Afebrile HSV-2 Encephalitis with Radiographic Atypia and Minimal Systemic Inflammation: A Case Report

Introduction

Herpes simplex virus (HSV) remains the leading cause of sporadic viral encephalitis in adults, with HSV-1 responsible for most cases. Classically, HSV-1 encephalitis involves the medial temporal lobes and limbic structures; it presents with fever, altered mental status, focal neurologic deficits, and seizures [1,2]. In contrast, HSV-2 has generally been associated with neonatal encephalitis and benign recurrent meningitis in adults [3]. HSV-2 contributes to less than 2% of all HSV encephalitis cases [4] and has a less defined radiologic profile [5]. Recent studies, however, indicate that HSV-2 can cause encephalitis with severity comparable to that of HSV-1, including altered consciousness, seizures, and clinically significant neurologic sequelae, even in immunocompetent individuals [6]. The clinical and radiologic features of HSV-2 encephalitis are often less typical than those observed in HSV-1 infection [7]. Temporal lobe involvement on magnetic resonance imaging (MRI), a hallmark of HSV-1 encephalitis, is less consistently observed in HSV-2 cases, particularly among immunocompromised patients [8]. In these patients, MRI abnormalities may appear diffuse or asymmetric; they also may be entirely absent [9].

Prompt recognition and treatment with intravenous acyclovir are essential to reduce morbidity and mortality. Cerebrospinal fluid (CSF) analysis typically demonstrates lymphocytic pleocytosis, elevated protein levels, and normal or mildly reduced glucose concentrations, but these findings are not pathognomonic [10]. Polymerase chain reaction (PCR) testing of CSF remains the diagnostic gold standard, with sensitivity and specificity exceeding 95% [10,11]. Early initiation of intravenous acyclovir has been associated with decreased mortality and improved neurologic outcomes [12].

This report describes a case of HSV-2 encephalitis in a 30-year-old woman with alcohol-related cirrhosis, without acquired immunosuppressive disease or medication use, who presented with an afebrile generalized tonic-clonic seizure and no leukocytosis. MRI revealed multifocal cortical and subcortical hyperintensities accompanied by T2*-weighted imaging hypointensities consistent with microhemorrhages. The case is notable for its radiologic atypia, minimal systemic inflammatory response, and diagnostic reliance on CSF PCR in the absence of characteristic imaging or clinical features. This report highlights the importance of maintaining a broad differential diagnosis and utilizing early CSF PCR testing in patients who present with seizures and encephalopathy, even when typical clinical features are absent, because timely treatment initiation can yield favorable outcomes.

Case Report

A 30-year-old woman presented to the emergency department with a chief complaint of seizure. On the day of admission, she had been in her usual state of health until she experienced sudden-onset numbness on the left side of her body, followed by a generalized tonic-clonic seizure lasting approximately 5 min. The seizure resolved spontaneously before arrival at the emergency department. She denied fever, chills, headache, or focal neurologic symptoms in the preceding days.

The patient’s medical history was notable for decompensated alcohol-related cirrhosis without acquired immunosuppressive disease. She reported abstaining from alcohol for the 2 months before admission but had previously consumed 10 shots (approximately 44 mL each) of vodka daily. She denied illicit drug use. A remote episode of generalized seizure had occurred more than 5 years earlier, lasting 1 to 2 min and resolving spontaneously without medical evaluation or further investigation. She had no history of epilepsy, head trauma, or immunosuppressive conditions. Human immunodeficiency virus test results were negative.

On arrival at the emergency department, her vital signs were within normal limits: blood pressure 106/60 mmHg, heart rate 99 beats/min, respiratory rate 23 breaths/min, and temperature 37.4°C. Physical examination revealed conjunctival icterus and generalized jaundice. The abdomen was distended but lacked shifting dullness or fluid wave. Neurologically, the patient was alert and oriented to time, place, and person. Mild asterixis was present, consistent with her usual state of health. No focal neurologic deficits were identified; cranial nerve function, motor strength, sensation, and deep tendon reflexes were intact.

Initial laboratory investigations revealed a complete blood count within normal limits; no leukocytosis was present (Table 1). Inflammatory markers were within normal ranges. Moderate hyponatremia and hypokalemia were noted, although the sodium level was consistent with the patient’s baseline, and no other clinically significant electrolyte abnormalities were identified. Non-contrast head computed tomography showed no evidence of intracranial hemorrhage but demonstrated areas of hypodensity. MRI of the brain, performed with and without contrast, revealed multifocal cortical and subcortical T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities, most prominently in the left parieto-occipital lobe, with trace restricted diffusion in this region and in the right parietal lobe. Additional hyperintense areas were observed in the left frontal, right occipital, and posterior left parietal lobes without accompanying diffusion restriction (Figure 1). T2*-weighted imaging sequences, used to detect microhemorrhages, demonstrated punctate hypointense foci in the bilateral parietal lobes, consistent with microhemorrhages (Figure 2).

An initial electroencephalogram was non-epileptiform and showed a normal posterior dominant rhythm. Lumbar puncture revealed an elevated opening pressure of 30 cmH2O and xanthochromic CSF. CSF analysis demonstrated a white blood cell count of 58/mm3 with 95% lymphocytes, a red blood cell count of 283/mm3, protein level of 174 mg/dL, and glucose level of 39 mg/dL. The CSF sample was tested using a multiplex polymerase chain reaction assay (FilmArray Meningitis/Encephalitis Panel; BioFire Diagnostics, Salt Lake City, UT, USA), which showed HSV-2 positivity (Table 2).

The differential diagnosis included alcohol withdrawal syndrome and hepatic encephalopathy. Alcohol withdrawal syndrome was considered unlikely because the patient had been abstinent from alcohol for the preceding 2 months, and her serum ethanol level was within normal limits. Hepatic encephalopathy was also considered less likely, given that the patient was alert and oriented to time, place, and person upon arrival. Mild asterixis was present but consistent with her usual state of health. She was adherent to her medications and reported regular bowel movements. Multiple sclerosis was excluded due to the absence of oligoclonal bands in CSF. Other potential causes, including electrolyte imbalance, intracranial hemorrhage, epilepsy, and bacterial meningitis, were excluded based on laboratory findings and imaging results.

Based on the clinical presentation of new-onset seizure, CSF findings suggestive of viral meningoencephalitis, and confirmatory PCR testing, the patient was diagnosed with HSV-2 encephalitis. Empiric antimicrobial therapy was initiated with intravenous acyclovir at 10 mg/kg every 8 h, along with ceftriaxone 2 g every 12 h, vancomycin, and dexamethasone 0.15 mg/kg every 6 h for presumed bacterial meningoencephalitis coinfection. Levetiracetam 1,000 mg twice daily was also started for seizure prophylaxis. After 72 h, bacterial culture findings remained negative; antibiotics and corticosteroids were discontinued. On hospital day 5, the patient experienced a second generalized tonic-clonic seizure, which resolved after intravenous lorazepam administration. This episode was accompanied by worsening asterixis and absence of bowel movement on the previous day. Her lactulose regimen was intensified, resulting in improved bowel function and resolution of asterixis. No further seizures occurred, and serial neurologic examinations remained stable throughout the remainder of hospitalization.

The patient was discharged to a skilled nursing facility to complete a 21-day course of intravenous acyclovir. At discharge, she was clinically stable with intact neurologic function and no additional seizure activity. Her baseline mental status persisted, and no new deficits were noted during hospitalization. Outpatient neurology follow-up was arranged to detect potential late complications or recurrence (Table 3).

Discussion

This report describes atypical presentation of HSV-2 encephalitis in an immunocompetent young woman with alcohol-related cirrhosis and highlights 2 notable findings. First, HSV-2 encephalitis may present with seizure as the initial symptom in the absence of fever or altered mental status, followed by spontaneous recovery. Second, clinicians should recognize that multifocal cortical and subcortical T2 hyperintensities with areas of microhemorrhage on brain MRI may indicate HSV-2 encephalitis in an immunocompetent adult. These features differ from the classical presentation of HSV encephalitis, which is typically caused by HSV-1 and characterized by limbic system predominance and acute febrile encephalopathy with seizures [13]. This case emphasizes the importance of recognizing atypical clinical and imaging features that may obscure timely diagnosis and treatment.

Timely diagnosis of HSV encephalitis is essential to preserve neurologic function. It is important to recognize that seizure is frequently the initial manifestation of HSV encephalitis and may occur without fever or encephalopathy, particularly in atypical cases. Delayed recognition and treatment often result from an incomplete or biased differential diagnosis, especially when clinical presentations deviate from the expected febrile or cognitive profiles [1,14]. Although HSV-1 remains the predominant cause of viral encephalitis in adults, clinicians must remain aware that HSV-2 can also cause encephalitis, including in immunocompetent individuals; it may present with subtle or misleading clinical features [15]. HSV-2 is more commonly associated with aseptic meningitis but has been increasingly recognized as a cause of encephalitis in immunocompetent adults [16]. In contrast to HSV-1 encephalitis, the clinical and radiologic features of HSV-2 encephalitis are often atypical [7]. Patients with HSV-1 encephalitis typically exhibit manifestations consistent with viral meningitis, such as fever or nuchal rigidity, and temporal lobe involvement on MRI is characteristic. These findings are less consistent in HSV-2 encephalitis, particularly among immunocompromised patients [8]. The prevalence of HSV-2 encephalitis in individuals with alcohol-related cirrhosis has not been well established [4], although cirrhosis may impair immune surveillance. In the present case, the patient’s alcohol-related cirrhosis likely contributed to the atypical presentation, and alternative diagnoses such as alcohol withdrawal and hepatic encephalopathy required exclusion. This case reinforces the importance of considering HSV infection in all patients with seizures of unclear etiology, regardless of the clinical course, spontaneous resolution, immune status, or absence of systemic signs, particularly among individuals with underlying medical conditions [17].

Atypical neuroimaging findings in HSV-2 encephalitis, particularly among immunocompetent individuals, represent an important diagnostic consideration. Unlike the classic mesiotemporal involvement characteristic of HSV-1 encephalitis [13], our patient demonstrated multifocal cortical and subcortical T2/FLAIR hyperintensities in the parietal, occipital, and frontal lobes, accompanied by scattered microhemorrhages on T2*-weighted imaging and absence of restricted diffusion on diffusion-weighted imaging. This atypical radiographic pattern has been noted in HSV-2 encephalitis in an immunocompetent adult; widespread cortical and subcortical involvement and microhemorrhages were also observed [18]. Another report described non-temporal cortical involvement in an immunocompetent adult with HSV-2 encephalitis, which led to diagnostic confusion with neoplasm, vasculitis, or autoimmune encephalitis [1]. Similarly, atypical cortical hyperintensities have been associated with diagnostic uncertainty and delays in initiating antiviral therapy [19]. Microhemorrhagic changes, as observed in the present case, are infrequently documented but may indicate more severe disease or improved detection through advanced imaging modalities [20]. In a comparative study, Moon et al. found that although HSV-1 was responsible for most cases of encephalitis, HSV-2 could cause overlapping imaging features, albeit less frequently and with fewer neurologic sequelae [5]. These findings collectively suggest a broader radiologic spectrum for HSV-2 encephalitis than previously recognized and emphasize the importance of including HSV-2 in the differential diagnosis of encephalitis with non-classical imaging features, even in immunocompetent individuals. This case also highlights how comorbidities, such as hepatic encephalopathy, can obscure the clinical picture and delay appropriate management. In patients with cirrhosis, overlapping metabolic and infectious etiologies should be carefully excluded through early lumbar puncture and PCR testing, particularly when imaging investigations reveal atypical findings.

Key clinical takeaways from this case include the recognition that HSV-2 encephalitis may present without fever or altered mental status, even in immunocompetent individuals. Seizure may be the sole initial symptom. MRI findings can involve extratemporal lobes and demonstrate microhemorrhages, rather than the mesiotemporal involvement typical of HSV-1 encephalitis. In such cases, CSF PCR testing remains essential for diagnosis, and clinicians should maintain a low threshold for early initiation of antiviral therapy to improve outcomes.

Conclusions

This case highlights that HSV-2 encephalitis may present with non-classical features, including afebrile onset, isolated seizure activity, and atypical neuroimaging findings. Such presentations can occur even in immunocompetent adults and may be easily overlooked. Our patient demonstrated a favorable short-term prognosis after early antiviral therapy, although long-term follow-up is required to detect potential neurologic sequelae. Early CSF PCR testing and prompt initiation of antiviral therapy are critical to avoid diagnostic delays and improve clinical outcomes. This report is limited to a single case, but its features align with emerging evidence that HSV-2 can cause clinically significant encephalitis in adults without immunosuppression or classic limbic involvement. These findings support a broader diagnostic approach in patients presenting with new-onset seizures or unexplained encephalopathy. Clinicians should remain vigilant for atypical presentations of viral encephalitis and include HSV-2 in the differential diagnosis, even in the absence of fever or characteristic imaging patterns. Future studies should further define the radiographic spectrum and long-term outcomes of HSV-2 encephalitis to inform evidence-based diagnostic and therapeutic strategies.