Bickerstaff brainstem encephalitis with Guillain-Barré syndrome overlap following chlamydia infection

Abstract

Bickerstaff brainstem encephalitis (BBE) is a rare autoimmune encephalitis characterised by ataxia, ophthalmoplegia and altered consciousness. An overlap between BBE with Guillain-Barré syndrome (GBS) shows similar clinical and immunological features. We report a case of BBE with GBS overlap secondary to Chlamydia pneumoniae infection. The triad of altered consciousness, ataxia and ophthalmoplegia were present in the patient. The investigations included cerebrospinal fluid cytoalbuminological dissociation, nerve conduction test that showed prolonged or absent F wave latencies, hyperintensity in the left occipital region on brain MRI and diffuse slow activity on the electroencephalogram. The chlamydia serology was positive indicating a postinfectious cause of BBE syndrome. He required artificial ventilation as his consciousness level deteriorated with tetraparesis, oropharyngeal and respiratory muscle weakness. Immunotherapy with intravenous immunoglobulin and methylprednisolone was commenced. He made good recovery with the treatment. Prompt recognition of this rare condition following chlamydia infection is important to guide the management.

Background

Bickerstaff brainstem encephalitis (BBE) is a rare variant of Guillain-Barré syndrome (GBS) presenting with alteration in consciousness which reflects the central nervous system involvement. Several antecedent infections play an important role in the pathogenesis of molecular mimicry. Although Chlamydia pneumoniae is largely a respiratory pathogen, it may also cause extrapulmonary manifestations such as cardiovascular (myocarditis, pericarditis and endocarditis) and neurological complications. Reported cases of encephalitis, meningitis, dementia, demyelinating disease and GBS have been described. However, there is scarcity of data regarding Chlamydia infection in BBE. This report illustrates the first case of BBE with GBS overlap following chlamydia infection.

Case presentation

A 48-year-old man without any medical illness, presented with fever, frontal headache associated with blurring of vision and vomiting for 8 days. There were no preceding respiratory symptoms, diarrhoea, cough or joint pain. He had gone for a camping trip in the local rainforest 3 months prior to the admission. He did not consume alcohol or smoke.

On examination, his Glasgow Coma Scale was 14/15 and he was disorientated to place and person. The blood pressure was 126/84 mm Hg, pulse rate of 90 beats per minute, temperature 39.6°C and oxygen saturation was 99% under room air. The general examination did not reveal pallor, jaundice or cyanosis. The neurological examination showed the pupils were 3 mm bilaterally, equal and reactive. Examination of the upper and lower limbs revealed normal tone, muscle power and deep tendon reflexes with downgoing plantar responses. The sensory examination was normal.

Investigations

Blood investigations showed haemoglobin 159 g/L, total white cell count 9.5×10⁹/L, platelet 287×10⁹/L and C reactive protein 1.75 mg/dL (<0.5 mg/dL). The renal function was normal apart from hyponatraemia of 125 mmol/L. The serum osmolality was 265 mOsm/kg (275–295 mOsm/kg), urine osmolality was 980 mOsm/kg (50–1200 mOsm/kg) and urine sodium 194 mmol/L supporting the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. Thyroid function test showed normal free T4 11.40 pmol/L (9–19.05 pmol/L) and thyroxine stimulating hormone 2.10 uIU/mL (0.35–4.94 uIU/mL). The liver function test and glucose levels were normal. The erythrocyte sedimentation rate was 47 mm/hour, complement levels and anti-double stranded DNA were normal. CT of the brain was normal. Lumbar puncture was performed and showed clear cerebrospinal fluid (CSF), opening pressure of 5.5 cmH₂0 and the ratio of CSF glucose 1.76 mmol/L: blood glucose 6.4 mmol/L was 0.28. The CSF protein was elevated at 883 mg/L (150–400 mg/L) and relatively acellular indicating cytoalbuminological dissociation. The rest of the CSF examinations including cryptococcal antigen, Indian ink, acid-fast bacilli direct smear, tuberculous culture, bacterial culture, LATEX agglutination test for Haemophilus influenzae, group B streptococcus, Streptococcus pneumoniae, Escherichia coli and Neisseria meningitidis were negative. The viral serology was negative.

He was treated as meningoencephalitis with intravenous ceftriaxone and acyclovir. His condition worsened the following day and his speech became incoherent and irrelevant. By the fifth day of admission, he became stuporous and was confined to the bed. There were new clinical signs as he developed bilateral facial weakness, ophthalmoplegia with ataxia and progressive weakness of both upper and lower limbs Medical Research Council (MRC) sum score 12/60. Ocular examination showed restriction of movements in all directions of gaze (video 1). The electroencephalogram (EEG) on admission showed diffuse delta activity (figure 1). Nerve conduction study showed mild prolongation of F-wave latencies in the left median, ulnar and tibial nerves and absent F-wave response in the left peroneal nerve suggestive of early demyelination (figure 2). The MRI of the brain showed gyriform hyperintensity in the left occipital region on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. The cortical gyriform abnormality enhanced following intravenous gadolinium administration. There was no restricted diffusion on diffusion-weighted imaging/apparent diffusion coefficient (DWI/ADC) sequences (figure 3).

Video 1.

Download video file ^{(10.7MB, mp4)}

DOI: 10.1136/bcr-2021-242090.video01

Figure 1.

The electroencephalogram showed diffuse delta activity.

Figure 2.

Nerve conduction study showed mild prolongation of F-wave latencies in the left median, ulnar and tibial nerves. The F-wave was absent in the left peroneal nerve.

Figure 3.

MRI of the brain in axial T1W (A), T2W (B), FLAIR (C), contrast-enhanced T1W (D), DWI (E) and ADC (F). The left occipital cortical gyriform hyperintensity on FLAIR and T2W, showed enhancement on T1W postgadolinium. DWI and ADC did not show restricted diffusion. The enhanced cortex was not thickened (arrow). FLAIR, Fluid-attenuated inversion recovery; DWI, Diffusion-weighted imaging; ADC, Apparent diffusion coefficient

Differential diagnosis

The initial diagnosis of meningoencephalitis was considered as the patient presented with fever and headache. However, the subsequent clinical findings of ataxia, ophthalmoplegia, encephalopathy and tetraparesis led to the diagnosis of BBE and GBS overlap, supported by neurophysiological studies. Other differentials include Wernicke’s encephalopathy, vasculitis, multiple sclerosis and cerebral lymphoma. The MRI brain did not show any demyelinating plaques or vasculitic lesions to support these diagnoses.

Treatment

The diagnosis of BBE and GBS overlap was made with the characteristic clinical signs, neurophysiological and neuroimaging findings. He was treated with intravenous immunoglobulin 0.4 g/kg/day and intravenous methylprednisolone 1 g daily for 5 days. He had to be intubated for airway protection in view of the deterioration in consciousness and respiratory failure. The C. pneumoniae IgM serology came back as positive subsequently. Mycoplasma pneumoniae, Campylobacter and H. influenzae serology and the ganglioside antibody were negative. His stay in the intensive care unit was complicated by Candida glabrata fungaemia which was treated with 2 weeks of anidulafungin. The muscle power gradually improved to MRC sum score 48/60 with return of the tendon reflexes followed by improvement of facial weakness and consciousness by the end of the fifth week of admission. A time line of the progress is seen in figure 4. He remained stable in the ward where aggressive physiotherapy and rehabilitation were performed.

Figure 4.

The time line of the patient’s progress.

Outcome and follow-up

He was discharged after 6 weeks with full muscle power and conscious state although he was still slow in answering questions. On follow-up at 2 months, there was complete recovery of his clinical condition with normal electroencephalogram. Nerve conduction study repeated during the follow-up was normal.

Discussion

BBE was first coined in the 1950s where cases with ophthalmoplegia and ataxia were accompanied by altered consciousness, extensor plantar response and hyper-reflexia.¹ This was in support of a central pathology whereas in Miller Fisher syndrome (MFS) patients were areflexic in keeping with a peripheral aetiology. Both conditions are characterised by GQ1b IgG antibodies,² which are linked via the same autoimmunity pathway. This led to the evidence that both conditions were part of a similar spectrum of disease involving an immune-mediated process, triggered by an antecedent infective episode. Odaka et al³ proposed a set of clinical diagnostic criteria to distinguish between BBE, MFS and GBS. The following features were required for the diagnosis. Bickerstaff’s brainstem encephalitis comprises of progressive, relatively symmetric ophthalmoplegia and ataxia by 4 weeks, either conscious disturbance or pyramidal signs and limb strength 5 or 4 on the MRC scale. MFS consists of progressive, relatively symmetric ophthalmoplegia and ataxia by 4 weeks, hyporeflexia or areflexia and limb strength 5 or 4 MRC scale. In acute ophthalmoparesis, there is progressive and relatively symmetric ophthalmoplegia by 4 weeks without ataxia or limb weakness.

In a study of 62 patients with BBE, the diagnosis was made by the strict criteria of progressive, relatively symmetrical external ophthalmoplegia and ataxia by 4 weeks and disturbance of consciousness or hyperreflexia.⁴ In the same study, abnormal MRI findings were reported in 23% of patients and electroencephalogram changes were seen in 70% of patients. Odaka et al⁴ reported that the clinical features apart from ophthalmoplegia and ataxia, disturbance of consciousness (74%), flaccid symmetrical tetraparesis (60%), facial diplegia (45%), Babinski’s sign (40%) and pupillary abnormality and bulbar palsy (34%) were present. In a large series of BBE, 60% of patients had antecedent respiratory infectious symptoms and 29% had diarrhoea.⁵ This case also had clinical features of ataxia and ophthalmoplegia that was preceded by fever and headache. External ophthalmoplegia has been reported in all patients with BBE and MFS.⁶

Impairment of consciousness is a distinguishing feature of BBE. The patient with BBE exhibits varying levels of consciousness which suggest that the brainstem reticular activating system is involved.⁶ The blood–brain barrier is protective against harmful effects of circulating large molecules. However, studies have demonstrated that the microcirculation of the postrema is relatively permeable that allows large molecules to penetrate the brainstem parenchyma.⁷ This may explain the involvement of the brainstem reticular formation due to the penetration of antibodies via this route. An in vitro study on the effects of BBE sera to the blood–brain barrier⁸ found that the blood–brain barrier was disrupted in BBE and was associated with increased secretion of matrix metalloproteinase secreted by human brain microvascular endothelial cells (BMECs). In comparison the patients with MFS sera had no effect on BMECs. These findings support the explanation of the central nervous system manifestations in patients with BBE.

Electrophysiological studies are useful to distinguish the presence of demyelination, axonal or motor conduction blocks. The nerve conduction study in this patient demonstrated absent or prolonged F-wave latencies. The presence of anti- GQ1b IgG in MFS and BBE suggest a common autoimmune mechanism which gives rise to overlapping features. In comparing between the groups of the positive and negative anti-GQ1b BBE, the former group had shown distinctive findings of preceding upper respiratory infection, sensory disturbance, lower CSF cell count or protein concentration and rarer abnormal brain MRI findings.⁹ The presence of antibodies binding to the GQ1b sites at the paranodes and the neuromuscular junctions of the oculomotor, trochlear and abducens may explain the ophthalmoplegia.¹⁰ Although this patient did not have positive antibody, the clinical features were in keeping with the diagnosis, supported by abnormal nerve conduction test, gyriform hyperintensity of the left occipital region and diffuse slowing in the EEG.

Several antecedent infections such as Campylobacter jejuni and H. influenzae that produces anti GQ1b antibody are found to be related to Fisher syndrome.¹¹ The mechanisms include molecule mimicry due to GQ1b-mimicking lipo-oligosaccharides on the bacteria. C. pneumoniae is an important respiratory pathogen and also had been linked to neurological manifestations such as dementia, demyelinating disease^{12 13} and meningoencephalitis. Its role as a possible aetiological factor has been reported in GBS.¹⁴ In a prospective study of paediatric GBS, C. pneumoniae was found in 8% of the study population.¹⁵ This patient had a positive Chlamydia blood serology. However, most of the reports are related to GBS and currently, there are no data regarding chlamydia infection on BBE with GBS overlap.

There have been no randomised clinical trials for treatment of MFS or BBE although intravenous immunoglobulin and plasmapheresis have been used in both conditions.¹⁶ The effectiveness of plasmapheresis has been described in a paediatric patient with BBE who did not respond to immunoglobulin.¹⁷ Treatment can be deferred as most cases have a good prognosis. It has been postulated that treatment may hasten the recovery period. However, the role of steroids has been controversial.^{18 19} Although there are case reports of improvement on steroids in BBE,¹⁹ it does not hasten recovery nor affect the long-term outcome. Our patient displayed marked improvement with the combination of intravenous immunoglobulin and methylprednisolone.

Learning points.

• Bickerstaff’s brainstem encephalitis, Miller Fisher syndrome and Guillain-Barré syndrome (GBS) is part of the spectrum of disease whereby antecedent infections can trigger the cascade of autoimmune process.

• Chlamydia has been identified as an antecedent infection in Bickerstaff brainstem encephalitis (BBE) with GBS overlap.

• Early recognition and treatment in BBE with GBS overlap may avoid deleterious consequences.