A 77-year-old female living in southern Germany developed in May 2020 nausea, vomiting, and flu-like symptoms for 3 days. Within the following 2 days she developed neurological symptoms, with onset of word-finding difficulties, gait ataxia, global disorientation, personality changes, and diffuse cognitive slowness. She was admitted to the hospital 5 days after her first symptoms. Her previous neurological status had been normal for her age.
On admission, the neurological examination (day 0) displayed a disoriented patient with cognitive slowness, unspecific personality changes, mild word-finding deficits, and diffuse cerebellar symptoms (mild gait-ataxia and dysmetria, saccadic eye pursuit). Peripheral systems were intact. The acute brain CT-scan (with CT-angiography) was normal. Chest CT scan was also unremarkable. On day 2 after admission, an MRI-scan of the brain showed preexisting microangiopathic alterations, without signs of encephalitis or an acute vascular event. Blood chemistry at this stage revealed mild leukocytosis (up to 11300/µl) along with severe and unexplained hyponatremia (121mmol/l). The electroencephalogram (EEG) on day 2 showed a theta-slowing without any sign of epileptic activity or triphasic waves. The lumbar puncture found a clear cerebrospinal fluid (CSF) with relatively mild pleocytosis (8 cells/µl), elevated protein (62mg/dl), mildly elevated lactate (3.0mmol/l), and signs of mild blood-brain-barrier (BBB) -leakage without signs of intrathecal IgG production, cumulatively indicative of a non-bacterial inflammatory process. A viral encephalitis was suspected and a corresponding CSF-diagnostic panel was ordered [6].
A therapy with aciclovir, levetiracetam, and methylprednisolone was empirically initiated until availability of the CSF results, yet without any treatment success. Hyponatremia was appropriately substituted, but did not return to normal levels. On day 3, the patient further deteriorated with development of fever, aggravated gait-ataxia, deterioration of cognitive functions (somnolence), meningism, epileptic seizures, global aphasia, and signs of latent right hemiparesis. She now fulfilled the criteria for confirmed encephalitis[6]. Due to further development of tachypnea, hypoxia, and lactate, she was admitted to the intensive care unit (ICU).
At that stage, the clinical and laboratory data supported a rapidly progressive (meningo-) encephalitis of yet unknown etiology, that manifested as a diffuse cortical process with additional diencephalic, brainstem, and cerebellar insult (severe hyponatremia, saccadic movement disorder, ataxia).
On day 5, the patient became comatose and was intubated for ventilator support. All repeatedly performed chest- and brain-CT scans remained unremarkable. The brain MRI scan on day 12 (Fig. 1-b1) revealed an atypical insular signal enhancement on the FLAIR sequence and discrete punctuate contrast-agent enhancement in the frontal and temporal lobes without corresponding correlates in FLAIR sequences. Remarkably, the patient remained comatose despite complete cessation of any analgosedation, showing rapidly progressive loss of cranial nerve and brainstem functions by day 14. Her hyponatremia also persisted.
On day 18, while being still comatose and dependent on invasive mechanical ventilation, the patient had a complete absence of brainstem reflexes (pupillary, corneal, ciliar, and pharyngeal/laryngeal brainstem reflexes). The EEG continued to deteriorate, showing a generalized theta-delta rhythm with spontaneous Burst-Suppression on day 21 (Fig. 1). Due to irresponsiveness to prior treatments, a quadruple anti-tuberculosis antibiotic regime was also empirically initiated but also proved ineffective.
An extensive diagnostic panel was repeated [6–8]. Any potential viral or bacterial causes were excluded by laboratory testing (PCR or IgM/IgG serology in serum and/or CSF). Paraneoplastic markers and anti-neuronal antibodies were also negative. Autoimmune etiologies, vasculitis, acute demyelinating pathology, degenerative processes (e.g. sporadic Creutzfeldt-Jacob disease), or an epileptic cause of the symptoms (e.g. a possible non-convulsive status epilepticus or epileptic discharges with postictal phenotype) were also excluded. SARS-CoV2 PCR was repeatedly negative. Rare causes of severe encephalitis (Japanese encephalitis, Dengue encephalitis, or West-Nile encephalitis) were clinically, radiologically, or epidemiologically also excluded [9].
Repeated CSF diagnostics on days 20 and 33 showed further increase in total protein levels (113 and 142mg/dl), IgG intrathecal production (99 and 315mg/dl), and lactate (5.3 and 6.1 mmol/L), as well as increasing lymphocytosis (40 and 110 leucocytes/ul), indicative of an unknown encephalitis unresponsive to previous treatment efforts. Increased CXCL13 indicated an unspecific intrathecal B cell-related immune activation.
On day 27 we additionally verified the loss of brainstem respiratory center function in our patient. Subsequently, the patient remained dependent on controlled invasive mechanical ventilation thereafter. The MRI brain scan performed on day 28 (Fig. 1-b2) did not correlate with the severity of her clinical status, showing only minimal increases in FLAIR-intensities compared to previous scans, some new punctual or diffuse gadolinium enhancement, and a diffuse increase of T2* signal in basal ganglia probably attributed to normal aging. Eventually, the EEG on day 41 showed a complete absence of electroencephalographic activity, indicating hemispheric death. A further continuation of critical care treatment deemed to be futile, and after discussions with her family, the patient died 42 days after admission.
The family provided informed consent for a diagnostic autopsy. Here, a BoDV-1 infection was revealed both by immunohistopathology and real-time PCR as the cause of the fatal encephalitis. Sequence analysis of the virus genome identified it within cluster 1A, phylogenetic similar to those isolated from the southeast area of Bavaria in other cases. The BoDV-1 antigens and related pathology were diffuse and severe in neocortical, subcortical, cerebellar and neurohypophysial areas (Fig. 2). Retrospectively, these lesions explained the presenting symptoms of the patient, namely cortical and subcortical deficits (aphasic disturbances, hemiparesis, confusion), cerebellar ataxia and the unexplained severe hyponatremia, the latter possibly attributed to the affected neurohypophysis and hypothalamus [10].
In light of the diagnosis, the patient´s family recalled a possible wild-animal attack on the patient´s domestic chickens a few days before the onset of symptoms, as a potential origin of infection with BoDV-1.