W.B.Q. Laumans (1), A. Yildirim (1,2), B. Mook (2), M. Koeman (1), S. Akin (1)
Departments of 1 Intensive Care and 2 Neurology, HagaZiekenhuis, The Hague, the Netherlands
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.
The fourth week, high-dose methylprednisolone was initiated because of signs of organising pneumonia (a late-phase complication of severe COVID-19) on a chest CT scan (figure 1), after which his respiratory status improved. Isoflurane inhalation was started in order to wash out the residual sedation and low-dose diazepam and methadone were given to prevent withdrawal symptoms. The prednisolone dose was quickly reduced to limit neurological side effects. Sodium and urea had nearly normalised and his liver function was not impaired. However, our patient remained encephalopathic.
In the fifth week, magnetic resonance imaging (MRI) of the brain showed very mild periventricular leucoaraiosis though, interestingly, no specific white matter lesions matching COVID-19 encephalopathy (figure 2). A second opinion from a neuro-intensivist from another hospital followed, offering no new insights or alterations in therapy. On day 35 the patient suddenly showed signs of rapid improvement: he was completely weaned from ventilation in one day and he was first able to follow motor commands the following day. After removing the tracheostomy tube, and before discharge from the ICU, his confusion and agitation persisted. The psychotropic drugs were gradually lowered as far as possible.
During his stay on the pulmonary medicine ward he recovered from his critical illness polyneuropathy and was able to walk without support. Two months after hospital admission, the patient showed signs of neurological improvement and he was able to communicate adequately. He was no longer confused or agitated when he was discharged to a medical rehabilitation clinic. After two weeks, he was able to go home with an impaired short-term memory as the only remaining neurological issue.
This case is unusual; there were no brain imaging abnormalities in a patient with severe and prolonged encephalopathy, where pulmonary recovery from COVID-19 preceded neurological recovery by a full month. This may suggest that the severity of the encephalopathy might not only be explained by the severity of the COVID-19 pneumonia and there might be an inflammatory neurological response. Multiple factors, including hypoxaemia, metabolic disequilibrium, residual sedation, sepsis, delirium and multi-organ failure may have contributed to the prolonged encephalopathy. However, COVID-19 seems to be the major contributing factor to the encephalopathy, since it remained after successfully treating other causes. Furthermore, the continuing need for mechanical ventilation due to impaired consciousness suggests that it was not solely prolonged delirium causing the impaired consciousness. A post-anoxic cause of encephalopathy seems unlikely, considering many COVID-19 patients presenting with very severe (‘happy’) hypoxia do not regularly develop encephalopathy. COVID-19 encephalopathy, however, remains a diagnosis of exclusion and cannot be properly distinguished from other causes of encephalopathy, exclusively based on symptoms.
Another key point that distinguishes this patient from other cases is that the severity and duration of the clinical symptoms did not correspond with the lack of MRI abnormalities (figure 2). Frequently, patients who have COVID-19 encephalopathy display cortical or subcortical white matter hyperintensity on neuroimaging. They may also show microbleeds or leukoencephalopathy. Interestingly, our patient did not show these imaging abnormalities, hence the severity of the clinical symptoms did not correspond with the normal brain imaging details. However, Uginet et al. reported that a small minority (8%) of patients with COVID-19 encephalopathy do not show MRI abnormalities and 15% of the patients with COVID-19 encephalopathy lack intracranial vessel gadolinium enhancement, similar to our case. These findings suggest that a minority of patients with COVID-19 are encephalopathic without displaying MRI abnormalities. Furthermore, it should be taken into account that the number of patients with MRI-negative COVID-19 encephalopathy is possibly underestimated. Patients hospitalised with COVID-19 are not systematically screened by a neurologist, but evaluated only on indication by their treating physicians: patients with subtle signs may be missed. An earlier case report described a useful role of brain perfusion single-photon emission computed tomography (SPECT)/CT in the evaluation of COVID-19 associated with nonspecific neurological manifestations.  In our case, not all currently available imaging techniques were used to exclude other neurological pathologies. Brain perfusion scintigraphy is one such imaging technique and may be particularly considered in patients for diagnostic work-up.
A limitation of this case report is that neither a lumbar puncture nor EEG were performed; consequently, meningitis or epilepsy as causes of encephalopathy cannot be completely ruled out. However, these causes were deemed unlikely in the absence of fever, seizures, meningism or nystagmus.
Our patient still showed signs of impaired short-term memory at the time of discharge from the rehabilitation clinic. This is consistent with the outcomes described in earlier case reports concerning neurological prognosis of post-COVID-19 encephalopathy. Heneka et al. suggest that the survivor is at risk of developing long-term neurological consequences, either by aggravating a pre-existing neurological disorder or by initiating a new disorder. This concern is supported by findings that show that at the time of discharge one third of patients have evidence of cognitive impairment and motor deficits.
With this case report, we present an example of late neurological recovery in COVID-19; in this patient prolonged treatment was necessary.More extensive research of COVID-19 encephalopathy is necessary, to give care providers, patients and family clear indications for treatment and information on prognosis.
The late neurological recovery suggests that the severity of encephalopathy may not only be related to the severity of the COVID-19 pneumonia. Multiple factors, including hypoxaemia, metabolic disequilibrium, residual sedation, sepsis and multi-organ failure possibly contributed to the prolonged encephalopathy. However, COVID-19 infection may also exert a severe influence on the central nervous system without showing imaging abnormalities. The aim of this case report is to give an example of late neurological recovery in COVID-19 in a patient in whom prolonged treatment was indicated.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. All authors declare no conflict of interest. No funding or financial support was received.
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