Cerebral Hemorrhage in Varicella-Zoster Virus Encephalitis: A Case Study

Introduction

Varicella-zoster virus (VZV) encephalitis results from VZV infection, and presents with diverse clinical features across age groups [1]. Children commonly exhibit cerebellar ataxia, whereas adults typically manifest focal nervous system signs, cranial neuropathy, and seizures [1]. VZV infection in 10% to 30% of individuals can reactivate as shingles, with adult-onset VZV encephalitis predominantly affecting the elderly and immunocompromised [2]. A hospital in Germany conducted a prognostic study involving 36 patients with VZV encephalitis or meningitis. The findings revealed that 33% of the patients had neurological sequelae at the time of discharge, while none of the patients experienced mortality [3]. Intracranial hemorrhage transformation may occur in some VZV encephalitis cases, exacerbating the condition and posing a life-threatening complication [4,5]. Moreover, sporadic VZV-induced viral encephalitis carries a mortality rate ranging from 9% to 20% [5].

Although the association between stroke and VZV was first reported in 1896 [4,6], and numerous cases of VZV encephalitis have been documented recently, instances of VZV encephalitis with high inflammation and protein levels in the CSF accompanied by hemorrhagic transformation remain relatively rare [1,4]. Moreover, there is a notable scarcity of clinical and basic research exploring the correlation between CSF levels of relevant proteins and inflammatory markers and the risk of hemorrhagic transformation in these patients [1,4,6]. Consequently, we present a case of VZV encephalitis characterized by high CSF inflammation and elevated protein levels, coupled with hemorrhagic transformation. This report presents the case of a 42-year-old man with VZV encephalitis associated with cerebral hemorrhage.

Case Report

On January 25, 2024, a 42-year-old male patient presented with a headache, fever reaching a peak of 38.9°C, limb seizures, loss of consciousness for several minutes followed by spontaneous recovery, and was subsequently admitted to our hospital’s emergency department in a state of altered consciousness. The patient had no history of immunosuppressive-related diseases, and it is unclear whether he had received the herpes zoster vaccine. Physical examination revealed neck stiffness, impaired coordination of eye movements, intact light reflex in both pupils, and autonomous limb movements. Herpes lesions were observed scattered across the head, neck, chest, and back, accompanied by erythema and increased skin temperature. Blood tests showed normal white blood cell and neutrophil counts, with a monocyte count of 0.94×109/L. Head CT scan revealed no significant abnormalities, while electroencephalogram (EEG) showed mild-to-moderate diffuse abnormalities (Figure 1). In detail, the EEG results indicated that the brain’s basic rhythmic activity consisted of low-amplitude beta waves with modulated amplitude, appearing approximately symmetrical on both sides, and no significant changes were seen in response to visual stimuli. Throughout the recording, there was a considerable presence of scattered and short bursts of diffuse medium-amplitude theta activity (4–6 Hz), as well as a small amount of medium-amplitude delta activity (2–3 Hz) observed in both hemispheres. The patient was unable to cooperate with deep breathing exercises.

Considering the possibility of intracranial infection resulting in viral encephalitis, based on the patient’s clinical presentation and examination findings, treatment with acyclovir as antiviral therapy, along with glycerol fructose and mannitol to alleviate headache, was initiated. The patient exhibited upward eye deviation and limb convulsions in the emergency department at night, which improved after receiving intravenous diazepam as a sedative. However, due to the progression of the disease, the patient developed a coma and was admitted to the inpatient department on January 26, 2024, for further evaluation and management. Reviewing the patient’s medical history revealed a recent febrile illness accompanied by cutaneous herpes lesions approximately 2 weeks prior, details of which were unclear. The patient neglected his symptoms, resulting in disease progression despite prior anti-infective treatment.

Upon admission, the patient was comatose with neck rigidity, spontaneous limb movements during orbital compression, and disseminated herpetic lesions on the head, neck, chest, and back. CSF analysis revealed a pale yellow appearance, elevated pressure (195 mmH2O; the normal range for CSF pressure is 80 to 180 mmH2O), glucose levels of 4.41 mmol/L, lactate levels of 3.8 mmol/L, chloride levels of 109.7 mmol/L, a protein concentration of 9049.3 mg/L, and a white blood cell count of 950×106/L, predominantly lymphocytes (80%). Immunoglobulin levels in the CSF were elevated, with IgG at 2790 mg/L, IgM at 86.8 mg/L, and IgA at 416 mg/L. Cytokine analysis showed elevated levels of IL-6 (2498.39 pg/mL), IL-8 (5524.02 pg/mL), IL-10 (457.26 pg/mL), interferon-α (23.74 pg/mL), and interferon-γ (46.42 pg/mL). Detection of viral pathogens in CSF revealed VZV with a sequence count of 10 795 and 94.08% coverage (Figure 2). MRI showed abnormal signal foci in bilateral temporal and right frontal lobes, consistent with herpes encephalitis (Figure 3). T1-weighted images (Figure 3A, 3C) revealed low-density lesions in the bilateral temporal lobes and right frontal lobe. Fluid-attenuated inversion recovery (Figure 3B, 3D) showed high-density lesions in the same areas.

Despite treatment with nasal catheter oxygen inhalation, methylprednisolone (500 mg for 5 days), acyclovir (0.5 g every 8 hours), and levetiracetam (0.5 g twice daily), along with intravenous diazepam administered at half the normal dose plus a continuous infusion of 50 mg of diazepam in 250 mL of normal saline during the initial hospitalization, and 20 mg of diazepam in a continuous infusion of 100 mL of normal saline during the hospital stay, the patient’s condition deteriorated. This decline culminated in loss of consciousness and bilateral pupil dilation following the first session of double filtration plasmapheresis (DFPP), which utilized nafamostat for anticoagulation at an initial dosage of 20 mg per hour, including priming. Immediate CT scan revealed hemorrhagic changes in the left frontal, parietal, and temporal lobes with intraventricular extension (Figure 4). Axial head CT scans (Figure 4A, 4B) revealed cerebral hemorrhages in the left frontal, parietal, and temporal lobes, as well as in the right frontal lobe, with extension into the ventricular system. The patient was promptly transferred to the neurosurgery department for evacuation of intraventricular hematoma, decompressive craniectomy, and external ventricular drainage implantation under general anesthesia on January 31, 2024. Intraoperatively, the left frontal intracerebral hematoma was found to have ruptured into the ventricle, with markedly elevated intracranial pressure. Postoperatively, CT imaging demonstrated hematoma evacuation with diffuse cerebral edema and evidence of cerebral infarction. Tragically, the patient was pronounced clinically dead on February 2, 2024.

Discussion

In this case report of VZV encephalitis, we address the challenges of managing the condition when there is significant inflammation and elevated protein levels in the cerebrospinal fluid, as well as the need for careful consideration when using DFPP treatment in such scenarios.

Viral encephalitis results from the inflammation of the brain parenchyma caused by viruses that invade the host from outside the central nervous system, reaching the spinal cord and brain via the bloodstream or through retrograde transmission from nerve endings. Common causes of viral encephalitis include herpes simplex virus, West Nile virus, and enteroviruses. Other viral pathogens include VZV, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6 and 7, measles virus, mumps virus, and rubella virus [7]. VZV encephalitis is a rare yet serious complication of VZV infection, exhibiting varied clinical presentations across different age groups [8]. While children commonly display cerebellar ataxia, adults often present with focal neurological signs, cranial neuropathy, and seizures [9]. VZV infection, which can reactivate as shingles in 10% to 30% of individuals, predominantly affects the elderly and immunocompromised, with adult-onset VZV encephalitis being particularly severe [10]. VZV encephalitis may undergo hemorrhagic transformation, further complicating the clinical course and increasing mortality rates. Despite advancements in medical care, sporadic VZV-induced encephalitis is associated with a significant mortality rate, ranging from 9% to 20% [5]. Another study indicates that the mortality rate for VZV-induced encephalitis may vary between 5% and 20% [11].

Chickenpox is contracted by inhaling infected aerosolized droplets. The initial infection occurs in the mucous membranes of the upper respiratory tract and then spreads to mucosal and epidermal lesions as well as local sensory nerves, generally being controlled by the immune system. Upon reactivation, it can cause postherpetic neuralgia or Ramsay Hunt syndrome. In some cases, VZV can affect the arteries of the neck and head, potentially leading to a stroke [12]. Between 10% and 50% of VZV viremia cases can result in pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulation [13]. The patterns of VZV encephalitis are classified into 3 types: large/medium vessel disease with bland or hemorrhagic infarctions, small vessel disease with ischemic/demyelinating mixed lesions, and ventriculitis/periventriculitis [14]. Effective treatment for VZV encephalitis necessitates the adequate use of antiviral medications [13]. The case we present here involved a 42-year-old man with epilepsy as the primary clinical manifestation of VZV encephalitis. The patient exhibited elevated CSF pressure, protein levels, and inflammation, which might be associated with hemorrhagic transformation. VZV, the second major pathogen of viral encephalitis after herpes simplex virus, often causes chickenpox upon initial infection [15]. In some cases, the virus remains latent in the posterior root of spinal or trigeminal ganglia and can reactivate, causing herpes zoster (shingles) or ascending to the central nervous system to induce encephalitis or myelitis. Reactivated VZV may increase the risk of stroke in affected patients [8,10,16].

Two major risk factors for increased susceptibility to VZV are being over 50 years of age and having immunosuppression due to T-cell-mediated immune dysfunction. Lizzi et al [17] reported a case of VZV encephalitis in a patient with these risk factors, whose hallucinations improved after treatment with acyclovir. Similarly, Rodrigues et al [1] described a case of VZV encephalitis in a 43-year-old man with a history of AIDS, where diplopia improved following acyclovir treatment. However, our reported patient did not possess the 2 major risk factors of advanced age and immunosuppression. The patient presented clinically with headache, fever, and seizures, and despite receiving antiviral treatment and DFPP, the outcome was ultimately fatal. Our case highlighted the presence of high CSF cell count and protein levels in VZV encephalitis, challenging traditional understandings of the CSF spectrum in viral encephalitis [18]. Compared with encephalitis caused by other viruses like Epstein-Barr virus, VZV encephalitis elicits a more intense inflammatory response, characterized by elevated levels of IL-6 and IL-8 in the CSF [16,19,20]. This heightened inflammatory response may contribute to blood-brain barrier disruption and subsequent CNS involvement. In the patient we reported, serum levels of IL-6 and IL-8 were 2498.39 pg/mL and 5524.02 pg/mL, respectively, during hospitalization. Following treatment with acyclovir, corticosteroids, and DFPP, these serum levels decreased to 5.49 pg/mL and 12.39 pg/mL, respectively. However, the progression of the patient’s condition could have been attributed to irreversible damage to nervous system tissue caused by the prior severe inflammatory response. Additionally, VZV-induced vasculitis can lead to hemorrhagic or ischemic changes in intracranial blood vessels, further complicating the clinical course [21–23].

Furthermore, matrix metalloproteinases play a role in vascular remodeling in VZV encephalitis, potentially leading to aneurysm formation or rupture due to vascular wall weakening [24]. Demyelinating changes associated with VZV infection may exacerbate vasculitis, further aggravating vascular changes [25].

The nonspecific clinical manifestations of altered consciousness in VZV encephalitis, coupled with intracerebral hemorrhage transformation, can delay treatment and increase the risk of extensive intracranial hemorrhage. Moreover, temporal lobe lesions predispose patients to epilepsy, exacerbating cerebral edema and increasing the likelihood of hemorrhagic transformation [26].

Treatment strategies for VZV encephalitis typically involve antiviral therapy combined with steroids [27]. However, in cases with high CSF protein and inflammatory factors, as seen in our patient, the addition of plasma exchange may be considered cautiously. Nafamostat was used here as an anticoagulant during plasma exchange at a dosage of 20 mg per hour. We employed DFPP, and the choice of nafamostat as an anticoagulant was based on its rapid metabolism as an extra-corporeal anticoagulant, with a half-life of 8 minutes, which has minimal impact on the patient’s coagulation function. Nonetheless, timely and adequate antiviral therapy, combined with steroid therapy, may help mitigate vascular lesions induced by VZV infection, potentially reducing stroke risk in affected patients [28].

Conclusions

In conclusion, our case highlights the complex pathophysiology and clinical challenges associated with VZV encephalitis, especially when complicated by hemorrhagic transformation. Further research is needed to elucidate the mechanisms underlying vascular changes in VZV encephalitis. In cases of rapidly progressing VZV encephalitis, the use of DFPP should be carefully considered to evaluate the treatment indications, as well as the associated benefits and risks. It is particularly important to determine the optimal treatment strategy for these patients to enhance their prognosis.