The Effect of a Combined Ganciclovir, Methylprednisolone, and Immunoglobulin Regimen on Survival and Functional Outcomes in Patients With Japanese Encephalitis

Abstract

Objective: There is currently no effective treatment for Japanese encephalitis, which has a high rate of morbidity and mortality. This study assessed the effectiveness of a ganciclovir, methylprednisolone, and immunoglobulin combination (TAGMIC) therapy in decreasing cognitive impairment and mortality among patients with Japanese encephalitis. Methods: We retrospectively assessed the clinical data of 31 patients diagnosed with Japanese encephalitis, who were admitted to an intensive care unit. Patients were divided into the TAGMIC and non-TAGMIC group according to their treatment regime. We compared the 60-day, 6-month, and overall mortality and survival curves between groups. We also compared Barthel Index scores, Montreal Cognitive Assessment (MoCA) scores, and diffusion tensor imaging (DTI) results. Results: There was no significant difference in the 30-day mortality rate or Kaplan-Meier survival curve between groups. The 60-day, 6-month, and overall mortality rates in the TAGMIC group were significantly reduced (P = 0.043, P = 0.018, and P = 0.018, respectively) compared with the non-TAGMIC group (0, 0, 0 vs. 31.25, 37.5, 37.5%, respectively). The 60-day, 6-month, and overall Kaplan-Meier survival curves were significantly different between groups (P = 0.020, P = 0.009, P = 0.009, respectively). There was no significant difference in the Barthel Index scores of surviving patients. Among the five patients who underwent MoCA and DTI, four had a score of 0/5 for delayed recall (no cue), while the remaining patient had a score of 2/5. All five patients were able to achieve a score of 5/5 with classification and multiple-choice prompts, and had sparse or broken corpus callosum (or other) fibre bundles. Conclusion: TAGMIC treatment can reduce mortality due to severe Japanese encephalitis. The memory loss of surviving patients is mainly due to a disorder of the memory retrieval process, which may be related to the breakage of related fibre bundles.

Keywords: Japanese encephalitis; combined regimen; ganciclovir; immunoglobulin; methylprednisolone.

Figure 1

Flow chart of patient inclusion, exclusion, and grouping. TAGMIC: ganciclovir, methylprednisolone, and immunoglobulin combination.

Figure 2

Magnetic resonance image and diffusion tensor imaging image of 1 patient. (A,B) Magnetic resonance images showed that the patient's thalamus (white arrow) and basal ganglia (white arrow) were lesions. (C,D) Diffusion tensor imaging showed that the patient's corpus callosum tract was partially broken. Three months later, the patient's corpus callosum rupture improved.

Figure 3

Comparison of 60-day, 6-month, and overall survival curves between TAGMIC group and Non-TAGMIC group. (A) Comparison of 60-day survival curves between TAGMIC group and Non-TAGMIC group. (B) Comparison of 6-month survival curves between TAGMIC group and Non-TAGMIC group. (C) Comparison of overall survival curves between TAGMIC group and Non-TAGMIC group. (C) Shows that due to the different dates of onset of patients, as of the end time of our follow-up (January 2020), the follow-up period of patients ranges from several weeks to several years. At the 10-month follow-up, 6 patients in the Non-TAGMIC group died (the part of the curve descending), and 4 patients were shorter than 10 months by the end of January 2020 (4 short vertical lines, 2 of which are almost overlapped due to the close distance.) Therefore, 6(16-6-4) patients over 10 months, need to continue to extend the display on the curve. There were no deaths in the TAGMIC group and no decline in the survival curve. For example, in the TAGMIC group, there are 3 patients with a follow-up period of fewer than 20 months (3 short vertical lines), and 12(15-3) patients with a follow-up period of more than 20 months, which need to be extended on the curve. TAGMIC: ganciclovir, methylprednisolone, and immunoglobulin combination.

Figure 4

Overview of pathogenesis and therapeutic drugs of Japanese encephalitis. Pathogenesis of disease: After the mosquito bites the human skin, it enters the lymph nodes and replicates in the lymph nodes, and then enters the blood system to form viremia, which stimulates the body to produce protective antibodies against the Japanese encephalitis virus. The virus mainly causes the following three aspects of damage, and the three drugs act on the following three aspects respectively. 1. The virus penetrates the blood-brain barrier and enters the central nervous system. The virus directly damages neurons. The antiviral drug ganciclovir may inhibit the replication of Japanese encephalitis virus and reduce the damage of the virus to neurons. Antiviral drugs may act on this pathogenesis. 2. After the virus enters the human body, the body produces IL-6, TNF-α, TLRs, and other cytokines and chemokines, causing inflammation of the whole body and brain parenchyma. Glucocorticoids fight inflammation. 3. The composition of the virus may be similar to that of the central nervous tissue, which stimulates the body's immune system to produce autoantibodies against its nervous tissue components, such as Anti-GM1 IgM/IgG and so on. The virus can also stimulate the body to produce autoantibodies against peripheral nerve tissue components, such as Anti-GM1 IgM/IgG, Anti-GM2 IgM/IgG, Anti-GD1a IgM/IgG, Anti-GD1b IgM/IgG, etc. Intravenous immunoglobulin mainly contains IgG monomer, which is used to neutralize autoantibodies such as IgM/IgG. JEV, Japanese encephalitis virus; IL-6, interleukin-6; TNF-α, tumour necrosis factors-α; TLRs, Toll-like receptors.