As of June 2020, our health maintenance organization treated 216 patients with COVID–19 and 106 (49%) patients required hospitalization. Of hospitalized patients, 21 (20%) required admission to the intensive care unit (ICU) and 18 (17%) required intubation. We identified 4 patients (22%) with clinicoradiologic evidence of acute necrotizing encephalopathy (ANE), two with associated areas of hemorrhage, in our small cohort in Oregon. Table 1outlines additional details each individual’s hospital course. All four patients had lymphopenia and elevated D-Dimer and lactic acid dehydrogenase (LDH) levels. Similar characteristics were also observed in our other patients with COVID–19 without CNS manifestations.
Patient 1: A 63-year-old Caucasian man without significant past medical history presented to the Emergency Department (ED) with 10 days of fevers, cough, headache, severe right ear pain and shortness of breath. Nasopharyngeal swab testing was positive for SARS-CoV–2 virus. The patient was intubated and transferred to the Intensive Care Unit on hospital day (HD) 5 for Acute Respiratory Distress Syndrome (ARDS). The patient had no neurologic deficits prior to intubation and initially required minimal sedation.
He later developed agitated delirium and required deep sedation. His hospital course was complicated by a deep vein thrombosis treated with heparin infusion. On HD 29 the patient was noted to have markedly decreased movement of left sided extremities. MRI of the brain revealed several acute to subacute infarcts involving the left cerebral hemisphere with areas of hemorrhagic transformation, as well as mildly expansiile T2 signal hyperintensity along the bilateral major forceps and medial thalami. These findings were superimposed upon innumerable tiny foci of susceptibility effect involving the cerebral hemispheres and brainstem. The constellation of findings is consistent with an acute hemorrhagic necrotizing encephalopathy. (Figure 1) The patient recovered from ARDS requiring minimal nasal cannula oxygen and his only neurologic debility is generalized weakness.
The patient discharged to a skilled rehabilitation facility on hospital day 89.
Patient 2: A 70-year-old Caucasian man with severe obesity, obstructive sleep apnea, hypertension, allergic rhinitis, and gastroesophageal reflux disease presented to the ED with 5 days of fevers, chills, cough, shortness of breath and fatigue but was neurologically intact and had no reported CNS symptoms. Nasopharyngeal swab testing was positive for SARS-CoV–2 virus. The patient was intubated on HD 1 for ARDS.
Hospital course was complicated by septic shock and acute renal failure requiring renal replacement therapy starting on HD 5. The patient was started empirically on a heparin infusion on HD 11. On HD 14 a non-contrast head CT was obtained due to ongoing coma despite stopping all sedatives for 72 hours. The CT revealed evidence of a posterior circulation stroke. The patient’s coma was not explained by the area of stroke and was thought to be related to the prolonged effects of deep sedation in the setting of acute renal failure. On HD 18 the patient developed agonal respirations and periods of apnea. A head CT and brain MRI revealed multifocal edema and gyriform hemorrhage with a few areas of subtle diffusion signal hyperintensity involving the right occipital/temporal lobes, right thalamus, and cerebellar hemispheres. Also noted were innumerable small foci of susceptibility effect throughout the affected brain parenchyma, which were not seen on a prior MRI performed in 2017. These findings are consistent with an acute hemorrhagic necrotizing encephalopathy. (Figure 2) The patient developed evidence of acute intracranial hypertension on HD 19. Pharmacologic stabilization measures were unsuccessful. After a goals of care discussion with the patient’s family, the patient was transitioned to comfort care and died on HD 19.
Patient 3: A 78-year-old Asian man with hypertension, stage 3 chronic kidney disease, prediabetes and dyslipidemia presented to the ED with fever and productive cough for 3 days. His family reported the patient having difficulty keeping track of conversations. On admission he had no shortness of breath initially despite pulmonary infiltrates on plain radiograph and an oxygen saturation of 92% on room air. Nasopharyngeal swab testing was positive for SARS-CoV–2 virus. On HD 2 the patient was intubated for ARDS. His course was complicated by septic shock, acute renal failure and atrial fibrillation. The patient slowly improved, recovered from shock, and had decreasing ventilatory needs but did not awaken after sedation was stopped.
Head CT imaging on HD 17 revealed ovoid hypodensities in the bilateral thalami; a large wedge-shaped hypodensity with loss of gray white differentiation involving the right parietal, posteromedial temporal, and occipital lobes; and a smaller hypodensity in the left occipital lobe compatible with acute necrotizing encephalopathy. (Figure 3) After discussion with his family the patient was discharged home to hospice care and died.
Patient 4: A 67-year-old Caucasian man with history of obstructive sleep apnea, type 2 diabetes mellitus, severe obesity, fatty liver, hyperlipidemia, and hypothyroidism presented to the ED following 10 days of fevers, chills, cough, malaise and 1 day of intermittent confusion. Nasopharyngeal swab testing was positive for SARS-CoV–2 virus. The patient was admitted to the Intensive Care Unit for ARDS and subsequently intubated. He was neurologically intact prior to intubation. The patient was very slow to wake after stopping sedation on HD 9. This was attributed to the prolonged duration of continuous IV sedation and declining renal function. On HD 17 the patient was awake enough to be extubated but required reintubation on HD 20 for an obtunded level of consciousness that progressed to coma. A lumbar puncture had bland CSF findings and SARS-CoV–2 testing was unable to be performed.
Brain MRI revealed subtle hyperintense signal involving the pons and midbrain with small diffusion hyperintense foci in the central pons, suggestive of an acute necrotizing encephalopathy primarily involving the brainstem (Figure 4).
The patient eventually discharged to a skilled rehabilitation facility on hospital day 115 cognitively intact with generalized muscle weakness requiring assistance of a front wheeled walker.