Isolated Hallucination as a Consequence of SARS-CoV-2 Infection in a 10-year-old Child

Introduction

The SARS-CoV-2 (severe acute respiratory syndrome-2) pandemic, which started in 2019, affects all areas of medicine. It is not the first time that psychiatric disorders are associated with infectious agents. During previous centuries, the occurrence of several neuropsychiatric disorders has increased as a consequence of influenza epidemics; for example, “encephalitis lethargica” is well-known as the Spanish flu pandemic-associated neuropsychiatric syndrome in the beginning of 20^th century. In 2003, SARS-CoV-1 (severe acute respiratory syndrome-1); in 2009, H1N1 (hemagglutinin-1 neuraminidase-1) influenza (swine flu) pandemic; and in 2012, MERS-CoV (Middle East respiratory syndrome coronavirus) also resulted in neuropsychiatric disorders (Manjunatha et al., 2011).

Numerous psychiatric symptoms associated with adult SARS-CoV-2 infection were described, including anxiety, delirium, cognitive impairment, mood disorder, and psychosis, caused by the virus’s direct effect on the central nervous system as well as the immune response to the virus. Symptoms, which are not age-specific, may appear during the acute or post-infection phases. One of these rare psychiatric symptoms is hallucination, which is mainly acoustic (Ferrando et al., 2020; Huarcaya-Victoria et al., 2020; Kozato et al., 2021; Paterson et al., 2020; Rogers et al., 2020; Troyer et al., 2020). Childhood psychiatric disorders have been reported in only a few cases, mainly as part of PIMS (pediatric inflammatory multisystem syndrome) (Hutchison et al., 2020). In childhood SARS-CoV-2 infection, hallucination was described in a 16-year-old girl, as a symptom of a complex neuropsychiatric syndrome only, but not yet as an isolated neuropsychiatric symptom (Gaughan et al., 2021).

Case report

A 10-year-old boy was admitted to our hospital in normal physical and neurological states after becoming suddenly agitated at home on a normal school-day. He pointed to a distant point, and said that an unseen man’s voice instructed him to go to a certain place further from the field of his view. The sound was very disturbing for him. Meanwhile, pronounced restlessness was observed; he was tense and “walked up and down.” Hallucination after half an hour slowly disappeared spontaneously. During the first night in the hospital, the instructional hearing reappeared for a short time connected to a kind of devil figure in a red tower. The boy spent the night calmly; the next day, however, his hearing of that voice reappeared. His restlessness subsided with clonazepam. During next four days, hallucinations did not recur in the hospital.

After 2-week hallucination-free period, his complaints returned several times per day as a repeated half-an-hour long imperative hearing, with pronounced tension, accompanied by restlessness, mild heteroaggression, and occasionally with self-harming thoughts. The hallucination could not be suppressed. The content of this recurring hallucination was always the same.

In his previous medical history, his psychomotor development was normal. He had febrile convulsion during infancy twice and his family was affected by epilepsy. In recent years, he had sporadic weather-related headache. Previously, he had no fever and no obvious sign of an infection, except a slight nasal congestion.

Currently, he is an excellent student, performance-oriented, mostly well-balanced boy. He is living in an ordinary family. His mother was treated for a few years for a mild panic disorder, but there is no other psychiatric disease in the family.

Laboratory blood test results and ophthalmologic examination were normal. EEG (Electro-encephalography) examination showed an episodic theta mixing above the centro-parietal and posterior areas, which raised the possibility of a mild local cortical dysfunction. Due to sudden onset of his psychiatric symptoms blood and CSF (cerebrospinal fluid) sampling for autoimmune encephalitis (NMDA (N-Methyl-D-aspartic acid or N-Methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), CASPR2 (contactin-associated protein-like 2), LGI1 (leucine-rich glioma-inactivated 1), and GABARB1/B2 (gamma-butyric acid receptor type B1/B2)) were also performed, ruling out the presence of any specific antibodies. Clinical signs and symptoms suggest para/postinfectious origin, which was confirmed by positive PCR (polymerase chain reaction) of SARS-CoV-2 and negative serology for herpes simplex virus 1/2, cytomegalovirus, Epstein‐Barr virus, varicella zoster virus, hepatitis A/B/C virus, human immunodeficiency virus, Mycoplasma, Borellia, Toxoplasma, and Toxocara. Brain MRI (magnetic-resonance imaging) examination revealed non-significant lateral ventricular asymmetry and no sign of vascular or inflammatory origin. Repeated blood (e.g., C-reactive protein, D-dimer, fibrinogen, and virus serologies) and CSF studies (electrophoresis and autoimmune tests) were normal, respectively.

His complaints were improved minimally after administration of benzodiazepine derivates (clobazam 0.5 mg/kg/day and alprazolam 0.005 mg/kg). Due to suspicion of PANS (pediatric acute-onset neuropsychiatric syndrome), clarithromycin treatment was started without improvement.

Three weeks after the onset of symptoms, complaints recurred several times daily for more than 10 days. Therefore, oral methyl-prednisolone therapy was started at a dose of 1 mg/kg, and hallucinations slowly and completely disappeared within a week. Corticosteroid treatment was tapered in 6 weeks’ time without recurrence of symptoms, and the boy was able to return to his normal daily activities.

Discussion

The SARS-CoV-2 belongs to Coronaviridae family, Orthocoronavirinae subfamily, genus Betacoronavirus. It is named after the spike proteins of the glycoprotein on its surface, showing similarity to a solar eclipse’s crown in an electron microscope image (Jin et al., 2020). SARS-CoV-2 is an enveloped, positive-stranded, single-stranded RNA virus with a helical nucleocapsid, consisting of genomic RNA and nucleocapsid protein inside the double lipid membrane. The main β-coronavirus carriers are bats and rodents. Currently, sources of SARS-CoV-2 are the infected patients themselves.

In the human body, this spike protein connects with high affinity to angiotensin-converting enzyme type 2 (ACE2) of the endothelium in the lungs, heart, kidneys, and intestine. As a consequence of structural rearrangement after binding, the viral membrane merges with the membrane of the host cell. Due to the initial rapid viral replication, a significant cell death is noted. Immune cells are activated, producing increased amounts of inflammatory mediators and cytokines evolving cytokine storm (Tsatsakis et al., 2020).

SARS-CoV-2 infection usually appears with flu-like symptoms. SARS-CoV-2 infection frequently occurs at first in the respiratory tract, but may extend to the gastrointestinal tracts, liver, and pancreas, causing gastrointestinal symptoms. It may affect the cardiovascular system and may cause renal failure, neurological, and psychiatric symptoms. Acute central nervous system symptoms are non-specific, such as dizziness, headache, hyposmia, ageuzia, delirium, sensory illness, mood disorder, anxiety, memory impairment, and insomnia (Mao et al., 2020). Symptoms caused by SARS-CoV-2 are more severe in adults compared to children (Liguoro et al., 2020).

The following potential mechanisms can be identified for the neuropsychiatric symptoms of SARS-CoV-2: direct viral infiltration in the central nervous system, cytokine dysregulation, and transmigration of peripheral immune cells into the central nervous system as a consequence of increased blood‐brain barrier permeability caused by inflammation (Troyer et al., 2020). Neuronal invasion into the central nervous system occurs via retrograde axonal transport and through epithelium of the olfactory bulb or in the intestinal lymphoid organs by infection of the vagal nerve (Esposito et al., 2020). Elevated levels of proinflammatory cytokines (interleukines: IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNFα)) in the blood are responsible for encephalopathy in the acute phase. Inflammatory cytokines inhibit enzymes responsible for the synthesis of dopamine, noradrenaline, serotonin production, and the basic compounds of cerebral neurotransmission, inducing psychiatric symptoms (Sperner-Unterweger et al., 2014).

Psychiatric symptoms are very rare in childhood as a consequence of SARS-CoV-2 infections. According to our present knowledge, there is no any predicting factor for occurrence of psychiatric signs in SARS-CoV-2 infections in childhood. In our case, the exact mechanism of symptoms could not be determined, but the time course and effective treatments presume two different phases of the disease with different mechanisms. At the time of infection there was a short acute phase, which could be treated by a benzodiazepine derivate and two weeks later, a longer postinfectious phase, which may have been a consequence of a mild encephalitis. It seems to be resolved by corticosteroids, as benzodiazepine derivates were ineffective.

In terms of differential diagnosis, hypervigil delirium could be considered. Acute onset and fluctuation of symptoms would confirm the diagnosis of hypervigil delirium, but the diagnostic criteria of delirium, a deep disorientation of consciousness with incapability of structured thinking and lack of orientation, are completely missing. Neither was insomnia observed in our particular patient. Restlessness and tension could be regarded more pronounced as a consequence of hallucination. Hallucination and restlessness of the child started at home, without changes during the days spent in the hospital. Benzodiazepine administered occasionally for his restlessness could be regarded as a symptomatic treatment without a curative effect. Antipsychotic drugs were not given. Antibiotic treatment, namely, clarythromycin, administered with suspicion of PANS, had no effect. As symptoms seemed to improve after the start of steroid treatment, a virus infection (SARS-CoV-2)-induced encephalopathy with organic hallucination could be regarded as the most plausible explanation for the nature of this case.

In conclusion, during the SARS-CoV-2 pandemic, when new psychiatric symptoms appear, screening for SARS-CoV-2 in childhood is essential, even in the absence of symptoms otherwise characteristic for SARS-CoV-2 infection. Psychiatric symptom improvement can be expected by the treatment targeting the suspected primary disease behind the psychiatric syndrome. In our case, the rapid onset of hallucination seems to be effectively treated with anti-inflammatory therapy.