Bickerstaff brainstem encephalitis (BBE) is considered a rare [1], often postinfectious, autoimmune encephalitis, first described in 1951 and 1957 by Bickerstaff et al. [1, 2], characterized by ophthalmoplegia, ataxia, and altered consciousness. The disorder shares some features with other inflammatory demyelinating neuropathies: Miller Fisher Syndrome (MFS) and Guillain-Barré Syndrome (GBS); the three diseases form a continuous spectrum of autoimmune and postinfectious diseases [3]. The Guillain-BarrBarré polyneuropathy is the most frequent of them, and it is characterized by acute onset, rapidly progressive, symmetrical muscular weakness, and hyporeflexia [2, 3, 4]. The MFS and BBE are reported to be less frequent than GBS. The MFS is characterized by a triad of ophthalmoplegia, ataxia and areflexia [5] and BBE by central nervous system (CNS) involvement with alteration of consciousness or long tract signs beyond the classical ophthalmoplegia and ataxia [5]. BBE occurs after a previous respiratory or gastro-enteric infection. After an apparent remission, the patient starts to show the main features: ophthalmoplegia, ataxia, hyperreflexia, loss of consciousness or drowsiness till coma.

However, the nosologic classification of Bickerstaff’s brainstem encephalitis, Guillain-Barré syndrome and Miller Fisher syndrome remains uncertain. In addition, many patients with overlap between these conditions have been reported, and there is variable CNS and PNS involvement in the spectrum of these diseases [6, 7].

Diagnosis is founded upon clinical findings, history for recent upper tract infections, and laboratory and instrumental studies. Brain Magnetic Resonance Imaging (MRI) can help diagnose BBE when lesions are evident. In most cases, brain MRI documents abnormalities with hyperintensity in white matter, especially in thalami regions. Anti-GQ1b IgG antibodies are positive in two-thirds of cases, but their detection could be possible even in MFS; despite this, its high specificity and sensitivity usually allow a correct diagnosis; a frequent observation is a raised protein level CSF with or without pleocytosis. Nerve conduction velocity (NCV) studies show a picture of demyelinating neuropathy with decreasing of NCV, presence of blockages, and other suggestive signs.

Standard treatment consists of Intravenous Immunoglobulin (IVIG) or steroid, single or as combined strategy, and plasmapheresis [8, 9, 10, 11, 12]. The diagnostically and therapeutical options are beyond the scope of our review. Moreover, in the suspicion of BBE is necessary to consider the possibility of belonging to a more complex group of disorders such as ophthalmoplegia, ataxia, and areflexia (SOAA). Some Authors reported one case of transient coma following SOAA after a previous type B flu infection. In addition, an extensive brainstem injury including reticular formation was found, and evidence of cerebrospinal CSF antibodies serum IgG anti-GQ1b in the acute phase.

This review explores 40 cases of pediatric BBE from an extensive search of medical literature focused on clinical signs. We reviewed all cases of pediatric BBE in the literature to determine if any patient showed features suggestive for BBE/GBS. This analysis has the primary objective to identify the pediatric phenotype of BBE in order not to risk not diagnosing the overlapping form.

A literature review was performed on three electronic medical databases (PubMed, Cochrane Library and Scopus Web of Science) by three authors (G.M., C.O., S.S.), evaluating cases published in the period until June 2020. In the search bar, we first introduced the MeSH term “Bickerstaff” and “pediatric”, and several 43 manuscripts were collected. Adding the term “clinical symptoms”, we identify 20 articles. We select articles by excluding systematic reviews involving a similar topic and choosing those in which the term “Bickerstaff” was included in the title of the article’s main content. We also excluded articles in which adults were enrolled, studies without accessible data, or a full-text available. Finally, we excluded duplicate studies. English articles were chosen, so obtaining a total of 14 items and 40 cases. A descriptive summary was performed. It was not possible to perform a meta-analysis and statistical analysis due to the different nature of the studies and the lack of controlled studies. We follow the rules of the Declaration of Helsinki, and the board approved our AOU Policlinico—San Marco, Catania (Ct 138843). We also followed the Prisma flow diagram of the literature selection and review process. Fig. 1 is a flow chart of the reviewed literature.

Fig. 1.

Flow diagram of literature selection and review process.

We considered 40 cases of pediatric BBE, analyzing the clinical symptoms and signs of the disease. The median of patients was 8 years; the youngest patient was 7 months [13]; the oldest was 18 years [14]. Sex was specified in all cases, of which 30 were male, and 10 were female (3:1 male to female ratio). 22 patients reported an acute (main duration 3.05 days ranging from 2 to 8 days), self-solving, illness preceding the onset of neurologic symptoms; in the others 18 cases, previous symptoms are not reported. Of these 22 patients, 8 reported an upper respiratory tract infection (URI), 6 reported gastroenteritis with diarrhea and emesis (in some cases, the culture was positive for Campylobacter jejuni), 4 patients had pneumonia (two with mycoplasma infection); 3 experienced a flu-like illness, and one patient had suffered from acute bronchitis and enteritis three weeks before admission and had laboratory evidence of recent infection with Epstein-Barr virus (EBV). In most cases, these symptoms had occurred a week earlier and had resolved before presentation, in addition to the characteristic triad of altered status, ophthalmoplegia, and ataxia (Fig. 2). The most commonly reported finding was altered reflexes with 24 cases of hyperreflexia (60%), 8 cases of areflexia (20%) and 7 cases of hyporeflexia (18%), only in 1 case deep tendon reflexes remained normal (2%) [15]. Babinski reflex was present in 5 patients. Visual deficit including diplopia, esotropia, decreasing of visual acuity were reported in 65% of cases (in one case was reported anisocoria [16]). In one case, the patient had a reoccurrence of diplopia one month after his presentation [15]. Facial/bulbar weakness was reported in 16 cases (40%), limbs weakness in 14 cases (35%), no apparent weakness in 7 patients (17%), global weakness in 3 patients (8%). Neuropathy or paresthesias in 3 patients (8%) (in one case with complete loss of sensation in lower extremities) [14]. 5 patients developed dyspnea (13%); intubation for mechanical ventilation was required in 3 patients (8%). In one of these cases, although the mechanical ventilation and the intensive care, BBE was recurrent with the fulminant course, and the patient expired due to cardiac failure [17]. In one case, the patient was polyuric, which was later attributed to concomitant central diabetes insipidus [17].

Fig. 2.

Clinical symptoms and signs in addition to the characteristic triad (altered status, ophthalmoplegia and ataxia).

There are cases with overlapping BBE/GBS—BBE/MFS. In the first [13], the patient had disturbance of consciousness, ataxia and ophthalmoplegia followed by a rapidly ascending paralysis of all four limbs. In addition, he developed respiratory failure requiring mechanical ventilation. In another [18], a 14-year-old girl developed diplopia and ataxic gait with impaired consciousness and tetraplegia. Several other case reports, where the authors described the case of a 4-year-old child with Miller Fisher Syndrome: ophthalmoplegia, ataxia and loss of tendon reflex, who had cerebral lesions evident on magnetic resonance imaging, suggesting a Miller-Bickerstaff spectrum [19, 20, 21]. The main differences between BBE, GBS and MFS are shown in Table 1.

Our group recently [22] published a review on all aspects of Bickerstaff’s brainstem encephalitis; here, we focus our attention on the clinical aspect of this disease.

In this review, we focus our attention on the clinical symptoms of Bickerstaff encephalitis. For us probably, these conditions have been under-diagnosed until now.

The BBE usually has a rapid and acute onset within 2–4 weeks, characterized by a typical picture of ophthalmoplegia and cerebellar symptoms such as ataxia. It usually begins with cranial nerve involvement progressing to various consciousness alterations, in some rare cases leading to coma [23]. Ocular disturbances start with diplopia and progressive ophthalmoplegia, usually symmetric, followed by gait disturbance within 4 weeks from the previous infection. However, ophthalmoplegia is familiar to BBE and MFS [24]. The subsequent manifestations of hyperreflexia or consciousness disturbances as drowsiness, sleepiness, or coma are more suggestive for central involvement, leading to a more probable clinical diagnosis of BBE. Several other symptoms or signs are commonly but not constantly reported, in common with GBS as weakness of the limbs (till to real flaccid symmetrical tetraparesis), superficial or deep sensory disturbances, facial weakness or palsy and oculomotor impairment as blepharoptosis, internal ophthalmoplegia, bulbar palsy, nystagmus, mydriasis or abnormalities of pupils. Other disorders recently associated with this condition are psychosis disturbances [25]. Nagamine and colleagues described a patient with atypical Bickerstaff brainstem encephalitis and psychosis [25]. Wada et al. [26] described two patients with BBE and delirium.

Although precise pathophysiology is unclear, BBE is associated with anti-GQ1b antibodies, indicative of autoimmune encephalitis, one of the most common causes of noninfectious encephalitis. There are various clinical manifestations among autoimmune encephalitis patients, including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders, and seizures [27]. In addition, some patients may present psychotic symptoms before neurological features, resulting in the first visit to a psychiatric hospital. Among BBE patients, however, psychosis is a rare condition.

Recovery in pediatric age is faster than in adulthood, resolving in most cases within 2 months depending on the severity of the clinical symptoms presented. However, BBE may be a “random” disease with so far little data on disease incidence.

PP, RF and GM conceived and designed the manuscript; MGP and PS performed the data search; FG, SS and AS analyzed the data; AF and CFO contributed reagents and materials; PP and RF wrote the paper; GM, SS, AF, FG, CFO, MGP, AS, PS, PP and RF prepare the final draft and the revision of the paper.

The institutional review board of the AOU Policlinico—San Marco, Catania approved 15-02-2016, code Ct 138843.

The authors would like to thank AME for the English language review. Certificate Verification Key: 744-574-569-832-441.

This research received no external funding.

The authors declare no conflict of interest.