Bickerstaff Encephalitis Prognosis

[Mireille Duhon]

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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 brainstem encephalitis (BBE) is a rare autoimmune disease characterized by the subacute onset of bilateral external ophthalmoplegia, ataxia, and decreased level of consciousness. BBE is part of a group of rare autoimmune diseases in children that can affect the nervous system at any level. The onset of neurological deficits is often sudden and nonspecific. The diagnosis is based on clinical findings and abnormal findings on cerebrospinal fluid (CSF), electroencephalography (EEG), electromyography (EMG), and magnetic resonance imaging (MRI). BBE is associated with the presence of the antiganglioside antibody, anti-GQ1b and anti-GM1. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments for these patients. We conducted a review on clinical presentation, diagnosis, treatment and outcome of reported cases of BBE. 74 cases are reported in the literature from the first cases described in 1951 to today. The prevalence is unknown while the incidence is higher in males. In 50% of cases, BBE occurs following respiratory or gastrointestinal tract infections. The most frequent initial symptoms were consciousness disturbance, headache, vomiting, diplopia, gait disturbance, dysarthria and fever. During illness course, almost all the patients developed consciousness disturbance, external ophthalmoplegia, and ataxia. Lumbar puncture showed pleocytosis or cytoalbuminological dissociation. Abnormal EEG and MRI studies revealed abnormalities in most cases. Anti-GQ1b antibodies were detected in more than half of the patients; anti-GM1 antibodies were detected in almost 40% of patients. Treatment guidelines are missing. In our analysis, steroids and IVIg were administered alone or in combination; as last option, plasmapheresis was used. BBE has a good prognosis and recovery in childhood is faster than in adulthood; 70% of patients reported no sequelae in our analysis. Future studies need to investigate pathogenesis and possible triggers, and therapeutic possibilities.

Copyright 2024 Giaccari, Mastria, Barbieri, De Maglio, Madaro, Paiano, Pace, Sansone, Pulito and Mascia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Thirty-six days after initial presentation, the patient presented to acute inpatient rehabilitation with flaccid tetraplegia, urinary retention, dysphagia with percutaneous endoscopic gastrostomy tube in place and on a ventilator with tracheostomy. Admission American Spinal Injury Association (ASIA) exam showed C5 ASIA impairment scale A tetraplegia with a zone of partial preservation of bilateral sensory/motor levels to T4. Patient underwent extensive therapy, was weaned off the ventilator on day 6 and had her tracheostomy decannulated on day 15. Her severe oropharyngeal dysphagia slowly resolved and she progressed to tolerate a general texture diet. Patient was further noted to have decreased articulatory precision of lingual sounds, which improved moderately, although remained at the time of discharge. Patient initially had autonomic instability and had several instances of low-grade autonomic dysreflexia, which resolved with draining a large amount of urine with a straight catheter. Upper extremity strength improved to 5/5 on manual muscle testing and full sensation reappeared to T6 with a broad area of constrictive transitional zone pain extending to T12 (treated with minimal success initially with gabapentin and then pregabalin). Lower extremities remained largely flaccid with absent deep tendon reflexes and Babinski reflexes bilaterally. Discharge ASIA exam demonstrated T6 ASIA impairment scale A paraplegia. Patient was, however, able to reflexively complete bowel care with self-initiated digital stimulation and developed tense rectal tone. She continued to have neurogenic bladder and was trained on scheduled intermittent self-catheterization. Motor functional independence measure (FIM) scores improved from 20 at admission to 66 at discharge and patient was able to return home with family and home therapies 96 days after initial presentation to the outside hospital.

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