The seventh member of the family of coronaviruses that infect humans, SARS-CoV-2, first became a concern for Chinese health officials in late December 2019.1 By March 11, 2020, the World Health Organization classified SARS-CoV-2 a pandemic, due to concern for the alarming rate of spread and severity of the disease.2 As the pandemic has progressed, most literature has focused on the respiratory illness associated with the virus. However, extra-pulmonary manifestations are being increasingly described particularly in pediatric patients.
At time of publication, there were a limited number of case reports focused on SARS-CoV-2 encephalopathy. A retrospective case series by Mao et al indicated that neurologic symptoms are common in SARS-CoV-2 patients with up to 36% of patients demonstrating neurologic involvement. Primarily, these manifestations include acute stroke, consciousness impairment and skeletal muscle injury, all seen more commonly in individuals classified as having severe disease.3 We present a case of SARS-CoV-2 related encephalopathy in a previously healthy 20-year old female with otherwise mild disease to highlight one of the lesser-discussed, but severe manifestations of SARS-CoV-2.
A 20-year-old female with past medical history of obesity and anxiety presented to the emergency department with 4 days of nasal congestion, fever, ageusia, insomnia and altered mental status (specifically, confusion with performing routine daily activities, hypervigilance and obsessive thinking). The patient had a family history notable for panic disorder in both parents and schizophrenia in a maternal aunt. On initial evaluation, the patient was oriented to person and place. She responded to questions appropriately, although with slight delay. Psychiatry consult recommended administration of lorazepam for anxiety, after which her mental status began to deteriorate and she was no longer able to answer questions.
Workup revealed a positive COVID-19 polymerase chain reaction (PCR) obtained by nasopharyngeal swab, a negative head CT, and CXR with faint right lower lung field opacity. Inflammatory markers were elevated with initial CRP 4.67 mg/dL (0–0.4 mg/dL), Ferritin 563 ng/mL (15–150 ng/mL) and D-Dimer 316 ng/mL DDU (0–230 ng/mL DDU). Thyroid levels resulted borderline with T4 Serum 11.6 µg/dL (4.6–12 µg/dL) and TSH 0.29 µlU/mL (0.27–4.2 µlU/mL). All other initially obtained labs were within normal limits. Patient was treated with levofloxacin, due to penicillin allergy, and acyclovir while awaiting cultures from cerebral spinal fluid.
On hospital day 2, the patient’s mental status further deteriorated in the setting of persistent fevers. She was alert but could not confirm that she was oriented x3. Her speech was repetitive, confused and stuttering, and she did not follow verbal directions. She was tremulous but able to move all extremities purposefully, and demonstrated urinary incontinence. As day 2 progressed her mental status progressed to catatonia. Video EEG demonstrated generalized slowing. Magnetic resonance imaging (MRI) brain was unremarkable. Testing for anti-NMDA receptor antibodies, anti-GAD antibodies, VGKC antibodies, Interleukin-1 Beta, Interleukin-6, Interleukin-10, Interleukin-2, ANA, ANCA, lactic acid, ammonia, C3, C4, Beta-2 glycoprotein IgA, Beta-2 glycoprotein IgM, anti-DNAse B and Antistreptolysin antibody were all within normal limits. Serum Thyroperoxidase antibodies were elevated at 1499 IU/mL (≤34.9 IU/mL). Results of elevated thyroid function tests were discussed with endocrinology and thought to be likely Hashimoto’s thyroiditis; however, in the setting of normal TSH and T4, no acute intervention was recommended. Cerebrospinal fluid (CSF) demonstrated cell count of 0 µ/L (0 µ/L), protein 18 mg/dL (15–45 mg/dL) and glucose 74 mg/dL (45–75 mg/dL), with negative PCR and Gram stain, and so both levofloxacin and acyclovir were discontinued.
Given the clinical picture and laboratory findings, our working diagnosis was Hashimoto’s Encephalopathy versus SARS-CoV-2 Encephalopathy. Subsequently, 1 g/day methylprednisolone was started. The patient did not demonstrate any improvement with steroids, and began to have auditory hallucinations with questionable visual hallucinations. Methylprednisolone was discontinued after the second day of administration, hospital day 6, due to concern for psychiatric deterioration secondary to steroid administration. Psychiatry recommended olanzapine 2.5 mg oral disintegrating tablet nightly for what they assessed to be delirium.
Lovenox 40 mg SQ BID for deep vein thrombosis prophylaxis was started on hospital day 4. Patient became intermittently tachypneic to the 50s and high flow nasal cannula was trialed. No significant improvement in her respiratory symptoms was demonstrated and it was subsequently discontinued. Repeat chest radiograph showed low lung volumes, trace bibasilar markings, no new consolidations or effusions, and no signs of fluid in the fissures. She remained with altered mental status, persistent fevers, insomnia, tremulousness and was adequately maintaining her airway.
Neurology recommended repeat MRI brain with and without contrast and repeat lumbar puncture for further evaluation of non-improving altered mental status. Peripherally inserted central catheter team was also consulted for initiation of TPN due to poor nutritional intake. On hospital day 11, repeat MRI brain was negative. Lumbar puncture results were limited by a traumatic tap, although CSF culture ultimately resulted negative.
On hospital day 12, patient was afebrile for the first time since admission, but still altered. On hospital day 13, she remained abulic and non-verbal, although she did begin visually tracking more consistently and did not appear to have any more hallucinations. On hospital day 14, patient began having spontaneous movements in her sleep, including lifting her leg. Her tremors were now noted to be intermittent. She began to visually track conversation and was noted to start crying whenever mother would relay the previous night’s events to her. She was not answering questions or following directions; however, her awareness appeared sharp when compared with prior evaluations.
On hospital day 16, patient’s mother endorsed that she asked a meaningful question of “where am I?” overnight. On hospital day 17, patient demonstrated ability to tolerate orally by eating puree diet. Patient continued to become more aware and started to intermittently answer some questions appropriately. On hospital day 20, the patient had regained enough motor strength to walk with a walker while assisted. Her mental status continued to improve and she was able to answer questions appropriately in complete but short sentences. On hospital day 21, patient became aware enough to endorse the need to urinate. On hospital day 22, TPN was discontinued with peripherally inserted central catheter line removed. On hospital day 23, repeat COVID-19 nasopharyngeal swab resulted negative. By hospital day 26, the patient was able to ambulate independently, tolerate orally, answer questions appropriately, and communicate her need to void/stool. She was cleared for discharge home with PT/OT services, and follow up with neuropsychiatry and physical therapy.
On neurology follow up 12 days after discharge, patient was noted to begin to participate in family activities, regain her ADLs, and was amnestic to her hospital stay. She appeared extremely nervous, but had normal speech and language, and followed instructions well. She was noted to walk and run with good walking balance and normal gait, and had no dysmetria on finger-to-nose test.
There is a lack of literature discussing the neurologic complications of novel COVID-19 in children. In fact, no neurologic complications were reported from Wuhan Children’s Hospital.4 More recently, a report was released of an 11-year-old previously healthy child who presented in status epilepticus after 2 days of generalized weakness, no respiratory symptoms, and no fever. She was found to be COVID-19-positive. CSF studies were consistent with viral encephalitis and recovery took 6 days with no formal treatment regimen.5
The aforementioned case differs from ours, as our patient had no evidence of encephalitis on CSF and did not have clinical or subclinical seizure activity. SARS-CoV-2 related viral encephalitis versus SARS-CoV-2 infection activating an immune-mediated psychiatric predominant encephalopathy, as the most likely underlying etiology of our patient’s symptoms, became an extensive conversation during treatment. At time of hospitalization, there were no FDA guidelines or testing capabilities to determine SARS-CoV-2 positive CSF. However, our patient’s stay in the PICU with cardiopulmonary findings was more consistent with SARS-CoV-2 than with Hashimoto’s symptomology. Moreover, discussion with neurology and endocrinology consultants lead to the decision to attempt methylprednisolone treatment, as Hashimoto’s encephalitis typically responds well to treatment with steroids, but this only exacerbated our patient’s mental status and was ultimately discontinued. Furthermore, our patient began to demonstrate signs of improvement only after being afebrile greater than 24 hours. Of note, the patient had 2 positive COVID-19 PCR tests while admitted and febrile, but her third PCR, the first to result negative, came only a few days after her first afebrile day and beginning signs of clinical improvement.
Attempts were made to find case reports discussing SARS-CoV-2 and possible exacerbations of psychiatric or autoimmune processes. While none were found during authorship of this piece, it should be noted that research linking viral processes to both psychiatric and autoimmune disease exacerbation (including immune mediated encephalopathies) has been ongoing for decades. Given the acute manifestation of neurologic deficits, our patient’s infectious symptoms and recovery coinciding with negative COVID PCR, SARS-CoV-2 encephalitis is the most likely diagnosis.
Health care providers should have a high index of suspicion for SARS-CoV-2 when evaluating patients exhibiting acute changes in mental status. Although the final steps of our treatment regimen were based more heavily on our patient’s symptoms and needs, rather than her diagnosis, the knowledge of the possibility of SARS-CoV-2 related encephalitis in future cases can help avoid unnecessary testing and stress on already ill patients.
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