Bickerstaff Brainstem Encephalitis (BBE) is a rare autoimmune disease that affects the peripheral nervous system and central nervous system (brainstem). It was first described by Bickerstaff & Cloake in 1951, and Bickerstaff alone later reported it as “a grave syndrome with benign prognosis” in 1957.
Typically, 1 to 4 weeks after a preceding infection, the triad of external ophthalmoplegia, ataxia, and impaired consciousness appears acutely or subacutely. It belongs to the same anti-GQ1b antibody syndrome spectrum as Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS), and is positioned as a subtype of immune-mediated polyneuritis.
A nationwide survey in Japan estimated an annual incidence rate of 0.078 per 100,000 population, with approximately 100 new cases per year4). The male-to-female ratio is 1.3 (slightly male predominant), and the median age of onset is 35 years (mean 39 years)4).
A nationwide survey in Japan estimated an annual incidence rate of 0.078 per 100,000 population, with approximately 100 new cases per year4). It is even rarer than Miller Fisher syndrome.
The frequency of major findings reported in the 62-case series by Odaka et al. 5) is shown below.
Ophthalmoplegia
External ophthalmoplegia: The most important finding, present in 100% of cases 5).
Ptosis: May appear with fluctuation.
Wall-eyed bilateral INO (WEBINO): Cases with bilateral adduction deficit have been reported 2).
Nystagmus: Present in 27% of cases 5).
Pupillary abnormalities: Mydriasis, delayed light reflex, etc., may occur.
Ataxia and Muscle Weakness
Ataxia: One of the three cardinal signs present in all cases.
Limb muscle weakness: Flaccid, symmetric muscle weakness occurs in 60% of cases5).
Hyporeflexia/areflexia: Observed in 58% of cases5).
Hyperreflexia: Conversely, 34% show hyperreflexia, suggesting pyramidal tract involvement4)5).
Babinski sign: Upgoing plantar reflex is positive in 40% of cases4)5).
Consciousness and Brainstem Symptoms
Impaired consciousness: Somnolence in 45%, stupor to coma in 29% of cases4).
Facial nerve palsy: Observed in 45% of cases 6).
Bulbar palsy: Dysarthria and dysphagia occur in 34% 6).
Deep sensory impairment: Observed in 16% of cases 4).
Fisher syndrome (MFS) is a disease primarily involving peripheral neuropathy, characterized by the triad of external ophthalmoplegia, ataxia, and areflexia. BBE is distinguished by the addition of consciousness disturbance and pyramidal tract signs (hyperreflexia, positive Babinski sign), indicating more prominent involvement of the central nervous system (brainstem). The two form a continuous spectrum, and overlapping types also exist.
A preceding infection is observed in 92% of cases, with an interval of usually 1 to 4 weeks between infection and onset of neurological symptoms5).
The structure of the pathogen from a preceding infection resembles GQ1b ganglioside, inducing cross-reactive anti-GQ1b antibodies (molecular mimicry). These antibodies are thought to target cranial nerve terminals, dorsal root ganglia, and the blood-brain barrier, causing neurological damage.
Diagnosis is primarily based on clinical findings. The clinical diagnostic criteria by Odaka et al. (2003) are “progressive, relatively symmetric external ophthalmoplegia + ataxia + impaired consciousness or hyperreflexia within 4 weeks”6).
The abnormal rates of major test findings are shown below.
| Test | Abnormal rate |
|---|---|
| Extraocular muscle palsy (clinical finding) | 100%5) |
| EEG abnormality | 57–70%5)6) |
| Anti-GQ1b antibody positive | 68–80%4)5) |
| MRI abnormality | 11–30%5)6) |
| CSF albuminocytologic dissociation | Approximately 25%5) |
CSF findings are relatively normal in two-thirds of patients1). Albuminocytologic dissociation (albumin-cytologic dissociation) is observed in about 25% of cases, which is less frequent than in GBS5). CSF protein elevation may progress over time.
Brain MRI is normal in two-thirds of cases. When abnormal, typical findings on T2/FLAIR are hyperintensities in the brainstem (pons and pontomesencephalic junction)2)3)6). FLAIR, T2, and coronal views are useful for detecting brainstem lesions. Contrast enhancement is often absent.
EEG abnormalities are found in 57–70% of cases5)6). Diffuse delta activity is characteristic1)6) and is useful for excluding non-convulsive status epilepticus2).
Findings often overlap with the GBS spectrum. Prolonged or absent F-waves (suggesting early demyelination)6), motor axonal polyneuropathy4), and reduced sensory nerve action potential (SNAP) amplitudes may be observed5). However, some cases show relatively normal results5).
The main clinical differences among BBE, MFS, and GBS are shown below.
| Feature | BBE | MFS | GBS |
|---|---|---|---|
| Impaired consciousness/pyramidal tract signs | Present | Absent | Absent |
| Main lesion site | Central (brainstem) + peripheral | Peripheral (predominant) | Peripheral |
| Anti-GQ1b positivity rate | 68–80% | 83–100% | Approximately 8%4)5) |
Other differential diagnoses that must be excluded include Wernicke encephalopathy, brainstem vascular disorders, multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis (ADEM), viral encephalitis, bacterial meningoencephalitis, myasthenia gravis, brainstem tumors, botulism, and Lyme disease.
The positivity rate of anti-GQ1b antibody in BBE patients is 68–80%, and negative cases account for 20–30% or more2)5). BBE is a clinical diagnosis; if the classic triad (external ophthalmoplegia, ataxia, and impaired consciousness or hyperreflexia) is present, the diagnosis is not ruled out even if the antibody is negative2).
Currently, there are no RCTs on the treatment of BBE 5)6). Many cases resolve spontaneously, and the prognosis is considered relatively favorable. Treatment is extrapolated from evidence for GBS.
Currently, there are no RCTs for the treatment of BBE5)6). IVIg and plasma exchange are used extrapolated from evidence in GBS, but their impact on final outcomes is unclear. Many cases recover spontaneously, and the prognosis is relatively favorable.
GQ1b ganglioside is abundantly expressed in the paranodes and neuromuscular junctions (NMJs) of the oculomotor (III), trochlear (IV), abducens (VI), glossopharyngeal (IX), and vagus (X) nerves. The paranodal and terminal regions of the oculomotor nerves have a higher density of GQ1b than other cranial nerves, which is the main cause of extraocular muscle palsy. GQ1b accounts for only 5–6% of gangliosides in peripheral nerve tissue, but 11–13% in cranial nerves 5).
It is also abundant in large cells (Ia neurons) of the dorsal root ganglia, leading to ataxia and areflexia due to impaired sensory input.
Peripheral Neuropathy Mechanism
Nerve terminal damage by anti-GQ1b antibodies: Blockade occurs at both pre- and postsynaptic sites in the terminals of cranial nerves III, IV, and VI.
Dorsal root ganglion Ia neuron damage: Loss of sensory input leads to ataxia and areflexia.
Node-paranodopathy: A new concept proposing the Ranvier node as the site of dysfunction. A pattern of damage that is neither “demyelinating” nor “axonal” 5).
Central nervous system damage mechanism (specific to BBE)
Blood-brain barrier (BBB) disruption: BBE serum increases mucocutaneous pemphigoid secretion in brain microvascular endothelial cells (BMECs), disrupting the BBB (in vitro study by Saito et al. 2013) 4)6). MFS serum does not affect the BBB, and the degree of BBB disruption determines the clinical phenotype of Fisher/BBE.
Development of consciousness disturbance: Due to damage to the brainstem reticular activating system 6).
Area postrema pathway: The microcirculation of the area postrema in the brainstem has relatively high permeability to large molecules, serving as a route for antibody entry into the brainstem 6).
In rare autopsy cases, perivascular lymphocytic infiltration, edema, and glial nodules are observed in the brainstem, with diffuse upregulation of HLA-DR-positive macrophages/microglia prominent throughout the brainstem 1). Lesions may also extend to the cerebellar white matter, corpus callosum, spinal gray matter, posterior funiculus, and spinal nerve roots 1).
In the autopsy case by Imam et al. (2022), focal reactive meningothelial proliferation and sparse chronic inflammatory cells were confirmed in the temporal leptomeninges. Immunohistochemistry showed diffuse upregulation of HLA-DR-positive macrophages/microglia throughout the brainstem, also present in the cerebellar white matter, corpus callosum, spinal gray matter, posterior funiculus, and spinal nerve roots 1).
Pattern changes from anti-GQ1b antibody negativity to positivity for other anti-ganglioside antibodies have been reported at recurrence, and conversely, seroconversion from negative to positive has been reported 12 years after the initial episode 5). Based on observations that anti-GQ1b antibody titers follow the clinical course, the possibility of predicting recurrence through serial anti-ganglioside testing is being investigated 5). The recurrence rate in MFS/BBE is approximately 14%, which is higher than that in GBS (4%) 5).
Multiple studies, including an analysis of 581 cases, have accumulated evidence that BBE, MFS, and GBS form a continuous spectrum 4)5)6). Reports of the Fisher-Bickerstaff overlap syndrome, an overlap between BBE and MFS, are also increasing.
There are reports of rituximab (anti-CD20 monoclonal antibody) being used for refractory cases that do not respond to standard IVIg or plasma exchange, but the evidence remains at the case report level 5).
Based on findings from cases complicated by ulcerative colitis (IBD), it has been suggested that immune dysregulation of the gut-brain axis may be involved in the pathogenesis of BBE 3). The association between non-biologic immunomodulators such as mesalazine and neurological complications is also being investigated 3).
