Bickerstaff 39;s Brainstem Encephalitis

[Rosalia Kemme]

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Bickerstaff brainstem encephalitis (BBE) is a rare, autoimmune disease of the peripheral and central nervous system (i.e., brainstem). BBE is considered a variant of other immune-mediated polyneuropathies, such as Guillain Barr syndrome (GBS) and Miller Fisher syndrome (MFS). BBE classically presents as an acute triad of ataxia, encephalopathy, and ophthalmoplegia, typically subsequent to infection[1].

The most common infections associated with BBE are C. jejuni and H. influenzae, with molecular mimicry being the proposed mechanism for BEE and other forms of acute demyelinating polyneuropathies[2]. A case study reported on an episode of BBE about one week following a positive SARS-CoV-2 test[3].

Although the precise pathophysiology of BBE is not completely clear, there are some well-documented proposed mechanisms. BBE is highly associated with the presence of IgG anti-GQ1b antibodies, with approximately two-thirds of BBE patients having these antibodies in their sera[4]. This overlaps with GBS, MFS, acute ophthalmoparesis without ataxia, the pharyngeal-brachial-cervical variant of GBS, and acute ataxic neuropathy. All of these syndromes, including BBE, can be collectively named the (anti-GQ1b antibody syndrome), as increasing evidence shows that they have a common pathogenesis.

The anti-GQ1b antibodies interact with the GQ1b gangliosides expressed on peripheral nerves. These gangliosides are primarily located at the paranodes and neuromuscular junctions of various cranial nerves, including the oculomotor, trochlear, abducens, glossopharyngeal, and vagal nerves[5]. Binding at these sites can potentially explain the ophthalmoplegia, ptosis, and oropharyngeal palsy that are common presentations of BBE.

There are even fewer clear data when considering the cause of ataxia. One in-vitro study showed a decrease in trans endothelial resistance across the blood-brain barrier when it was exposed to BBE serum[6]. However, a central cerebellar cause of ataxia is questionable given there is no research showing that GQ1b is expressed in cells of the central nervous system.

Given the low prevalence of BBE, reliable epidemiological data is difficult to gather. It is however evident that BBE is more common in southeast Asian countries compared to Western countries. A national survey of Japan estimated the annual incidence to be approximately 0.078 per 100,000 inhabitants. The survey also revealed that the disease slightly favored males (1.3 male/female ratio) and presented with a median age of onset of 35 years old (average: 39 years)[7].

BBE typically follows a monophasic course, usually following an upper respiratory tract or gastrointestinal infection. Patients generally develop progressive external bilateral ophthalmoplegia and ataxia within four weeks, with the additional presence of impaired consciousness or hyperreflexia. Symptoms commonly spontaneously resolve by 12 weeks following the onset of disease[7].

The classic triad of acute bilateral ophthalmoplegia, ataxia, and encephalitis are highly suggestive of BBE. However, the absence of any one of these symptoms or presence of additional symptoms does not rule out the diagnosis. Other symptoms that can be seen with BBE include dysarthria, hyperreflexia, hyporeflexia, and limb weakness[8].

The encephalitis commonly presents in the form of altered sensorium, ranging in severity from mild drowsiness to coma, which has been seen in up to 20% of cases. This effect has been shown to likely be a result of activation of the reticular activating system in the brainstem. Because BBE has an effect on the CNS, altered sensorium is a useful feature to differentiate BBE from some of the other anti-GQ1b antibody syndrome conditions[2]. Patients can have either limb or truncal ataxia, though it can be more localized as well[9].

The diagnosis of BBE is largely clinical, though other lab tests and imaging can be useful. Most significantly, positive serum analysis for anti-GQ1b antibodies with consistent clinical presentation is very supportive for the presence of BBE or other syndromes in the disease spectrum. However, a negative test does not rule it out. A study of over 500 cases showed anti-GQ1b antibody seropositivity in only 68% of patients[10].

Other diagnostic tests are less specific. Because of its effect on the CNS, abnormal EEG findings are commonly found (57% of patients). MRI findings are even less conclusive, with 11% of patients having abnormal imaging[5]. Cerebrospinal fluid analysis of BBE patients reveals that about 25% of patients presented with albuminocytological dissociation, which is characterized by an increased protein level with normal cell count[10].

Being a part of the anti-GQ1b antibody syndrome, BBE must be considered alongside the other associated conditions, including GBS, MFS, acute ophthalmoparesis without ataxia, and the pharyngeal-brachial-cervical variant of GBS. Clinical features of BBE can significantly overlap with many of these conditions[8]. Thus, complete neurological examination should be undergone to make a proper diagnosis.

There have not been any randomized control trials conducted for treatment of BBE due to its rarity and favorable prognosis without treatment. Both intravenous immunoglobulin and plasmapheresis are often used to improve recovery in BBE patients. Specifically, intravenous immunoglobulin (IVIg) has been shown to slightly speed up recovery, though the final outcome of the disease does not seem to be affected[5]. Treatment recommendations vary based on country, and availability but consideration of high costs and possible side effects of IVIG, as well as disease severity and other patient factors should be made.

Barring disease complications such as pneumonia or seizures, disease prognosis is good. The majority of patients make a complete recovery within 6 months, even without medical intervention[2]. The first symptoms to resolve are usually ataxia with a median of 32 days and ophthalmoplegia with a median of 88 days[5]. However atypical presentations or relapses can infrequently, so patients require ongoing monitoring during their recovery[11][12].

Bickerstaff encephalitis, also known as Bickerstaff brainstem encephalitis, is a rare immune-mediated condition, often a phenotype of the anti-GQ1b antibody syndrome.

MRI brain is most commonly normal 4. When abnormal, Bickerstaff encephalitis may transiently involve the brainstem and basal ganglia and is characterized on MRI by regions of high T2 signal with little - if any - enhancement. Typically these regions also demonstrate some minor restricted diffusion 1.

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In the 1950s, Bickerstaff and Fisher independently described cases with a unique presentation of ophthalmoplegia and ataxia. The neurological features were typically preceded by an antecedent infection and the majority of patients made a spontaneous recovery. In the cases with Bickerstaff brainstem encephalitis, there was associated altered consciousness and in some, hyperreflexia, in support of a central pathology whereas in Fisher syndrome, patients were areflexic in keeping with a peripheral aetiology. However, both authors recognised certain similarities to Guillain-Barr syndrome such as the presence of peripheral neuropathy and cerebrospinal fluid albuminocytological dissociation. The discovery of immunoglobulin G anti-GQ1b antibodies in patients with Fisher syndrome and later in Bickerstaff brainstem encephalitis was crucial in providing the necessary evidence to conclude that both conditions were in fact part of the same spectrum of disease by virtue of their common clinical and immunological profiles. Following this, other neurological presentations that share anti-GQ1b antibodies emerged in the literature. These include acute ophthalmoparesis and acute ataxic neuropathy, which represent the less extensive spectrum of the disease whereas pharyngeal-cervical-brachial weakness and Fisher syndrome overlap with Guillain-Barr syndrome represent the more extensive end of the spectrum. The conditions can be referred to as the 'anti-GQ1b antibody syndrome'. In this review, we look back at the historical descriptions and describe how our understanding of Fisher syndrome and Bickerstaff brainstem encephalitis has evolved from their initial descriptions more than half a century ago.

Fisher syndrome is an uncommon paralysing illness, usually caused by autoimmune inflammation of nerves following an infection. Fisher syndrome is characterised by impairment of eye movements, abnormal co-ordination and loss of tendon reflexes. It is a variant of Guillain-Barr syndrome. Unlike Guillain-Barr syndrome, it does not cause limb or respiratory muscle weakness. In Western countries Fisher syndrome represents between 5% and 10% of Guillain-Barr syndrome cases, but it is more common in Eastern Asia, for example 25% of cases in Japan. Bickerstaff's brain stem encephalitis shares many clinical features but also includes altered consciousness and signs of central nervous system inflammation. Treatment strategies tried have been immunotherapies such as plasma exchange or intravenous immunoglobulin which are used in Guillain-Barr syndrome. This systematic review found no randomised controlled trials of treatments for Fisher syndrome, Bickerstaff's brain stem encephalitis or their variants. Observational studies suggest that Fisher syndrome always and Bickerstaff's brain stem encephalitis usually recovers completely. Randomised controlled trials are needed to establish the value of immunotherapies or other treatments.

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