Overlap of Bickerstaff brainstem encephalitis/Guillain–Barré syndrome simulating brain death
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.241342
Source of Support: None, Conflict of Interest: None
Guillain–Barré syndrome (GBS) is an immune-mediated peripheral nerve disorder typically presenting with acute flaccid paralysis. However, the clinical presentation of GBS is diverse. Miller Fisher syndrome (MFS), the most recognizable GBS variant, is characterized by an acute onset of ataxia, areflexia, and ophthalmoplegia, and when there is associated disturbance of consciousness, the condition is referred to as Bickerstaff brainstem encephalitis (BBE)., Together, classical GBS, MFS, and BBE form part of a continuous clinical spectrum which shares a common autoimmune pathophysiology. This is further supported by descriptions of overlap syndromes such as MFS/GBS and BBE/GBS. In the latter case, the clinical presentation can result in total paralysis and loss of brainstem reflexes resembling brain death.,, This rare entity of BBE/GBS overlap syndrome can be clinically challenging to diagnose and manage.
Here, we report a case of BBE/GBS overlap, rapidly evolving to a state mimicking that of brain stem death. We describe the clinical and electrophysiological characteristics and review the existing literature on this extreme variant of GBS.
A 65-year old man presented with ascending weakness and numbness in his extremities evolving over a period of 2 days. He had a history of fever and rash 4 days before the onset of weakness. On examination, there was no facial weakness or ophthalmoplegia. Neck flexion was weak [Medical Research Council (MRC) grade 4] and muscle power was reduced in all four limbs (MRC grade 3 in the upper limbs and MRC grade 2 in the lower limbs). There was global areflexia and the plantar response was flexor bilaterally. The following day, he deteriorated further with the development of type 2 respiratory failure (pO2 83 mmHg; pCO2 48 mmHg) necessitating emergency intubation and mechanical ventilation. The cerebrospinal fluid (CSF) analysis showed albumin-cytological dissociation with no cells and an elevated protein of 1.72 g/L. Nerve conduction studies (NCS) performed at day 3 showed an axonal pattern of sensorimotor neuropathy with sparing of sural nerves [Table 1]. IgG antibodies against gangliosides GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b were negative. A diagnosis of acute motor and sensory axonal neuropathy (AMSAN) variant of GBS was made and intravenous immunoglobulin (IVIG) therapy was initiated. There was autonomic dysfunction with fluctuations in blood pressure (BP) [the systolic BP ranging between 180–240 mm Hg] and persistent tachycardia (heart rate 130 beats per minute) necessitating the initiation of labetalol infusion. At this stage, he developed external ophthalmoplegia with facial diplegia, and his limb power was MRC grade 0 in all muscle groups. He was alert and able to communicate through limited eye movements and head nodding.
On day 8 of illness, he was noted to be less responsive. There was no extraocular movement and his pupils were dilated and unresponsive to light or accommodation. Doll's eye and corneal reflexes were absent. On suctioning, there was absence of gag, cough, and tracheobronchial reflexes. His BP (174/86 mmHg) and heart rate (97 bpm) were stable. An urgent brain magnetic resonance imaging (MRI) was normal. Electroencephalogram (EEG) showed diffuse theta-delta slowing, non-reactive to visual, tactile, or auditory stimuli. Toxic, septic, and metabolic screen were unremarkable. Clinically, the patient appeared to be brain dead. However, given the initial diagnosis of GBS with evolution to an altered state of consciousness, the possibility of severe BBE/GBS overlap was considered and full supportive treatment was continued.
His condition remained unchanged until day 15 of illness, when he was noted to move his jaw. There was still complete ophthalmoplegia and mydriasis. Repeat NCS showed inexcitable nerves and needle electromyography (EMG) showed no spontaneous or voluntary activity [Table 1]. As recovery was poor, a second course of IVIG was given at day 22. At day 33, there were flickers of movement in both shoulders and his fingers. There was also some limited eye movement which gradually improved and by day 67, diplopia was noted only at extremes of horizontal gaze. By day 82, the patient was able to breathe spontaneously. He continued to improve with intensive rehabilitation, regaining independent swallowing by day 102. A third set of NCS revealed inexcitable nerves, while needle EMG revealed active denervation changes in distal limb muscles, namely, tibialis anterior, vastus medialis, and first dorsal interosseus muscles [Table 1].
Five months after the onset of illness, he was discharged home. At this stage, he was wheelchair-dependent. His proximal and distal muscle power assessments were MRC grades 4 and 3, respectively, in the upper limbs; and MRC grades 3 and 2, respectively, in the lower limbs. At his 15-month review, his proximal power was MRC grade 5, but distally there was persistent wasting and weakness of small muscles of his hands and bilateral foot drop. He was able to mobilize with a walking frame and was independent in his activities of daily living.
We describe a case of BBE/GBS overlap simulating brain death with electrically inexcitable peripheral nerves. The striking features were rapid progression to a state of total paralysis and unresponsiveness within 8 days of onset. The brainstem reflexes were absent and the patient appeared clinically brain dead. However, EEG showed diffuse slow waves rather than electrocerebral inactivity indicating some preservation of cortical function. The initial diagnosis of GBS prompted the consideration that the disease had extended to involve the central nervous system, and a diagnosis of BBE/GBS overlap syndrome was made. This diagnosis was supported by the history of antecedent illness, flaccid paralysis, CSF albumin-cytological dissociation, and initial electrodiagnosis of acute motor and sensory axonal neuropathy (AMSAN) with a sural sparing pattern.
BBE has been reported to overlap with GBS, lending support that they are a part of a continuous clinical spectrum, which is an antibody-mediated process. We have summarized the overlap cases reported to date in [Table 2]. In a study of 62 patients with BBE, 37 (60%) had significant limb weakness with 12 (32%) of them being MRC grade 3 and below. Based on the proposed criteria, this group of patients had BBE/GBS overlap syndrome. In the same report, IgG anti-GQ1b antibody was detected in 66% of BBE and 70% of BBE with limb weakness. The pathogenic role of anti-GQ1b was still debatable. One of the hypotheses was that the anti-GQ1b antibody reaches the brainstem through break down of blood–brain barrier and attacks the reticular formation. This would explain the altered conscious level in BBE. As for ophthalmoplegia and ataxia, studies had shown that GQ1b is highly expressed at the paranode of oculomotor, trochlear and abducens nerves, and the group Ia afferents in muscle spindles., The involvement of peripheral motor nerves in BBE/GBS was reported to be of predominantly axonal subtype. In one study, 27% of BBE/GBS overlap had IgG antibodies against gangliosides GM1 or GD1a, a condition which is closely associated with the axonal form of GBS.,
There have been numerous reports of cases of adult GBS (n = 37) mimicking brain death [Table 3]. Most have referred to such cases as fulminant forms of GBS or locked-in syndrome. Collectively, these reports including our case suggest a mean age at onset of 47.8 years (range 14–78 years) with a male: female ratio of 3.2:1. Antecedent infections were reported in 63.2% (24/38) of cases, and in five cases, the microorganisms isolated included Campylobacter jejuni (3), varicella zoster virus (1), and hepatitis A virus (1). CSF albumin-cytological dissociation was detected in 89.5% (34/38) of patients. The common clinical feature in all the reported cases was the rapid progression of symptoms to the status of maximum deficit [mean = 5 days (range 1–21 days)]. Neurophysiology demonstrated inexcitable nerves in 60.5% (23/38) of cases. Serial studies were performed in 11 cases, of which 5 were inexcitable, 4 demyelinating, and 2 axonal. Eight patients were tested for anti-ganglioside autoantibodies. Only one was positive for anti-GQ1b antibody suggesting that the target antigen in such cases remains elusive. In the current case, IgG against ganglioside antibodies was negative at the initial pre-treatment stage of the disease. Serological analyses of IgG against ganglioside antibodies were not repeated post-treatment and thus, the possibility of detecting a peak in antiganglioside antibody levels at the height of the disease cannot be entirely excluded. Sural nerve biopsy was performed in 7 of 38 (18.4%) patients, which revealed primary demyelination in five cases and primary axonal degeneration in two. In 34 cases, the EEG findings were diffuse slow waves (n = 13), normal waveforms (n = 12), and a non-reactive alpha or alpha coma (n = 9). In 28 (73.7%) patients, immunotherapy was given as follows: IVIG (10 patients), plasma exchange (9 patients), plasma exchange with IVIG (6 patients), plasma exchange with corticosteroid (2 patients), and IVIG with corticosteroid (1 patient). Of those who were treated, the outcomes were variable ranging from complete recovery in two patients (7.1%) to death in seven patients (25.0%). Eleven (39.3%) patients showed a poor recovery with persistent disabling weakness, whereas eight (28.6%) patients recovered with minimal residual distal weakness and were independent in activities of daily living.
In conclusion, BBE/GBS overlap at its most extreme can simulate brain death. The clinical progression to “absence of brainstem reflexes” in such cases was rapid, occurring within a week. The majority of cases had a history of antecedent illness, CSF albumin-cytological dissociation, and inexcitable nerves on neurophysiology. Despite immunotherapy, most were left with persistent disabling neurological deficits. Recognition of this extreme presentation of BBE/GBS overlap is crucial as some patients may be misdiagnosed as being in a state of brainstem death, potentially leading to the withdrawal of ventilatory support.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors thank Nobuhiro Yuki for help with serological assay of ganglioside antibodies.
Financial support and sponsorship
Dr. Cheng-Yin Tan received research fund from University of Malaya (BK074-2017).
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]