Treat the lungs and wait for the brain in COVID-19: a case report of severe COVID-19 encephalopathy
Encephalopathy is a severe and underestimated neurological complication of COVID-19 infection, with a high prevalence in COVID-19 patients in intensive care. We present a case of a 68-year-old male with severe COVID-19 encephalopathy and prolonged lowered consciousness, without showing any brain imaging abnormalities. There are multiple mechanisms of cause, such as inflammatory, hypoxic-metabolic and sepsis-related factors, and residual sedation, which were treated as described without effect on the encephalopathy. Interestingly, our patient showed no abnormalities on brain imaging and the encephalopathy only disappeared a full month after respiratory recovery. Encephalopathy considerably prolonged his ICU stay and after discharge from the medical rehabilitation clinic, he still showed mild neurological impairment. The late neurological recovery suggests that the severity of encephalopathy may not only be related to the severity of the COVID-19 pneumonia and there might be an inflammatory neurological response, without showing brain imaging abnormalities.
Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and has resulted in a global pandemic. Since the virus was first identified in Wuhan, China, in December 2019, it has caused more than 6.2 million deaths worldwide according to the latest reports of the World Health Organisation. Common symptoms of COVID-19 include cough, fever, fatigue and dyspnoea. Neurological symptoms of COVID-19 have been frequently reported, including headache, dizziness and altered consciousness or encephalopathy. Furthermore, some COVID-19 patients develop severe neurological complications such as ischaemic stroke, intracranial haemorrhage or Guillain-Barré syndrome. Neurological symptoms in COVID-19 are mainly observed in critically ill patients or in older patients (>50 years of age) with multiple comorbidities.[2-4] Neurological disease in COVID-19 patients (including stroke) is associated with higher death rates, delirium and disability. However, Garg et al. indicated that in the majority of patients neurological disease improved following management in the intensive care unit (ICU).
Encephalopathy, defined as diffuse brain dysfunction, can be part of multi-organ failure in the critically ill patient. Encephalopathy manifests as altered consciousness, which can range from delirium to coma. The underlying aetiology is generally multifactorial: inflammation (such as in COVID-19), intoxication, metabolic disequilibrium, hypoxia, coagulopathy and sepsis. Central nervous system invasion by COVID-19 can occur through different mechanisms. The most likely mechanism involves viral binding to the angiotensin-converting enzyme 2 (ACE2) receptor (present on neurons, the olfactory system and the cribiform plate), allowing viral migration across the blood-brain barrier. ACE2 receptor presence has been demonstrated on neurons and endothelial cells that facilitate SARS-CoV-2 virus entry to the brain. Alternatively, retrograde axonal transport may take place from the lungs and gut to the brain. Prevalence of encephalopathy or delirium in COVID-19 patients is higher in the ICU (84.3%) than at presentation to the emergency department (28%) or than during general admission (19.6%). COVID-19 encephalopathy can last from 5 to 14 days.[4,9] It has been proposed that patients can remain encephalopathic even after respiratory symptoms have ceased, and this has been shown to be associated with brain imaging abnormalities. However, this article reports on a case of severe COVID-19 encephalopathy without abnormalities on brain imaging, where pulmonary recovery of COVID-19 pneumonia preceded neurological recovery.
A 68-year-old male with a history of mild primary hyperparathyroidism presented with progressive symptoms of dyspnoea for a few days; a PCR test for SARS-COV-2 was positive. He was admitted directly to our ICU and intubated due to severe hypoxia, delirium and exhaustion.
In the first week of admission he was treated with dexamethasone, tocilizumab and high-dose prophylactic low-molecular-weight heparin; no pulmonary embolisms were seen on chest computed tomography (CT) (figure 1). The hypoxaemia quickly resolved while on mechanical ventilation and his respiratory status improved to weaning conditions. A wake-up trial was performed. Neurological examination on day six of the ICU admission showed impaired consciousness (E4M4Vtube), pinpoint pupils and roving eye movements without nystagmus, bilateral weakness of upper and lower extremities, low reflexes, and no Babinski sign. There were no clinical signs suggestive of meningitis (no signs of nuchal rigidity or fever) or epilepsy (no nystagmus or convulsions); consequently, electro-encephalography (EEG) and lumbar puncture were not performed. CT scan of the brain showed no intracranial haemorrhages or ischaemia (figure 2). The limb weakness was deemed a likely result of critical illness polyneuropathy. There were no clinical signs of infection and laboratory examination showed normal leucocytes and low C-reactive protein (possibly explained by use of immunosuppressants), mildly elevated liver transaminases, hypernatremia and uraemia.
In the second week, his respiratory status improved significantly and in order to start weaning from ventilation, a tracheostomy was performed on day ten, sooner than in our average COVID-19 patient. However, weaning and wake-up failure occurred due to a persisting encephalopathy, with confusion and agitation as the main symptoms. In order to reduce his confusion and agitation, treatment with several psychotropic drugs was attempted, though without significant clinical improvement.
A new CT scan of the brain was performed in the third week, showing no explanation for the lowered consciousness (figure 2). At the same time, the patient developed sepsis following ventilator-associated pneumonia (which was treated with antibiotics) with multi-organ failure (respiratory distress, oliguria and metabolic disequilibrium). At that point, the encephalopathy was most likely the result of multi-organ failure/sepsis and residual sedation, caused by use of psychotropic medication in combination with renal impairment.
- WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. https://covid19. who.int/ Accessed 24-04-2022.
- Payus AO, Liew Sat Lin C, Mohd Noh M, Jeffree MS, Ali RA. SARS-CoV-2 infection of the nervous system: A review of the literature on neurological involvement in novel coronavirus disease-(COVID-19). Bosn J Basic Med Sci. 2020;20:283-92.
- Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77:683-90.
- Garg RK, Paliwal VK, Gupta A. Encephalopathy in patients with COVID-19: A review. J Med Virol. 2021;93:206-22.
- Shah VA, Nalleballe K, Zaghlouleh ME, Onteddu S. Acute encephalopathy is associated with worse outcomes in COVID-19 patients. Brain Behav Immun Health. 2020;8:100136.
- Helms J, Kremer S, Merdji H, et al. Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. Crit Care. 2020;24:491.
- Kennedy M, Helfand BKI, Gou RY, et al. Delirium in Older Patients With COVID-19 Presenting to the Emergency Department. JAMA Netw Open. 2020;3:e2029540.
- Romero-Sánchez CM, Díaz-Maroto I, Fernández-Díaz E, et al. Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry. Neurology. 2020;95:e1060-70.
- Maury A, Lyoubi A, Peiffer-Smadja N, de Broucker T, Meppiel E. Neurological manifestations associated with SARS-CoV-2 and other coronaviruses: A narrative review for clinicians. Rev Neurol (Paris). 2021;177:51-64.
- Sisniega DC, Reynolds AS. Severe Neurologic Complications of SARS-CoV-2. Curr Treat Options Neurol. 2021;23:14.
- Uginet M, Breville G, Assal F, COVID-19 encephalopathy: Clinical and neurobiological features. J Med Vir. 2021;93:4374-81.
- Chun KJ, Zamora E, Coco M. Brain perfusion single-photon emission computerized tomography/computerized tomography: Stroke-like manifestations of COVID-19 with transient antiphospholipid elevation. World J Nucl Med. 2021;20:405-7.
- Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12:69.