Rare manifestation of initial central nervous system involvement in severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis: a case report

Article information

encephalitis. 2024;.encephalitis.2024.00108
Publication date (electronic) : 2024 December 27
doi : https://doi.org/10.47936/encephalitis.2024.00108
1Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
2Laboratory for Neurotherapeutics, Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
3Center for Hospital Medicine, Seoul National University Hospital, Seoul, Korea
Correspondence: Kon Chu Department of Neurology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail: stemcell.snu@gmail.com
Received 2024 September 12; Revised 2024 December 3; Accepted 2024 December 18.

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal infectious disease if not diagnosed and treated promptly. Typical clinical features include fever, thrombocytopenia, and lymphadenopathy. However, we encountered a case of SFTS in a 60-year-old male who initially did not exhibit these hallmark symptoms. The patient presented with headache and myalgia, but fever did not develop until the 4th day of hospitalization. Initial neuroimaging and cerebrospinal fluid (CSF) analysis revealed no abnormalities. When the fever emerged, follow-up imaging revealed findings consistent with meningitis as a complication of SFTS. The patient was successfully treated with antibiotics and made a full recovery. This case underscores the challenges in diagnosing SFTS in patients who lack fever, CSF pleocytosis, or typical neuroimaging findings at presentation. Additionally, it highlights the importance of differentiating SFTS-related meningitis from other causes of encephalitis to avoid inappropriate treatments, such as immunosuppressive therapy, which could worsen viral infections.

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease that is caused by the genus Phlebovirus in the family Bunyaviridae [1]. The clinical progression of SFTS is typically divided into three main phases: the fever phase, the multiple-organ dysfunction (MOD) phase, and the convalescent phase [2,3]. In the early stages of infection, during the fever phase, patients primarily present with acute high fever and a high viral load, often accompanied by thrombocytopenia, leukopenia, and sometimes lymphadenopathy. This initial phase is followed by the development of MOD, usually around 5 days after symptom onset, marked by a combination of hemorrhagic symptoms, progressive neurological abnormalities, declining platelet counts, disseminated intravascular coagulation, and multi-organ failure that may ultimately lead to death [4]. Neurological manifestations, including lethargy, tremors, seizures, and coma, often occur in the final stages of the disease [4,5]. On the other hand, in patients with a milder or self-limited form of the infection, the disease course often bypasses MOD and progresses directly into the convalescent phase. Alongside these clinical stages, laboratory findings typically show significant increases in serum markers such as alanine aminotransferase (ALT), aspartate transaminase (AST), blood urea nitrogen, creatine kinase myocardial band fraction, lactate dehydrogenase (LDH), and prolonged activated partial thromboplastin time (aPTT). Diagnosis of SFTS is conducted through serological and molecular biological tests, with treatment primarily focusing on symptom relief. We report a case of encephalopathy in an SFTS patient who experienced the three stages mentioned above. Written informed consent was obtained for the publication of this case report and accompanying images.

Case Report

A previously healthy 60-year-old male was admitted to another hospital in May due to a headache. The patient, who resides in a townhouse on a golf course, had been working in weed control the day before admission but denied insect bites. Three days later, he suffered generalized malaise and myalgia. Brain magnetic resonance imaging (MRI) at the local hospital was unremarkable (Figure 1A). Initial cerebrospinal fluid (CSF) analysis showed no white blood cells (WBCs), and the levels of protein and glucose were 38.9 mg/dL and 60 mg/dL, respectively, which are within normal ranges. On the 6th day of admission, he showed symptoms of disorientation, fever, and worsened headache. While planning the transfer to our hospital for further evaluation, the patient experienced a seizure.

Figure 1.

Brain MRI scan images

(A) Images obtained on the 3rd day of admission. (B) Follow-up brain MRI shows diffuse leptomeningeal enhancement in the left parieto-occipital area.

MRI, magnetic resonance imaging.

Upon admission, the patient had elevated blood pressure at 153/67 mmHg and a fever of 37.9 °C. On examination, the patient had reddish swelling with a heat sensation in the right inguinal area. Neurological examinations showed stuporous mental status with Glasgow Coma Scale scores of eye-opening of 2, verbal response of 1, and motor response of 4 (E2V1M4). He was disoriented, responded only to his name, and could not follow simple commands. Motor examination could not be performed due to irritability, and deep tendon reflexes were normal. Nuchal rigidity was present.

Elevation of AST at 302 IU/L (normal range, 1–40 IU/L) and ALT at 165 IU/L (normal range, 1–40 IU/L), serum LDH at 1,590 IU/L (normal range, 100–225 IU/L), and mild prolongation of aPTT at 39.0 seconds (normal range, 27.1–37.8 seconds) were observed. CSF analysis revealed 36 WBCs (10 lymphocytes, 26 others), protein elevation at 104 mg/dL, and normal glucose level at 53 mg/dL. Gadolinium-enhanced brain MRI revealed diffuse leptomeningeal enhancement in the left parieto-occipital area (Figure 1B). Abdominopelvic computed tomography scans showed edema with multifocal retroperitoneal fluid collection in the right thigh and prominent lymph nodes in the right inguinal, external iliac, and retroperitoneum areas, suggesting a possible inflammatory/infectious condition, such as retroperitoneal fasciitis. Initial electroencephalography (EEG) findings showed discontinuous electrical activity by background attenuation, showing a mixture of alpha and delta activities (Figure 2). Differential diagnoses included viral and autoimmune encephalitis, and an extensive diagnostic workup including CSF and autoimmune antibody test was performed (Table 1), although these conditions were eventually ruled out. Later, the serum polymerase chain reaction test showed a highly positive result for SFTS.

Figure 2.

Electroencephalography of the patient 2 days after admission

A low-amplitude state was seen in all leads.

Laboratory test results performed in serum and cerebrospinal fluid

The diagnosis was SFTS-associated encephalitis, and the patient was started on empirical ceftriaxone, doxycycline, and acyclovir. Levetiracetam treatment (500 mg twice a day) was initiated due to EEG findings. Initially, the patient opened his eyes and showed a pupillary response to painful stimuli, but meaningful interaction was not possible. However, within a few days of treatment, the patient showed remarkable improvement and could attend to daily activities with minimal assistance. After maintaining doxycycline, ceftriaxone, and levetiracetam for 8 days, the patient was discharged without any sequelae. The patient is currently on regular follow-up without neurologic signs or symptoms via the outpatient clinic (Figure 3).

Figure 3.

Clinical timeline of the patient

This figure highlights the key clinical manifestations from upon admission to discharge.

HD, hospital days; CT, computed tomography; LFT, liver function test; LDH, lactate dehydrogenase (U/L); CSF, cerebrospinal fluid; WBC, white blood cell (cells/μL); MRI, magnetic resonance imaging; PCR, polymerase chain reaction; SFTS, severe fever with thrombocytopenia syndrome; Prot, protein (mg/dL); FU: follow-up; CK, creatine kinase (U/K); EEG, electroencephalography.

Discussion

SFTS is an emerging infectious disease caused by the SFTS virus (SFTSV), primarily transmitted by ticks and endemic to East Asia. In China, the incidence rate of SFTS has been reported to be approximately 0.5 to 1.3 cases per 100,000 people, with more than 5,000 cases reported in recent years. In South Korea, the incidence is estimated to be 0.3 to 0.6 cases per 100,000 people, while Japan reports a similar range of 0.3 to 0.5 cases. Although the overall number of cases may seem small, the fatality rate ranges from 12% to 30%, underscoring the serious nature of the disease. Neurological complications, such as meningitis or encephalitis, are less common, occurring in about 10% to 20% of cases. In our case, central nervous system (CNS) involvement was evident despite normal CSF findings, further highlighting the significance of this report. Our patient resided in a townhouse on a golf course and engaged in outdoor activities such as weed control, which could have contributed to his exposure to tick-borne pathogens. This residential and occupational history highlights the potential role of environmental factors in the risk of SFTS, particularly in endemic areas. Recognizing such associations is essential in evaluating SFTS patients, as lifestyle and environmental exposure can influence both disease presentation and diagnostic considerations. Given the rising incidence of SFTS in endemic regions and the rarity of such presentations, this case offers valuable insights into the neurological impact of the virus and the diagnostic challenges involved.

While the exact mechanisms underlying the pathogenesis of SFTS remain unclear, research suggests that viruses within the Bunyaviridae family have neuroinvasive properties. Viral transcripts of novel Bunyaviruses have been identified in the brain and spinal cord of animal models, such as ferrets, supporting the hypothesis that these viruses may contribute to CNS involvement in human SFTS and lead to neurological symptoms [6]. The SFTSV may impact the CNS through mechanisms such as direct viral invasion, excessive cytokine production, and immune dysfunction. Studies [7-11] have reported elevated levels of cytokines, including interferon (IFN)-α, IFN-γ, interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α, and monocyte chemotactic protein (MCP)-1, in the blood of SFTS patients. Among those with CNS symptoms, IL-8 and MCP-1 concentrations in the CSF are significantly higher than in the blood [7]. This finding suggests that heightened cytokine activity may disrupt the blood-brain barrier, allowing SFTSV to infiltrate the CNS. Interestingly, in SFTS patients with neurological complications, CSF typically exhibits normal protein and glucose levels, with infrequent elevated WBC count. However, when clinical or epidemiological suspicion is strong, especially in regions where SFTS is prevalent, testing for MCP-1 and IL-8 in both CSF and serum can provide valuable diagnostic information. Additionally, detecting viral RNA in the CSF is recommended to confirm the diagnosis.

Patients with SFTS may experience neurological effects, typically emerging around 5 days after disease onset. These effects are considered complications of SFTS and are classified as SFTS-associated encephalopathy/encephalitis (SFTSAE) [7]. SFTSAE is characterized by symptoms such as headaches, seizures, irritability, altered mental status, cognitive deficits, limb convulsions, and impaired consciousness. In numerous instances, a marked decline in consciousness, including progression to coma, occurs before the condition is accurately identified, frequently leading to an unfavorable outcome.

The specific treatment for SFTS remains unclear, though recent studies have explored new therapeutic approaches for patients. Corticosteroid pulse therapy is a potential treatment option for encephalitis or encephalopathy linked to SFTS. By targeting the overproduction of cytokines, this therapy seeks to minimize the likelihood of organ failure [12]. However, despite its role in controlling inflammation, the use of steroids may pose challenges, particularly in preventing secondary infections like invasive pulmonary aspergillosis in SFTS patients. Additionally, since lymphocyte counts are already significantly reduced in the early stages of SFTS, the use of steroids could further suppress lymphocytes, potentially impairing the body’s immune response [12,13]. A study conducted in Korea evaluated the impact of steroid treatment in patients with SFTS and found no definitive benefit in reducing mortality or improving outcomes in many cases. On the contrary, discontinuation of steroids could potentially allow the immune system to recover and manage the viral load more effectively [14].

Studies have indicated that gamma globulin can inhibit macrophage activation and alleviate cytokine storms associated with Crimean-Congo hemorrhagic fever virus infections. Additionally, its therapeutic use in managing severe cases of SFTS has been reported [15]. Its mechanism involves blocking viral replication by supplementing nonspecific immunoglobulin G antibodies that target viruses, bacteria, and other pathogens, helping to neutralize toxins. Nevertheless, more research is required to establish robust evidence supporting the use of gamma globulin in treating SFTS patients. In our case, the patient’s condition improved with antibiotic treatment, and the administration of gamma globulin was not necessary. However, if the encephalopathy symptoms had persisted or worsened, we would have considered gamma globulin as part of the treatment strategy.

In conclusion, diagnosing SFTS with neurological complications requires a multifaceted approach involving clinical, laboratory, and neuroimaging evaluations. Early recognition and treatment are crucial to preventing severe outcomes. Regular follow-up is essential to monitor for potential long-term neurological sequelae. This case adds valuable insight to the expanding understanding of SFTS, highlighting the importance of vigilance and readiness in addressing this emerging infectious disease.

Notes

Conflicts of Interest

Kon Chu has served on the editorial board of encephalitis, and he was not involved in the review of this article. No other potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: all authors; Supervision: Ahn SJ, Lee HS; Writing–original draft: Kim HS; Writing–review and editing: all authors

References

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Article information Continued

Figure 1.

Brain MRI scan images

(A) Images obtained on the 3rd day of admission. (B) Follow-up brain MRI shows diffuse leptomeningeal enhancement in the left parieto-occipital area.

MRI, magnetic resonance imaging.

Figure 2.

Electroencephalography of the patient 2 days after admission

A low-amplitude state was seen in all leads.

Figure 3.

Clinical timeline of the patient

This figure highlights the key clinical manifestations from upon admission to discharge.

HD, hospital days; CT, computed tomography; LFT, liver function test; LDH, lactate dehydrogenase (U/L); CSF, cerebrospinal fluid; WBC, white blood cell (cells/μL); MRI, magnetic resonance imaging; PCR, polymerase chain reaction; SFTS, severe fever with thrombocytopenia syndrome; Prot, protein (mg/dL); FU: follow-up; CK, creatine kinase (U/K); EEG, electroencephalography.

Table 1

Laboratory test results performed in serum and cerebrospinal fluid

Category Tests performed
Infection tests performed in serum HIV, RPR, Rickettsia tsutsugamushi Ab, SFTS PCR, Japanese B encephalitis, TBEV RT-PCR, Mycoplasma Ab, measles IgM Ab, VZV IgG Ab, EBV VCA IgM/G, parasite-specific Ab IgG
Infection tests performed in CSF Routine culture, AFB agar/broth culture, fungal culture, India ink stain, VZV IgG Ab, Cryptococcus Ag, VDRL, FTA-ABS
DNA-PCR of HSV1, HSV2, EBV, CMV, VZV, Enterovirus, respiratory virus, HHV6, HHV8, JCV, Mycoplasma, TB/NTM
Rheumatologic, SREAT screening in serum ANCA (MPO Ab, PR3 Ab), ANA, RF, anti-CCP, LA, anti-dsDNA, anti-Ro/La Ab, anti-cardiolipin Ab IgM/G, Anti-TPO Ab

HIV, human immunodeficiency virus; RPR, rapid plasma reagin; Ab, antibody; SFTS, severe fever with thrombocytopenia syndrome; PCR, polymerase chain reaction; TBEV, tick-borne encephalitis virus; RT-PCR, reverse transcription PCR; IgM, immunoglobulin M; IgG, immunoglobulin G; VZV, varicella zoster virus; EBV, Epstein-Barr virus; VCA, viral capsid antigen; CSF, cerebrospinal fluid; AFB, acid fast bacillus; Ag, antigen; VDRL, venereal disease research laboratories test; FTA-ABS, fluorescent treponemal antibody absorbed test; HSV, herpes simplex virus; CMV, cytomegalovirus; HHV, human herpesvirus; JCV, John Cunningham virus; TB/NTM, tuberculosis/nontuberculous mycobacterium; SREAT, steroid responsive encephalopathy associated with autoimmune thyroiditis; ANCA, antineutrophil cytoplasmic antibodies; MPO, myeloperoxidase; PR3, proteinase 3; ANA, antinuclear antibody; RF, rheumatoid factor; CCP, cyclic citrullinated peptide; LA, lupus anticoagulant; dsDNA, double-stranded DNA; TPO, thyroid peroxidase.