Bickerstaff brainstem encephalitis (BBE) was first described by Bickerstaff and Cloake in 1951 under the title “Mesencephalitis and rhombencephalitis” (1). A few years later, Bickerstaff named this condition “brainstem encephalitis” (2).

BBE is a rare autoimmune disease characterized by the subacute onset of bilateral external ophthalmoplegia, ataxia, and decreased level of consciousness (3). Pupillary abnormalities, bilateral facial paralysis, Babinski’s sign, and bulbar paralysis are commonly present (4). Presence of limb weakness indicates overlap with Guillain–Barré syndrome (GBS) (3, 4).

The prevalence is unknown. According to a Japanese nationwide survey, the annual incidence of BBE is estimated to be approximately 0.078 per 100,000 inhabitants (5). The incidence of BBE is higher in males (male/female ratio 1.3) with an average age at onset of 39 years (5).

BBE has been reported to occur often after upper respiratory or gastrointestinal tract infections (6, 7). Although the exact pathological mechanism is not completely understood, BBE is associated with the presence of the antiganglioside antibody, anti-GQ1b. These antibodies are highly specific for patients with BBE and also GBS, Miller Fisher syndrome (MFS), and external ophthalmoplegia (8); anti-GQ1b antibodies are present in 68% of patients with BBE (9). Anti-GQ1b antibody testing are not necessary for a definitive diagnosis of BEE (3). The detection of these antibodies, however, is useful to confirm the diagnosis of BBE when incomplete syndromes or atypical symptoms are present, or when an altered mental status does not allow the evaluation of ataxia.

Clinical features include a classic triad of ataxia, ophthalmoplegia and altered consciousness (10). Other common features include hyperreflexia, Babinski’s sign, deep sensory impairment, facial weakness, bulbar palsy and nystagmus (10).

Despite the diagnosis being based on clinical findings, abnormal findings on cerebrospinal fluid (CSF), electroencephalography (EEG), electromyography (EMG), and magnetic resonance imaging (MRI) are common. CSF analysis often shows evidence of albumin-cytologic dissociation and pleocytosis (9, 10). At first, albumin-cytologic dissociation occurred in 25% of the BBE and pleocytosis in 32% of the BBE; during the second week, albumin-cytologic dissociation of CSF occurred in 46% of the BBE patients and pleocytosis in 31% of the BBE (9). EEG and EMG are indicative of central nervous system (CNS) impairment and predominantly in the brainstem (9). Patients with BBE showed a characteristic “unarousable sleep-like” EEG (11). In about one-third of the BBE patients, MRI shows high-intensity areas on T2-weighted images of the brainstem, thalamus, cerebellum and cerebrum (12).

There is a lack of consensus on the management of the BBE (13). Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments for these patients (13).

The BBE course is generally monophasic with complete remission of symptoms within 6 months in over half of the patients.

Very few studies investigated pediatric BBE and its incidence rate is unknown (14–16). BBE is part of a group of rare autoimmune diseases in children that can affect the central or peripheral nervous system at any level (17, 18).

We included 41 studies (20–60), for a total of 74 cases. 73% of cases were among males (54 males, 20 females). The mean age at onset was 8.65 ± 4.93 years (7 months – 18 years).

According to the literature (14–18), BBE is quite uncommon especially in children. The onset of neurologic deficits is often sudden, although nonspecific symptoms may precede neurologic manifestations by several weeks. Diagnosis by MRI and CSF analysis is essential in children when autoimmune encephalitis is suspected. The central diagnostic test is the search for neural antibodies. There is no difference in the therapeutic approach to children/adolescents and adults.

Our review provides a case analysis of BEE in childhood focusing on clinical presentation, diagnosis, treatment and outcome.

The prevalence is unknown while the incidence is higher in males. Our analysis showed a 3:1 male to female ratio, as in previous studies (15, 16). This is in contrast to general data that females are more susceptible than males to a variety of autoimmune diseases (61).

In 50% of cases an infection is reported in the 2 weeks before the onset of neurological symptoms. BBE occurs following respiratory or gastrointestinal tract infections, most frequently caused by M. pneumoniae, H. influenzae, and C. jejuni. A case study reported on an episode of BBE following COVID-19 vaccination (41). SARS-CoV-2 infection is associated with other neurological condition, such as Guillain-Barrè syndrome (62) and Miller Fisher syndrome (63). The etiology is unfortunately unknown, as for other neurological syndromes (64). A transient autoimmune response to myelin or other self-antigens through molecular mimicry during the infectious episode preceding symptoms, leading to destruction of the cerebral white matter, spinal cord, and optic nerves causing demyelination (64).

BBE is usually a monophasic disease; only one case of recurrent BBE is reported (24). 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. Ocular motor weakness and ptosis, facial weakness, and bulbar weakness were common manifestations. Extensor plantar response (Babinki’s sign) was present. Deep tendon reflexes were usually absent or decreased, but can be normal or brisk. Sensory disturbance and autonomic instability may occur.

When atypical initial symptoms such as symmetrical flaccid limb weakness and dysesthesias occur, these cases were classified as BBE with overlapping/coexisting GBS (25, 31, 40, 47).

Lumbar puncture is a high-priority test in cases of suspected central nervous system disease (65). In our analysis, an abnormal lumbar puncture was found in more than half of the patients; the main CSF alterations found were albuminocytological dissociation (33.3%) and pleocytosis (21.7%). Albuminocytological dissociation occurs during the first week of illness in 25% of cases and increases up to 46% of cases in the second week; 32% of the BBE patients show CSF pleocytosis (9). These CSF findings prove an inflammatory origin of neurological disturbances compatible with autoimmune encephalitis, such as BBE (66).

EEG abnormalities were reported in more than 85% of cases in which the exam was performed. The frequency of abnormal EEG findings indicated CNS involvement, consistent with disturbance of consciousness. EEG changes correlate with the level of consciousness in patients with BBE and often show predominant N1 and/or N2 sleep patterns, even with external stimuli (“unarousable sleep-like” EEG), including the fusiform coma pattern (11). The deterioration of consciousness in BBE may be caused by a dysfunction of the brainstem reticular formation (11).

Abnormal EMG was found in more than 50% of patients in this analysis. Electrophysiologically studies showed reduced or non-recordable compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs). This is evidence of demyelination or axonal degeneration and is found in half of cases (9, 12).

CT scans showed no abnormalities. MRI is the gold standard technique for brain imaging in encephalitis (67). Abnormal MRI lesions, such as high-intensity areas on T2-weighted images of the brainstem, thalamus, cerebellum and cerebrum, were present in BBE patients (12). This alteration corresponds to vasogenic edema and may be reversible and not visible on MRI. When performed, MRI showed abnormalities in 41.4% of cases.

Anti-GQ1b antibodies were detected in more than half of the patients. The oculomotor (III), trochlear (IV), and abducens (VI) nerves, muscle spindles in the limbs, and the reticular formation in the brainstem have significantly higher percentages of GQ1b (8, 68). Infection by microorganisms bearing the GQ1b epitope can induce the production of anti-GQ1b immunoglobulin G (IgG) antibodies in susceptible patients. Anti-GQ1b antibodies bind to GQ1b antigens expressed on cranial nerves and muscle spindles inducing FS. It is possible that in some cases the antiGQ1b antibodies reach the brainstem and bind to GQ1b, inducing BBE (8, 68).

The presence of anti-GM1 antibodies was detected in almost 40% of patients. The role of antiganglioside antibodies in the pathogenesis of BBE as well as other diseases is not completely understood. They could participate in direct damage to the structure they bind to, be a consequence of several types of infectious diseases, or facilitate many immune-mediated pathological mechanisms (7).

In the included studies, the diagnosis of BBE was not based only on the symptoms, which were not always typical (external ophthalmoplegia, ataxia, disturbance of consciousness). In our analysis, typical MRI images (high signal lesion on T-2-weighted images located in the brainstem) and high titers of anti-GQ1b antibodies may contribute to the diagnosis of BBE.

There are no established guidelines for treatment and currently different regimens are used based on the patient’s clinical status and the doctor’s opinion. Autoimmune encephalitis, including BBE, responds to immunomodulatory therapy such as IVIG and plasmapheresis (69). This treatment is accompanied by the administration of intravenous corticosteroids (69). In our analysis, steroids and intravenous immunoglobulins were administered alone or in combination. As last option, plasmapheresis was used.

Among corticosteroids, methylprednisolone is commonly used at a dose of 1 g per day for 3–5 days followed by oral prednisone 1 mg/kg/day for 1–4 weeks (64, 69). IVIG has many immunomodulatory and anti-inflammatory effects; it is used for many neurological disorders. The IVIG doses range is between 400 mg/kg/day for 5 days or a more rapid course of 1–2 g/kg given over 1–2 days (64, 70). Plasmapheresis is a reasonable option to consider in BBE patients with no or limited improvement after corticosteroids or IVIG (71). Normally 1 session is performed every other day for 5–7 cycles (30, 64). Patients included in this review did not require the use of second-line agents, such as rituximab or cyclophosphamide.

The length of hospitalization was approximately 24 days. More than 20% of patients required ICU admission for an average of approximately 13 days, mainly due to depressed level of consciousness and respiratory insufficiency. Almost all of them required mechanical ventilation. These rates are lower compared to the adult population with autoimmune encephalitis; in an observational study, 57% of patients were intubated for an average of approximately 1 month and 68% of them required tracheostomy (72). No particular characteristics were identified in BBE cases requiring ICU admission.

BBE has a good prognosis and recovery in childhood is faster than in adulthood, usually resolving within 4 to 6 weeks after starting treatment (14, 16). Concerning the outcome, 70% of patients reported no sequelae in our analysis. The death rate was 2.7% (24, 59). Death is a very rare outcome in patients with BBE receiving optimal treatment.

BBE is a rare autoimmune disease, even in childhood. Its knowledge is essential for the early recognition of the patient suffering from BBE and therefore for its management. The pathogenesis is unclear. The combination of clinical, radiological and laboratory data is the basis of a correct diagnosis. There are few indications for correct treatment which is mainly based on immunomodulatory therapy including IVIG and in the most serious cases on plasmapheresis. Fortunately, the prognosis is good, with a good recovery rate. Future studies need to investigate the pathogenesis, possible triggers and therapeutic possibilities.

LG: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. DM: Supervision, Writing – review & editing. RB: Data curation, Formal analysis, Methodology, Writing – review & editing. RM: Data curation, Formal analysis, Methodology, Writing – review & editing. FM: Data curation, Formal analysis, Methodology, Writing – review & editing. GPa: Data curation, Formal analysis, Methodology, Writing – review & editing. MP: Data curation, Formal analysis, Methodology, Writing – review & editing. PS: Data curation, Formal analysis, Methodology, Writing – review & editing. GPu: Supervision, Validation, Writing – review & editing. LM: Supervision, Validation, Writing – review & editing.