Saudi Journal for Health Sciences

: 2022  |  Volume : 11  |  Issue : 1  |  Page : 77--79

Neuropsychiatric presentation of coronavirus disease 2019

Yafa Abdulrahman Alshamlan1, Salman Aljarallah1, Omar Alzuman2, Nuha M Alkhawajah1,  
1 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Emergency Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Correspondence Address:
Yafa Abdulrahman Alshamlan
Department of Medicine, College of Medicine, King Saud University, P.O. Box 361540, Riyadh 11313
Saudi Arabia


Coronavirus disease 2019 (COVID-19) pandemic has caused more than 1,000,000 deaths worldwide. Neurological manifestations are increasingly being recognized, mostly with severe systemic illness. Here, we describe two previously healthy males who developed encephalopathy with psychosis, fever, and headache. Investigations were remarkable only for severe acute respiratory syndrome coronavirus 2 RNA in the nasal swab without cerebrospinal fluid pleocytosis or brain imaging abnormalities. Patients received supportive management. One recovered in a short period, while the other deteriorated and passed away. The latter had elevated inflammatory blood markers, which can be useful prognosticators even in patients with neuropsychiatric manifestations.

How to cite this article:
Alshamlan YA, Aljarallah S, Alzuman O, Alkhawajah NM. Neuropsychiatric presentation of coronavirus disease 2019.Saudi J Health Sci 2022;11:77-79

How to cite this URL:
Alshamlan YA, Aljarallah S, Alzuman O, Alkhawajah NM. Neuropsychiatric presentation of coronavirus disease 2019. Saudi J Health Sci [serial online] 2022 [cited 2023 Jun 4 ];11:77-79
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Full Text


Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a pandemic at the end of 2019 and throughout 2020, affecting more than 45 million individuals worldwide.[1] The syndrome commonly manifests with an upper respiratory tract infection or pneumonia. Neurological manifestations are increasingly being recognized and vary in frequency from 36.4% to 57.4% of hospitalized patients.[2],[3] This could be in the form of headache, dizziness, anosmia, ageusia, encephalopathy, or stroke. Encephalopathy in COVID-19 typically occurs in older patients or patients with comorbid conditions and is associated with the respiratory illness.[4],[5] Young patients presenting with COVID-19 and neuropsychiatric features have been rarely reported.[6] Here, we report two young patients who developed severe neuropsychiatric manifestations with variable outcomes. These two cases can help shed light on the relationship between systemic inflammatory response and the possibility of symptoms' recurrence, indicating autoimmunity.

 Case Report

Patient #1

A previously healthy 40-year-old man presented with an altered mental status. Five days prior, he reported headaches, neck pain, blurred vision, nausea, and reduced appetite. A few days later, he developed olfactory hallucinations of a strange smell and a sense of impending doom. To him, reality felt like a dream, and people around him seemed all dead. At the peak of his symptoms, he described being surrounded by light and divine waters flowing through windows, as if he was God. People around him described him as very irritable, confused, and agitated.

In the hospital, he was hemodynamically stable but had a low-grade fever. He was confused, agitated, and delusional but did not have meningeal or focal neurological signs. He was empirically started on meningoencephalitis treatment with intravenous (IV) antibiotics, acyclovir, and dexamethasone. He had moderate hypernatremia and elevated blood levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase, and D-dimer. However, his interleukin-6 (IL-6) level was only minimally elevated (7.53 pg/ml, the normal is 1.5–7.00 pg/mL), and ferritin was normal. COVID-19 nasopharyngeal swab came back positive. Cerebrospinal fluid (CSF) analysis was acellular, but the protein was mildly elevated (0.52 g/L), and glucose was normal. Therefore, antibiotics were discontinued. Chest X-ray and brain computed tomography (CT) were normal. His agitation was managed with haloperidol and valproic acid. The patient gradually recovered to his normal baseline within 3 days and was discharged. Two weeks later, he had a relapse of agitation and psychosis, requiring admission for 10 days before improving and being discharged. This time, he had no COVID-19 symptoms, and SARS-CoV-2 polymerase chain reaction (PCR) was negative. The psychiatric evaluation concluded that his psychosis is not typical for a primary psychiatric disorder and likely to be of organic etiology.

Patient #2

A 46-year-old man without medical illnesses brought with a decreased level of consciousness. Two days prior, he had fever, headache, and psychosis. He had vivid visual hallucinations with paranoid and persecutory delusions. He became increasingly aggressive and combative. He did not use illicit drugs or abuse alcohol. On admission, he was febrile (body temperature of 39.3°C), tachycardiac (130 beats/min), and hypotensive (84/55 mmHg). He required 2 L of oxygen. He was arousable to voice but was disoriented to time, place, and person. He spoke in nonintelligible words and had difficulty comprehending complex phrases. His neck was stiff. There were no focal neurological deficits on examination. Brain CT on arrival was unremarkable, and the initial chest X-ray was normal. Laboratory tests were remarkable for microcytic hypochromic anemia, thrombocytopenia, metabolic acidosis, elevated D-dimer, ESR, CRP, and creatinine. His serum IL-6 level was significantly elevated at 64.12 pg/mL. He received ceftriaxone, vancomycin, and acyclovir without steroids. The antibiotics were discontinued when the CSF showed normal protein and glucose levels without evidence of pleocytosis. COVID-19 nasal swab came back positive. Unfortunately, his hospital course was complicated by worsening respiratory status, persistent fevers with negative cultures, acute kidney injury, and hypernatremia. He was started on broad-spectrum antibacterial in addition to therapeutic anticoagulation due to concerns of pulmonary embolism, given the worsening of respiratory status and high D-dimers. His oxygen requirements continued to increase, and his level of consciousness deteriorated before he was intubated and transferred to the intensive care unit on the 11th day of hospitalization. Antiepileptics were initiated after an episode of facial twitching, but he remained unresponsive. He received IV dexamethasone 6 mg/day for 4 days and hydrocortisone 150–250 mg/day for 7 days. Brain magnetic resonance imaging showed a thin rim of subdural collection consistent with hematoma. However, the patient's condition worsened, and he passed away due to sepsis and cardiorespiratory arrest on the 21st day of his hospitalization.


We report two patients who developed neuropsychiatric manifestations as an initial presentation of COVID-19. The first patient had minimal systemic involvement, evident by the mild elevation in blood markers and no respiratory dysfunction. This contrasts with the second patient, who, despite presenting with a similar neuropsychiatric syndrome, had a more protracted course ending by his unfortunate demise.

In both patients, it is highly likely that the neuropsychiatric dysfunction is a complication of the COVID-19 infection, either via direct viral invasion or indirectly via activation of a secondary immune response. We considered and excluded other possibilities, such as herpes simplex encephalitis, bacterial central nervous system (CNS) infection, drug toxicity, and ischemic stroke. Intriguingly, the first patient had a recurrence of his symptoms, which prompted the consideration of an underlying primary psychiatric disorder unmasked by COVID-19 infection. However, neither he exhibited any psychiatric symptoms prior nor did he have a family history of psychiatric disorders. His visual hallucination, disorientation, and elevated protein are more consistent with a secondary cause of psychosis.


Neuropsychiatric symptoms are being increasingly recognized in COVID-19. The majority of the cerebral manifestations occur in the context of a delirium, typically in the older patient.[4] Pure neuropsychiatric presentations are rare. A large systematic review of neuropsychiatric symptoms associated with different coronavirus infections reported psychotic symptoms in only 0.7% of patients and is mostly attributed to steroids.[7] In a recent UK study of 153 patients with COVID-19 who had neuropsychiatric symptoms, only 10 were noted to have new-onset psychosis.[8] Similar to our cases, here, they also observed an unexpected overrepresentation of younger patients presenting with a pure neuropsychiatric picture.

Mechanisms underlying neuropsychiatric disorders in COVID-19 are being investigated.[5] A commonly discussed theory is a direct viral invasion of the CNS. Evidence for direct viral invasion comes from infection of mice transgenic for the human angiotensin-converting enzyme 2 (ACE2) receptor. When these mice are infected with SARS-CoV, the mice's brains showed evidence of neuronal invasion with little or no inflammation.[9] Coronaviruses have been shown to enter through the olfactory nerve, followed by transsynaptic transfer from the affected neurons.[9] Other methods of entry include vascular endothelium infection or leukocyte crossing blood–brain barrier.[5] After the invasion of the CNS, coronaviruses can persist in the human brain for a very long time, although the consequences of this are unclear.[10] Of interest, histological analysis of 18 brains of patients with systemic COVID-19 failed to show evidence of viral components.[11] It is prudent to mention that, in this series, none of the patients had a predominantly neurologic picture, and almost all died from systemic complications. In the case of the two patients reported here, testing for SARS-CoV-2 RNA in the CNS would have been helpful; however, the test was not available at the time of puncture.

Careful analysis of the course of both cases favors the theory of a secondary autoimmune mechanism, rather than a direct infection for several reasons. The first patient had a recurrence of his syndrome despite a negative COVID-19 PCR, while the second patient's neurologic status deteriorated in line with the worsening of his systemic status and increasing IL-6 levels. Moreover, we did not observe the typical findings of invasive viral encephalitis, such as leptomeningeal enhancement, cerebral parenchymal changes, or CSF pleocytosis.

Secondary immune-mediated encephalopathy can occur in the context of SARS-CoV-2 infection, either as a complication of a systemic cytokine storm or as a CNS-specific autoinflammatory process. An autopsy of six brains from patients with severe COVID-19 infection showed evidence of focal perivascular and interstitial inflammation with neuronal cell loss and axonal degeneration.[12] A CNS-specific autoimmune response complicating viral infections is not a novel concept. For example, cases of NMDA receptor (NMDA-R) encephalitis complicating herpes simplex virus (HSV) encephalitis are well described.[13] Moreover, recent reports from the current COVID-19 pandemic showed that encephalitis with anti-NMDA-R antibodies could also be a secondary manifestation of COVID-19 infection.[14] Given the negative SARS-CoV-2 PCR in the first patient's second presentation, lack of fever, or systemic manifestations, we postulate that the symptom recurrence is caused by a secondary CNS-specific autoinflammatory response. Unfortunately, by the time of patient discharge, this was neither entertained nor tested. Nevertheless, he did not exhibit typical dyskinesia or dysautonomia that is typically seen in NMDA-R encephalitis.


Regarding the outcome, we notice a striking variation between the two patients. We hypothesize that in COVID-19 patients who present with encephalopathy, the overall prognosis is heavily influenced by the degree of the systemic inflammatory response and respiratory disease. This is in agreement with other literature on patients with COVID-19 who present with pneumonia.[15]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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