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. 2023 May 22;2(1):100133. doi: 10.1016/j.psycr.2023.100133

COVID-19 psychosis versus psychosis due to cytotoxic lesion of the corpus callosum (CLOCC): A case report and review

Yuval Levin a, Ayyub Imtiaz b,⁎, Benedicto Borja c
PMCID: PMC10200715  PMID: 37251527

Abstract

Background

Cytotoxic lesions of the corpus callosum syndrome (CLOCC) is an inflammatory disorder caused by various etiologies such as medications, malignancies, seizure, metabolic abnormalities, and infections, especially COVID-19. It presents on MRI as an area of restricted diffusion in the corpus callosum. We present a case of psychosis and CLOCC in a patient with mild active COVID-19 infection.

Case

A 25-year-old male with a history of asthma and unclear past psychiatric history presented to the emergency room with shortness of breath, chest pain, and disorganized behavior. His-COVID-19 PCR was negative, and he was voluntarily admitted to psychiatry for management of unspecified psychosis. Overnight, he spiked a fever and was diaphoretic with headache and altered mental status. Repeat COVID-19 PCR at this time was positive and cycle threshold indicated infectivity. A brain MRI showed a new restricted diffusion within the midline of the splenium of the corpus callosum. Lumbar puncture was unremarkable. He continued to have flat affect and exhibit disorganized behavior with unspecified grandiosity, unclear auditory hallucinations, echopraxia, and poor attention and working memory. He was started on risperidone, with an MRI after 8 days showing complete resolution of the lesion in the corpus callosum and symptoms.

Conclusion

This case discusses diagnostic difficulties and treatment options for a patient presenting with psychotic symptoms and disorganized behavior in the context of active COVID-19 infection and CLOCC and highlights differences between delirium, COVID-19 psychosis and neuropsychiatric symptoms of CLOCC. Future research directions are also discussed.

Keywords: Covid-19, Psychosis, Cytotoxic lesions of corpus callosum, Delirium

1. Introduction

Psychosis refers to a condition that affects the mind and results in one's altered interpretation of people and events around them with symptoms including but not limited to hallucinations, delusions, disordered thought content or speech, and inappropriate behavior. Psychosis is commonly seen in primary psychiatric disorders, such as schizophrenia; however, it is also commonly associated with medical conditions or medications.  One medical condition that has become more apparent in its role in inducing psychosis over the last few years is SARS-CoV-2, also known as COVID-19. Studies have shown increased rates of psychosis in patients with no prior psychiatric history following COVID-19 infection, though it is poorly understood if this presentation is in fact delirium associated with infection or rather the result of an inflammatory process in the brain (Smith et al., 2021; Kulaga and Miller, 2021). Furthermore, it is important to consider the impacts of medications often used to treat significant inflammation such as glucocorticosteroids, which have a known role in the development of psychosis.

Another condition that has been more recently related to COVID-19 is cytotoxic lesions of the corpus callosum syndrome (CLOCC), which is an inflammatory disorder with various causes and is identified on brain imaging as areas of restricted diffusion in the corpus callosum, usually in the splenium. Various causes and presentations of CLOCC have been reported in the literature, including psychosis and other psychiatric manifestations, especially in the pediatric population (Starkey et al., 2017; Yilmaz Çelebi et al., 2021). While it is important to note different diagnostic tools such as EEG and MRI to differentiate between COVID-19 encephalopathy/delirium, COVID-19 psychosis, and CLOCC secondary to COVID-19 infection, there is considerable overlap in the symptomatology and diagnostic work up may be non-conclusive.

Though there have been reports of COVID-19 delirium and COVID-19 psychosis, to our knowledge, there are few reported cases of CLOCC psychosis in the setting of COVID-19. Additionally, the majority of literature reporting symptomatic CLOCC have been reported in patients with severe manifestations of the infection, such as COVID-19 pneumonia, with some exceptions (Elkhaled et al., 2020; Kubo et al., 2022). Consequently, little is understood about the neuropsychiatric effects of CLOCC and even less about the proper management and long-term implications of the condition. This case discusses the diagnostic difficulties and treatment options for a patient presenting with psychotic symptoms and disorganized behavior in the context of active mild COVID-19 infection and CLOCC and highlights differences between COVID-19 delirium, COVID-19 psychosis, and CLOCC psychosis secondary to COVID-19 infection.

2. Case

2.1. INITIAL PRESENTATION

Patient is a 25-year-old assigned male at birth who presented to the emergency department complaining of symptoms and ECG concerning for pulmonary embolism. He was COVID-19 vaccinated and initial PCR was negative. Chest imaging and workup were all normal, including negative urine drug screen. Repeat ECG after some observation showed resolution and return to sinus rhythm.

During observation in the emergency room, he was paranoid and tangential. There were collections of old food that he was hiding in various parts of his clothing. He was later found in another bed completely naked stating that “I've decided to give my clothes away. I am here to say my life story.” Psychiatry was consulted for disorganized thought process and behavior.

2.2. HISTORY AND EXAMINATION

Patient reported coming to the hospital because he was “doing too much of everything” and reported that others may want to hurt him because he was “trying to do too much.” When asked to elaborate, he would say "too busy doing everything, cooking, cleaning.” His-thought process was very disorganized, constantly referring to people and objects by letters and spoke in a vague superlative manner, stating “yes,” “everything,” or “anything” to many interview questions.

The patient endorsed thought broadcasting and unspecified grandiosity, stating that he needed to learn new things in order to teach others. He also reported auditory hallucinations and was seen overtly responding to internal stimuli throughout the interview. He denied delusions of reference, thought withdrawal, thought insertion, suicidal ideation, homicidal ideation, and any symptoms of mood, anxiety, posttraumatic stress, or obsessive-compulsive disorders.

The patient said he has a family history of psychosis, as well as a recent psychiatric hospitalization secondary to psychosis. This other recent hospitalization which occurred 3 weeks prior, was also in the context of a COVID-19 positive infection. He was discharged from that hospital stay on 2 mg risperidone by mouth which he had been adherent to.

On examination, the patient appeared diaphoretic, removing his clothes, but calm with no significant psychomotor agitation or retardation. He had a flat affect and spoke in a monotone but normal volume and rate. Digit span was 3 during initial assessments. Patient exhibited echopraxia without automatic obedience. Mini-Mental Status Examination score was 22/30, with difficulty with attention, calculation, immediate and recent memory, writing, and coping intersecting pentagrams.

2.3. HOSPITAL COURSE

Patient was admitted to the psychiatry inpatient unit for diagnostic clarification, medication management, and psychiatric stabilization. He was started on risperidone 1.5 mg by mouth twice a day.

Overnight, he developed fever, diaphoresis, neck stiffness, headache, and photophobia. He was dumping ice on his bed and lying down in it naked. A repeat COVID-19 PCR was done which returned positive with a cycle threshold level of 19.5. MRI head was done which showed a small focal area of restricted diffusion within the midline splenium of the corpus callosum (Fig. 1 ).

Fig. 1.

Fig 1

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Selected sequential axial slices of various MRI techniques of the head on Day 4 of admission revealed a focal area of restricted diffusion in the midline splenium of the corpus callosum. Originally read as a potential acute infarction of the corpus callosum by the radiologist, this was later determined to be a cytotoxic lesion of the corpus callosum (CLOCC) and reversible.

He was shifted to the medical floor for further evaluation and management of possible meningitis or encephalitis. Patient continued to respond "yes" or "everything" to most questions. Other disorganized behavior seen included taking off all his clothes, lying face first on the floor, standing with his face towards walls, spitting out his food stating “I have to save it for the people who need it”, throwing all the bed sheets and pillows in the trash bin, washing his mouth with soap, as well as pulling out intravenous lines. He would report auditory hallucinations of unknown people telling him to do all those behaviors and would be seen overtly responding to internal stimuli during these examinations.

Blood cultures, lumbar puncture, and CSF workup for various pathogens and autoimmune conditions were all negative. An EEG was done at this time as well which demonstrated normal posterior dominant rhythm (Fig. 2 ). The patients’ symptoms improved over the next few days, including orientation, working attention, auditory hallucinations, and disorganized behavior. At the complete resolution of his symptoms, his COVID-19 cycle threshold was 32.7 and repeat MRI of the brain showed complete resolution of the corpus callosum lesion (Fig. 3 ). He was discharged on risperidone 3 mg by mouth twice a day and trazodone 25 mg by mouth as needed at bedtime.

Fig. 2.

Fig 2

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An electroencephalogram (EEG) that was conducted during the period of time he was exhibiting psychiatric symptoms. There was a normal posterior dominant rhythm and was deemed a normal EEG by neurology.

Fig. 3.

Fig 3

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Selected sequential axial slices of various MRI techniques of the head on Day 12 of admission shows complete resolution of the focal area of restricted diffusion in the midline splenium of the corpus callosum. Repeat imaging with improvement in psychiatric symptoms confirmed the diagnosis of a cytotoxic lesion of the corpus callosum (CLOCC).

2.4. DIAGNOSIS

There are multiple potential causes for a patient presenting to the emergency room with symptoms of psychosis and disorganized behavior. Initial differential included COVID-19 encephalopathy/delirium versus COVID-19 psychosis versus CLOCC psychosis due to COVID-19. As the EEG was normal, delirium was ruled out. COVID-19 psychosis was considered a possibility as the patient had 2 episodes of psychosis only in the context of an active COVID-19 infection. However, in the current presentation, the psychiatric symptoms correlated and resolved with the timeline of the corpus callosum lesion seen on MRI. The neuropsychiatric presentation combined with the reversibility of the lesion highly suggests CLOCC, most likely secondary to the active COVID-19 infection in our case. Furthermore, the demographic variables of the case, especially age, correlate well with the increased probability of psychiatric symptoms, specifically psychosis, due to CLOCC secondary to COVID-19, as compared to an older population which primarily manifest CLOCC as neurological symptoms. This is different to the picture seen in COVID-19 psychosis where imaging has mostly been normal in the literature. These distinctions are discussed in great detail in the sections below.

3. Discussion

3.1. COVID-19 ENCEPHALOPATHY/DELIRIUM

Acute viral illnesses and other acute medical conditions are known to potentially precipitate a pre-existing primary psychotic disorder leading to decompensation (Rentero et al., 2020). Most acute infections can present as delirium and have psychotic symptoms as well as attention difficulties, such as the patient in the case.

The patient had a previous short lived psychiatric hospitalization with complete resolution of psychotic symptoms also in the context of an acute COVID-19 infection. An acute decompensation with confirmed medication adherence could mean another episode of delirium, possibly from re-infection. As COVID-19 testing can remain positive for many months after the initial episode, a cycle threshold test is useful to determine acute versus past infection for COVID-19. Cycle thresholds less than 20 tend to indicate infectivity, and cycle thresholds over 30 for non-infectivity (Waudby-West et al., 2021). In our case, the patient had demonstrated low cycle thresholds during the periods of symptoms and a cycle threshold over 30 at the resolution of symptoms.

Since psychotic symptoms can be a sign of delirium, it can be difficult to determine what the underlying cause of the psychosis is. A scoping review of patients in ICU settings found that EEG findings, especially occipital slowing, are almost always prevalent in a patient with delirium, and a negative EEG makes delirium unlikely (Wiegand et al., 2022). Our patient had a normal EEG with a normal posterior dominant rhythm. Additionally, articles have suggested patients presenting with psychosis and COVID-19 infection were misdiagnosed with COVID-19 psychosis and were actually presenting with delirium (Tripathy et al., 2021).

The patient was started on antipsychotics during his admission, and the dose was up titrated. While the use of antipsychotics in non-agitated delirium remains controversial, there is an agreement on treating the underlying condition causing the encephalopathy (Nikooie et al., 2019). In the case of a mild systemic COVID-19 infection, as well as most other viral infections, supportive care is recommended. It is possible that no antipsychotic would be required in such cases of non-agitated COVID-19 delirium.

3.2. COVID-19 PSYCHOSIS

Coronaviruses, including COVID-19, and many other viruses such as HIV, HCV, and HSV have demonstrated neurovirulence, leading to psychosis in some individuals. However, SARS and Middle East Respiratory Syndrome have not been associated with psychosis (Rogers et al., 2020). Both have associations with memory issues, fatigue, and depression long term, which are shared symptoms with the neuropsychiatric symptoms of Long COVID (Davis et al., 2023). COVID-19 infections have resulted in acute psychosis in patients requiring long term medication without any past history of psychiatric conditions. Hence it is highly plausible that a unique infectious pathophysiology is resulting in COVID-19 psychosis.

Multiple reviews have been done examining the association between COVID-19 and psychosis (Smith et al., 2021; O’Leary and Keenmon, 2023; Chaudhary et al., 2022). The median age appears to be between 40 and 44 years depending on sex, with males closer to 40 and females closer to 44 years (Smith et al., 2021; Chaudhary et al., 2022). Various potential causes of COVID-19 psychosis have been theorized, from direct neurovirulence, inflammatory consequences, or immunological processes (Tripathy et al., 2021). COVID-19 symptoms are thought to persist for a longer duration compared to delirium and symptoms are present in the context of normal neuroimaging, EEG, and CSF analysis (Lim et al., 2020). Our case had findings on neuroimaging but had a normal EEG and normal CSF examination during the period of psychotic symptoms, which aligns with presentations of COVID-19 psychosis. However, the majority of cases included in the reviews resolved over a very short period of time, on less than adequate dose of antipsychotics, and for a duration of treatment less than expected before response (O’Leary and Keenmon, 2023; Chaudhary et al., 2022). This contradicts the clinical definition of COVID-19 psychosis (Lim et al., 2020). It is highly possible that many of the reported cases of COVID-19 psychosis in the literature were actually COVID-19 delirium, which the reviews acknowledge (Smith et al., 2021; O’Leary and Keenmon, 2023; Chaudhary et al., 2022). One of the articles removed cases from the analysis that they thought were clearly demonstrating delirium despite the original publication diagnosing COVID-19 psychosis (Smith et al., 2021). Nonetheless, there have been documented cases of long-term psychosis, with recurrence of symptoms on medication nonadherence, prolonged treatment, and mild residual symptoms which appear to follow along the prolonged neuropsychiatric sequelae of previous coronavirus endemics.

In the most recent systematic review on COVID-19 psychosis, they included neuroimaging findings described in the cases (Chaudhary et al., 2022). Only 2 out of 57 cases in the review mentioned patients who had CLOCC on imaging, with the rest having no findings or unreported findings. These were in a 23-year-old male and a 33-year-old female, which are considerably younger patients than the median age demonstrated for COVID-19 psychosis in the literature. COVID-19 is known to affect older ages in different ways than younger ages, so there may be a different pathophysiology at play for CLOCC than COVID-19 psychosis (Mueller et al., 2020).

3.3. CLOCC PSYCHOSIS

Cytotoxic lesions of the corpus callosum (CLOCC) were previously known as mild encephalopathy with a reversible splenial lesion (MERS), reversible splenial lesion syndrome (RESLES), and transient lesions of the splenium of the corpus callosum (Gaillard et al., 2023). It is thought to develop from high levels of cytokine release due to cell-cytokine interactions from the inflammatory response. This results in elevated levels of extracellular glutamate causing a shift of sodium into cells. The increased concentration within neurons leads to a movement of water and development of cytotoxic edema (Starkey et al., 2017). This results in the neural dysfunction in the corpus callosum and microglia, which are the immune cells in the central nervous system. Often misread on radiology as an ischemic infarction (Starkey et al., 2017), similar to our case, CLOCC has various other etiologies. These include seizures, metabolic disturbances, infections including COVID-19, malignancy, medications such as antipsychotics, and in some cases of subarachnoid hemorrhage (Gaillard et al., 2023).

CLOCC has a heterogenous presentation of neurological and psychiatric symptoms. Psychiatric presentations of CLOCC, specifically psychosis, are often seen by mental health professionals, and there have been documented reports of CLOCC without COVID-19 infection (Tatar et al., 2022; Kuczynska et al., 2022). A review conducted on CLOCC secondary to COVID-19 found 30 cases and demonstrated a wide range of symptom presentation across various ages (Kubo et al., 2022). The median age was 40 years old, which is like the median age found in COVID-19 psychosis. Most of the cases also had no previous medical or psychiatric history. CSF examination was done in many of the reported cases and were normal, similar to our patient. However, many of the patients listed in the review and other found case reports had significant medical issues as well due to the COVID-19 infection, including hypoxemia and COVID-19 pneumonia in adult population and Multisystem Inflammatory Syndrome in Children (MIS-C) in the pediatric population (Kubo et al., 2022; Inalkac Gemici and Tasci, 2021; Gursoy et al., 2021; Abid et al., 2023).

Furthermore, the majority of the CLOCC psychosis secondary to COVID-19 was shown in patients under the median age (Kubo et al., 2022), which is further corroborated by systematic reviews on COVID-19 psychosis which report that patients who had psychotic symptoms and CLOCC were younger (Chaudhary et al., 2022). Patients closer to the median age and older appeared to have more neurological symptoms of CLOCC making it less likely that they were seen by mental health professionals (Inalkac Gemici and Tasci, 2021; Gursoy et al., 2021). However, no studies testing this hypothesis showing statistical significance were found. It is theoretically possible that CLOCC psychosis secondary to COVID-19 and COVID-19 psychosis have slightly different pathophysiology and further study is required.

Mild COVID-19 infection with CLOCC psychosis has not been demonstrated in the literature, except for the case described in the review article (Kubo et al., 2022). However, the patient was 61 years old, has a past history of Alzheimer's, and presented with primarily neurological symptoms. CLOCC has been usually reported as a self-limiting condition with the treatment and prognosis catered towards the underlying cause. Antipsychotic use for patients with psychiatric symptoms of CLOCC due to COVID-19 is not well studied and could have potential harmful effects as antipsychotics have also been associated with CLOCC development (Gaillard et al., 2023).

4. Future directions

While there appear to be distinct differences based in the literature between COVID-19 delirium, COVID-19 psychosis, and CLOCC psychosis secondary to COVID-19, more studies are needed to determine if these conditions are truly separate clinical entities or conditions that result from an inflammatory response. Furthermore, studies examining potential risk factors for COVID-19 psychosis need to be conducted. The authors suggested that age could be a potential factor in differentiating COVID-19 psychosis from CLOCC with psychiatric symptoms, but there are no current studies to determine statistical or clinical significance. Lastly, there is a gap in knowledge about management of these conditions, and further studies determining the role of antipsychotics, and the dose and duration of treatments are required.

Funding

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

Ethical statement

Informed consent was obtained for publication by the patient. All personal and identifying information has been removed.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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