Herpes simplex virus associated rhomboencephalitis mimicking demyelination: a case report

Abstract

Background

Herpes simplex virus (HSV) is an uncommon but important cause of brainstem rhomboencephalitis, especially in immunocompetent individuals. Its presentation can mimic demyelinating disorders such myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), posing a diagnostic challenge.

Case Presentation

We report a case of a 31-year-old previously healthy male who presented with holocranial headache followed by bilateral limb and facial numbness, right hemibody sensory loss, left temporal visual field deficit, and unsteadiness while walking. Neurological examination revealed dissociated sensory loss, gaze-evoked nystagmus, and impairment of cranial nerve functions, including visual field deficit and facial sensory loss, indicating involvement of the optic and trigeminal nerves, respectively. MRI showed hyperintensities in the pontine tegmentum and middle cerebellar peduncles with enhancement of bilateral trigeminal nerves. CSF analysis revealed lymphocytic pleocytosis. MOG and AQP4 antibodies were negative. VEP showed left optic pathway involvement. Initial treatment with intravenous methylprednisolone showed no improvement. A viral etiology was considered, and CSF PCR was positive for HSV. The patient improved significantly following a 21-day course of intravenous acyclovir.

Conclusion

This case underscores the importance of considering HSV rhomboencephalitis in the differential diagnosis of brainstem syndromes, particularly those mimicking demyelination. Early identification and antiviral therapy are crucial to prevent long-term neurological sequelae.

Introduction

Rhomboencephalitis refers to inflammation of the rhombencephalon (brainstem and cerebellum) and can arise from various etiologies, including infections, autoimmune disorders, paraneoplastic syndromes, and demyelinating conditions. Distinguishing these causes is crucial, as early treatment significantly influences outcomes. Infectious rhomboencephalitis, characterized by inflammation of the brainstem and cerebellum, is most commonly associated with Listeria monocytogenes, enteroviruses (particularly Enterovirus 71), and herpesviruses, including Herpes Simplex Virus (HSV), Varicella-Zoster Virus (VZV), and Epstein-Barr Virus (EBV). Less frequently, Cytomegalovirus (CMV), Human Herpesvirus 6 (HHV-6), and Mycobacterium tuberculosis have been implicated. HSV-associated brainstem encephalitis may mimic demyelinating conditions such as Neuromyelitis optica spectrum disorders (NMOSD), Acute Disseminated Encephalomyelitis (ADEM) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD), especially in monophasic forms without classical encephalopathy or seizures [1–3]. While HSV encephalitis is more frequently seen in immunocompetent individuals, the rhombencephalitis pattern in HSV, or disseminated involvement, may actually be more common in immunocompromised patients. To date, only one case report of HSV-1–associated rhomboencephalitis and two case reports of HSV-2–related brainstem rhomboencephalitis have been documented in the literature. In addition to Listeria, other infectious agents that can cause rhomboencephalitis include enteroviruses, VZV, EBV, HIV, and TB, though HSV remains a rare cause in comparison. This case presents a diagnostically challenging instance of brainstem HSV rhomboencephalitis, initially presenting with multifocal sensory deficits and transient visual symptoms.

Case presentation

A 31-year-old right-handed male bus driver, with no significant past medical history except chronic tobacco use, presented with a 3-day history of holocranial headache. On the following day, he developed numbness affecting both upper and lower limbs, as well as reduced sensation over the bilateral face and the right side of his body, including the chest and trunk. One day later, he experienced reduced vision in the left temporal visual field. Additionally, he had difficulty walking, characterized by swaying to the right, which was more pronounced in the dark or with his eyes closed. There were no associated symptoms of motor weakness, seizures, personality changes, or signs of raised intracranial pressure. He denied fasciculations, band-like sensations, nuchal rigidity, bladder or bowel dysfunction, or changes in voice or phonation.

Neurological examination findings

Upon examination, the patient’s higher mental functions were intact (MMSE score − 28). Sensory deficits suggested dorsal and lateral column involvement, particularly over the right face, upper and lower limbs, and trunk. Muscle tone, strength, and deep tendon reflexes were normal, with flexor plantar responses. No pathological reflexes (such as Hoffman and Wartenberg signs) were elicited. The cerebellar examination was unremarkable except for Romberg’s sign, which was positive, with instability toward the right. Cranial nerve examination revealed no relative afferent pupillary defect (RAPD), preserved light reflexes, and gaze-evoked nystagmus in both horizontal and vertical planes. Ocular pursuit and saccadic movements were intact, and the jaw jerk was absent.

Investigations and differential diagnosis

The routine laboratory investigations revealed normal CBC, DLC, and liver and kidney function, with no abnormalities in blood parameters (Table 1). Initial differential diagnosis included demyelinating disorders (such as MOGAD, ADEM and NMOSD), viral rhomboencephalitis, and vasculitis. Autoimmune screening (ANA, ANCA), and viral markers (HIV, HBsAG, HCV), were negative. The MRI scans revealed T2/FLAIR hyperintensities in the pons, primarily affecting the pontine tegmentum and bilateral trigeminal nerve tracts. Additionally, hyperintensity was noted along the left hemi-medulla (Fig. 1). MOGAD was considered as the initial working diagnosis because of the brainstem lesion and visual involvement, which were suggestive of a demyelinating process, but without classical MS features such as periventricular lesions or typical optic nerve involvement. Fundus examination was normal, and visual acuity was measured at 6/24 in both eyes. HUF (Humphrey Visual Field) perimetry did not show initial field defects. CSF analysis revealed lymphocytic pleocytosis with normal glucose and protein levels. MRI of the brain with orbit screening showed hyperintensities in the pontine tegmentum and middle cerebellar peduncles, along with enhancement of the bilateral trigeminal tracts and root entry zones. There was sparing of the optic nerves, and no involvement of the diencephalon, periventricular regions, or spinal cord. Anti-AQP4 and anti-MOG antibodies were negative. Neuro-Behçet’s disease was considered, but no corroborative features (e.g., oral/genital ulcers, pathergy, uveitis) were present. Visual Evoked Potential (VEP) showed increased P100 latency, suggesting conduction delay along the visual pathway. This abnormality, despite a normal MRI, indicates subclinical demyelination, as VEP can detect such changes before they are evident on imaging. A working diagnosis of a monophasic demyelinating illness, likely MOGAD, was made.

Table 1.

Laboratory investigations

Parameter	Result	Normal Range
Complete Blood Count (CBC)
Hb (g/dL)	15.1	13–17
TLC (x10^3/uL)	10.36	4.0–11.0
DLC (%) (N/L/M/E	63.6/24.2/9.2/2.4/0.1	Neutrophils: 40–60%, Lymphocytes: 20–40%, Monocytes: 2–8%, Eosinophils: 1–4%, Basophils: 0.5-1%
HCT (%)	46.8	38.3–48.6
PLT (x10^3/uL)	295	150–450
MCV (fL)	90.1	80–100
CSF studies
Cytology	Color: Colorless Appearance: Clear Clot/Coagulum: Absent Improved Neubauer’s Chamber Count: RBC- 20 cells/cumm WBC- 13 cells/cumm Microscopic Examination: Post centrifugation smears examined are paucicellular showing occasional lymphomononuclear cells in a clear background. No atypical cells seen.
CSF Biochemistry	Glucose: 69 mg/dL Chloride:129 mmol/L Protein: 35 mg/dL	Glucose : 45–80 mg/dL Chloride: 118–130 mmol/L Protein: 15–60 mg/dL
CSF Viral PCR	HSV 1 – Detected HSV 2 – Not Detected Adenovirus – Not Detected Enterovirus – Not Detected Epstein Barr Virus – Not Detected Varicella Zoster Virus – Not Detected Cytomegalovirus – Not Detected Human herpesvirus 6 - Not Detected Human herpesvirus 7 - Not Detected
NMO; Anti Aquaporin 4 IgG	Negative
MOG antibodies	Negative
Serum and CSF OCB	No band

Fig. 1.

Axial T2 MRI images [1, 2] and Sagittal, coronal, and axial (3 to 5) Flair MRI images of the brain show T2/Flair hyperintensity in the pons predominantly involving the pontine tegmentum and bilateral trigeminal nerve tracts. T2 flair hyperintensity is also seen along the left hemi-medulla

Treatment and outcome

Intravenous methylprednisolone (15 mg/kg) was administered for 5 days, but the patient showed no clinical improvement. In light of the lack of response to steroids, an infectious etiology was reconsidered, and multiplex CSF BioFire testing was performed. The CSF PCR test returned positive for herpes simplex virus 1 (HSV-1). Following this, intravenous acyclovir therapy was initiated, and the patient showed significant improvement over the next three weeks. By the end of the 21-day course of antiviral treatment, the patient experienced complete resolution of visual and sensory deficits. At follow-up, his visual acuity and gait were normal, and a repeat neurological examination revealed no residual deficits.

Discussion

Diagnostic challenge and autoimmune mimics

HSV encephalitis most commonly involves the temporal lobes, but rare variants with predominant brainstem involvement have been reported, particularly in immunocompetent young adults [4]. The absence of typical temporal lobe signs and encephalopathy can delay diagnosis. The presenting features in our patient—dissociated sensory loss, gaze-evoked nystagmus, and postural instability—are more characteristic of demyelinating disorders such as MOGAD, NMOSD or ADEM [5, 6]. These overlapping symptoms can lead to misdiagnosis, particularly when imaging findings, including involvement of the middle cerebellar peduncles and cranial nerve enhancement, further mimic demyelinating pathology.

Imaging findings and literature comparison

MRI findings in our patient showed T2/FLAIR hyperintensity involving the pons, specifically the pontine tegmentum, and bilateral trigeminal nerve tracts. These imaging features are highly suggestive of demyelination, but they also align with those observed in previous cases of HSV-related rhomboencephalitis, as demonstrated in a case reported by Tien and Dillon, where a 33-year-old male developed left facial numbness with MRI showing T2 hyperintensity in the pons and middle cerebellar peduncle, as well as gadolinium enhancement of the cisternal segment of the trigeminal nerve [7]. This case mirrors our findings, particularly in terms of MRI features and cranial nerve involvement, underscoring the potential for HSV to masquerade as demyelinating conditions through retrograde viral spread from the trigeminal ganglion.

In our case, the Visual Evoked Potential (VEP) showed increased P100 latency, suggesting conduction delay along the visual pathway. This abnormality, despite a normal MRI, indicates subclinical demyelination, as VEP can detect such changes before they are evident on imaging. MRI findings, including normal optic nerves, do not exclude demyelination, as VEP abnormalities can occur even in the absence of visible lesions on MRI. Additionally, the reduced amplitude of the VEP may indicate axonal loss, pointing to a more permanent and irreversible insult rather than a transient dysfunction.

Role of CSF PCR in confirming HSV

The definitive diagnosis in our case was confirmed by HSV PCR positivity in CSF, a diagnostic test with high sensitivity (94%) and specificity (96–97%) [8]. Although HSV typically affects the temporal lobes, variants with predominant brainstem involvement have been increasingly recognized, particularly in immunocompetent hosts. This entity may mimic autoimmune demyelination both clinically and radiologically, often leading to delayed initiation of appropriate antiviral therapy if not promptly considered [4, 9].

Treatment response and steroid use

Given the clinical suspicion for a demyelinating monophasic illness, the patient in our report was initially treated with IV methylprednisolone. Though corticosteroids are not standard treatment for HSV encephalitis, some studies suggest adjunctive steroids may be beneficial in controlling excessive inflammation, especially in brainstem syndromes mimicking autoimmune demyelination [10]. Upon confirmation of HSV PCR positivity, IV acyclovir was appropriately initiated, leading to significant clinical improvement. The rapid neurological recovery observed after a combined antiviral and anti-inflammatory approach emphasizes the importance of early therapeutic intervention.

Clinical implications and learning points

This case demonstrates the diagnostic complexity in young patients presenting with multifocal neurological deficits and brainstem MRI changes. It underscores the need for considering HSV-related rhomboencephalitis in the differential diagnosis, particularly in cases mimicking MOGAD or NMOSD. The use of MRI characteristics, CSF analysis, and targeted PCR assays is critical for timely diagnosis and intervention. MOGAD and NMOSD are important differentials in young adults with brainstem syndromes. However, in this case, the absence of longitudinally extensive spinal cord lesions, optic nerve sparing on imaging, and negative antibody titers made these less likely. Behçet’s disease, another mimic of rhomboencephalitis, was excluded based on clinical features, pathergy negativity, and lack of uveitis or oral/genital ulcers.

Prompt initiation of IV acyclovir and corticosteroids led to rapid neurological improvement. Although steroids are not standard in HSV encephalitis, their use in cases with extensive inflammation and radiological resemblance to demyelination may be beneficial [9]. This case underscores the importance of integrating clinical presentation, imaging, serological, and molecular diagnostics in distinguishing infectious from immune-mediated rhomboencephalitis. Timely antiviral therapy is crucial, as delays are associated with higher morbidity and risk of permanent neurological deficits.

Conclusions

This case highlights the diagnostic challenge of brainstem syndromes in young adults, where clinical and radiological features can closely resemble demyelinating conditions like MOGAD or NMOSD. Trigeminal nerve enhancement, sensory dissociation, and visual pathway involvement initially pointed to a monophasic demyelinating process. However, the patient’s lack of response to corticosteroids and subsequent HSV PCR positivity in CSF led to the diagnosis of viral rhomboencephalitis. This highlights the importance of considering viral etiologies in atypical demyelinating presentations. Early identification and timely antiviral therapy not only facilitate neurological recovery but also prevent unnecessary immunosuppressive treatments, ensuring better patient outcomes.

Abbreviations

ADEM

Acute disseminated encephalomyelitis

ANA

Antinuclear antibody

ANCA

Antineutrophil cytoplasmic antibody

AQP4

Aquaporin–4

CBC

Complete blood count

CMV

Cytomegalovirus

CSF

Cerebrospinal fluid

DNA

Deoxyribonucleic acid

EBV

Epstein–Barr virus

FLAIR

Fluid–attenuated inversion recovery

HHV

Human herpesvirus

HSV

Herpes simplex virus

HUF

Humphrey Visual Field

MOGAD

Myelin oligodendrocyte glycoprotein antibody–associated disease

MRI

Magnetic resonance imaging

MS

Multiple sclerosis

NMO

Neuromyelitis optica

NMOSD

Neuromyelitis optica spectrum disorder

OCB

Oligoclonal bands

PCR

Polymerase chain reaction

RAPD

Relative afferent pupillary defect

TB

Tuberculosis

VEP

Visual evoked potential

VZV

Varicella–zoster virus

Authors’ contributions

NL, MAT, PB, UK, ZS, and SDT were involved in the conception and design of the study, acquisition of clinical data, literature review, and drafting of the manuscript. HY contributed to the acquisition, analysis, and interpretation of radiological findings, and assisted in manuscript drafting. DK and MKG, as senior faculty, provided critical revision of the manuscript for important intellectual content, ensured methodological accuracy, and supervised the overall project. All authors contributed to the interpretation of data and approved the final version of the manuscript.

Funding

No funding was provided or sought.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

It was taken and written informed consent was obtained from the patient for the publication of clinical details and imaging findings included in this manuscript.

Consent for publication

Informed consent was obtained from the patient for the publication of clinical details and imaging findings included in this manuscript.

Competing interests

The authors declare no competing interests.