Bickerstaff 39;s Neurological Examination In Clinical Practice Pdf Download

[Algernon Alcala]

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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].

New England Journal of Medicine. But in contradistinction to BBE, these patients had no change in sensorium and almost universally these patients were areflexic. The majority of patients achieved spontaneous recovery without the need for treatment despite the alarming initial presentation of BBE.

The discovery that a large number of affected patients tested positive for the Anti-Gq1b antibody led to a greater understanding of BBE. Because Anti-Gq1b antibody seropositivity is also seen in other conditions such as GBS and Miller Fisher Syndrome (MFS), many clinicians believe that BBE is not a distinct neurological entity but lies at one end of a spectrum of diseases known as the Anti-Gq1b syndromes. In this article we review some of the key features of BBE including pathophysiology, epidemiology, presentation and investigations, differential diagnosis, and management and treatment.

BBE can occur without any preceding symptoms, but the majority of cases see a preceding infectious illness. Infection as a precipitant for neurological disease has been largely accepted for both GBS and MFS. In a review of 194 cases of Anti-Gq1b Syndrome, antecedent illness was seen in 94 percent of patients, with upper respiratory tract infection being most common.3 For both BBE and MFS, case-control studies have shown an increased prevalence of seropositivity to both Campylobacter Jejuni and Haemophilus Influenzae.4

The Anti-Gq1b antibody may have a role in the pathophysiology of BBE and MFS, however the absolute underlying pathogenesis has yet to be discovered. Common seropositivity between these two conditions highlights their pathophysiological and clinical similarities. Anti-Gq1b antibody is one that interacts with the peripheral nerve ganglioside, Gq1b.5 Intrinsically, Gq1b is predominantly expressed at neuromuscular injections, sensory nerves, and proximal segments of cranial nerves, such as the oculomotor, trochlear, and abducens nerves.4,6 Binding at these sites by the Anti-Gq1b antibody can be a potential explanation for presenting symptoms and signs such as ophthalmoplegia and ptosis.4 Presence of oropharyngeal palsy can also be explained by expression of Gq1b on the glossopharyngeal and vagus nerves.4 A recent in-vitro study tested for the integrity of the blood-brain barrier when exposed to sera from BBE and MFS patients.6 Conduction studies revealed a decrease in trans endothelial resistance exclusively from exposure to BBE serum, which may be an explanation for the central pathogenesis of BBE, compared to a peripheral one for MFS.6 However, there has been no evidence to suggest that the Gq1b ganglioside is expressed in cells in the central nervous system.

The incidence of BBE is higher in Japan compared to Western nations. The precise incidence and prevalence of BBE in the United States and other Western nations is currently unknown, which can be attributed to the rarity of the disease and confusion and overlap with other Anti-Gq1b antibody syndromes. A recent nationwide survey of patients in Japan with BBE estimated that the annual incidence of BBE is approximately 0.078 per 100,000 individuals.

There is a lack of similar large-scale BBE epidemiological studies in Japan and in the rest of the world. An increased incidence in Japan and other Asian countries is observed in the summer months.8 The estimated prevalence of MFS in GBS cases in Western populations is one to five percent.4 As with BBE, a higher number of MFS cases have been seen in Asian nations, with incidence of up to 25 percent in Japan.4 GBS is much more commonly encountered by physicians, experiencing an incidence of approximately 1.11 cases per 100,00 person-years.6 The overlap of GBS with BBE and MFS that is not uncommonly encountered may be an indication that BBE and MFS are not as rare as we assume.

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