A young lady who presented with unilateral VI nerve palsy
Bickerstaff’s brainstem encephalitis (BBE) is a very rare cause of VI nerve palsy as reflected by its incidence. I report, from my personal experience, a young lady who presented with sudden onset of diplopia and rapid deterioration of consciousness. Investigations showed positive Anti-Gangliosides antibodies and a markedly raised Mycoplasma Pneumoniae titre. The patient was treated with intravenous immunoglobulin and steroid. The patient recovered fully six weeks after onset.
Bickerstaff’s brainstem encephalitis is a very rare cause of VI nerve palsy. Other common causes of VI nerve palsy are vasculopathic (diabetes, hypertension, atherosclerosis), trauma and idiopathic.
A 21-year-old lady presented with sudden onset of diplopia with fever and headache. Upper respiratory tract symptoms were present before admission. She enjoys a good past health and she is a non-smoker and social drinker. She traveled to Philippines one week before admission and received Human Papilloma Virus vaccine during the trip. She denied any insect bites during her travel period. She was found to have right VI nerve palsy and mild right leg drift on elevation. Physical examination was otherwise unremarkable. Her conscious state rapidly deteriorated over one day and the Glasgow Coma Scale remained around five to nine. Neurological examination revealed positive Babinski’s sign and spastic limbs. The patient was unable to cooperate neurologically for testing of ataxia. In view of the presence of long tract signs and brainstem signs, the lesion was localized to the brainstem and skull base.
Computed Tomography of the brain did not reveal any abnormality. Magnetic Resonance Imaging (MRI) of the brain on admission and two weeks later were normal. Lumbar puncture showed opening pressure of 15 cm H2O. There was normal cell count, glucose and protein. Gram stain and acid-fast bacilli smear were all normal. The results of cerebrospinal fluid (CSF) for Herpes Simplex Virus and Japanese Encephalitis titre came back to be negative. In addition, CSF did not show oligoclonal band. Tests including malaria screening and human immunodeficiency virus antibody were negative as well. Autoimmune markers including anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. Tumor markers including carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 19.9 and carbohydrate antigen 125 were checked and they were all within normal limit. Electroencephalography (EEG) showed bilateral temporal slow wave and frontal delta wave. Subsequent electroencephalography showed persistent epileptiform discharge and inter-ictal seizure activities. A markedly raised Mycoplasma Pneumoniae titre was noted in the blood. Mycoplasma Pneumoniae titre was negative in CSF. Chest X-ray did not show any abnormality. Anti-N-Methyl-D-aspartate receptor antibody and anti-acetylcholine receptor antibody were negative. Anti-Gangliosides screening was positive for anti-GD1b IgG, anti-GD1a IgG and anti-GQ1b IgG. Nerve conduction test was not done because of unstable conditions.
She was treated with ceftriaxone and acyclovir initially. A total of five days of intravenous immunoglobulin and three days of pulse methylprednisolone were given due to suspected post-viral autoimmune disease. Intravenous thiamine was given for possible metabolic or nutritional cause. In view of the risk of aspiration after nasogastric tube insertion for feeding during comatose period, she was put on mechanical ventilation in intensive care unit. Tracheostomy was performed for prolonged endotracheal mechanical ventilation. Phenytoin was initiated for seizure control. Valproate and propofol were added for better seizure control because of the persistent epileptiform discharge despite phenytoin. However, this was complicated by impaired liver function so that levetiracetam was started. The seizure was controlled and liver function gradually improved. Her consciousness gradually improved and she became fully conscious three weeks after admission. The tracheostomy was removed. She could walk unaided six weeks after admission. The final diagnosis is ‘Probable’ Bickerstaff’s brainstem encephalitis and the cause is Mycoplasma Pneumoniae infection. The reason I said it is only 'Probable' because there is no formal documented association between Mycoplasma Pneumoniae and anti-GQ1b antibodies.
Possible causes for the long tract signs and brainstem signs at the level of brainstem or skull base include vascular, infective, demyelination, autoimmune, post-viral infection, post-vaccination (acute disseminated encephalomyelitis, ADEM), neoplastic, and nutritional or metabolic. Vascular cause, demyelination, and ADEM are unlikely in view of normal MRI findings. The normal CSF findings did not support bacteria as a cause of the disease. Paraneoplastic encephalitis was less likely in view of the normal tumor markers. Autoimmune causes were ruled out by the negative autoimmune markers.
Bickerstaff’s brainstem encephalitis was firstly described by Bickerstaff and Cloake (1) in 1951 when they reported three cases of similar presentations. Each patient presented with general symptoms including fever, headache, back pain or abdominal pain for a few weeks. Drowsiness and oculomotor disturbances such as ptosis and diplopia were early symptoms. Lower brainstem involvement such as bilateral V nerve palsy, bilateral facial nerve palsy and dysarthria were found. The other parts of the nervous system were comparatively uninvolved. CSF showed marked mononuclear pleocytosis without biochemical change or elevated protein without cellular reaction. They had a slow neurological recovery with a complete restitution of function varying from two to ten months. The terms ‘mesencephalitis’ and ‘rhombencephalitis’ were given to reflect the involvement of the midbrain.
According to Bickerstaff (2) and Al-Din et al (3), ‘progressive, relatively symmetric external ophthalmoplegia and ataxia by 4 weeks’ and ‘disturbance of consciousness or hyperreflexia’ are required for diagnosis of Bickerstaff’s brainstem encephalitis. Vascular disease involving the brainstem, Wernicke’s encephalopathy, botulism, myasthenia gravis, brainstem tumour, pituitary apoplexy, acute disseminated encephalomyelitis, multiple sclerosis, neuro-Behcet disease, vasculitis and lymphoma must be excluded. (4)
Antecedent upper respiratory infection is found in 73% of the patients. Common initial symptoms are diplopia (52%), gait disturbance (35%), dysaesthesia (19%), and consciousness disturbance (13%). Neurological signs are external ophthalmoplegia (100%), ataxia (100%), limb weakness (60%), absent or decreased tendon reflex (58%), drowsiness (45%), and Babinski’s sign (40%). (4) CSF pleocytosis was found in 36% of patients in first week and 21% in third and fourth week. CSF sample showed albuminocytological dissociation which was defined as high protein with normal cellularity but it was found in only 19% of patients during first week and 57% of patients during third and fourth week. (4) It is an autoimmune disease with positive anti-Gangliosides screening for IgM and IgG to GM2, GM1, GD1a, GalNAc-GD1a, GD1b, GT1b and GQ1b by enzyme-linked immunosorbent assay. (5) Sixty six percent of patients showed positivity to GQ1b and 18% showed positivity to GD1b. (4)
Another nationwide questionnaire survey in Japan (5) found that BBE shows a male predominance with a male to female ratio of 1.3:1. The incidence was estimated to be 0.078 per 100,000 population. The peak age of presentation is 20-30 years old. Antecedent infectious symptoms were frequently seen in 78% of patients, particularly upper respiratory tract infections (61%). Besides the triad of external ophthalmoplegia, ataxia and impaired conscious level, characteristic neurological features also included oropharyngeal palsy (62%), absent or decreased tendon reflex(67%) and objective sensory disturbance at the distal extremities (33%). The abducent predominant limitation of eye movement was more often seen in BBE patients than in those with other brainstem encephalitis (58% vs 33%). The patients’ disabilities peaked at one week of presentation in 62% of patients. Assisted ventilation was required for 20% of the patients. IgG anti-GQ1b antibodies were positive in 75% of the patients. CSF analysis showed pleocytosis or increased protein in 44% and 38% of the patients respectively. Abnormal MRI findings were found in 23% of the patients.
Fisher-Bickerstaff syndrome and anti-GQ1b antibody syndrome (8)
The presence of anti-Gangliosides antibody in Fisher syndrome and BBE suggests that they may be closely related. The GQ1b antigen is highly expressed in the oculomotor, trochlear and abducens nerves, muscle spindles in the limbs, and probably reticular formation in the brainstem. Infection by microorganisms bearing the GQ1b epitope may induce production of IgG anti-GQ1b antibodies in the patients. It is the binding of the antibodies to different parts of the nervous system results in a spectrum of clinical syndrome and it is called Fisher-Bickerstaff syndrome or broadly anti-GQ1b antibody syndrome. The binding of the antibodies to the peripheral nervous system (relevant cranial nerves and muscle spindles in the limbs) leads to Fisher syndrome with classical triad of ataxia, ophthalmoplegia and areflexia. The presence of drowsiness in Bickerstaff’s brainstem encephalitis differentiates itself from Fisher Syndrome. This is because the anti-GQ1b antibodies enter the brainstem and leads to BBE. One of the function of the blood-brain barrier is to protect the brain from unwanted effects of large molecules in the blood, it is deficient in the area of postrema so that it allows the large molecules including anti-GQ1b antibodies to penetrate the brainstem. (9) (10) The antibodies attack the reticular formation results in consciousness impairment but this needs further experimental confirmation.
Molecular mimicry theory
Antecedent infection or prodrome is commonly found in the BBE. How does an infectious agent induce the autoimmune disease? One possibility is an immune-mediated process with the formation of autoantibodies and in this case the anti-GQ1b antibodies. Although the GQ1b epitope has not been found in Mycoplasma Pneumoniae, (12) we can get an insight into this theory by exploring the case of Campylobacter jejuni (C. jejuni) infection. This is only a postulation because it awaits experimental confirmation in case of BBE.
Lipo-oligosaccharide (LOS) is a major component of the outer membrane of C. jejuni. Mass spectrometry analysis identified a C. jejuni strain from a Fisher syndrome patient, which carried a GT1a-like LOS-mimicking GQ1b. A GD1c-like LOS, which mimics GQ1b, also has been identified in C. jejuni isolates from Fisher syndrome patients. Immunization of GQ1b/GT1a-deficient mice with GT1a-like LOS generated monoclonal IgG antibodies that reacted with GQ1b and GT1a. There are four criteria needed to be satisfied in order to confirm the molecular mimicry theory. ‘These criteria are (i) establishment of an epidemiological association between the infectious agent and immune-mediated disease, (ii) identification of T cells or antibodies directed against the patient’s target antigens, (iii) identification of microbial mimics of the target antigen and (iv) reproduction of the disease in an animal model.’ GBS is divided into acute inflammatory demyelinating neuropathy and acute motor axonal neuropathy (AMAN) based on pathological studies. It fulfils all the four criteria of ‘(i) establishment of an epidemiological association between GBS and C. jejuni infection in a prospective case-control study, (ii) identification of autoantibodies against GM1 and GD1a gangliosides in patients with AMAN subsequent to C. jejuni enteritis, (iii) identification of molecular mimicry between GM1 or GD1a and the LOS of C. jejuni isolated from AMAN sufferers and (iv) reproduction of the AMAN model by active immunization with GM1 or C. jejuni LOS and by passive transfer of anti-GD1a antibodies.’ In other words, ganglioside-like LOS is a cause of GBS. (12)
Pathology of the BBE showed perivascular lymphocytic infiltration with perivascular oedema and glial nodules. (4) A case of BBE admitted to intensive care unit found that multiple sections through the brainstem showed a mild perivascular lymphocytic infiltrate, consisting of mainly B-lymphocytes (CD-20 positive) and scattered microglial nodules. The neurons including oculomotor, trochlear, abducens, facial and hypoglossal nuclei were significant for central chromatolysis. A mild lymphocytic infiltrate was also found in the cranial nerves accompanied by ongoing axonal degeneration and loss. Sections from the cervical, lumbar, and sacral spinal cord showed anterior horn neurons with central chromatolysis and a mild lymphocytic infiltrate in the spinal nerve roots and leptomeninges. (6)
MRI findings (4) are present in one-third of BBE patients with abnormal high-intensity areas on T2-weighted images of the brainstem, thalamus, cerebellum and cerebrum. Normal MRI findings also reported in some BBE patients. The MRI findings (14) in a remitting-relapsing case of BBE showed hypointense foci on T1-weighted images and hyperintense on intermediate and T2-weighted images. Positive MRI findings support the diagnosis of BBE when clinical differentiation between Fisher syndrome and BBE is not clear.
EEG findings (4) for BBE patients may show slow-wave activity in the theta to delta range and it indicated the central nervous system involvement with impairment of consciousness.
Treatment and prognosis
It is said that no specific treatment is necessary because of its benign prognosis and treatment is only effective for coma and it will not shorten the duration of the disease. (15) Others suggested that treatment is necessary and it includes steroid, plasmapheresis and intravenous immunoglobulin (IvIg). Combination therapy of IvIg and high dose methylprednisolone was preferred. (4) Most of the patients made good recovery. Complement activation is an important nerve injury mechanism for producing anti-ganglioside antibody-mediated neuropathy, future development of the treatment will be complement inhibitors such as eculizumab and nafamostat mesilate. (13)
BBE carries a benign prognosis and most patient recover completely. Is recurrent attack possible? There are two cases of recurrent BBE in the literatures, one is a 53-year-old Malay man with no identifiable antecedent illness and overlapped with Fisher syndrome and GBS. (16) He is negative for anti-GQ1b antibodies. Another case is a 46-year-old Chinese man presented with recurrent FBS in the interval of eight months. He was treated with IvIg during each episode and made good recovery. One systemic study showed that there is no known factors related to recurrent BBE or FBS. Serological human leucocyte antigen (HLA) typing showed that HLA-DR2 may be associated with recurrence. There is no systemic study about the outcome of recurrent attacks but it points towards the direction of a benign outcome. (17)
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DECLARATION 27 December 2019
This article was submitted to the University of Hong Kong for publication. I declare that it was not submitted to other institutes for other purposes.