COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia

A 59-year-old woman presented to the emergency department with recurrent fleeting episodes of vacant staring and speech arrest associated with flexion of both shoulders and a brief witnessed generalized tonic-clonic seizure (GTCS), followed by postictal reduced consciousness. Shortly after arrival in the emergency department, the patient vomited and had a further GTCS. She had a history of aplastic anemia treated with intermittent red blood cell and platelet transfusions. The patient had no significant paroxysmal nocturnal hemoglobinuria clone. She had received immunosuppressive therapy in the past, but not recently. She had returned from a trip to Afghanistan 3 weeks before presentation and developed transient abdominal pain and diarrhea. Ten days before her neurologic presentation, she developed a persistent cough, sore throat, shivering, and headache, with subsequent shortness of breath and myalgia. Three days before presentation, she had a routine telephone hematology clinic consultation and the following day underwent a blood test (table, day-2) which showed a stable platelet count (33 × 10⁹/L), anemia (hemoglobin 103 g/L), and leukopenia (total white cell count 3.8 × 10⁹/L, lymphocyte count 1.4 × 10⁹/L, neutrophil count 1.8 × 10⁹/L).

Physical examination revealed reduced consciousness with a Glasgow Coma Score (GCS) of 11 of 15, body temperature of 36.9°C, blood pressure of 130/63 mm Hg, pulse of 82 beats per minute, respiratory rate of 22 breaths per minute, and oxygen saturation of 97% on ambient air. Neurologic assessment found no focal deficits. Chest radiography showed right basal consolidation, and a CT scan of the head showed early swelling of the brain stem (figure 1). On admission, her blood cell count showed unchanged anemia and thrombocytopenia (platelet count 29 × 10⁹/L) which was consistent with the patient's history of aplastic anemia (table). Unlike previous blood counts, there was new lymphopenia (lymphocytes 0.3 from 1.4 2 days earlier). Nasopharyngeal swab RT-PCR testing for SARS-CoV-2 returned positive, thus confirming a diagnosis of COVID-19. The patient was started on levetiracetam and IV ceftriaxone, aciclovir, amoxicillin, and clarithromycin. In light of the severe thrombocytopenia and risk of hemorrhage, human leukocyte antigen-matched platelets (because of known platelet HLA antibodies) were transfused intermittently to maintain the platelet count >50 × 10⁹/L.

Twelve hours after admission, the patient's GCS fell to 5 (E1, V1, and M3), with associated development of an extensor left plantar response and an unreactive left pupil. Although the patient's respiratory symptoms remained relatively mild, she underwent endotracheal intubation for airway protection and was transferred ‬to the intensive care unit for mechanical ventilation. Repeat head CT showed increased hypodensity and swelling of the brain stem, and a new area of cortical and subcortical hypodensity in the left occipital lobe initially suggested an acute posterior circulation infarct. A subsequent computed tomography angiogram excluded an acute vascular occlusion but showed worsening brain stem swelling with subtle intrinsic pontine hemorrhage and new symmetrical hypodensities in the deep gray matter and amygdalae (figure 1). Appearances were suggestive of a rapidly evolving encephalopathy with severe involvement of the brain stem. On the fifth day of admission, lumbar puncture was performed immediately after platelet transfusion. CSF opening pressure was 28 cm water, and CSF analysis showed increased protein concentration (2.3 g/L) and a normal white cell count of 4/mm³. Subsequent standard CSF virology PCR (herpes simplex virus 1 and 2, varicella zoster virus, adenovirus, cytomegalovirus, Epstein-Barr virus, enterovirus, parechovrius, and human herpesvirus 6), CSF PCR for SARS-CoV-2, and CSF culture were negative.‬‬‬‬‬‬‬‬‬‬

On the sixth day of admission, an MRI of the head demonstrated extensive, relatively symmetrical changes throughout the supratentorial and infratentorial compartments. There was diffuse swelling and hemorrhage in the brain stem and both amygdalae. Extensive abnormal signal and microhemorrhage were found in a symmetrical distribution within the dorsolateral putamina, ventrolateral thalamic nuclei, subinsular regions, splenium of the corpus callosum, cingulate gyri, and subcortical perirolandic regions (figure 2). These regions demonstrated severe swelling and restricted diffusion with peripheral enhancement (figure 3). There was partial effacement of the ventricles, temporal uncal herniation, effacement of the basal cisterns, and moderate cerebellar tonsillar herniation secondary to the severe cerebral and pontine swelling. Overall imaging features supported a diffuse hemorrhagic acute necrotizing encephalopathy (ANE) with involvement of the brain stem. Neurologic examination after withdrawal of sedation revealed intact corneal reflexes and normal pupillary responses to light. Doll's eye response was reduced. She coughed on suction and initiated breathing but required pressure support mechanical ventilation. She displayed no response to verbal command or painful stimuli. However, based on the severity of the MRI findings, the patient was deemed to have a very poor neurologic prognosis. She showed no sign of neurologic improvement after high dose dexamethasone and on the 10th day of admission died after the withdrawal of ventilatory support. Her family declined a postmortem study.

To our knowledge, we report the second case of presumptive COVID-19-related hemorrhagic ANE. Similar to the previously reported case, our patient had relatively symmetrical hemorrhagic lesions in the amygdalae and thalamic nuclei although, by contrast, there was also extensive involvement of the pons and medulla and, to a lesser extent, the striatum and subcortical perirolandic regions.² In our case, the patient's aplastic anemia with severe thrombocytopenia likely contributed to the hemorrhagic component of the encephalopathy. However, outside of bone marrow transplantation and active immunosuppressant therapy, there is no reported predisposition to encephalopathy in patients with aplastic anemia.^3,4 Our patient was not lymphopenic before COVID-19, and therefore, it is unlikely‬ that the aplastic anemia caused an impaired immune response.‬‬‬‬‬‬

ANE is a rare encephalopathy most frequently encountered in children and characterized by multiple, symmetrical lesions in the thalami, striatum, cerebral white matter, and brain stem.^5,6 ANE has previously been linked to several infective agents including influenza-A, herpes simplex virus, influenza-B, mycoplasma, and human herpes virus-6.^6,7 As in this case, ANE is often rapidly progressive with seizures, reduced consciousness, and vomiting, usually occurring 12–72 hours after symptom onset of the viral infection.^5,7 As in our case, CSF analysis frequently shows an elevated protein concentration but a normal white blood cell count.^5,7 The precise etiology and pathophysiology of ANE remains unclear. In reported cases, the suspected causative pathogen is rarely detected in the CSF by PCR assay.^5,7 In an autopsy of a patient with ANE secondary to H1N1 influenza, a notable absence of perivascular or meningeal inflammation was found.⁶ Therefore, ANE is not believed to be a product of direct infection but the result of an immune-mediated process involving proinflammatory cytokines.^8,9 A possible hyperinflammatory response in COVID-19 is supported by the recent observation that COVID-19-related acute respiratory distress syndrome may be driven by a macrophage activation syndrome or cytokine storm.¹⁰ Unfortunately, in our case, testing for interleukins in the serum or CSF was not possible. Despite this, an immune-mediated phenomenon, as opposed to a neurotropic effect, is suggested because CSF RT-PCR testing for SARS-CoV-2 was negative and no other potential causative agent was identified.

Further exploration of potential COVID-19-related CNS pathology is needed and requires national and international collaboration to collect large, organized data sets. The possibility of an immune-mediated process and its therapeutic implications also warrants greater study.