Overlap of Bickerstaff brainstem encephalitis/ Guillain Barré syndrome simulating brain death

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1 Overlap of Bickerstaff brainstem encephalitis/ Guillain Barré syndrome simulating brain death Sir, Guillain Barré syndrome (GBS) is an immune mediated peripheral nerve disorder typically presenting with acute flaccid paralysis. [1] 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, [2] and when there is associated disturbance of consciousness, the condition is referred to as Bickerstaff brainstem encephalitis (BBE). [3,4] Together, classical GBS, MFS, and BBE form part of a continuous clinical spectrum which shares a common autoimmune pathophysiology. [5] 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. [6 8] 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 (po 2 83 mmhg; pco 2 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 () 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 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, he was noted to be less responsive. There was no extraocular movement and his pupils were dilated Table 1: Serial electrophysiological test results Day of Day 3 Day 17 Day 59 Day 102 Motor NCS Median DML (ms) 4.43 NR NR NR Wrist 5.4 NR NR NR Elbow 4.9 CV (m/s) 45.2 NR NR NR Ulnar DML (ms) 3.65 NR NR NR Wrist 4.4 NR NR NR BE 5.2 AE 3.8 CV (m/s) Wrist BE 57.3 NR NR NR BE AE 38.4 Tibial DML (ms) 4.48 NR NR NR Ankle 6.3 NR NR NR PF 3.8 CV (m/s) 36.7 NR NR NR Peroneal DML (ms) NR NR NR Ankle 0.7 NR NR NR Fibula 0.3 Knee 0.3 CV (m/s) Ankle fibula 36.4 NR NR NR Fibula knee 41.7 Sensory NCS Median SNAP (µv) NR NR NR NR CV (m/s) NR NR NR NR Ulnar SNAP (µv) 2.7 NR NR NR CV (m/s) 33.1 NR NR NR Sural SNAP (µv) 12.8 NR NR NR CV (m/s) 38.4 NR NR NR Contd Neurology India, Neurological Society of India Published by Wolters Kluwer - Medknow 1475

2 Table 1: Contd... Day of Day 3 Day 17 Day 59 Day 102 Electromyography Tibialis anterior SA (Fib/PSW) Nil Nil Gastrocnemius SA (Fib/PSW) Nil Nil ND 2+ MUAP recruitment No activity ND No activity Vastus medialis SA (Fib/PSW) Nil Nil 2+ Nil FDIO SA (Fib/PSW) Nil Nil Biceps SA (Fib/PSW) Nil Nil Nil 2+ NCS=Nerve conduction study; DML=Distal motor latency; CMAP=Compound muscle action potential; CV=Conduction velocity; BE=Below elbow; AE=Above elbow; SNAP=Sensory nerve action potential; PF=Popliteal fossa; NR=No response; SA=Spontaneous activity; Fib=Fibrillation; PSW=Positive sharp wave; MUAP=Motor unit action potential; FDIO=First dorsal interosseus; ND=Not done; =Reduced 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 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, 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 after the onset of, 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, flaccid paralysis, CSF albumin cytological dissociation, and initial electrodiagnosis of acute motor and sensory axonal neuropathy () 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. [9] Based on the proposed criteria, [5] 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. [9] 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. [4] 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. [10,11] 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. [5,12] 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 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 1476 Neurology India Volume 66 Issue 5 September October 2018

3 Table 2: Clinical characteristics of reported adult cases of BBE/GBS overlap syndrome Case Age/ sex Yuki et al. (1997) Odaka et al. (2001) Yuki et al. (2001) Arai et al. (2002) Stevenson et al. Susuki et al. Odaka et al. Odaka et al. Santos et al. (2009) Fujii et al. (2012) Han et al. (2012) Pegg et al. (2016) Antecedent Day of coma or neurological nadir Day of first improvement CSF albumincytological dissociation 71/F URTI Day 9 Day 60 Pleocytosis; protein Organism identified Initial NCS Serial NCS Gangliosides antibodies Axonal NR GQ1b+ Loss of large myelinated fibers Nerve biopsyinitial EEG Treatment Outcome Poor alpha activity IVMP Died at 22 24/M URTI Day 3 Day 6 Yes NR NR NR NR NR IA Recovered at day 39 60/M Cough, vesicular rash Day 3 Day 9 Yes HSV 1 Motor conduction block NR GQ1b+, GT1a+, GD1b+ NR NR IVIG Partial recovery at 4 34/F URTI Day 5 Day 9 NR NR NR GQ1b+ NR Alpha activity PE Recovered at dominant 5 43/F URTI Day 10 Day 18 Yes Demyelinating NR GM1+ NR NR IVIG Recovered at day 27 37/M URTI Day 6 Day 24 Pleocytosis; Axonal NR GQ1b+, GT1a+ NR Background PE Disabled at protein 7 8 Hz, 1 year 37/M Flu like Day 1 Day 15 Pleocytosis; protein Axonal NR GM1+, GD1a+, GD1b+, GalNac GD1a+, GQ1b+ NR NR IA + IVIG Died at day 45 54/M Cough, Day 4 Day 24 No Axonal NR GQ1b+, GT1b+, NR NR IA Recovered at diarrhea GD1a+, GD1b+ 2 28/F GIT Day 14 Yes Axonal- NR Negative NR Slow cortical PE + IVIG Died activity x2 72/F URTI Day 5 Day 30 No Axonal- NR GM1+, GD1a+, NR Background IA + IVIG x2recovered at GQ1b+, GT1a+ 7 8 Hz 10 20/M Asthma Day 21 Day 37 Yes Axonal- NR Negative NR Diffuse theta CS Partial exacerbation slow activity recovery at day /M Mild cough ~ 6 weeks >6 weeks Yes Axonal- NR GQ1b+, GD1a+ NR Slow IVIG x2 + Independent background PE at 3 activity CSF=Cerebrospinal fluid; NCS=Nerve conduction studies; EEG=Electroencephalogram; URTI=Upper respiratory tract infection; NR=Not reported; IVMP=Intravenous methylprednisolone; HSV=Herpes simplex virus; IA=Immunoadsorption; IVIG=Intravenous immunoglobulin; GIT=Gastrointestinal ; =Acute motor and sensory axonal neuropathy; CS=Corticosteroid; PE=Plasma exchange; M=Male; F=Female Neurology India Volume 66 Issue 5 September October

4 Table 3: Clinical characteristics of reported adult cases of fulminant GBS simulating brain death/locked in syndrome Case Age/ sex Carroll et al. (1979) Kotsoris et al. (1984) Al Din et al. (1985) Al Din et al. (1985) Al Din et al. (1985) Drury et al. (1987) Kanda et al. (1989) Coad et al. (1990) Hassan et al. (1991) Fuller et al. (1992) Marti Masso et al. (1993) Tan et al. (1995) Bohlega et al. (1997) Hughes et al. (1997) Berciano et al. (1997) Ragazzoni et al. (2000) Ragazzoni et al. (2000) Vargas et al. (2000) Stojkovic et al. (2001) Rajdev et al. Antecedent Day of suspicion of brain death Day of first improvement CSF albumincytological dissociation Organism identified Initial NCS Serial NCS Gangliosides antibodies Nerve biopsy Initial EEG Treatment Outcome 45/M Viral URTI Day 6 Day 14 Yes NR NR NR NR Alpha, non NR Independent at 12 44/M NR Day 2 Day 42 Yes Inexcitable NR NR NR Alpha, NR Disabled at 3 non 56/M NR Day 21 Day 26 No NR NR NR NR Delta slow NR Recovered at 4 45/M Chickenpox Day 3 Day 8 Yes Varicella NR NR NR NR NR NR Disabled at 3 zoster 20/M NR Day 2 Day 4 Yes NR NR NR NR NR PE Disabled at 4 63/M URTI Day 2 Day 47 Yes Inexcitable NR NR NR Alpha, NR Improved over 47/M URTI Day 6 Yes Axonal AMAN NR NR Demyelination NR PE Died on day 7 43/M Influenza like Day 4 Day 9 Yes NR NR NR NR Alpha, non NR Recovered progressively 45/M GIT Day 3 Day 5 No NR NR NR NR Alpha, NR Disabled at 14 non 63/M NR Day 3 Day 11 Yes Inexcitable NR NR Demyelination Alpha, PE + CS Died on day non 18 58/F Cold Day 2 Day 16 Yes Axonal Axonal NR NR Alpha, PE Independent non at 12 50/F GIT Day 8 Day 21 No Inexcitable Demyelinating NR NR Alpha, IVIG Died on day 98 45/M NR Day 3 Day 33 Yes Inexcitable Demyelinating Negative Demyelination NR PE + IVIG Disabled at 2.5 years 27/M URTI Day 5 Day 42 Yes Demyelinating NR NR NR Delta slow IVIG Disabled at 8 67/M URTI Day 3 Yes C. jejuni Inexcitable Inexcitable Negative Demyelination Theta, PE + CS Died on day 18 40/M Viral URTI Day 2 Day 15 Yes Inexcitable Inexcitable NR NR Alpha, PE Independent at 4 46/M NR Day 4 Day 14 Yes Inexcitable NR NR NR Alpha, PE Died on day 66 45/F Nonspecific Day 1 Day 21 Yes Inexcitable NR NR Demyelination Alpha, PE Disabled at 8 axonal non degeneration 47/M Head injury Day 9 Day 18 Yes Demyelinating NR Negative NR Theta, non 14/M NR Day 5 Day 11 Yes Inexcitable NR NR NR Slow, IVIG Independent at 6 IVIG Disabled at 12 Contd Neurology India Volume 66 Issue 5 September October 2018

5 Table 3: Contd... Case Age/ sex Friedman et al. Friedman et al. Moussouttas et al. (2004) Primavera, 2005 Primavera, 2005 Kang et al. (2007) Rivas et al. (2008) Joshi et al. (2008) Joshi et al. (2008) Rigamonti et al. (2009) Bernard et al. (2010) Liik et al. (2012) Ahmed et al. (2013) Gordon Chaves et al. (2014) Prasanna et al. (2015) Ravikumar et al. (2016) Rouge et al. (2016) Antecedent Day suspicion of brain death Day of first improvement CSF albumincytological dissociation Organism identified Initial NCS Serial NCS Gangliosides antibodies 57/F URTI Day 6 Day 16 Pleocytosis Inexcitable Axonal- 27/M URTI Day 5 Day 47 Yes C. jejuni Axonal- NR Axonal degeneration Nerve biopsy Initial EEG Treatment Outcome Inexcitable NR NR Alpha, non 47/F Head trauma Day 5 Day 15 Yes Inexcitable Demyelinating NR NR Slow, non Day 2 Day 21 Yes Inexcitable NR NR NR Alpha 57/F Flu like syndrome 78/F Influenza vaccination, diarrhea Theta slow NR Disabled at 16 and theta, Day 1 Day 30 Yes Axonal NR NR NR Diffuse alpha, IVIG Disabled at 17.5 PE + IVIG Complete recovery PE Recovered at 10 IVIG Independent at 2 years 32/M Viral hepatitis Day 7 Day 30 Yes Hepatitis Inexcitable Demyelinating NR NR Alpha, IVIG + CS Independent A A at 3 55/M Head injury Day 7 Day 23 Yes Inexcitable NR NR Axonal Alpha, PE Disabled at 6 degeneration non 34/M GIT Day 2 Day 14 Yes Inexcitable NR NR NR Normal NR Disabled at 3 59/M NR Day 11 Day 56 Yes Inexcitable NR NR NR Normal NR Disabled at 4 61/F Diarrhea Day 14 Day 33 Yes Inexcitable Inexcitable Negative NR Normal IVIG Independent at 12 73/M Diarrhea, Day 5 Day 15 Yes Axonal- NR GQ1b+ NR Theta, IVIG Died on day surgery /F Pneumonia Day 3 Day 11 Yes Inexcitable NR NR NR Theta, IVIG Disabled at 29 27/M Nil Day 3 Day 37 Yes NR NR NR NR Slow, PE Disabled at /M Nil Day 5 Day 18 Yes Inexcitable NR Negative NR Posterior IVIG, PE + Independent alpha IVIG after 9 44/M GIT Day 2 Yes Demyelinating NR NR NR Intact cortical function Present case 65/M Viral syndrome 60/M Pneumonia Day 7 Day 14 Yes Inexcitable NR Negative NR Alpha, 47/M Diarrhea Day 3 Several weeks Yes C. jejuni Demyelinating NR NR NR Paradoxical sleep Day 8 Day 15 Yes Axonal- Inexcitable Negative Not done Theta delta, non CSF=Cerebrospinal fluid; NCS=Nerve conduction studies; EEG=Electroencephalogram; URTI=Upper respiratory tract infection; NR=Not reported; PE=Plasma exchange; GIT=Gastrointestinal ; CS=Corticosteroid; IVIG=Intravenous immunoglobulin; =Acute motor and sensory axonal neuropathy PE + IVIG Died at x2 6 weeks IVIG + PE Disabled at 6 IVIG x4 + Disabled at PE 9 years IVIG x2 Independent at 15 Neurology India Volume 66 Issue 5 September October

6 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 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, 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. Acknowledgement 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 (BK ). Conflicts of interest There are no conflicts of interest. References 1. Shahrizaila N, Yuki N. Guillain Barré syndrome animal model: The first proof of molecular mimicry in human autoimmune disorder. J Biomed Biotechnol 2011;2011: Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Eng J Med 1956;255: Bickerstaff ER. Brain stem encephalitis: Further observations on a grave syndrome with benign prognosis. Br Med J 1957;1: Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and Fisher syndrome: Anti GQ1b antibody syndrome. 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Serum anti GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain Barré syndrome: Clinical and immunohistochemical studies. Neurology 1993;43: Liu JX, Willison HJ, Pedrosa Domellof F. Immunolocalization of GQ1b and related gangliosides in human extraocular neuromuscular junctions and muscle spindles. Invest Ophthalmol Vis Sci 2009;50: Ogawara K, Kuwabara S, Mori M, Hattori T, Koga M, Yuki N. Axonal Guillain Barré syndrome: Relation to anti ganglioside antibodies and Camplylobacter jejuni infection in Japan. Ann Neurol 2000;48: Cheng Yin Tan, Sherrini Bazir Ahmad, Khean Jin Goh, Lydia Abdul Latif 1, Nortina Shahrizaila Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, 1 Department of Rehabilitation Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Address for correspondence: Dr. Cheng Yin Tan, Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. E mail address: cytan@ummc.edu.my This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Website: DOI: / PMID: xxxx Access this article online Quick Response Code How to cite this article: Tan CY, Ahmad SB, Goh KJ, Latif LA, Shahrizaila N. Overlap of Bickerstaff brainstem encephalitis/ Guillain Barré syndrome simulating brain death. Neurol India 2018;66: Neurology India, Neurological Society of India Published by Wolters Kluwer - Medknow 1480 Neurology India Volume 66 Issue 5 September October 2018