels via the olfactory bulb (64) , transient viral presence in frontal lobe regions could conceivably trigger local inflammation disrupting nearby motivational networks.

Pre-existing Neuropsychiatric Vulnerability Individuals with pre-existing neuropsychiatric illness may have underlying abnormalities in brain function that predispose to abulia in the setting of COVID. Given that massive inflammatory cytokine release may disrupt dopamine synthesis and function in reward and motivation neurocircuitry (31, 65) , patients with decreased functional reserve in the dopamine system may then be especially vulnerable to AM, which is associated with dopamine depletion states, due to selective dopamine receptor vulnerability. Indeed, AM has been described in COVID-19 patients with schizophrenia, Parkinson's disease, and Lewy Body Dementia after profound delirium (4, 66) . Furthermore, prior neuropsychiatric illness may confer sensitivity not only to dopamine depletion but other insults such as hypoxic-ischemic injury, toxic-metabolic disturbance, and the neurotoxic effects of delirium itself (1) . Cumulatively, multiple mechanisms may converge to produce AM features in the neurologically vulnerable.

COVID-associated AM has exhibited a transient course within the period of 1-2 weeks among the small sample of reported cases, consistent with an immuno-metabolic rather than structural process. Early management should aim at assessing for life-threatening or readily reversible causes of decreased responsiveness. Brain imaging, preferably MRI, should be obtained to exclude CVA and unusual presentations such as acute disseminated encephalomyelitis (67); EEG should be performed to exclude NCSE. Risk/benefit considerations will favor lorazepam challenge for catatonia in most cases, though caution should be used in patients with severe respiratory compromise. Lumbar puncture should be conducted when AM occurs in the absence of severe respiratory illness or fails to show steady improvement over the course of one week in post-intubation cases to rule out CNS invasion or autoimmune meningoencephalitis as a complication of COVID-19. In addition to routine cell counts and chemistries, oligoclonal bands, as well as viral and autoimmune encephalitis panels should be obtained. Vigilant supportive care and anticoagulation should be sufficient to prevent complications of immobility given the reported time course of recovery. In persistent manifestations (that is, cases lasting longer than one week without any improvement), it is reasonable to consider pro-dopaminergic medications such as amantadine or methylphenidate (24) , which may also aid in minimizing residual apathy during rehabilitation. The role of immunotherapy is beyond the scope of this review but may offer a targeted therapeutic approach in select cases.

AM is marked by diminished speech and movement due to damage to neural circuits subserving motivation. AM has been reported in COVID-19 patients manifesting decreased responsiveness. Preliminary clinical, electrophysiological, and functional imaging data suggest disruption of frontal-subcortical circuitry in COVID encephalopathy, which may explain AM presentations. Cases of COVID-19 AM have occurred in association with 1) severe respiratory illness, 2) CSFnegative meningoencephalitis, and 3) patients with pre-existing neuropsychiatric vulnerability. The balance of putative mechanisms may differ in each context, but may include immunemediated, hypoxic-ischemic, vascular, and metabolic factors. Management of AM in COVID should include exclusion of other life-threatening or reversible causes, as well as judicious consideration of medication based on clinical trajectory. 

Delirium in Older Patients With COVID-19 Presenting to the Emergency Department

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Neurological manifestations and complications of COVID-19: A literature review

Delirium in COVID-19: A case series and exploration of potential mechanisms for central nervous system involvement

Encephalopathy in patients with COVID-19: A review

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy

The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up

Frontal encephalopathy related to hyperinflammation in COVID-19

Akinetic mutism with an epidermoid cyst of the 3rd ventricle

American Congress of Rehabilitation Medicine. Recommendations for use of uniform nomenclature pertinent to patients with severe alterations in consciousness

The minimally conscious state: definition and diagnostic criteria

Comprehensive Systematic Review Update Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research

Disorders of consciousness after acquired brain injury: the state of the science

Honored guest presentation: abulia minor vs. agitated behavior

Diagnostic criteria for apathy in neurocognitive disorders

Chronic disorders of consciousness. The Lancet

The neurology of decreased activity: abulia

Akinetic mutism -A serious complication to tacrolimus-based GVHD prophylaxis

Akinetic mutism and status epilepticus due to Epstein Barr virus encephalitis

The syndrome of delayed post-hypoxic leukoencephalopathy

On the pathophysiology and treatment of akinetic mutism

Update on diagnosis in disorders of consciousness

Minimally conscious state "plus": diagnostic criteria and relation to functional recovery

Catatonia' due to disulfiram toxicity

Electroencephalographic Abnormalities are Common in COVID-19 and are Associated with Outcomes

Neurological Manifestations of COVID-19: A systematic review and current update

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive

Parkinson's disease after COVID-19

The subjective experience in catatonia: systematic study of 24 catatonic patients

Psychiatrische Praxis

The Madness of Fear: A History of Catatonia

Alternative treatment strategies for catatonia: A systematic review

COVID-19-Associated Encephalopathy and Cytokine-Mediated Neuroinflammation

COVID-19-related encephalopathy presenting with aphasia resolving following tocilizumab treatment

Pediatric Parainfectious Encephalitis Associated With COVID-19

Neurologic Features in Severe SARS-CoV-2 Infection

Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact

Akinetic mutism associated with bicingular lesions: Clinicopathological and functional anatomical correlates

Cingulate-basal ganglia-thalamo-cortical aspects of catatonia and implications for treatment

Akinetic mutism following stroke

Systematic review of EEG findings in 617 patients diagnosed with COVID-19

Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19

Nervous system involvement after infection with COVID-19 and other coronaviruses

COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Relevance

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19

Changes in blood coagulation in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis

Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies

Applying (or Not?) CAR-T Neurotoxicity Experience to COVID-19 Delirium and Agitation

Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy

SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses

Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Akinetic Mutism Induced by Tacrolimus

Integration of Hypernatremia and Angiotensin II by the Organum Vasculosum of the Lamina Terminalis Regulates Thirst

Pearls & Oysters: Bilateral globus pallidus lesions in a patient with COVID-19

Frontal lobe and cingulate cortical metabolic dysfunction in acquired akinetic mutism: A PET study of the interval form of carbon monoxide poisoning

Delayed post-hypoxic leucoencephalopathy presenting akinetic mutism after traumatic cervical cord injury: A case report

Leukoencephalopathy associated with severe COVID-19 infection: Sequela of hypoxemia?

How COVID-19 Affects the Brain

Cerebrospinal fluid in COVID-19: A systematic review of the literature

Autoimmune and inflammatory diseases following COVID-19

Orbitofrontal involvement in a neuroCOVID-19 patient

Akinetic mutism in COVID-19-related encephalopathy: A cytokine-mediated maladaptive sickness behavioral response? Brain Behav Immun -Health

The Effect of the COVID-19 Pandemic on People with Parkinson's Disease

COVID-19-associated acute disseminated encephalomyelitis (ADEM)

None.J o u r n a l P r e -p r o o f

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Drs. Beach and Fricchione received speaking honoraria for a presentation on catatonia and related concepts at the American Neuropsychiatric Association 2021 Annual Meeting.