European Journal of Cardiovascular Medicine

Guillain Barré Syndrome (GBS) is an acute immune mediated polyradiculoneuropathy typically presenting with progressive limb weakness, areflexia, and variable sensory and autonomic dysfunction⁴. While the classic form of GBS follows a well-defined trajectory, atypical variants can manifest with unusual patterns of weakness, cranial nerve involvement, or severe autonomic and respiratory dysfunction, presenting significant diagnostic and therapeutic challenges⁵. Recognizing these atypical patterns is vital for timely intervention, as diagnostic delays can lead to increased morbidity and prolonged recovery⁶.

This case series highlights diverse and atypical manifestations of GBS, including bulbar/cranial nerve variants mimicking myasthenia gravis, hip predominant acute motor axonal neuropathy (AMAN), severe AMSAN with ventilatory failure, and isolated bulbar AMSAN presenting as a stroke mimic. These cases reveal the heterogeneity of GBS and underscore the importance of considering atypical variants in acute neuromuscular presentations⁷. Through detailed analysis of clinical presentations, diagnostic findings, and treatment responses, this study aims to raise awareness of rare GBS subtypes, emphasize early electrophysiological and cerebrospinal fluid (CSF) evaluation, and explore evolving therapeutic strategies for severe and refractory cases⁸. By broadening our understanding of atypical GBS, we seek to improve early recognition and refine management for better patient outcomes.

1: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) with Treatment-Related Fluctuations and Positive U1-snRNP Antibody

A 49-year-old male presented with a chronic progressive sensory-motor polyneuropathy, initially manifesting as tingling and numbness in the bilateral lower limbs for seven months, followed by progressive weakness over four months, first noticed as slippage of chappals and difficulty rising from a squatting position. Upper limb weakness developed two months before admission. Neurological examination revealed symmetric weakness (upper limbs: 4/5, lower limbs: 3/5) with areflexia, while muscle bulk and tone were normal. Electrophysiological studies (EMG-NCV) confirmed acquired demyelinating polyradiculoneuropathy, showing partial conduction block, motor conduction slowing, and delayed F-wave latency, consistent with Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). CSF analysis demonstrated albuminocytological dissociation (elevated protein with a normal WBC count), further supporting the diagnosis. Autoimmune workup revealed U1-snRNP positivity, suggesting an overlap with Mixed Connective Tissue Disease (MCTD), while normal creatine phosphokinase (CPK) levels (47 U/L) ruled out a primary myopathy.

The patient was initially treated with intravenous immunoglobulin (IVIG) for five days, leading to an improvement in lower limb power (from 3/5 to 4/5), and was discharged in stable condition. However, 11 days post-IVIG, he experienced worsening weakness (upper limbs: 2/5, lower limbs: 3/5), raising suspicion of treatment-related fluctuations (TRF), which occur in about 25% of CIDP cases. Given the relapse, Rituximab (1 g IV) was administered, followed by a second dose 15 days later, resulting in a significant improvement in limb power (4/5 in all limbs). Given the suspected CIDP-MCTD overlap and IVIG dependency, Rituximab maintenance therapy was planned at six-month intervals.

Case 2: Bulbar and Cranial Nerve Variant Mimicking Myasthenia Gravis

A 17-year-old male presented with a three-day history of dysphagia, dysphonia, diplopia, facial weakness, and mild left upper limb weakness. Neurological examination revealed bilateral ptosis, facial weakness, and bulbar dysfunction (dysphagia, dysarthria, dysphonia), along with asymmetric upper limb weakness (left: 3/5, right: 4/5) and areflexia in all limbs. Given the predominant bulbar involvement, myasthenia gravis (MG) was initially suspected. However, further investigations led to a revised diagnosis. Brain MRI was normal, ruling out brainstem pathology, and anti-AChR antibodies were negative. Additionally, repetitive nerve stimulation (RNS) was normal, making a neuromuscular junction disorder less likely. In contrast, CSF analysis showed albuminocytological dissociation (elevated protein with normal WBC count), strongly suggesting Guillain-Barré Syndrome (GBS).

With these findings, a diagnosis of atypical GBS with predominant bulbar involvement was made. The patient was promptly treated with intravenous immunoglobulin (IVIG), leading to significant improvement by Day 3, particularly in cranial nerve function and limb strength. He was discharged in stable condition and showed a full recovery on follow-up.

Case 3: Pure Motor Hip-Predominant Acute Motor Axonal Neuropathy (AMAN)

A 26-year-old male presented with an acute onset proximal lower limb weakness manifesting as difficulty rising from a sitting position since 3 days, reporting marked hip weakness while being able to walk with support. Neurological examination revealed proximal weakness (hip power: 3/5 in all ranges of motion), while distal lower limb and upper limb strength remained intact (5/5). Reflexes were preserved in all joints, including the hip, and sensory and cranial nerve examinations were unremarkable. Given the isolated proximal weakness, differentials such as myopathy or inflammatory myositis were initially considered; however, further investigations suggested a neuropathic process. CSF analysis showed albuminocytological dissociation (elevated protein with normal WBC count), and nerve conduction studies (NCS) revealed findings consistent with acute motor axonal neuropathy (AMAN), a pure motor variant of Guillain-Barré Syndrome (GBS).

With a confirmed diagnosis of AMAN with isolated proximal weakness, the patient was treated with intravenous immunoglobulin (IVIG) and intensive physiotherapy to improve mobility. By discharge, hip power improved to 4/5, and at a one-month follow-up, strength had fully recovered (5/5) with no residual deficits. This case highlights an atypical presentation of AMAN, where proximal muscle involvement predominated without the classic ascending weakness pattern of GBS. Unlike the demyelinating forms of GBS, AMAN may present with preserved reflexes, which can further obscure the diagnosis. The presence of albuminocytological dissociation in CSF and characteristic axonal changes on NCS played a crucial role in confirming the condition.

Case 4: Severe Acute Motor Sensory Axonal Neuropathy (AMSAN) with Ventilatory Failure

A 42-year-old female developed acute, rapidly progressive weakness in all four limbs over two days. She initially experienced fine motor difficulties, such as trouble buttoning and unbuttoning clothes, followed by distal weakness, evident from frequent chappal slippage. The weakness rapidly progressed to involve proximal muscles, making it difficult for her to raise her arms and stand from a seated position. Within 24 hours of admission, she became tachypnoeic, and her single-breath count deteriorated, indicating respiratory muscle involvement. Due to impending respiratory failure, she required urgent intubation and mechanical ventilation.

Diagnostic workup revealed acute motor sensory axonal neuropathy (AMSAN) on nerve conduction studies, while cerebrospinal fluid (CSF) analysis showed albuminocytological dissociation, confirming Guillain-Barré Syndrome (GBS). She was started on intravenous immunoglobulin (IVIG); however, no significant improvement in limb power was observed even after three months. Suspecting critical illness neuropathy, a repeat NCS confirmed persistent AMSAN. Given her refractory course, plasmapheresis was initiated (seven cycles over three weeks), but yielded only minimal improvement in limited joints. Due to ongoing weakness and poor response to conventional therapies, Rituximab (1 g IV) was administered, with a second dose planned at six months. Over time, her condition improved gradually, allowing successful weaning off mechanical ventilation. She was discharged with ongoing physiotherapy and follow-up for further rehabilitation.

Case 5: Recurrent GBS with Treatment-Related Fluctuations (CIDP Evolution)

A 30-year-old male presented with progressive lower limb weakness. Neurologically, he was able to stand and walk with support, with motor strength of 4/5 in all ranges of motion at the bilateral ankle, knee, and hip joints, and his reflexes were present. His medical history revealed a similar episode in 2020, which was accompanied by dysphagia. At that time, he had been diagnosed with acute inflammatory demyelinating polyneuropathy (AIDP) and had achieved complete recovery following intravenous immunoglobulin (IVIG) therapy. Given his recurrent symptoms, nerve conduction studies (NCS) were performed, confirming recurrent AIDP, raising the suspicion of recurrent Guillain-Barré syndrome evolving into chronic inflammatory demyelinating polyneuropathy (CIDP). Ganglioside IgM antibody testing was negative, ruling out certain immune-mediated neuropathies. He was treated with intravenous methylprednisolone pulse therapy (1 g/day for five days), followed by oral steroids (1 mg/kg) with gradual tapering. Under this regimen, his muscle power stabilized, and he remains under regular follow-up.

Case 6: Isolated Bulbar Palsy Variant of AMSAN

A 34-year-old male presented with acute dysphagia and dysarthria for two days. Neurological examination revealed an absent gag reflex but no limb weakness, with normal deep tendon reflexes in the limbs. Given the isolated bulbar symptoms, an initial concern was a brainstem stroke; however, MRI of the brain was normal. Additionally, anti-acetylcholine receptor antibody testing was negative, ruling out myasthenia gravis. Further evaluation with nerve conduction studies (NCS) revealed findings consistent with acute motor sensory axonal neuropathy (AMSAN), a severe Guillain-Barré Syndrome (GBS) variant. Cerebrospinal fluid (CSF) analysis showed albuminocytological dissociation (elevated protein with a normal WBC count), further supporting the diagnosis. Within 24 hours of presentation, the patient developed respiratory depression requiring intubation and mechanical ventilation. IV immunoglobulin (IVIG) therapy was initiated, and a gradual improvement in bulbar and respiratory function was observed. With supportive care, the patient was successfully extubated and achieved full recovery at discharge.This case highlights a rare, isolated bulbar variant of AMSAN with rapid respiratory deterioration. Isolated bulbar symptoms in GBS are uncommon, and the absence of initial limb weakness can lead to diagnostic uncertainty.

Comparative Study: Diagnostic and Therapeutic Approach

Key Observations:

• All cases had albuminocytological dissociation in CSF, reinforcing its diagnostic value.
• NCS helped in differentiating subtypes (AMAN, AIDP, AMSAN, CIDP).
• IVIG was the first-line treatment, with additional therapy (plasmapheresis, Rituximab, steroids) in refractory cases.
• CIDP cases benefited from steroids and immunomodulatory agents like Rituximab.
• Physiotherapy played a crucial role in functional recovery, particularly in axonal variants.

This case series highlights the diverse and atypical manifestations of GBS, including purely motor presentations, recurrent forms, severe axonal variants, and isolated cranial nerve involvement. While IVIG remains the mainstay of treatment, some patients require additional immunomodulatory therapies.

Comparison with Literature:

1. CIDP with Treatment-Related Fluctuations:
   Literature supports the use of Rituximab in refractory CIDP cases⁹, as seen in Case 1.
2. Bulbar Variant Mimicking Myasthenia Gravis:
   Similar cases report that RNS and anti-AChR antibodies are essential to rule out myasthenia gravis¹⁰, supporting our findings in Case 2.
3. AMAN with Predominant Hip Involvement:
   Reports suggest that proximal AMAN presentations are rare but respond well to IVIG and physiotherapy¹¹, as seen in Case 3.
4. Severe AMSAN with Ventilatory Failure:
   Literature supports plasmapheresis in severe AMSAN, with some cases requiring Rituximab¹² in treatment-resistant forms.
5. Recurrent GBS and CIDP Evolution:
   Similar cases show that AIDP can evolve into CIDP, requiring steroid therapy¹³, as observed in Case 5.
6. Isolated Bulbar Palsy with Respiratory Involvement:
   Case reports highlight that bulbar variants of AMSAN are rare but can lead to severe respiratory failure¹⁴, reinforcing the need for early IVIG therapy.

Atypical variants of Guillain-Barré Syndrome (GBS) can present with diverse clinical features, often mimicking other neurological disorders, which complicates early diagnosis. While the hallmark of GBS remains progressive weakness with areflexia, these variants may exhibit selective muscle involvement, cranial nerve dysfunction, or fluctuating disease courses, making differentiation from other neuromuscular diseases crucial.

Clinical Variability and Mimics

Atypical GBS presentations often overlap with conditions such as myasthenia gravis, brainstem stroke, inflammatory myopathies, and motor neuron disease. In Case 2, predominant bulbar symptoms (dysphagia, dysphonia, diplopia, and facial weakness) led to an initial suspicion of myasthenia gravis. The presence of ptosis, fatigability, and oropharyngeal involvement strongly suggested a neuromuscular junction disorder. However, negative anti-acetylcholine receptor antibodies and normal repetitive nerve stimulation (RNS) tests ruled out myasthenia, while CSF findings of albumin-cytological dissociation confirmed GBS. Similarly, in Case 6, isolated bulbar palsy raised concerns for a brainstem stroke, but an unremarkable MRI and subsequent nerve conduction study (NCS) confirming AMSAN solidified the diagnosis.

In Case 3, hip-predominant weakness presented a diagnostic dilemma, as it is uncommon in GBS and could mimic proximal myopathies such as polymyositis or metabolic myopathies. However, normal serum creatine kinase levels, preserved distal strength, and NCS findings consistent with AMAN ruled out a myopathic process. Similarly, in Case 5, recurrent weakness resembling relapsing-remitting GBS raised concerns about CIDP evolution, requiring careful differentiation from monophasic GBS.

The Role of Ancillary Testing

The CSF analysis, showing albumin-cytological dissociation (high protein without pleocytosis) in all six cases, provided a strong diagnostic clue. However, early in the disease course, CSF protein levels may be normal, necessitating repeat lumbar puncture if clinical suspicion persists.

Nerve conduction studies (NCS) remain the cornerstone for differentiating GBS subtypes.

• Case 1 (CIDP variant): Demonstrated demyelinating features, including prolonged distal motor latencies, conduction block, and reduced nerve conduction velocities.
• Cases 3, 4, and 6 (AMAN/AMSAN variants): Revealed axonal degeneration, with markedly reduced compound muscle action potentials (CMAPs) but normal conduction velocities.
• Case 5 (Recurrent AIDP evolving into CIDP): Initially showed demyelination, but repeat studies demonstrated chronic changes, supporting a CIDP diagnosis.

Although anti-ganglioside antibodies (GM1, GD1a, GQ1b) are associated with AMAN and Miller Fisher Syndrome, they were negative in our cases, highlighting that seronegative forms exist.

Treatment Considerations in Atypical GBS

The standard treatment for GBS consists of intravenous immunoglobulin (IVIG) or plasmapheresis, both of which are equally effective. However, atypical and refractory cases require individualized treatment approaches.

IVIG and Its Variable Response

All six patients received IVIG as the first-line therapy, but their responses varied based on disease subtype:

• Cases 2, 3, and 6 (Bulbar-predominant & Pure Motor AMAN): Responded rapidly within three days, suggesting a more responsive disease course.
• Cases 1 and 5 (CIDP Evolution): Showed initial improvement but subsequent worsening, requiring long-term immunosuppression.
• Case 4 (Severe AMSAN): Failed to improve with IVIG alone, necessitating plasmapheresis.

The Role of Plasmapheresis

Plasmapheresis was used in Case 4 (AMSAN with ventilatory failure) after an inadequate IVIG response. This aligns with studies showing axonal GBS variants may respond better to plasmapheresis due to its ability to remove pathogenic antibodies and complement components more effectively than IVIG.

Steroids and Immunosuppressants in Chronic or Relapsing Cases

• Steroids are generally ineffective in acute GBS but were used in Case 5 (Recurrent GBS evolving into CIDP). The response to intravenous methylprednisolone followed by oral steroids supported the CIDP
• Rituximab, a B-cell-depleting monoclonal antibody, was successfully used in Cases 1 and 4 (CIDP with treatment fluctuations and severe AMSAN). This suggests a role for biologic agents in refractory or chronic GBS variants.

Mechanical Ventilation and Supportive Care

In Cases 4 and 6, bulbar and respiratory involvement necessitated ventilatory support.

• Monitoring single-breath count, negative inspiratory force, and serial FVC measurements was critical in predicting respiratory failure.
• Early intubation prevented aspiration pneumonia and hypoxic complications.

Long-Term Rehabilitation and Recovery

• Cases 2, 3, and 6 (Bulbar-predominant & AMAN): Achieved near full recovery within 4-6 weeks.
• Case 4 (AMSAN with ventilatory failure): Showed minimal recovery despite aggressive therapy, demonstrating the poor prognosis associated with severe axonal variants.
• Cases 1 and 5 (CIDP evolution): Required long-term immunosuppressive therapy but achieved functional stability.

Prognostic Implications of Atypical GBS

The prognosis of GBS depends on the disease variant, severity, and response to treatment.

Factors Associated with Good Prognosis

• Predominantly demyelinating forms (AIDP, CIDP-like variants)
• Rapid response to IVIG
• Absence of respiratory involvement
• Pure motor involvement without sensory deficits (Case 3, AMAN)

Factors Associated with Poor Prognosis

• Axonal involvement (AMSAN > AMAN > AIDP)
• Failure to respond to IVIG (as seen in Case 4)
• Need for prolonged mechanical ventilation (>1 month)
• Fluctuating weakness (suggesting CIDP evolution, as seen in Case 1 and 5)

Emerging Therapies and Future Directions

While IVIG and plasmapheresis remain the mainstays of therapy, newer immunomodulatory treatments are being explored:

• Rituximab (Anti-CD20 monoclonal antibody) was beneficial in refractory CIDP (Case 1) and AMSAN (Case 4).
• Eculizumab (C5 complement inhibitor) is being studied for severe axonal variants.
• Autologous stem cell transplantation has been considered in treatment-resistant CIDP.

The Importance of Long-Term Monitoring

• CIDP evolution requires long-term immunomodulation and frequent reassessments.
• Rehabilitation and physiotherapy remain crucial for functional recovery, especially in severe AMSAN cases.

Atypical GBS presentations require high clinical suspicion for early diagnosis and management. CSF analysis and NCS remain crucial for confirmation. While IVIG is the first-line therapy, severe or refractory cases benefit from additional immunomodulatory treatments like Rituximab, plasmapheresis, and steroids. This case series underscores the need for individualized therapeutic strategies to optimize outcomes in atypical GBS variants.

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