Excellent Outcome of Acute Necrotizing Encephalopathy in an Adult With Bacterial Infections, Case Report

Abstract

Acute necrotizing encephalopathy (ANE) is a rare para-infectious encephalopathy that classically occurs in children. However, ANE should be considered in the differential diagnosis of adults with symmetric brain lesions after a prodromal illness given recent reports of coronavirus disease of 2019 (COVID-19) to presumably cause ANE in adults. We report a case of a 29-year-old male presenting with fever, malaise, and rapid deterioration into coma. Brain magnetic resonance imaging revealed multifocal symmetric areas of diffusion restriction and surrounding vasogenic edema involving bilateral thalami, pons and cerebellar hemispheres with a core of susceptibility artifact, and minimal thalamic contrast enhancement, most consistent with ANE. Extensive infectious workup revealed isolated Escherichia coli and Neisseria gonorrhoeae in his urine. Despite the severe encephalopathy on initial presentation, the patient improved with intravenous antibiotics and supportive management with minimal residual deficits at 9 months follow-up. We aim to provide an overview of the radiological features, differential diagnosis, treatment and prognosis of ANE. Becoming familiarized with this rare but devastating disease will improve detection, treatment, and ultimately prognosis, especially in the era of a new pandemic.

Introduction

ANE is a rare disease that was first described in 1995 in a group of previously healthy Japanese children post respiratory tract infection.¹ Since then ANE has been reported in the western hemisphere without racial predilection and in a small number of adults.^2,3 Individuals with ANE often develop an exaggerated immune response following viral infections; although the exact pathogenesis of ANE remains unclear.⁴ Certain rare genetic mutations are associated with familial and recurrent forms of ANE and have been reported in only 17 families. ANE carries a mortality rate of 30% in the pediatric population. Recently, there is an increasing number of case reports describing COVID-19 associated ANE in adults with poor clinical outcome,^5-7 This highlights a knowledge gap in our understanding of the disease pathogenesis and treatment. We present an unusual case of ANE in an adult with Escherichia coli and Neisseria gonorrhoeae infections without identifiable viral precipitant. Through this case report, we aim to provide an overview of the differential diagnosis and disease pathogenesis of ANE as well as highlight a need for better prognostication metrics and treatment.

Case Report

A 29-year-old African-American man with a history of discoid lupus, not on immunosuppression, presented to the emergency department with 10 days of progressive fever, malaise, and dysuria. He was initially diagnosed with septic shock and given fluids and broad-spectrum antibiotics, but rapidly became comatose requiring intubation. Exam revealed impaired up-gaze, facial diplegia, quadriparesis, and diffuse hyperreflexia. Brain magnetic resonance imaging (MRI) on hospital day 3 revealed multifocal symmetric areas of diffusion restriction and surrounding vasogenic edema involving bilateral thalami, pons and cerebellar hemispheres with a core of susceptibility artifact, and minimal thalamic contrast enhancement (Figure 1). MRI findings appeared most consistent with ANE based on the published criteria.⁴ Cerebral spinal fluid (CSF) examination showed red blood cell count 0 cells/cumm, white blood cell count 0 cells/cumm, glucose of 65 mg/dL, and protein of 88 mg/dL. Infectious workup was remarkable for positive E. coli and N. gonorrhoeae in the urine. Blood and CSF aerobic cultures were negative for organism growth. Respiratory pathogen panel was negative for influenza A, influenza B, parainfluenza, coronavirus HKU1/ NL63/ 229E/ OC43, Mycoplasma pneumoniae, Bordetella pertussis, chlamydophila pneumoniae, adenovirus, metapneumovirus, respiratory syncytial virus, rhinovirus, and enterovirs. Polymerase chain reaction virus screen in the CSF was negative for West Nile virus, herpes simplex virus, and varicella zoster virus. Plasma aspartate transaminase and alanine transaminases peaked at 93 IU/L and 89 IU/L, respectively. Ammonia was not obtained. Additional evaluations included patent venous sinuses, normal computed tomography angiography, and no major plasma sodium, glucose, or blood urea nitrogen abnormalities or fluctuations. Given no history of alcoholism or malabsorption, combined with atypical thalamic pattern without mammillary body involvement on MRI, Wernicke encephalopathy was unlikely; nevertheless, he received empiric high-dose intravenous thiamine. Ceftriaxone and doxycycline were started for pyelonephritis and prostatitis. His cognition improved with supportive management, with successful extubation on day 5 and discharge to a rehabilitation hospital on day 11. Discharge exam revealed akinetic mutism, intact extraocular movements with direction-changing nystagmus, hypophonia, right facial weakness, right pronator drift, and mild bilateral ataxia. At 9 month follow-up, he had made a full recovery of motor and coordination function. He endorsed mild sensation changes, a subjective sense of disequilibrium, and mild cognitive slowing.

Figure 1.

MRI of the brain. Apparent diffusion coefficient (A, E, I) shows symmetric restriction in thalami, pons, and cerebellum. Thalami lesions (A) are characterized by concentric layers of hemorrhagic necrosis at the inner core, followed by cytotoxic edema in the middle layer, and vasogenic edema at the outermost layer. FLAIR (B, F, J) hyperintensities in thalami, pons, and cerebellum encompass more territory and have edematous appearance. Echo planar imaging (EPI) shows hemosiderin deposition in bilateral thalami lesions (C, G, K). Faint contrast enhancement only seen on thalami lesions on T1 weighted images with gadolinium contrast (T1 + G) (D, H, L).

Discussion

We present a case of ANE with classic clinical and radiological features in an adult with atypical infectious precipitants. Proposed ANE diagnostic criteria, based mostly on pediatric literature, include acute encephalopathy following viral infection, cyto-albuminologic dissociation, and multifocal symmetric lesions commonly involving thalami, periventricular white matter, internal capsule, putamen, upper brainstem tegmentum, and cerebellar medulla.⁴ Alternative diagnoses producing similar clinical and radiographic characteristics, such as mitochondrial cytopathies, osmotic myelinolysis, Wernicke encephalopathy, viral encephalitis, and arterial or venous infarction, should be excluded (Table 1).⁸

Table 1.

Differential Diagnosis for an Adult Presenting With Bi-Thalamic Lesions.

Disease	Salient differentiating features
Leigh disease	A group of heterogeneous mitochondrial cytopathies that results in progressive neurologic deterioration with motor and intellectual developmental delay. Symptoms typically occur in childhood but rare cases of adult onset have been described.
Osmotic myelinolysis	Clinically accompanied by rapid shifts in serum osmolarity, such as rapid correction of hyponatremia, hyperglycemia, or uremia. T2 and DWI hyperintense lesions typically extend beyond thalamus to pontine white matter tracts.
Wernicke encephalopathy	Clinical history of chronic malnutrition, alcohol abuse, or intractable nausea and vomiting, resulting in thiamine deficiency. T2 hyperintense lesions typically focused on dorsomedial thalami, mammillary bodies, and periaqueductal grey.
Venous infarction	Cerebral venous thrombosis involving the deep cerebral veins such as the straight sinus, vein of Galen, and internal cerebral vein may produce bilateral thalamus infarction. Non-visualization of the deep cerebral veins are demonstrated on CT and MR venography.
Arterial infarction	Artery of Percheron is a variant of the posterior cerebral circulation characterized by a single arterial trunk supplying blood to the paramedian thalami and the rostral midbrain bilaterally. Occlusion of the artery of Percheron can produce bilateral thalami infarction, but it should not produce lesions in the anterior cerebral circulation.
Viral encephalitis	Many viral encephalidities involve the thalami. Eastern Equine Encephalitis virus (restricted to the Gulf Coast states) and West Nile Encephalitis virus are pertinent to the United States. Diagnoses are made based on positive viral PCRs and a CSF profile with lymphocytic pleocytosis.
Acute disseminated encephalomyelitis	Occurs a few days to weeks after an infection. MRI exhibits multiple, bilateral asymmetric, T2 hyperintense “fluffy” lesions in the subcortical and deep white matter, deep nuclei, cerebellum, brainstem and spinal cord.
Wilson disease	Autosomal recessive inborn error of copper metabolism, characterized by excess copper storage in the liver, brain, and corneas. Symptoms include progressive neurological, psychiatric, and hepatic deterioration. Serum ceruloplasmin level is typically reduced with elevated urine copper excretion.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; CSF, cerebrospinal fluid.

Our patient fits the diagnostic criteria for ANE with the exception of an identifiable viral cause. His ANE could be precipitated by sepsis from his bacterial infections, making this the first reported case of ANE associated with E. coli and N. gonorrhoeae. Although ANE is classically seen in the setting of viral illness, an association with Mycoplasma pneumoniae, an atypical bacteria, has been reported.^2,9 Thus, the pathogenesis of ANE is likely not unique to viruses. While it is possible that ANE is caused by the direct invasion of pathogens to the brain, the infrequency of finding such pathogens in the CSF suggests otherwise. Consistent with that, we did not detect E. coli and N. gonorrhoeae in the CSF aerobic culture of our patient. In other cases, autopsy specimens showed evidence of petechial hemorrhage, congestion of capillaries, erythrocyte extravasation, and vasogenic edema, consistent with blood brain barrier breakdown.¹ Other studies reported elevated plasma concentration of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).⁴ IL-6 is neurotoxic at high concentrations, while TNF-α damages endothelium at the blood brain barrier. Thus, ANE is likely mediated by overproduction of cytokines, causing cerebral microvasculature injury and blood brain barrier disruption, eventually leading to axonal injury and cell death.⁴ It is thus conceivable that for our patient, sepsis, as a result of E. coli and N. gonorrhoeae co-infection, produced an exaggerated immunologic response and caused secondary damage to the blood brain barrier. Furthermore, his history of discoid lupus may have made him more susceptible to ANE. An antibody specifically targeting the brain microvascular endothelium was reported in a patient with systemic lupus erythematosus complicated by ANE.¹⁰

Our patient is also unusual due to his excellent recovery despite the severity at initial presentation. Based on ANE severity scale, our patient fits the high risk category given age over 48 months, shock at onset, presence of brainstem lesions and CSF protein exceeding 60 mg/dl.¹¹ However, this risk scale was derived from a pediatric population and may not be generalizable to adults. In the pediatric cohort, 15 of 17 patients classified as high risk had severe sequelae, defined as developmental or intelligence quotient < 30, loss of ambulation, inability to sit unsupported, or death. Likewise, there is also a discrepancy between our patient’s actual clinical outcome and his predicted outcome based on his MRI findings.⁹ Evidence of brainstem involvement, white matter involvement, and presence of hemorrhage, all present on our patient’s MRI, are historically associated with poor clinical outcome in children. Current clinical and radiological predictors, developed from pediatric cohorts, may not generalize to adults. Further research is needed to identify sensitive clinical and radiological biomarkers for predicting disease severity and clinical outcome.

Various immunomodulation therapies, such as intravenous glucocorticoids, immunoglobulin, and plasmapheresis, have been administered empirically in the pediatric population and a few adult cases, with unclear benefits.⁴ Given our patient’s excellent outcome with supportive care and intravenous antibiotics alone, despite initial severe presentation and extensive MRI changes, a systematic approach is needed to study the efficacy of these treatments. In addition, research on immune therapy targeting specific components of the pro-inflammatory cytokine pathway may be warranted.¹²

As a study limitation, while we tested extensively for the majority of known viral precipitants, we did not test for human herpesvirus (HHV)-6, HHV-7, and measles. Since most of ANE cases come from the pediatric literature, it is not surprising to find an association between ANE and HHV-6 and HHV-7. Infections caused by either viruses are ubiquitous and are frequent causes of encephalopathy in the pediatric population.¹³ However, the causative role of encephalitis by HHV-6 and HHV-7 in immunocompetent adult population is uncertain, particularly given high seroprevalence in the adult population.¹³ Thus testing for HHV-6 and HHV-7 in an immunocompetent adult is uncommon in clinical practice. Likewise, measles is not endemic to our region nor did the patient exhibit any stigmata of measles infection, thus testing for measles was not clinically indicated. COVID-19 was not tested as our case presentation predated the current pandemic. Furthermore, an ammonia level was not obtained in our patient, but we suspect it to be normal since his serum aminotransferase level was only mildly abnormal. While elevation in serum aminotransferase level is a proposed diagnostic criteria for ANE, normal values have also been described in this condition. In one study, aspartate transaminase and alanine transaminases were normal in 18% and 30% of cases, respectively.¹⁴

In the current COVID-19 era, there are rising cases of neurological complications linked to this novel virus. Certain cases exhibited multifocal symmetric lesions classically seen in ANE,^5,6 while others reported asymmetric hemorrhagic lesions,⁷ which by strict definition is not ANE. Regardless of the nomenclature, the underlying pathophysiological mechanism is likely the same. Similar to ANE, the pathogenesis of COVID-19 is characterized by high-concentrations of pro-inflammatory cytokines and microvascular endothelial injury.¹⁵ Thus it is not surprising to see numerous reports of COVID-19 causing ANE and ANE-like illness. Interestingly, one of the potential ANE treatments,¹² tocilizumab, an IL-6 inhibitor, is actively undergoing randomized control trials for patients with severe COVID-19 symptoms. Becoming familiarized with this rare but devastating disease will improve detection, guide treatment, and ultimately prognosis, especially in the era of a new pandemic.