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.

This report was approved by the research ethics committee at Aseer Central Hospital.

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).

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.