Brainstem encephalitis and anti-GQ1b antibody syndrome triggered by varicella-zoster virus presenting as intractable hiccups: a first reported case

Abstract

Background

Varicella-zoster virus (VZV) reactivation without rash (zoster sine herpete, ZSH) is a known cause of neurological disease. However, its association with an overlap syndrome of brainstem encephalitis and anti-GQ1b antibody syndrome is exceedingly rare, and its presentation with intractable hiccups as the initial symptom has not been previously reported.

Case presentation

We describe a 35-year-old male whose illness began with isolated intractable hiccups, which progressed to include brainstem signs such as cranial neuropathies and autonomic failure. Diagnosis was confirmed by a triad of findings: CSF next-generation sequencing positive for VZV, serum anti-GQ1b/GM4 antibodies, and a corresponding medullary lesion on MRI. Despite aggressive treatment with intravenous acyclovir and immunoglobulin, his condition deteriorated rapidly, culminating in fatal respiratory and circulatory failure.

Conclusions

This case suggests that intractable hiccups can be the initial sign of a life-threatening neurologic emergency. It underscores the need for high clinical suspicion of ZSH and overlapping anti-ganglioside antibody syndromes, even in the absence of a rash. Therefore, early and concurrent testing for VZV and anti-ganglioside antibodies is warranted to guide the timely intensive combined therapy, as this approach could be critical to altering the disease course.

Background

Intractable hiccups, defined as persistence beyond 48 h, often signal an underlying organic disease [1]. Their occurrence can be a sentinel sign of brainstem irritation, explained by the anatomy of the hiccup reflex arc. This arc involves afferent vagal fibers, central medullary integrators (the nucleus tractus solitarius and dorsal vagal nucleus), and efferent phrenic pathways; inflammatory insults to this circuit, particularly in the medulla, can cause intractable symptoms [2].

As a neurotropic pathogen, the varicella-zoster virus (VZV) establishes latency in sensory ganglia such as those of the vagus nerve after primary infection. Although reactivation can occur without the characteristic rash, a condition termed zoster sine herpete (ZSH), its absence poses a significant diagnostic challenge [3–5] retrograde transport along the vagus nerve, the virus can invade the brainstem, triggering viral encephalitis [6, 7]. Notably, VZV infection can also act as a trigger for an autoimmune response, eliciting the production of anti-GQ1b antibody and leading to anti-GQ1b antibody syndrome [8]. This syndrome encompasses a broad clinical spectrum, including Miller-Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE), and Guillain-Barré syndrome with ophthalmoplegia, among other variants [9].

However, cases of VZV-induced brainstem encephalitis complicated by anti-GQ1b antibody syndrome are exceedingly rare. To our knowledge, the presentation of this overlap syndrome with isolated intractable hiccups as the sole initial manifestation has not been described. As the first such case documented herein, it aims to alert clinicians to this potential diagnostic pitfall and to illustrate a possible underlying pathophysiological mechanism.

Case presentation

A 35-year-old male was admitted to our hospital with the chief complaint of “intractable hiccups for 2 months, with recent onset of facial asymmetry and dysarthria for 3 days.” Two months prior to admission, following a period of psychological stress, the patient developed intractable hiccups accompanied by a dry cough. Despite a thorough gastroenterological workup, his symptoms remained refractory and progressive. For several weeks, intractable hiccups constituted the sole neurological manifestation. Consultations with multiple departments (Gastroenterology, Psychological Medicine, and Otorhinolaryngology) revealed unremarkable findings.

In early January 2025, the clinical course reached a critical transition with the emergence of dizziness and gait instability. His neurological condition then deteriorated markedly three days prior to admission (January 12, 2025), as he rapidly developed facial asymmetry and dysarthria against the backdrop of persistent hiccups. An emergency head CT scan revealed no abnormalities, raising the suspicion of a neurological disorder and leading to his admission on January 14, 2025. His past medical history was significant only for photosensitive dermatitis.He denied any condition or medication use that could cause immunosuppression (including HIV, chronic organ failure, active malignancy, hematologic disorders, or malnutrition). He also denied neuropathic pain in any dermatomal distribution.

Neurologic examination

On admission, the patient was lethargic with dysarthria; higher cortical functions remained intact. Cranial nerve examination revealed an unobservable right pupil due to prior trauma. The left pupil measured 2.5 mm with a prompt light reflex. Ocular findings included misalignment (right hypotropia), bilateral ptosis, limited left abduction, and absent right adduction. Left-sided facial weakness manifested as loss of forehead wrinkling, incomplete eye closure, flattened nasolabial fold, and rightward mouth deviation. Additional findings included trismus, inability to protrude the tongue, absent gag reflex, diminished cough reflex, and reduced facial sensation. Motor examination demonstrated full strength in all limbs, normal tone, symmetrical reflexes, and no pathological signs. Autonomic dysfunction featured sympathetic overactivity (hypertension and tachycardia) along with severe postural blood pressure instability (e.g., a decrease in systolic pressure of > 25 mmHg was documented during repositioning), indicative of significant autonomic failure.

Laboratory data

Brain MRI (Fig. 1) revealed a focal lesion in the left medulla, characterized by hypointensity on T1-weighted images, hyperintensity on T2-weighted and FLAIR sequences, isointensity on both DWI and ADC maps, and no contrast enhancement. These features are consistent with a subacute inflammatory or demyelinating lesion of the medulla. Cerebrospinal fluid (CSF) analysis on admission (January 14) showed an opening pressure of 40 mmH₂O, lymphocytic pleocytosis (127 × 10⁶/L, 93% mononuclear), normal glucose (3.45 mmol/L), elevated total protein (0.40 g/L), and elevated inflammatory cytokines (IL-6 164.17 pg/mL, IL-10 34.26 pg/mL). Metagenomic next-generation sequencing detected VZV-specific sequences (2 reads). Follow-up CSF analysis on January 22 revealed a characteristic evolving pattern: the opening pressure increased to 160 mmH₂O, the white cell count decreased to 22 × 10⁶/L (70% mononuclear), cytokine levels declined (IL-6 108.73 pg/mL, IL-10 10.65 pg/mL), while the total protein concentration rose sharply to 1.06 g/L. Glucose was 3.10 mmol/L and chloride 139.3 mmol/L.Serological and cerebrospinal fluid testing was positive for anti-GQ1b and anti-GM4 antibodies but was negative for aquaporin-4 (AQP4) antibodies.Additional findings included vitamin B1 and B9 deficiencies (1 ng/mL and < 2 ng/mL, respectively), and comprehensive immunologic workup: polyclonal hypergammaglobulinemia (IgG 37.27 g/L, IgE 141.13 IU/mL), normal lymphocyte subsets (CD4 + T-cell count and CD4/CD8 ratio), normal complement levels (C3, C4), and positive autoimmunity markers including antinuclear antibody (speckled 1:100) with strong anti-SSA/Ro-52 reactivity. HIV antibody testing was negative.

Fig. 1.

Axial brain MRI at the level of the medulla. The images demonstrate a lesion in the left medulla (white arrows) across different sequences: A T1-weighted image, B T2-weighted image, C FLAIR, D diffusion-weighted imaging (DWI), E apparent diffusion coefficient (ADC) map and F contrast-enhanced T1-weighted image. The lesion shows hypointensity on T1, hyperintensity on T2 and FLAIR, isointensity on both DWI and the ADC map, and shows no contrast enhancement

Hospital course

The treatment regimen initiated upon admission included intravenous acyclovir (10 mg/kg q8h), intravenous immunoglobulin (IVIG at 0.4 g/kg/day for 5 days), vitamin B₁ supplementation, and empiric antimicrobial coverage. Within 24 h, the patient’s clinical status declined with the development of lethargy and respiratory distress, requiring mechanical ventilation; ataxic breathing was observed. Further progression occurred over the next 48 h, characterized by the appearance of right peripheral facial palsy, generalized limb weakness (Medical Research Council grade 3), obtundation, and cardiogenic shock (left ventricular ejection fraction 37%) with systemic shock. Methylprednisolone pulse therapy was administered but was discontinued after 24 h because of gastrointestinal hemorrhage. Subsequent deterioration was evidenced by minimal spontaneous respiration and refractory hypotension requiring high-dose vasopressor support. After consultation with the family, life-sustaining measures were withdrawn, resulting in a fatal outcome.

Discussion

This report describes the first documented case of an overlap syndrome between VZV-induced brainstem encephalitis and anti-GQ1b antibody syndrome. The inaugural manifestation was intractable hiccups. This case is distinguished by three salient features: the persistence of hiccups as the sole initial symptom, rapid progression to life-threatening medullary failure, and a fulminant course refractory to combined therapy. This distinctive profile offers valuable insights into the possible pathogenesis and may inform the management of this severe disease complex.

The hiccup reflex arc comprises afferent vagal fibers, medullary integration centers, and efferent phrenic nerve pathways. The early manifestation of intractable hiccups indicated sustained excitation of this circuit. Pathogenetically, VZV reactivation in vagal sensory ganglia likely underlies this presentation. Potential trajectories include: (1) herpes zoster pharyngitis [10]; (2) cranial nerve zoster [11]; and (3) brainstem encephalitis, wherein delayed antiviral therapy permits retrograde viral spread to the brainstem. In our patient, left medullary T2 hyperintensity and ipsilateral cranial nerve palsies support this mechanism of viral migration along the vagus nerve [10]. Thus, persistent hiccups warrant prompt evaluation with CSF mNGS and neuroimaging to enable early intervention.

In our patient, the simultaneous detection of VZV and anti-GQ1b/GM4 antibodies suggests the possibility of a dual-hit process. This could involve concurrent direct viral invasion and an antibody-mediated response, though their precise interaction remains to be fully elucidated.Anti-GQ1b antibody syndrome triggered by VZV is exceedingly rare.We hypothesize that VZV neurotropism for the vagus nerve, coupled with subsequent immune activation, may promote anti-GQ1b antibody production in susceptible individuals [12]. This antibody-mediated response, triggered by the initial infection, could explain the rapid clinical deterioration.Anti-GQ1b antibody syndrome is an infection-triggered autoimmune disorder characterized by serum anti-GQ1b antibody positivity. Its clinical spectrum is broad, ranging from mild, isolated syndromes to severe forms involving the overlap of multiple subtypes [13]. The target GQ1b ganglioside is predominantly enriched in the myelin sheaths of cranial nerves III, IV, VI, and VIII, with minor expressionin the glossopharyngeal and vagus nerves. Anti-GQ1b antibodies binding to these antigens are associated with combined injury [14], which could help explain the ophthalmoparesis and bulbar symptoms. Furthermore, concurrent production of anti-GM4 antibodies may have acted synergistically to amplify neural damage, a pattern linked to BBE/GBS overlap syndrome with poor prognosis [15, 16].

Autonomic dysfunction was a core clinical manifestation. We propose two potential, non-exclusive explanations for this: first, direct VZV invasion of the dorsal vagal nucleus, disrupting sympathetic-parasympathetic balance and causing cardiovascular dysregulation; second, antibody-mediated effects targeting presynaptic autonomic ganglia. It is hypothesized that such antibody-mediated processes could trigger complement-dependent damage that might impair neurotransmitter release [17], exacerbating dysautonomia. Importantly, anti-GM4 antibodies appear to synergistically enhance cholinergic inhibition, which was likely associated with the patient’s end-stage heart failure and refractory shock.

Despite the administration of adequate acyclovir and intravenous immunoglobulin (IVIG) upon diagnosis, the patient’s condition deteriorated rapidly. This treatment failure may be explained by several factors: a diagnostic delay of nearly two months allowing irreversible neuronal injury; structural deficits from severe demyelination that likely limited the efficacy of IVIG [18]; and the potential inadequacy of IVIG monotherapy to clear high-affinity antibodies or suppress intense complement activation in such rapidly progressive overlap syndromes [16]. Therefore, for severe cases, we propose that an aggressive combination of antiviral therapy and early plasma exchange should be considered at diagnosis to rapidly remove pathogenic antibodies.

Integrated pathophysiological interpretation

The evolving CSF profile provides key insights. The initial profile (marked pleocytosis with elevated IL-6/IL-10) was consistent with active VZV brainstem encephalitis. The follow-up pattern (decreasing cellularity and cytokines alongside a sharp rise in protein) suggests a transition towards a protein-elevating, likely antibody-mediated process. Furthermore, the patient’s lack of cutaneous manifestations, together with the low VZV read count in the CSF, is more consistent with the pattern of VZV reactivation described in hosts with relatively preserved immune function [19].Therefore, our revised interpretation is that this case represents a sequential “infection-triggered autoimmunity” mechanism: primary VZV brainstem encephalitis initiated a severe anti-GQ1b/GM4 antibody-mediated response that drove the catastrophic neurological decline.

Limitations of the study

This study is subject to several limitations inherent in a single case report. The proposed ‘dual-hit’ mechanism, though supported by diagnostic findings (VZV DNA and anti-GQ1b/GM4 antibodies), remains speculative without pathological confirmation. The low number of VZV-specific reads and a single timepoint measurement of antibody titers represent methodological constraints that preclude deeper virological or immunological analysis. Finally, the recommended aggressive immunotherapy was not administered, thus its potential efficacy remains untested in this context.

Conclusions

To our knowledge, this first-reported case illustrates a novel ‘infection-autoimmunity’ dual-hit mechanism for a fatal overlap syndrome and suggests that intractable hiccups can be the initial sign of a life-threatening neurologic emergency. Based on this experience, we highlight three critical clinical considerations: (1) Intractable hiccups, especially when accompanied by pharyngeal symptoms, should prompt consideration of ZSH and subsequent anti-GQ1b antibody syndrome, even in the absence of a rash. (2) Diagnosis relies on an integrated approach incorporating CSF mNGS, anti-ganglioside antibody testing, and brain MRI. (3) In severe cases, early and aggressive combination therapy with high-dose antivirals and immunomodulation (e.g., plasma exchange) should be considered, as this approach could be critical to altering the disease course. Future studies are needed to elucidate the molecular mechanisms and optimize multidisciplinary management.

Abbreviations

ADC

Apparent diffusion coefficient

ANA

Antinuclear antibody

AQP4

Aquaporin-4

BBE

Bickerstaff brainstem encephalitis

CSF

Cerebrospinal fluid

CT

Computed tomography

DWI

Diffusion-weighted imaging

FLAIR

Fluid-attenuated inversion recovery

GBS

Guillain-Barré syndrome

HIV

Human immunodeficiency virus

Ig

Immunoglobulin

IL

Interleukin

IVIG

Intravenous immunoglobulin

MFS

Miller-Fisher syndrome

mNGS

Metagenomic next-generation sequencing

MRI

Magnetic resonance imaging

NMOSD

Neuromyelitis optica spectrum disorder

VZV

Varicella-zoster virus

ZSH

Zoster sine herpete

Authors’ contributions

GW and YG contributed to the clinical management of the patient and the acquisition of data. HJ contributed to the analysis and interpretation of data. CL was the corresponding author and a major contributor in writing and revising the manuscript. All authors read and approved the final manuscript.

Funding

None.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian (wife) for the publication of this case report, including all personal and clinical details, and any accompanying images.

Competing interests

The authors declare no competing interests.