A rare clinical presentation after COVID-19: Manic episode with psychotic features

Neuropsychiatric manifestations of the COVID-19, caused by SARS-CoV-2, are under close scrutiny as the virus is shown likely to either directly or indirectly affects the central nervous system although it mainly targets the respiratory tract. Here, we describe a middle-aged male who developed acute psychiatric symptoms after a recent COVID-19 infection with no prior personal or family history of psychiatric disorder. Although there are reported cases of diagnosed psychosis or affective disorders following COVID-19 infection in the literature, to our knowledge, this is the first case where the development of autoimmune encephalitis after COVID-19 was considered and ruled out. This case report describes the comprehensive evaluation of all possible organic etiology. We also aimed to discuss possible biological underpinnings of such an exceptional comorbidity.


Introduction
The coronavirus disease 2019 (COVID-19) pandemic resulting from the infection with SARS-CoV-2 has devastated the world in general medicine alongside a significant mental health burden. Although the virus primarily infects the respiratory system and the most common symptoms include cough, dyspnea and fever, current evidence suggests that the clinical manifestations of COVID-19 are not limited to the respiratory system ( Lai et al., 2020 ). Patients with first-episode psychosis or mania-like symptoms after SARS-CoV-2 infection have been reported ( Szcze ś niak et al., 2021 . The neuropsychiatric manifestations of COVID-19 are varied; moreover, in terms of the pathophysiology it is unclear whether the SARS-CoV-2 infection is related to damage to the central nervous system (CNS) or another mechanism such as neurotropism ( Sen et al., 2021 ). The possible ways of neurodegeneration were offered as direct viral infiltration into the central nervous system, proinflammatory cytokine oversecretion via angiotensin-converting enzyme receptor-2, immune cells such as infected leukocytes or monocytes transmigration to the brain, and autoimmunity related to molecular mimicry Troyer et al., 2020 ). Here we present the case report of a patient recovering from COVID-19, who presented a manic episode with psychotic features with no history of mental disorder.

Case report
A 58-year-old male with no prior mental disorder or a significant psychiatric family history was admitted to our emergency unit with a sudden onset of altered behavior including increased activity and energy, unusual talkativeness, reduced need for sleep, and irritability over the last 2 weeks. Forty days prior to the admission, the patient was diagnosed with COVID-19 by the real-time reverse transcription polymerase chain reaction (RT-PCR) test from a nasopharyngeal swab and was hospitalized. At that time C-reactive protein (CRP), d -dimer, and ferritin levels were high in the blood screening (CRP: 106.3 mg/L (reference range: < 7 mg/L), d -dimer: 1.12 mg/L (reference range: < 0.5 mg/L), Ferritin 1603.56 μg/L (reference range: 21.81-274.66 μg/L)). High ferritin levels may be suggestive of hemochromatosis, however, since our patient has not other identified major findings of hemochromatosis (e.g. endocrinopathies, skin involvement, unexplained brain iron accumulation in the brain imaging), we excluded it. According to the existing guidelines, the patient was evaluated in the severe illness clinical category and was treated with favipiravir and oxygen therapy administration using a nasal cannula or a high-flow oxygen device. He had not received corticosteroids for the treatment of COVID-19. After the completion of treatment, he was discharged 3 weeks before the admission to our unit. At the current admission, initial physical examination re- vealed no pathological findings. The blood oxygen saturation was 98% with no fever; however, neurological examination revealed left hemiparesis, which the patient had never experienced previously. Cranial and spinal magnetic resonance imaging and cranial computed tomography scan were non-contributory for any neurological pathology. An electroencephalogram evaluation was also normal. Examination of the patient's mental state revealed the following findings: consciousness was clear and orientation was intact, psychomotor activity was increased while speech was pressured. Referential and persecutory delusions were identified. Substance or alcohol use were excluded through the clinical examination and confirmed via urine screening. A SARS-CoV-2 RT-PCR test from a nasopharyngeal swab was negative. Due to agitated behavior and hostility, the patient was admitted to our inpatient unit with an initial diagnosis of manic episode with psychotic features. The patient received intramuscular injection of 10 mg haloperidol per day during the first week. In the first week of admission, we performed a lumbar puncture (LP) to exclude any organic etiology including acute encephalitis or autoimmune encephalitis. An opening pressure of 145 mm H 2 O with the LP was recorded, while biochemical studies reported normal total protein and glucose in the cerebrospinal fluid (CSF). Microbiological analyses of the CSF sample revealed 5/mm 3 leukocytes, no lymphocytic pleocytosis or neutrophilic predominance. Furthermore, culture of the sample was sterile and the Gram stain was concluded negatively. CSF-PCR tests for Herpes Simplex Virus, Cytomegalovirus, Epstein-Barr Virus, Mycobacterium tuberculosis, and SARS-CoV-2 were concluded as negative. Oligoclonal IgG bands were also negative both in the CSF and serum. To rule out autoimmune encephalitis, we further evaluated Anti-N-methyl-d -aspartate-Receptor, -Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic-Acid Receptor (AMPA-R) − 1, AMPA-R2, Contactin associated protein-2 (CASPR-2), Leucine-Rich-Glioma Inactivated-1 (LGI-1), and Gama-amino-butyric-acid-receptor antibodies, all of which were negative.
After ruling out any organic etiology by detailed clinical assessments and laboratory findings, a diagnosis of bipolar disorder manic episode with psychotic features was confirmed. Accordingly, we switched the treatment to aripiprazole 5 mg/day that was potentiated to 20 mg/day within ten days. The patient's delusions improved and he was remitted within three weeks. However, hemiparesis did not improve during the stay in hospital. Antipsychotic medication had been continued with aripiprazole 20 mg/day for 25 days, after which the score of The Young Mania Rating Scale decreased from 39 to 2, and the total score of Positive and Negative Symptom Scale decreased from 81 to 31. He was discharged from the hospital with the treatment of aripiprazole 20 mg/day.

Discussion
We have described a middle-aged male, who developed acute psychiatric symptoms after a recent COVID-19 infection, in the absence of personal or family history of psychiatric disorder. While infectious or autoimmune encephalitis are possible etiologies, the extensive laboratory workup did not reveal any findings supporting these diagnoses. Since the beginning of the pandemic, several cases of patients diagnosed with psychosis and manic episode have been reported ( Sen et al., 2021 ). Although it is not known whether direct virus neurotropism or neuroinflammation can be implicated, a combined effect of both the immune system activation and viral infection could damage the CNS and lead to neuropsychiatric symptoms, even in the absence of any findings on laboratory studies . Previous studies have reported positive PCR and antibody tests for specific IgG carried out in the CSF for SARS-CoV-2, which suggest that neuroinvasion is a likely mechanism for the pathophysiology ( Lu et al., 2020 ). However, immune system disturbances are also considered to be the major determinant of neuroinflammatory processes that feature in both the etiology and the course of bipolar disorder ( Kirlioglu et al., 2019 ). COVID-19 has been found to be related to cytokine dysregulations, tryptophan metabolism alterations, sleep disorders, and structural changes in the CNS that are similar to BD ( Lorkiewicz and Waszkiewicz, 2022 ). It is suggested that all these changes may trigger or unmask the development of BD ( Lorkiewicz and Waszkiewicz, 2022 ;Del Casale et al., 2022 ). In addition, our patient had a severe illness which may be related to the emergence of neuropsychiatric manifestations, which are considered to worsen the prognosis. Indeed, a recent systematic review revealed that COVID-19 severity is associated with psychiatric sequelae ( Schou et al., 2021 ). Additionally, one of the symptoms of the patient in the current study was hemiparesis accompanying acute-onset psychiatric symptoms, which may implicate a neuroinvasive effect of the virus. It has been reported that subarachnoid hemorrhage, ischemic and hemorrhagic stroke could be induced by SARS-CoV-2 with several mechanisms including hypercoagulability, dysregulated renin-angiotensin system, endothelial dysfunction, and neuroinvasion Small et al., 2022 ). Although hemiparesis has been previously associated with the concurrent ischemic stroke in COVID-19, as far as we know, this is the first patient developed hemiparesis without an ischemic cerebrovascular incident, in the literature ( Hamidi et al., 2020 ). This manifestation could also be evaluated as the direct evidence of neuroinvasion of SARS-CoV-2. In addition, our patient did not received corticosteroids during COVID-19 treatment as corticosteroids are known to trigger mood episodes ( Rogers et al., 2020 ). Another patient, diagnosed with a manic episode after a possible SARS-CoV-2 infection, has been reported ( Park et al., 2021 ). In that case, although the patient's COVID-19 diagnosis had not been confirmed with a RT-PCR test for SARS-CoV-2, patient's psychiatric manifestation had been associated with a possible COVID-19 infection. Russo et al. (2022) highlighted that the existing case reports have a significant inhomogeneity of diagnostic workups which hampered defining the common clinical features of COVID-19 in their systematic review. ( Russo et al., 2022 ) Our case report has several limitations. First, the patient had a manic episode after a severe illness which was a significant stressor for him. It is known that environmental experiences such as psychological stress, play an important role in the occurrence and relapses of bipolar episodes ( Monroe and Slavich, 2020 ). Therefore, it is not possible to completely rule out the role of increased stress in the emergence of manic episode. Secondly, even though our medical work-up including CSF-PCR test for SARS-CoV-2 was non-contributory, we could not measure specific IgG level in the CSF for SARS-CoV-2, which could strengthen our diagnosis.
Overall, our report suggests that various neuropsychiatric manifestations may appear not only during COVID-19 infection but also in the post-COVID phase in patients recovered from the infection. It is noteworthy to mention that follow-up studies are needed for a better understanding of the neuropsychiatric manifestations of COVID-19. Physicians should be aware of and monitor these possible symptoms at the point of defining the disease.

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.

Funding
The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Considerations
The authors declare that they have obtained all appropriate patient consent forms. In the form, the patient has given his written consent for his clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and all efforts will be made to conceal identity