An Unusual Case of COVID-19 Presenting as Acute Psychosis

Introduction

The pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) has resulted in over 50 million infected and over a million dead worldwide. ¹ COVID-19 is the newest in the family of 6 other coronaviruses including severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS). ² The first reported case in the United States occurred on January 20, 2020. ³ Since then, over 12,000,000 cases have been reported. The hallmark symptoms of COVID-19 are fever, shortness of breath, cough, as well as malaise, sore throat, anosmia, and ageusia. ⁴ Yet new revelations about presentations and complications continue to pour in to the medical community, including neurological manifestations. Timing of symptoms have been reported to occur anywhere from 2 to 14 days, with an average incubation time of approximately 5 days.

Previous coronaviruses have shown the potential to affect the Central Nervous System (CNS) causing neurological manifestations.^5,6 Definitive pathogenic mechanisms involving CNS invasion remain undetermined.^6,7 Proposed mechanisms include dissemination via the blood into the CNS, translocation from the ethmoid bone to the olfactory bulb, through immune mediated responses, as well as through cells that express angiotensin converting enzyme 2 (ACE-2) lining the blood-brain barrier.^7,8

Neurological symptoms vary, and previous reports have identified patients with anosmia, ageusia, psychosis, delirium, viral encephalitis, seizure, toxic encephalopathy, stroke, and acute hemorrhagic necrotizing encephalopathy.^5,9-12 The occurrence of these neurological symptoms have been observed more frequently in severe cases of COVID-19.^10,13,14 Prevalence of these neurological symptoms has varied. Roughly 35% of patients in a cohort of 214 patients in the Wuhan area experienced neurological symptoms. ¹⁰ Neurological symptoms were also seen in a cohort in France, where over 80% of patients experienced neurological issues at some point in their disease process, ranging from encephalopathy to ischemic stroke. ¹⁵ In patients who developed acute respiratory distress syndrome Helms and colleagues reported neurological features in 58 out of 64 consecutive patients, the majority occurring after treatment with neuromuscular blockade and sedation were withheld. ¹⁶ Described symptoms included agitation, confusion, and lack of response to commands.

We report an unusual case of a patient presenting with acute psychosis in the absence of other clinical findings consistent with COVID-19.

Case Summary

A 58-year old male presented to emergency department accompanied by his daughter. The patient reported that he did not know why he came to the emergency department. The daughter stated that he became increasingly confused and was not acting appropriately, which she had not previously observed. He denied any fever, chills, chest pain, shortness of breath, or gastrointestinal symptoms. Past medical history included coronary artery disease, chronic hepatitis C, polysubstance abuse (including cocaine and alcohol), liver disease, anxiety, and panic disorder. His active medications on presentation included furosemide, lactulose, and spironolactone. Temperature was 98.3°F, pulse was 83 beats per minute, respiratory rate was 18 breaths per minute with oxygen saturation of 97% on room air, and blood pressure was 145/89 mmHg. Physical examination was benign other than the confusion. Pertinent laboratory values included glucose of 130 mg/dL, sodium of 133 mmol/L, potassium of 3.8 mmol/L, serum creatinine of 0.84 mg/dL, total bilirubin of 1.5 mg/dL, AST of 126 IU/L, ALT of 114 IU/L, ammonia of 40 µmol/L, and white blood cell (WBC) count of 2400 cells/µL. Urine drug screen was negative for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, and PCP. Alcohol was not detected in blood. Non-contrasted computed tomography of the head showed no acute process.

The patient was admitted to the hospital for hepatic encephalopathy with chronic hepatitis C. The patient was continued on lactulose. A liver ultrasound was performed on day 2 which demonstrated questionable hepatic cirrhosis, splenomegaly, and ascites. Behavior became more erratic on day 2, as the patient was threatening the staff, throwing objects, and describing hallucinations. The hospitalist of record believed this to be a new onset acute psychotic episode, unrelated to hepatic encephalopathy. He was placed in 4-point restraints and psychiatry was consulted. The patient remained afebrile at this time. Per psychiatry’s subsequent evaluation, the patient appeared highly impaired with unusual disruptions in his cognition and speech patterns that could suggest issues in Wernicke’s area in addition to possible hepatic encephalopathy. He was diagnosed with psychosis (unspecified) was prescribed haloperidol 2.5 mg at bedtime and lorazepam 1 mg every 8 hours as needed for agitation.

On day 3, the patient made some improvement and the decision was made to transfer the patient to an inpatient psychiatric facility. Upon arrival, the patient was noted to have a cough, which triggered a reflex for COVID-19 rule out. He was transferred to a tertiary care facility for further evaluation and COVID-19 work up. A nasopharynx swab was obtained and sent for analysis using Cepheid Gene X-pert rapid polymerase chain reaction (PCR) for COVID-19. During this admission, the patient continued the same abnormal behavior. However, at this time, vital signs showed a temperature of 100.1°F, heart rate 101, respiratory rate of 18 with oxygen saturation of 93% on room air, and WBC count of 2300 cells/µL. He also acknowledged that he had a cough, body aches, chills, and nausea/vomiting. He was admitted for severe sepsis and started on antibiotics. Additional labs included lactate 1 mmol/dL, C-reactive protein of 6.5 mg/L, ferritin 110 ng/mL, and creatinine kinase of 723 IU/L.

COVID-19 by PCR returned positive. The patient was initiated on hydroxychloroquine 400 mg orally every 12 hours for 2 doses, then 200 mg orally every 12 hours. Infectious Diseases was consulted who discontinued hydroxychloroquine due to lack of evidence. Antibiotics were stopped and the patient was continued on supportive care only. The patient continued uncooperative behavior with uncontrollable outbursts, and refusal of physical examination. Oxygen saturation without supplemental oxygen remained above 94% throughout his stay. By day 6, the patient began to calm down, though still complaining of cough. On day 8, the patient continued to remain calm and was able to sit upright in a chair and converse. COVID-19 PCR was repeated on day 9 and 10. The first repeat test was negative however the second was positive. The patient continued to remain calm and was orienting to commands. The daughter agreed to take him home safely and to continue quarantine. The patient was discharged to his daughter’s care and to follow up with primary care physician in 5-7 days.

Discussion

Data remain limited on cases of COVID-19 in patients who present with psychosis without the established respiratory symptoms of the virus. Speculation is that the encephalitis and altered state of consciousness may arise from inflammatory responses and edema in the brain. ¹⁷ Neuroinflammation has been recognized as a key pathway in the development of psychiatric issues including acute psychosis. ¹⁸

A case report from Los Angeles described a patient who presented with symptoms of meningitis (neck stiffness) and was diagnosed with COVID-19, despite showing no respiratory symptoms on initial presentation. ¹⁹ She improved with hydroxychloroquine, but not before experiencing disorientation and hallucinations, though CSF results were never able to conclude the COVID-19 had penetrated her meninges. ¹⁹ In contrast a patient in Japan presented with fever and fatigue, initially presumed to be influenza, which progressed to meningitis. A nasopharyngeal sample was negative for COVID-19, however cerebrospinal fluid results confirmed the presence of COVID-19. ²⁰ He was treated with antibiotics for bacterial pneumonia and favipiravir for 10 days for COVID-19. ²⁰ Additionally, a trio of patients in the Northeast United States presenting to their local emergency department all tested positive for COVID-19, without exhibiting COVID-19 specific symptoms, but with altered mental status, anxiety, and acute psychosis. ²¹ In those patients elevated C-reactive protein (CRP) was consistent across patient laboratory results, which has been hypothesized as being related to potential neuropsychiatric symptoms. ²¹

Other COVID-19 patients have been admitted to facilities showing signs of acute psychosis with the question of what caused the episode to originate; virus versus treatment. ²² Psychosis related to SARS, and other coronaviruses, has been reported, and attributed to patients at higher risk for psychosis from family history, personal history of psychiatric issues, and stressors such as family members being infected with the virus.^23-25 With the known similarities in structure between SARS and COVID-19, these similar manifestations are expected. ²⁶ In the SARS pandemic multiple patients who were treated with high doses of steroids consequently experienced hallucinations and manic disorders, with these subsiding post treatment being stopped. ²⁷ MERS has also been found to be involved with neurological manifestations, with patients presenting with altered mental status and seizure. ¹⁴ Multiple variants within the coronavirus family have been found to be at a higher prevalence in patients who are diagnosed with psychosis and levy that the viral exposure could play a role in the development of long-term psychosis. ²⁸

Fear related to the virus itself, as well as precautionary measures enacted by governments that have led to social isolation among other things, also may play a potential role in inciting psychotic episodes among individuals who have not tested positive for the virus.^29,30 Multiple case reports exists of individuals having psychotic episodes and heightened anxiety requiring hospitalization and medication due to fears related to contracting COVID-19. ³⁰ These cases while often being reported in those with a history of mental illness have also been seen in patients without any known psychiatric conditions. ²⁵

Treatment regimens specific for neurological involvement of COVID-19 have not been reported. Treatment has ranged from supportive therapy to use of experimental treatments, with varying levels of success for general treatment of the virus.^31-34 Limited data exhibiting CSF penetration of drugs that have been used for COVID-19 are available. ³⁵ Animal and human models have shown hydroxychloroquine as the most penetrating (brain: plasma ratio 21%) with similar levels for the janus kinase inhibitor baricitinib (20%) versus the very low penetrating azithromycin and favipiravir. ³⁵ Symptoms of psychosis were reportedly controlled by use of low dose antipsychotics where treatments were described.^25,27 These reports on treating psychotic symptoms with COVID-19 correspond to the patient we report on, where use of low dose antipsychotics in combination with anxiolytics helped to alleviate the patient’s psychosis.

Exact causality is not possible in this case due to several limitations. It is possible that the patient’s hepatic encephalopathy contributed to his presentation. Additionally, the patient was tested on day 3. It is possible that the patient developed COVID-19 upon admission, though unlikely. A recent hepatitis C viral load was not available; correlation between COVID-19 and Hepatitis C could not be performed.

Conclusion

In conclusion, the disease presentation for COVID-19 continues to evolve beyond the established respiratory related symptoms. As with previous coronaviruses, including the SARS pandemic, neurological involvement has been repeatedly linked to patients diagnosed with COVID-19. It is important for providers to be aware of the wide range of possible manifestations, including neurological symptoms, of the virus when complicated cases present themselves. Effective treatments for the virus continue to be researched, however, very little of this work has been related to the neurological symptoms of the disease. How the virus causes neurological symptoms is still not fully understood, though research is ongoing and should continue. Research should continue to elucidate how COVID-19 can present itself across its range of symptoms so that the most effective therapies can be established. Current best treatment appears to be largely supportive and symptom based for neurological complications. If penetration of the blood brain barrier is suspected careful consideration of treatment should be considered based on its ability to reach therapeutic levels in the CSF.