key: cord-0828870-lipme817
authors: Hutchison, Lisa; Plichta, Anna M.; Lerea, Yehuda; Madora, Marlee; Ushay, H. Michael
title: Neuropsychiatric Symptoms in an Adolescent Boy with Multisystem Inflammatory Syndrome in Children (MIS-C)
date: 2020-06-30
journal: Psychosomatics
DOI: 10.1016/j.psym.2020.06.015
sha: ec498a8a5905f015c61a2f09c0cdfd7efe24ac8e
doc_id: 828870
cord_uid: lipme817

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) related to coronavirus disease-2019 (COVID-19) is an emergent syndrome affecting children globally in the wake of the SARS-CoV-2 pandemic. The clinical presentation has similarities to Kawasaki disease and toxic shock syndrome. As knowledge of the cardiac and gastrointestinal manifestations has been emerging, little is known about the impact on the brain. METHOD: This case describes a 14-year-old boy who developed prominent neuropsychiatric symptoms including delirium followed by impairments in executive functioning in the context of MIS-C with positive SARS-CoV-2 antibodies. These symptoms improved in correlation with improvements in inflammatory markers. RESULTS: Neuropsychiatric manifestations including confusion, irritability, and headaches have been reported in pediatric patients with MIS-C. Potential mechanisms include direct neurotropic effect of SARS-CoV-2, secondary effects of systemic inflammation, and/or adverse side effects of treatment. CONCLUSIONS: MIS-C is a novel and poorly understood syndrome related to SARS-CoV-2 with effects on multiple organ systems including the central nervous system. As additional cases are reported and research expands, so too will our understanding of the neuropsychiatric manifestations. Better understanding of the underlying pathophysiology would aid in determining targeted interventions.

The recent SARS-CoV-2 pandemic has been associated with emergence of a new syndrome referred to as Multisystem Inflammatory Syndrome in Children (MIS-C) related to coronavirus disease-2019 (COVID- 19) . As this is an emerging syndrome, knowledge of its presentation and pathophysiology is evolving. MIS-C is currently defined by the presence of fever, inflammation, and multi-organ dysfunction in the context of present or recent SARS-CoV-2 infection or known COVID-19 exposure (1). The syndrome has similarities to Kawasaki disease and toxic shock syndrome. Case series out of Europe and the United States have described presenting symptoms variably including fever, gastrointestinal symptoms, rash, mucosal changes, adenopathy, edema, and respiratory symptoms (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . Headache, irritability, and confusion have also been described, but details regarding these neuropsychiatric symptoms have not been provided. Given the paucity of knowledge concerning this syndrome's effect on the nervous system, the intent of this case report is to describe the neuropsychiatric symptoms in one 14-year-old boy presenting with multisystem inflammatory syndrome and positive SARS-CoV-2 antibodies.

Case A 14-year-old African American boy, with no past medical or psychiatric history, presented to an emergency department in New York City with abdominal pain, fever, and truncal rash in mid-May, 2020. The patient had no known sick contacts and no members of his family had been diagnosed with COVID-19. In the emergency department, the patient was found to have a painful, distended abdomen and was febrile to 102.8 o F with tachycardia and hypotension concerning for shock. Laboratory studies were notable for low white blood cell count (3.8 k/μL) and elevations in c-reactive protein (CRP) (30.2 mg/dL), creatinine (1.4 mg/dL), erythrocyte sedimentation rate (53 mm/h), ferritin (1,305 ng/mL), D-dimer (> 20 μg/mL), bilirubin (2.2 mg/dL), and liver enzymes (ALT 31 U/L, AST 53 U/L). SARS-CoV-2 polymerase chain reaction (PCR) testing was negative. Chest and abdominal computed topography (CT) showed diffuse enterocolitis and bilateral ground glass opacities in the lungs. The patient received fluid resuscitation, empiric antibiotics, and a surgical evaluation. He was admitted to the pediatric intensive care unit (PICU) where he required initiation of norepinephrine to support falling blood pressure. Arterial and central venous catheters were inserted using brief sedation with ketamine and midazolam.

On the day of admission, the patient was started on a five-day course of methylprednisolone 0.5mg/kg every six hours, as well as anticoagulation with low molecular weight heparin. He was placed on high flow nasal cannula for worsening respiratory distress and was noted to have peripheral and facial edema, likely secondary to fluid resuscitation. Serum interleukin-6 (IL-6) was significantly elevated at 5,651 pg/mL (normal < 17.4 pg/mL) while interleukin-1 (IL-1) was mildly elevated at 3.4 pg/mL (normal < 3.0 pg/mL). Echocardiogram showed a left ventricular ejection fraction of 58% and mild coronary artery dilation (z-score < 2.5). During the first night of hospitalization, the patient was noted to be restless, agitated, and confused. Soft wrist restraints were temporarily applied after he pulled out his femoral central line and nasogastric tube. Ketamine was administered for replacement of the central line and a dexmedetomidine drip was started to reduce agitation.

On the second hospital day, the patient's parents felt that he was back to his usual self, though sleepy. Due to concerns for worsening cytokine storm the patient received a single dose of anakinra to target the multisystem inflammation. A repeat echocardiogram showed worsening left ventricular function (ejection fraction 42%) and milrinone was started. Repeat SARS-CoV-2 PCR testing was again negative. As the day progressed, the patient again became disoriented and confused, intermittently sleeping for 10-15 minutes at a time, then awakening and attempting to leave the bed. This culminated in an episode of agitation in the early afternoon during which the patient was disoriented, appeared to respond to internal stimuli, and became aggressive. Several staff members were required to physically restrain the patient to prevent injury and haloperidol 5mg was given intravenously (IV) to target psychosis. Haloperidol was perceived to worsen the agitation, so twenty minutes later, lorazepam 2mg IV was administered, after which the patient calmed and fell asleep. The child and adolescent psychiatry team was consulted but were unable to perform a full evaluation due to medication effects. The psychiatry team suspected hyperactive delirium due to the fluctuation changes in awareness and attention, though the reported worsening of agitation with haloperidol and improvement with lorazepam raised concern for possible agitated catatonia. With this differential in mind, the team recommended olanzapine 5mg by mouth at bedtime. The dexmedetomidine drip was also increased. By that afternoon, the patient had met diagnostic criteria for atypical Kawasaki disease, so a course of 2 gram/kg of intravenous immunoglobulin (IVIG) was initiated, divided over 4 days due to concerns for excess fluid volume in a patient with diminished ventricular heart function and persistent tachypnea.

On hospital day three, the patient remained sedated on dexmedetomidine with intermittent restlessness and verbal aggression inconsistent with the patient's baseline character, which was described as quiet and shy. On hospital day four, the dexmedetomidine drip was discontinued and immediately the patient demonstrated confusion, disorientation, delusions, and aggression. He again received lorazepam 2mg IV, which had a calming effect, and dexmedetomidine was restarted. The patient was given an additional dose of olanzapine 5mg by mouth for refractory delirium and the standing dose was increased to 5mg twice a day. A noncontrast magnetic resonance imaging (MRI) study of the brain was obtained and was unremarkable. A lumbar puncture (LP) was considered but not performed due to the patient's anticoagulation status. Laboratory studies showed ferritin at its peak (1753 ng/mL) while ddimer declined for the first time to 13.37 μg/mL, and CRP (which peaked on day of admission) had come down to 7.8 mg/dL.

On hospital day five, the dexmedetomidine drip was once again discontinued, this time without emergent agitation. The pediatric neurology team evaluated the patient and found him to be sleepy, inattentive, and unable to follow multi-step commands. Tone, strength, and sensation were all intact.

Over hospital days six to eight, the patient showed gradual improvements. He was able to wean off norepinephrine and milrinone, markers of kidney and liver injury improved, and inflammatory markers continued to come down. Coronavirus antibody testing showed presence of SARS-CoV-2 immunoglobulin G antibodies. The olanzapine was decreased from twice a day to once a day and then discontinued. Ongoing abnormalities in mental status documented by PICU staff included increased speech latency, flat affect, and minimal spontaneous activity.

By hospital day nine, the patient was stable on room air. He had been off antipsychotics for over 24 hours and had not had recurrence of agitation. This was the first occasion when the psychiatry team was able to perform a formal, in-person mental status exam while the patient was awake. The exam was significant for flat affect, poor eye contact, and minimal spontaneous movement or speech. His thought process was concrete but linear. On cognitive assessment, the patient was oriented to self, date, and location (hospital), but not circumstances. He believed that he was still in the emergency department and was unaware of how long he had been in the hospital. He had significant impairment in attention, concentration, and short-term memory demonstrated by inability to perform serial 7s (became stuck after first subtraction) or serial 3s (adding instead of subtracting, despite several prompts), inability to say days of the week backwards (reversed directions after two days), and difficulty recalling events from earlier in the day. Strength and tone were normal, but he showed slowing on rapid alternating movements.

The patient was able to follow simple commands ("Touch my finger") but not multi-step commands ("Touch my finger then touch your ear"). He had no difficulty repeating sentences ("No ifs, ands, or buts"), but he demonstrated impairments in executive functioning on the clockdrawing task, needing to have instructions reiterated repeatedly and initially writing all the numbers on one side. He positioned the clock hands to show 6:00 rather than the time instructed (2:50). There was no evidence on exam of hallucinations, delusions, or waxing and waning of his mental status.

As of hospital day eleven, the patient appeared to be back to his baseline neurocognitive status per his parents' assessment: that of a typically developing 8 th grader. On mental status exam, spontaneous movement and speech had returned, and affect was reactive and appropriate.

He exhibited good eye contact, full cooperation, and ability to follow complex multi-step commands ("Touch my finger, then touch your ear and close your eyes"). Attention, concentration, and short-term memory were all improved as demonstrated by ability to complete serial 7s without hesitation, successfully spelling WORLD backwards, and detailed recall of recent events and conversations. Repeat inflammatory markers showed IL-6 49 pg/mL, ferritin 584 ng/mL, D-dimer 2 μg/mL, CRP 5 mg/dL. He was discharged home the following day.

identically, to Kawasaki disease (KD), an inflammatory syndrome associated with systemic vasculitis (12) . Classic KD presents with fever in combination with rash, cervical lymphadenopathy, conjunctivitis, mucosal changes, and swelling/redness of the extremities (13) .

Most cases of MIS-C reported thus far have not met full criteria for KD, but overlapping symptoms have been present to varying degrees (11) . Based on review of ten case series published so far, fever is the most prevalent presenting symptom (part of the case definition), followed by gastrointestinal complaints (present in 60-100% of cases) . Rates of neurological and/or neuropsychiatric symptoms have ranged from 25-56% with the most common symptom being meningism, followed by headache and irritability. Confusion has been reported less frequently but the exact incidence is unclear due to lumping with other neurological symptoms (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . Five of the ten case series reviewed specifically mentioned confusion as a presenting symptom in at least one of the included patients (4-6, 9, 11) . Overt delirium and/or neurocognitive changes have not been specifically reported.

The relationship between MIS-C and SARS-CoV-2 remains undetermined. An epidemiological study of MIS-C in France demonstrated that cases of MIS-C peaked approximately 4-6 weeks following the peak of COVID-19 cases in that country (14) . This finding suggests a post-infectious inflammatory process, though the temporal relationship with the virus is still under investigation. Across case series, the number of patients with MIS-C who had a positive SARS-CoV-2 PCR ranged from 13-69% while the number of patients with positive serology ranged from 53-97% (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . Some of the discrepancy across and within studies is due to changes in the availability of these tests over time. Our patient's positive antibodies with negative PCR supports the post-infectious theory, though the finding of ground glass opacities on chest CT raised concern for active infection. four cases with facial nerve palsy, one with hemiplegia, and a final patient had both facial palsy and hemiplegia (16) . Cases with more diffuse central nervous system (CNS) involvement include one describing a four-year-old with hypotonia, coma, hemiparesis, and seizures during the acute phase of KD illness followed by prolonged neurocognitive impairment resembling autism with intractable seizures (17) . Another case series described four patients with the syndrome of mild encephalopathy with a reversible splenial lesion (MERS) in the context of KD.

The clinical symptoms in these patients included delirium and drowsiness lasting 3-8 days with normal CSF studies and characteristic findings on MRI (18) . Finally, a team in Serbia described a 7-year-old boy who presented with generalized convulsive status epilepticus and depressed mental status which was attributed to cerebral vasculitis secondary to KD. His symptoms improved significantly with IVIG and steroid treatment (19) .

There are several potential mechanisms for our patient's neuropsychiatric symptoms and the etiology was almost certainly multifactorial. First, delirium and other neuropsychiatric symptoms ranging from encephalitis to focal neuropathies, changes in taste and smell, and acute brainstem dysfunction have been described in patients with COVID-19 (20) (21) . The relationship between the SARS-CoV-2 virus and these neurological manifestations may be primary, secondary, or both. A portion of the neuropsychiatric manifestations are likely due to secondary mechanisms such as hypoxia, systemic inflammation, and coagulopathy, but CSF studies and pathological analysis of brain tissue in some patients have shown evidence for direct neurotropic activity by the virus (22) . While our patient's SARS-CoV-2 PCR testing was negative, we cannot rule out active infection.

Cytokine neurotoxicity is also high on the differential as elevated interleukin-6 has been independently linked to delirium in adults (23) (24) . Cytokine storm has been documented in COVID-19 infections and cytokines are similarly thought to play an important pathologic role KD (13, 25) . Knowledge of the neurotoxicity of cytokines is primarily derived from experience with T-cell therapies which are known to trigger cytokine release syndrome. This cytokine release has been associated with confusion, delirium, and language disturbances (26) .

Neurotoxicity from cytokines would explain why the patient manifested the most severe symptoms during the period when his inflammatory markers were most elevated.

Another potential explanation is direct involvement of the CNS by autoantibodies.

Autoantibodies targeting the CNS in the post-infectious period has been documented in syndromes including acute disseminated encephalomyelitis (ADEM) and autoimmune encephalitis (27) . Since no lumbar puncture was performed, it was not possible to directly evaluate the CSF for evidence of a humoral immune process, which could include presence of white blood cells, elevated proteins, or oligoclonal bands. Our patient's unremarkable MRI is inconclusive given that MRIs are often normal in autoimmune encephalitides, especially in the early phases of illness (28) . The effectiveness of IVIG in the treatment of MIS-C suggests that antibodies likely play a role in the pathophysiology, though as in KD, the exact role of antibodies is yet unknown (29) .

Finally, the neuropsychiatric symptoms could have been secondary to treatment with high-dose corticosteroids. Corticosteroids carry significant risk of neuropsychiatric side effects including mood changes, psychosis, delirium, and changes in executive functioning (30) . The patient's symptoms began approximately 18 hours after methylprednisolone was initiated and significantly improved after its discontinuation. Since steroid exposure and the peak of the inflammatory process were temporally correlated, it remains difficult to tease apart their individual effects. Iatrogenic administration of other deliriogenic medications including ketamine, midazolam, and lorazepam may also have contributed to symptoms, though the patient's exposure to these medications was sporadic and failed to temporally associate with symptoms.

As the SARS-CoV-2 pandemic progresses, cases of MIS-C associated with COVID-19 are expected to increase and with it, our understanding of the underlying pathophysiology and potential manifestations. There are not, as of yet, any evidence-based treatment guidelines and due to the potentially serious outcomes of the presenting syndrome (shock, cytokine storm, vasculitis), early treatment with potent pharmacologic agents is empirically initiated. This case represents one example of neuropsychiatric symptoms associated with MIS-C, but it is not the only one in which similar symptoms were reported. As additional cases are described, a pattern of neuropsychiatric manifestations may emerge, or evidence of an iatrogenic mechanism may become apparent. Hopefully, additional experience and research will provide a better understanding of this syndrome and more targeted interventions.

The authors declare that they have no conflicts of interest to report.

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