Abstract
Guillain–Barré syndrome (GBS) and its variants represent a spectrum of acute, immune-mediated polyneuropathies with heterogeneous clinical presentations and underlying etiologies. While infectious triggers are common precursors to these disorders, the association between viral infections and autoimmune neurological conditions remains an area of active investigation. Here, we report a case of GBS/Miller–Fisher syndrome overlap syndrome in an 80-year-old male presenting with dysarthria, dysphonia, ophthalmoplegia, areflexia, and postural instability following an upper respiratory tract infection. Cerebrospinal fluid analysis revealed the unexpected detection of herpes simplex virus type 1 DNA. Treatment with intravenous immunoglobulin therapy and acyclovir resulted in a progressive recovery of neurological symptoms. This case emphasizes the role of viral infections in differential diagnosis or as potential triggers for autoimmune neurological disorders highlighting the efficacy to addressed therapy in such complex cases.
Keywords
Introduction
Guillain–Barré syndrome (GBS) represents a spectrum of acute, immune-mediated polyneuropathies and one of the major emergencies in the neuromuscular domain. GBS is a multifaceted disorder, characterized by an array of phenotypes, electrophysiological features, and prognostic outcomes. 1
The recognition of GBS as a spectrum of disorders with discrete, complete, and incomplete forms that sometimes overlap is critical for understanding its various clinical and electrophysiological variants and their underlying mechanisms. This spectrum includes typical presentations as well as atypical forms such as Miller–Fisher syndrome (MFS), which is characterized by ophthalmoplegia, ataxia, and areflexia, often with the presence of anti-GQ1b antibodies.2,3
Overlapping clinical features between GBS and MFS, particularly in cases involving limb weakness and motor nerve abnormalities, have led to the classification of GBS/MFS overlap syndromes.1,4,5 While a variety of noninfectious triggers such as surgical procedures, trauma, certain medications (notably immune checkpoint inhibitors), vaccinations, and systemic illnesses have been identified as antecedents or risk factors for GBS, infectious events are the predominant precursors to its clinical onset.6,7 This association is highlighted by the frequent occurrence of GBS following respiratory or gastrointestinal infections, with pathogens like Campylobacter jejuni, Cytomegalovirus (CMV), and Epstein–Barr virus (EBV) being commonly implicated. 8 In particular, molecular mimicry between antigens on nerve endings and those carried by pathogens plays a crucial role in the pathogenesis of GBS. 9
Despite the frequent history of an infectious antecedent, presence of a pathogen in the cerebrospinal fluid (CSF) should lead to a reevaluation of the diagnosis. There are only a few reports10,11 that assess co-infection in the CSF.
Given their rarity, the precise relationship between CNS infections and acute autoimmune polyneuropathies is still unclear. We hereby report a rare case of GBS/MFS overlap syndrome associated with the unexpected detection of herpes simplex virus type 1 (HSV-1) in the CSF, further highlighting the complex interplay between infectious triggers and autoimmune neurological disorders.
Case report
An 80-year-old male presented at the emergency department with the sudden onset of dysarthria, dysphonia, and gait instability that had appeared the day before and worsened in the last few hours. He had a self-resolved flu-like episode, characterized by mild fever, sore throat, and fatigue, occurring a week before the onset of neurological symptoms. His past medical history was unremarkable, except for prostate cancer that was successfully treated with radiotherapy 4 years earlier. During the initial neurological assessment, the patient displayed a slight limitation of horizontal conjugate gaze in both directions with associated diplopia only in distance vision, moderate dysarthria with a nasal quality, likely linked to weakness of the oropharyngeal muscles, and mild postural instability requiring a wide-based stance that worsened with eye closure. The patient also experienced tingling paresthesias in the distal fingertips of his hands.
Blood tests showed normal values except C-reactive protein 1.96 mg/dL (normal value 0–0.5 mg/dL). A brain computed tomography was performed, showing no acute pathological findings. Over the following 8 h, the symptoms deteriorated, with marked dysarthria almost progressing to a state of anarthria when assuming a seated position with the head flexed forward, swiftly regressing upon returning to the supine position, likely associated with weakness of the oropharyngeal muscles. Additionally, he exhibited external ophthalmoparesis with significant limitation of ocular motility in all gaze directions and associated diplopia, initial clumsiness in fine hand movements, tingling paresthesias in the palmar regions of the hands and fingers, and lost deep tendon reflexes in ankles and in the upper limbs. No weakness in the lower limbs, defined numbness, swallowing difficulties, exertional dyspnea, or sphincter dysfunction were detected.
In the following days, the patient showed further deterioration, developing a complete ophthalmoplegia, mild bilateral facial weakness, and diffuse areflexia in all four limbs.
A diagnostic lumbar puncture was performed. CSF analysis revealed normal white blood cell count, absent red blood cells, normal protein level, and normal glucose level; a high copy number of HSV-1 DNA was detected (Table 1). Serology test results for HIV, CMV, and HSV-1 immunoglobulin G (IgG) and IgM were negative. Nerve conduction studies (NCS) performed on the fourth day after symptom onset revealed reduced recruitment in the facial muscle district and slight decreases in the compound motor action potentials of the tibial nerves, while F-waves were present in all the examined extremities (Table 2). Brain magnetic resonance imaging (MRI) with contrast revealed some non-specific T2/FLAIR hyperintensities in the periventricular and subcortical white matter, without pathological enhancement following contrast administration. In the suspicion of GBS–MFS overlap syndrome, the patient was initiated on intravenous immunoglobulin (IVIg) therapy (2 g/kg divided over 5 days) and acyclovir for HSV-1 infection (10 mg/kg every 8 h for 14 days). Clinical improvement was noted within the second week with gradual resolution of ophthalmoplegia, dysarthria, and facial paresis, along with the reappearance of deep tendon reflexes in all four limbs. Furthermore, the patient no longer reported postural instability, tingling paresthesias in the hands, and regained manual skills in the fine movements. NCS repeated on the 12th day after symptom onset revealed a slowed motor conduction velocity and increased F-wave latency recorded from the right tibial nerve, disappearance of the sensory nerve action potentials from the left ulnar and left sural nerves, while the needle electromyography (EMG) examination showed an improvement in motor unit recruitment in the left orbicularis oris muscle. These findings were consistent with a predominantly demyelinating sensory-motor polyneuropathy (Table 2).
Cerebrospinal fluid analysis.
The first lumbar puncture was performed 1 day after symptom onset, while the second lumbar puncture was conducted 2 weeks after symptom onset and subsequent to IVIg therapy (2 g/kg divided over 5 days) and acyclovir treatment for HSV-1 infection (10 mg/kg every 8 h for 14 days). All laboratory investigations were conducted at the same analytical laboratory.
HSV-1, herpes simplex virus type 1; IVIg, intravenous immunoglobulin.
Lower and upper limbs motor and sensory NCS.
First (I) and second (II) electrophysiological exams were performed 4 and 12 days after the onset of symptoms.
NCS, nerve conductions studies.
A second lumbar puncture was performed 2 weeks after symptoms onset and CSF analysis revealed a normal white blood cell count, absent red blood cells, and normal glucose levels, with a mild elevation in protein levels, HSV-1 DNA was not detected (Table 1). The detection of anti-GQ1b IgG antibodies in the serum resulted negative.
Discussion
GBS and MFS are not distinct entities but are rather part of a spectrum of disorders whose common underlying mechanism seems to be the “molecular mimicry” between antigens located on nerve terminations and antigens carried by pathogens.9,12
The self-limiting flu-like symptoms experienced by our patient prior to admission may suggest an infection involving an unspecified respiratory virus, which could have initiated a primary immune response, creating a state of immune activation. Concurrently, the reactivation of HSV-1 may have further complicated the immune landscape, triggering or exacerbating the clinical picture. HSV-1 is known for its ability to establish latency in the sensory ganglia of the cranial nerves.13,14 Reactivation of the virus can induce both localized and systemic infections, which may precipitate a spectrum of neurological symptoms, including those affecting the cranial nerves. In the context of GBS/MFS overlap syndrome, HSV-1’s reactivation may contribute to cranial nerve dysfunction. The virus’s affinity for cranial nerves, combined with the immune system’s response to HSV-1, may exacerbate or trigger an autoimmune attack on these nerves, leading to the clinical manifestations observed in this case. Beyond cranial involvement, the immune response against both pathogens may also play a role in peripheral nerve pathology through mechanisms such as molecular mimicry.
CSF examination helps confirm the diagnosis of GBS and rule out alternative causes. The key finding is a significant increase in protein levels with a normal cell count, known as albuminocytological dissociation. This indicates increased blood–nerve barrier permeability, especially at the proximal nerve root.
Albuminocytological dissociation is absent in over half of GBS patients during the first week but appears in more than 90% by the second week. A mild increase in cell count (10–20 cells/mm3) occurs in up to 5% of cases, but counts exceeding 50 cells/mm3 suggest other conditions. In our patient, a slight increase in CSF protein was noted 2 weeks after symptom onset, with a normal cell count electrophysiology. Examinations, including NCS and needle EMG examination, are carried out according to established electrophysiological guidelines to confirm GBS diagnosis,15–19 rule out similar conditions, provide insights into the prognosis by distinguishing between axonal and demyelinating forms, and assess the degree and location of axonal damage. If electrodiagnostic testing performed at the initial presentation is nondiagnostic, repeat testing may be performed 1–2 weeks apart.20,21 The subsequent test offers a more accurate classification of the subtype and evaluates the extent of axonal damage, which is crucial for predicting the outcome. In patients diagnosed with GBS/MFS overlap syndrome, electrophysiological studies frequently reveal abnormalities in both motor and sensory nerves.22,23 This is in contrast to classic MFS distinguishing it from classic MFS, where the involvement is often limited to sensory nerves or may even be entirely normal.2,24 In the case described, clinical finding of mild bilateral facial weakness, along with electrophysiological findings included reduced recruitment in the facial muscle district, reduced motor conduction velocity, increased F-wave latency, and the disappearance of sensory action potentials, confirming both motor and sensory involvement, consistent with an overlap syndrome. Despite what is described in the literature, where brain MRI with gadolinium is an excellent confirmatory test for diagnosing MFS, there has been no observed anomalous contrast enhancement of the cranial nerves in our patient.25,26 However, a normal brain MRI does not exclude the diagnosis, notably in atypical cases such as MFS–GBS overlap syndrome. 27 Anti-GQ1b is the most frequent antiganglioside antibody detected in MFS patients’ sera (approximately 85%–90% of patients). GQ1b gangliosides are located at the neuronal endings of oculomotors nerves (III, IV, and VI cranial nerves), dorsal roots of spinal cord, and fibers of neuromuscular spindles, explaining the classic symptomatic triad observed in patients. Despite anti-GQ1b antibodies are frequently associated with MFS and GBS/MFS overlap syndromes, their absence does not rule out the diagnosis.6,9,15 This may be due to fluctuations in antibody levels during the course of the disease. Furthermore, the sensitivity of the test can vary, and in some instances, the autoimmune response may target other gangliosides or epitopes not covered by standard testing. The clinical presentation and diagnostic tests such as CSF analysis and electrodiagnostic studies often take precedence over serological findings. In cases where the clinical features suggest GBS/MFS overlap syndrome, the absence of anti-GQ1b antibodies should not preclude the diagnosis, especially if other supportive evidence is present.
The specific treatment of GBS and its variants typically involves administering IVIg and plasma exchange therapy,2,28–30 resulting in gradual recovery for most patients. In the presented case, the combination of immunomodulatory therapy with IVIg along with specific antiviral therapy led to a progressive and almost complete recovery.
Bies et al. 11 recently reported a case of a patient diagnosed with MFS with the detection of HSV-1 in the CSF following a Campylobacter jejuni acute infection, treated with dual intravenous therapy with immunoglobulins and acyclovir, resulting in a significant clinical improvement within the first 72 h. Although the majority of cases described in the literature regarding the rare association between HSV-1 and GBS spectrum-related syndromes present a mildly severe phenotype and respond well to dual therapy, Dilena et al. 10 ’s study describes a case of a fulminant infantile GBS variant presenting as peripheral locked-in syndrome associated with HSV-1 infection with no response to acyclovir and IVIg.
Conclusion
The presented case highlights the heterogeneous nature of GBS and its variants. It also underscores the importance of considering viral infections in differential diagnosis and as potential triggering or facilitating factors in the manifestations of autoimmune neurological disorders, such as MFS. In our patient, the overlap syndrome of GBS–MFS associated with HSV-1 detection in the CSF suggests a possible link between viral infection and the development of autoimmune pathology.
The involvement of both sensory and motor nerves in electrophysiological studies of GBS/MFS overlap syndrome provides a crucial diagnostic clue that distinguishes it from classic MFS. This distinction is essential for guiding appropriate treatment strategies, as GBS/MFS overlap syndrome may require more aggressive immunomodulatory therapy compared to isolated MFS. The recognition of these electrophysiological patterns can also help clinicians anticipate the potential for more extensive neurological impairment and adjust management plans accordingly.
Timely and targeted therapeutic management, combining IVIg immunomodulatory therapy with specific antiviral therapy led to progressive recovery of neurological symptoms in the patient. This highlights the importance of a multidisciplinary approach in treating such complex conditions. Nonetheless, there is still a dearth of literature directly correlating the potential of HSV-1 to precipitate or hasten the development of MFS.
Further research is warranted to better understand the underlying mechanisms linking viral infections to the development of autoimmune neurological disorders and to optimize treatment strategies for affected individuals.
