Insights into adjunctive corticosteroid therapy in fulminant herpes simplex virus encephalitis: case analysis with contrasting outcomes
Article information
Abstract
Herpes simplex virus (HSV) encephalitis, predominantly caused by HSV-1, presents with significant morbidity and mortality challenges. This research investigates the particular role of adjunctive corticosteroid therapy in fulminant HSV encephalitis through in-depth analyses of two contrasting cases. Corticosteroids show potential benefits to improve an exaggerated immune response and limit viral dissemination within the brain. Daily assessments and frequent neuroimaging, particularly using magnetic resonance imaging, aid in the management of fulminant cases. Although existing evidence relies on limited case series and retrospective comparisons, the results of the present study emphasize the necessity for large-scale controlled trials to establish definitive guidelines. The discretion of the treating neurologist governs the decision to implement corticosteroids, emphasizing the imperative need for continued research and evidence-based strategies for this challenging neurological condition.
Introduction
Herpes simplex virus (HSV) encephalitis is a predominant cause of sporadic encephalitis globally, with HSV-1 being the primary causative agent and an annual incidence ranging between two and four cases per 1 million individuals across all age groups [1]. The untreated course of this viral infection has a 70% mortality rate, and despite timely acyclovir intervention, a substantial portion of survivors experience pronounced neuropsychiatric sequelae. Furthermore, the prospect of returning to normal health for adult patients is limited, with fewer than 50% experiencing a full recovery [2].
The introduction of acyclovir in the mid-1970s significantly decreased the mortality associated with HSV encephalitis, reducing the range to 5.5%–28%. However, multifaceted pathogenic mechanisms involving direct virus-mediated tissue damage, robust inflammatory responses, and autoimmune, virus-independent structural alterations are the subsequent outcomes of this condition [3]. In response to these complexities, there has been sporadic exploration of steroid administration, as evidenced by a few case reports and animal studies. Despite these investigations, the evidence supporting the routine use of steroids in treating this life-threatening viral infection remains inconclusive [4].
The present research delves into the clinical narratives of two immunocompetent females who presented with fulminant HSV encephalitis. The therapeutic approach included aggressive acyclovir administration coupled with adjunctive use of steroids. One patient recovered, while the other died. These case reports provide insights into the nuanced role of steroids as adjunctive therapy in HSV encephalitis, showing the potential benefits and unforeseen consequences.
Case Report
This report was approved by the research ethics committee at Aseer Central Hospital.
Case 1
A healthy 14-year-old female, fully immunized, presented with a 3-day history of unilateral temporal headache following an upper respiratory infection. Accompanied by continuous fever, she experienced a witnessed seizure characterized by “whole body shaking with tongue biting,” diaphoresis, and perioral cyanosis. Despite multiple emergency room visits over the subsequent 3 days, where nonsteroidal anti-inflammatory drugs and oral antibiotics were administered, the patient’s headaches persisted. Described as an “aching pain,” the severity was rated at 8/10 on the numeric rating scale upon admission.
Initial examination revealed a fever of 38.5 °C, a lateral tongue laceration, and photophobia. Neurologically, the patient exhibited comprehension of simple commands, apathy with mental slowness, and expressive aphasia. Cranial nerves (II–XII) and sensory system examinations were normal; however, the motor examination showed global non-focal symmetrical weakness, brisk reflexes, and bilateral upturned toes. The score of the modified Rankin scale upon admission was 5.
Blood tests, including a full blood count and biochemical panel, were within normal ranges. Electroencephalography (EEG) showed generalized slow waves and epileptiform discharges with frequent rhythmic spike and wave complexes. Brain computed tomography (CT) showed left temporoparietal cortical-subcortical hypodensity involving the insula with loss of sulci and gyri. The patient was promptly admitted to the inpatient medical unit and started on empirical therapy, including intravenous (IV) acyclovir at 10 mg/kg/dose every 8 hours, ceftriaxone 2 g IV twice daily, and vancomycin 1 g twice daily. She also received an IV loading dose of levetiracetam 60 mg/kg infused over 15 minutes. She was maintained on levetiracetam 750 mg twice daily through a nasogastric tube.
Lumbar puncture revealed clear cerebrospinal fluid (CSF) with lymphocytic pleocytosis (CSF cell count 180, 90% lymphocytes), and CSF glucose and protein levels were within normal limits. Polymerase chain reaction (PCR) testing for HSV-1 was positive. Brain magnetic resonance imaging (MRI) showed left temporal, left insular, left pulvinar, left cortical parietal, bilateral cingulate, bilateral basifrontal, and right posterior mesial temporal areas of T2-weighted/fluid-attenuated inversion recovery hyperintensity with restricted diffusion and related overlying leptomeningeal enhancements predominantly in the left temporal region (Figure 1).
Brain MRI findings
Brain MRI showing T2/fluid-attenuated inversion recovery hyperintensity with restricted diffusion in the left temporal, left insular, left pulvinar, left cortical parietal, bilateral cingulate (left predominant), bilateral basifrontal (left predominant), and right posterior mesial temporal areas, accompanied by minimal rightward midline shift measuring up to 0.3 cm.
MRI, magnetic resonance imaging.
Despite initial therapy, the patient’s clinical condition continued to decline, with further worsening of consciousness from drowsy to stupor and a Glasgow Coma Scale (GCS) score of 8/15. These results prompted the introduction of pulse steroid therapy (1,000 mg of methylprednisolone IV daily for 5 days) on day 8. However, by day 13, the patient had experienced another seizure, and brain MRI revealed worsening of the previously observed hyperintense lesions with a hemorrhagic component in the temporal and occipital lobes (Figure 2). The dose of levetiracetam was increased to 1,000 mg twice daily with no recurrence of seizures.
Brain MRI findings
Brain MRI showing the extension of lesions to the right occipitoparietal lobes, presenting diffuse underlying leukomalacia with delineation of multifocal hemorrhagic areas, predominantly located in the left temporal lobe.
MRI, magnetic resonance imaging.
Upon completing a 21-day course of acyclovir, the patient exhibited persistent mental slowness, expressive speech difficulties, and controlled seizures while receiving levetiracetam 1,000 mg orally every 12 hours. A comprehensive physiotherapy program was initiated, resulting in gradual improvements in communication, expression, and daily life activities. Six weeks later, her score on the modified Rankin scale was 4, with expected further improvement over time.
Case 2
A previously healthy 22-year-old female presented to the emergency department with a 4-day history of fever and headache, culminating in confusion and seizures on the day of presentation. Despite an absence of antecedent upper respiratory tract infection, dysuria, or trauma, the patient exhibited signs of significant neurological involvement. Physical examination revealed a febrile state (38 °C) with no respiratory distress, cyanosis, or meningeal irritation. However, she showed confusion, agitation, and a GCS score of 12/15, without focal neurological signs, long tract dysfunction, or cranial neuropathy.
Blood tests, including a full blood count and biochemical panel, were within normal ranges. Brain CT in the emergency room yielded essentially normal results. Lumbar puncture showed a clear CSF with lymphocytic pleocytosis (CSF cell count, 240; 95% lymphocytes) and normal CSF glucose and protein levels. PCR testing for HSV-1 was positive, prompting the initiation of empirical therapy involving IV acyclovir, ceftriaxone, and vancomycin.
The patient’s condition rapidly deteriorated, leading to refractory status epilepticus necessitating intubation, mechanical ventilation, and sedation using two antiseizure medications, propofol and midazolam. Despite negative anti–N-methyl-ᴅ-aspartate receptor antibodies and administration of maximal doses of two antiepileptic agents (levetiracetam and valproate) as well as addition of an anesthetic agent (ketamine), recurrent seizures persisted. Consequently, a third antiepileptic agent (lacosamide) was introduced. The duration of intermittent convulsive status epilepticus was 3 days, with subsequent intermittent nonconvulsive status epilepticus for 5 days.
On the 4th day of admission, a brain MRI revealed encephalitic changes and cytotoxic edema with the hyperintense signal on T2-weighted images and hypointense signal on T1-weighted images, accompanied by significant diffusion restriction. Concordant bleeding was not observed in the inferior frontal lobes and medial temporal lobes bilaterally, and a notable mass effect or midline shift was not present (Figure 3). Subsequent MRI on hospital day 8 showed substantial disease progression, confirming the radiological diagnosis of fulminant HSV encephalitis with patchy hemorrhagic transformation.
MRI findings of hyperintense lesions and diffusion restriction
Brain MRI exhibiting hyperintense lesions on T2-weighted images, with notable diffusion restriction observed in the inferior frontal lobes and medial temporal lobes bilaterally.
MRI, magnetic resonance imaging.
In response to the escalating severity, pulse steroid therapy (1,000 mg of IV methylprednisolone daily for 5 days) was administered on hospital day 8. Despite these interventions, the patient’s clinical course took a critical turn on day 15, marked by hemodynamic instability necessitating inotropic support. Aside from persistent hyponatremia treated with desmopressin, laboratory workup revealed values within normal ranges. Despite a comprehensive 21-day antiviral course, the patient’s health continued to decline, and the EEG showed persistent focal epileptiform discharges. She succumbed to multiorgan failure 6 weeks after admission. The brain CT obtained two days prior to her death is shown in Figure 4. The cause of death was cerebral edema, severe intracranial hypertension, and herniation.
CT scan findings of brain
CT scan of the brain showing global loss of gray-white matter differentiation with hyperdensity of hemorrhagic components in the left frontoparietal regions with near complete effacement of the ventricular system and extra-axial CSF cisterns with features indicative of tonsillar herniation.
CT, computed tomography.
Discussion
The global prevalence of HSV encephalitis is high, with the disease being the foremost cause of sporadic encephalitis in the human population. Type HSV-1 is implicated in more than 90% of cases, while HSV-2 accounts for approximately 5%. HSV-1 encephalitis is a severe condition, causing morbidity in 40% of cases and mortality in 70% of untreated that is reduced to 15% with treatment. Clinical manifestations typically include fever, rapid alterations in consciousness, focal neurological signs, and seizures. Pathologically, HSV-1 encephalitis manifests as inflammation, congestion, and hemorrhage in one or both temporal lobes, extending into adjacent areas of the limbic system. Immunocompromised patients may exhibit more extensive cerebral involvement, affecting the cerebrum, cerebellum, and brainstem [5].
Acyclovir, a nucleoside analog, selectively inhibits the replication of HSV-1, HSV-2, and varicella-zoster virus. The drug mechanism involves phosphorylation, culminating in the production of the active form, acyclovir triphosphate that competes with deoxynucleotide analogs for incorporation into replicating DNA. Furthermore, acyclovir terminates viral DNA chain elongation due to the absence of the three-hydroxylated group needed for this process [6]. Clinical trials have demonstrated the efficacy of acyclovir in reducing mortality, establishing it as the standard of care. Delaying initiation beyond two days from admission increases the risk of severe neurological sequelae and death [7].
Adjunctive corticosteroid therapy has shown favorable outcomes in HSV-1 encephalitis via both genomic and non-genomic mechanisms. Genomic effects involve interactions between glucocorticoid receptors and transcription factors, regulating the expression of genes that modulate inflammatory and immune responses. Specifically, corticosteroids bind to glucocorticoid receptors in the cytoplasm, forming a receptor-ligand complex that translocates to the nucleus and binds to glucocorticoid response elements on DNA. This binding influences the transcription of anti-inflammatory genes, such as those encoding interleukin 10 and annexin-1, and repressing pro-inflammatory genes including those encoding for interleukin 6 and tumor necrosis factor alpha. Non-genomic effects involve the rapid modulation of intracellular signaling pathways independent of direct gene transcription. Corticosteroids can interact with cell membrane-bound glucocorticoid receptors or other receptors to influence signaling cascades, utilizing kinases such as phosphoinositide 3-kinase and mitogen-activated protein kinase. These interactions can quickly alter cellular activities, leading to reduced production of pro-inflammatory cytokines and stabilization of cell membranes, which helps in diminishing cerebral edema and intracranial pressure. By combining corticosteroids with acyclovir, the severity of the infection is reduced and viral replication is hindered. Corticosteroids help modulate the inflammatory response, reducing inflammation-associated damage within the brain. However, the use of corticosteroids must be carefully balanced due to potential adverse effects. High-dose corticosteroids can suppress cell-mediated immunity crucial for controlling viral infections. This immunosuppressive action may impair the body’s ability to counteract viral replication effectively, potentially prolonging the infection and exacerbating encephalitis symptoms. Furthermore, immunosuppression increases the risk of secondary infections or reactivation of latent viruses, complicating the clinical course of the disease. Therefore, although corticosteroids can provide significant benefits in reducing inflammation and associated neurological damage, their use must be carefully evaluated against the potential risks of immunosuppression and secondary infections. Assessment of the benefits versus the associated risks is warranted when considering corticosteroid adjunct therapy combined with acyclovir treatment [8] (Table 1).
Pros and cons of corticosteroid administration in viral encephalitis
Antiviral resistance is a rare phenomenon in HSV encephalitis treatment. In cases of non-response or refractory status epilepticus, genotypic testing can reveal resistance-associated mutations, prompting consideration of second-line drugs such as foscarnet [9]. Neither patient in this report displayed signs of antiviral resistance.
The timing of adjunctive steroid therapy remains a topic of debate, with results of animal studies indicating improved survival when initiated on the third day after disease onset [10]. In the presented cases, steroid therapy was started on day 8 after admission, yielding contrasting outcomes: significant improvement in one patient and death in the other. We believe that steroid therapy in the first patient had positive effects in reducing the neuroinflammatory process; however, this effect was not achieved in the second case, possibly due to the severity of the disease and difficulty controlling seizures. This underscores the intricate nature of HSV-1 encephalitis, necessitating further research to refine treatment strategies, define the role of complications including seizures, and optimize patient outcomes. Despite the few publications and reports on the role of adjunctive steroid therapy in HSV-1 encephalitis, the two cases presented in this report provide unique clinical and paraclinical information that differs from previous reports. The results of these two cases can provide a basis for clinicians, virologists, and neuroimmunologists to perform more research on the topic.
The utilization of adjunctive steroid therapy in the management of fulminant HSV-1 encephalitis should be cautiously considered, with initiation occurring 3 days after starting acyclovir treatment during the peak of the inflammatory response. The rationale for corticosteroid administration is the potential to decrease an exaggerated inflammatory response and limit viral dissemination within the brain. Comprehensive and frequent assessments, coupled with neuroimaging, particularly MRI, can aid the treating physician(s) in managing the complexities of fulminant cases. The existing evidence is limited to small case series and retrospective comparisons, emphasizing the need for robust clinical data. Thus, large-scale controlled trials are necessary to establish definitive guidelines. Trials in which the efficacy and safety of corticosteroids in different dosages and timing relative to antiviral therapy are evaluated should be meticulously designed. Randomized controlled trials with stratified randomization to account for patient heterogeneity could provide high-level evidence. In addition, longitudinal cohort studies with standardized follow-up protocols could provide insights into long-term outcomes and potentially delayed adverse effects of adjunctive steroid therapy. Further research should also explore the role of biomarkers in predicting treatment response and guiding therapeutic decisions. Advanced neuroimaging techniques and neuroinflammatory markers could be incorporated into future studies to delineate the pathophysiological mechanisms underpinning the variable responses to corticosteroid therapy. Furthermore, multicenter collaborations could facilitate the recruitment of sufficient number of patients, enhancing the generalizability of findings. Despite the current paucity of evidence, the decision to incorporate corticosteroids into the treatment regimen and determine the optimal timing remains a discretionary prerogative of the treating neurologist. Patients exhibiting a lack of response to aggressive therapeutic measures could be an indication of potential drug resistance or the emergence of autoimmune encephalitis. Thus, further research and evidence-based guidelines are imperative to continually refine and enhance the management strategies for fulminant HSV-1 encephalitis.
Notes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: Algahtani H, Abdelghaffar N; Data curation: Algahtani H, Jamaluddin HA, Abdelghaffar N; Formal analysis: Algahtani H, Shirah B; Project administration, Resources, Supervision: Algahtani H; Visualization: Algahtani H, Shirah B, Abdelghaffar N; Writing–original draft: all authors; Writing–review & editing: all authors.