Bickerstaff Brainstem Encephalitis

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Disease Entity

Disease

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

Etiology

The most common infections associated with BBE are C. jejuni and H. influenzae, with molecular mimicry being the proposed mechanism for this 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].

Pathophysiology

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.

Epidemiology

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].

Diagnosis

History

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].

Signs/symptoms

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].

Diagnostic Workup

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].

Differential diagnosis

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.

Other potential differential diagnoses include Wernicke’s encephalopathy, multiple sclerosis, acute disseminated encephalomyelitis, brainstem strokes, brainstem tumors, myasthenia gravis, and botulism[9]. A careful investigation and thorough clinical history, including brain imaging and electrophysiological testing, can be useful to help differentiate these conditions.

Management

Medical therapy

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, but consideration of high costs and possible side effects of IVIG, as well as disease severity and other patient factors should be made.

Prognosis

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].

References

  1. Yoshikawa K, Kuwahara M, Morikawa M, Kusunoki S. Bickerstaff brainstem encephalitis with or without anti-GQ1b antibody. Neurol Neuroimmunol Neuroinflamm. 2020 Sep 15;7(6):e889. doi: 10.1212/NXI.0000000000000889. PMID: 32934014; PMCID: PMC7524576.
  2. 2.0 2.1 2.2 Shameem, Raji, et al. “Expert Opinion: Bickerstaff's Brainstem Encephalitis: A Rare Variant Of The Anti-Gq1b Antibody Syndrome.” Practical Neurology, Bryn Mawr Communications, 2013, practicalneurology.com/articles/2013-sept-oct/bickerstaffs-brainstem-encephalitis-a-rare-variant-of-the-anti-gq1b-antibody-syndrome.
  3. Llorente Ayuso L, Torres Rubio P, Beijinho do Rosário RF, Giganto Arroyo ML, Sierra-Hidalgo F. Bickerstaff encephalitis after COVID-19. J Neurol. 2020 Sep 3:1–3. doi: 10.1007/s00415-020-10201-1. Epub ahead of print. PMID: 32880723; PMCID: PMC7471525.
  4. Cleaver J, James R, Chohan G, Lyons P. Bickerstaff's brainstem encephalitis associated with anti-GM1 and anti-GD1a antibodies. BMJ Case Rep. 2020 Sep 18;13(9):e236545. doi: 10.1136/bcr-2020-236545. PMID: 32948528; PMCID: PMC7511636.
  5. 5.0 5.1 5.2 5.3 Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome. J Neurol Neurosurg Psychiatry. 2013 May;84(5):576-83. doi: 10.1136/jnnp-2012-302824. Epub 2012 Sep 15. PMID: 22984203.
  6. Aranyi Z. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. European Journal of Neurology 2012. 19:15-20.
  7. 7.0 7.1 Koga M, Kusunoki S, Kaida K, Uehara R, Nakamura Y, Kohriyama T, Kanda T. Nationwide survey of patients in Japan with Bickerstaff brainstem encephalitis: epidemiological and clinical characteristics. J Neurol Neurosurg Psychiatry. 2012 Dec;83(12):1210-5. doi: 10.1136/jnnp-2012-303060. Epub 2012 Jul 31. PMID: 22851608.
  8. 8.0 8.1 Yuki N. Fisher syndrome and Bickerstaff brainstem encephalitis (Fisher-Bickerstaff syndrome). J Neuroimmunol. 2009 Oct 30;215(1-2):1-9. doi: 10.1016/j.jneuroim.2009.05.020. Epub 2009 Jul 29. PMID: 19643503.
  9. 9.0 9.1 Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, Kuwabara S. Bickerstaff's brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain. 2003 Oct;126(Pt 10):2279-90. doi: 10.1093/brain/awg233. Epub 2003 Jul 7. PMID: 12847079.
  10. 10.0 10.1 Ito M. Bickerstaff’s brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases. Journal of Neurology 2008. 255:674–82.
  11. Sharma V, Chan YC, Ong, Teoh HL, Wilder-Smith EP: Bickerstaff’s brainstem encephalitis: can it recur? J Clin Neurosci 2006, 13(2):277–279.
  12. Renaud M, Aupy J, Camuset G, Collongues N, Chanson JB, de Seze J, Blanc F. Chronic Bickerstaff's encephalitis with cognitive impairment, a reality? BMC Neurol. 2014 May 6;14:99. doi: 10.1186/1471-2377-14-99. PMID: 24885623; PMCID: PMC4040113.