Acute necrotizing hemorrhagic leukoencephalitis
Acute hemorrhagic leukoencephalitis of Weston Hurst is at the extreme end of the spectrum of demyelinating diseases. It typically follows a viral upper
Mar. 26, 2021
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Prior to the discovery of IgG antibodies against GQ1b, there were clinical variants that were considered linked to Guillain-Barré syndrome due to common clinical features shared with Guillain-Barré syndrome. The most notable are Miller Fisher syndrome, which is characterized by acute ophthalmoplegia, ataxia, areflexia, and Bickerstaff brainstem encephalitis, in which consciousness is also affected. Following the discovery in 1992 of an association of anti-GQ1b antibodies with Miller Fisher syndrome, other neurologic presentations with similar serological profiles emerged in the literature, which include Bickerstaff brainstem encephalitis, acute ophthalmoplegia, acute ataxic neuropathy, pharyngeal-cervical-brachial weakness, and acute vestibular syndrome. In this article, the author discusses the current understanding behind the anti-GQ1b antibody syndrome.
• Anti-GQ1b antibody syndrome represents a group of disorders that share a common serological profile with links also to Guillain-Barré syndrome.
• Anti-GQ1b antibodies are a serological marker of Miller Fisher syndrome and Bickerstaff brainstem encephalitis but can been detected in other neurologic syndromes as a continuous spectrum.
• The overall prognosis is good even without immunotherapy in those patients who have typical Miller Fisher syndrome or acute ophthalmoplegia, but intravenous immunoglobulin (IVIg) or plasma exchange is recommended when there is altered consciousness, limb weakness, or bulbar palsy.
• Important mimics to be excluded include brainstem syndromes and neuromuscular junction disorders. The presence of anti-GQ1b antibodies would make the latter disorders unlikely.
• It should be noted that Miller Fisher syndrome or cranial neuropathies can occur as early neurologic manifestations of SARS-CoV-2 infection without detection of anti-GQ1b antibodies.
The most recognizable variant of Guillain-Barré syndrome is Miller Fisher syndrome, which was first described in 1956 by Charles Miller Fisher. He reported 3 patients who presented with a triad of total external ophthalmoplegia, ataxia, and areflexia subsequent to upper respiratory tract infection (12). The presence of cerebrospinal fluid albuminocytological dissociation and antecedent infection likened Miller Fisher syndrome to Guillain-Barré syndrome.
Prior to this, in 1951, Bickerstaff and Cloake described 3 patients who presented with prominent drowsiness followed by brainstem signs causing ophthalmoplegia, facial palsy, bulbar palsy, and ataxia following a prodrome of infective illness. The etiology of this condition was speculated to be similar to that of Guillain-Barré syndrome based on the presence of prodromal symptoms in all 3 patients, areflexia with CSF albuminocytological dissociation in 1 patient, and subsequent recovery of neurologic symptoms in all 3 patients (04). Six years later, Bickerstaff extended his observations including an additional 5 patients with similar patterns of brainstem signs, emphasizing the benign outcomes in all but 1 patient, who died following a seizure (03). This condition has since been referred to as Bickerstaff brainstem encephalitis.
In 1992, Chiba and colleagues identified IgG antibodies against ganglioside GQ1b in 6 patients with typical Miller Fisher syndrome (07). The anti-GQ1b IgG antibodies were initially considered as a serological marker of Miller Fisher syndrome. However, the antibodies were also detected in patients with acute postinfectious ophthalmoplegia without ataxia (05), Guillain-Barré syndrome with ophthalmoplegia (05), and Bickerstaff brainstem encephalitis (69; 23). The latter findings supported the continuity between the 2 syndromes, with Miller Fisher syndrome representing 1 end of the spectrum and Bickerstaff brainstem encephalitis the other, with involvement of the central nervous system. Patients with milder clinical features, such as ophthalmoparesis without ataxia (67), or more extensive involvement with limb weakness (41), were also found to have anti-GQ1b IgG antibodies on serological testing. In view of the common serological profile shared by this group of patients, it has been referred to as "anti-GQ1b antibody syndrome" (54).
Patients with "anti-GQ1b antibody syndrome" can present with a range of neurologic features. The classical triad of ophthalmoplegia, ataxia, and areflexia continues to be the commonest presentation in Miller Fisher syndrome (12). Patients develop a relatively symmetrical external ophthalmoplegia causing them to complain of double vision and limb ataxia severe enough to cause them problems with ambulation. Aside from these 2 characteristic features, other clinical features are recognized. In a study of 50 consecutive patients with Miller Fisher syndrome patients there were signs of blepharoptosis (58%) and pupillary mydriasis (42%), both occurring frequently at the height of illness (41) (see Clinical vignette case #1). Some patients were also noted to have facial palsy (32%) and bulbar palsy (26%). Sensory symptoms are less frequent than would be expected given the gross ataxia. Common sensory complaints include symptoms of dysesthesia and reduced superficial sensation and vibratory sense. Although atypical, some patients with Miller Fisher syndrome may have a Babinski sign and rarely require ventilatory support (23). There have been additional reports on the development of delayed facial palsy in patients with Miller Fisher syndrome (24; 55; 56). In such instances, facial palsy develops after cardinal features of Miller Fisher syndrome have reached a nadir or started to improve.
At the milder end of the spectrum are patients with "incomplete forms of Miller Fisher syndrome" who present with acute ophthalmoplegia, acute ptosis, acute mydriasis, acute oropharyngeal palsy, and acute ataxic neuropathy (without ophthalmoplegia). Acute vestibular syndrome with anti-GQ1b antibodies has also been reported (33).
Bickerstaff brainstem encephalitis represents the other end of the spectrum of "anti-GQ1b antibody syndrome," where patients present not only with ataxia and ophthalmoplegia, but also features that suggest involvement of the CNS, such as altered levels of consciousness and brisk reflexes (03). Patients can also present with an overlap with either Guillain-Barré syndrome or pharyngeal-cervical-brachial variant (43; 42). Atypical presentations of Bickerstaff brainstem encephalitis with only hypersomnolence and ataxia, without ophthalmoplegia, have also been reported and have been associated with the presence of anti-GQ1b antibodies supporting the diagnosis (61). The area postrema syndrome, characterized by intractable nausea, vomiting, hiccups, or singultus, has also been described in a small group of patients with Bickerstaff brainstem encephalitis; however, no anti-GQ1b antibodies were detected in such cases (70). A paper from the GBS Classification Group proposed inclusive diagnostic criteria that can facilitate early diagnosis of variants of Miller Fisher syndrome (62).
A paper reported the differences in clinical characteristics between anti-GQ1b antibody-positive and antibody-negative Bickerstaff brainstem encephalitis. Compared to patients without antibodies, those with antibodies more frequently had preceding upper respiratory infection (70% vs. 20%) and dysesthesia (44% vs. 0%), less frequently brain MRI abnormalities (8% vs. 50%), and lower median CSF cell count (12.5/µL vs. 75.9/µL) and median protein levels (63.5 mg/dL vs. 159 mg/dL), and more shorter median time to get recovery of consciousness (10 das vs. 23 days), indicating that Bickerstaff brainstem encephalitis with anti-GQ1b antibodies has homogeneous features (65).
The functional outcome of patients with anti-GQ1b antibody syndrome is usually good in either typical Miller Fisher syndrome or Bickerstaff brainstem encephalitis. In Miller Fisher syndrome, patients tend to make a spontaneous recovery. Improvement in ataxia is reported to start a median of 12 days (range, 3-41 days) after the onset, followed closely by improvement in ophthalmoplegia, median 15 days (range, 3-46 days). The median periods between the onset and complete recovery of ataxia and ophthalmoplegia were 32 days (range, 8-271 days) and 88 days (range, 29-165 days), respectively (41). Facial palsy may develop subsequently, even when ataxia or ophthalmoplegia have started to improve (24; 55; 56).
Although Miller Fisher syndrome can recur following an antecedent illness associated with anti-GQ1b antibodies, the outcome is favorable in most patients (17). In a study, recurrences occurred more frequently in patients with Miller Fisher syndrome or Bickerstaff brainstem encephalitis compared with those with Guillain-Barré syndrome (22). Symptoms and signs were less severe during relapses than during the initial episode in recurrent patients (22) (see Clinical vignette case #2).
Bickerstaff brainstem encephalitis is also associated with a good recovery, but mortality has been described (03; 01; 43), which may be due to a central respiratory depression or secondary to complications such as a concurrent infection. The majority of patients will achieve complete remission by 6 months, but in a minority, symptoms of dysesthesia, diplopia, or ataxia may persist (43).
Overlap can occur between Miller Fisher syndrome and Guillain-Barré syndrome as well as other variants including pharyngeal-cervical-brachial variant and Bickerstaff brainstem encephalitis. A study found the overlap syndrome to occur in 50% of pure Miller Fisher syndrome cases, typically within 7 days of the onset of Miller Fisher syndrome (52). In cases where there is an overlap of Guillain-Barré syndrome the prognosis will depend on the severity of Guillain-Barré syndrome. Limb weakness can persist for those who have a severe axonal degeneration. Complications related to autonomic dysfunction such as cardiac arrhythmias should also be borne in mind, and close monitoring is warranted in the early stages of the illness. A case of Takotsubo cardiomyopathy associated with Bickerstaff brainstem encephalitis has also been reported (50).
Below are 2 cases. Case #1 is a picture of eye movements recorded from a 39-year-old woman who developed total ophthalmoplegia and facial diplegia associated with anti-GQ1b antibodies (see case #1 figure); case #2 is a 39-year-old man who developed a total of 4 episodes of Guillain-Barré syndrome or Miller Fisher syndrome.
Case #1: eye movements with facial diplegia.
Case #2: representative case of recurrent Guillain-Barré syndrome or Miller Fisher syndrome.
A 39-year-old man was admitted to our hospital with Miller Fisher syndrome in 2004 but he had 2 similar episodes that required a hospitalization in 1994 and 1998.
In February 1994, at 29 years of age, the patient was admitted to another hospital with Guillain-Barré syndrome.
The patient had been well until 2 weeks before admission, when fever, vomiting, and diarrhea developed, followed by diplopia, bilateral leg weakness, tingling sensation in his left arm and bilateral legs, and dysphagia. He was initially treated with oral prednisolone 15 mg daily at a local clinic but muscle weakness further progressed in all limbs, ultimately leading to a hospitalization to a local hospital. The patient was initially treated with intravenous high-dose methylprednisolone but soon transferred to another hospital where he was diagnosed with Guillain-Barré syndrome and started on immunoadsorption plasmapheresis followed by double filtration plasmapheresis, resulting in improvement. He was discharged on the 22nd hospital day with mild bilateral abducens palsy, hyporeflexia, and mild muscle weakness but his symptoms had resolved subsequently.
Four years later, in December 1998 at 33 years of age, the patient was readmitted to the same hospital with a similar episode. Two weeks before admission, sore throat and cough developed. Then he began to have diplopia, dizziness, and tingling sensation in the left hand and sole of the feet. On admission the patient had bilateral abducens palsy, ataxia, areflexia, mild muscle weakness, and mild bulbar palsy. Anti-GQ1b IgG antibodies were detected in the serum. The patient was treated with 4 rounds of immunoadsorption plasmapheresis, resulting in resolution of the symptoms. On discharge he had mild horizontal diplopia and hyporeflexia but the diplopia had disappeared subsequently.
Six years later, in May 2004 (at the age of 39 years) the patient was admitted to our hospital with recurrence of Miller Fisher syndrome. One week before admission, sore throat and cough developed without fever. One day before admission, diplopia and tingling sensation in his left hand and leg developed. He also had severe anorexia and nausea. The next day dizziness, dysesthesia in the right hand, and retroorbital pain also developed. He was admitted to our hospital.
On examination the temperature was 37.0°C, the blood pressure 112/70 mm Hg, and the pulse 72 beats per minute. Physical examination was unremarkable. On neurologic examination the patient was alert and well oriented. His speech was normal. The pupils were 4.0 mm, equal, both reacted sluggishly to light. Both eyes were esotropic in primary gaze position; there was bilateral abduction palsy, mild upward gaze palsy, and ptosis on the right. There was no nystagmus. The remainder of the function of the cranial nerves was intact, including the muscle power of the orbicularis oculi. He had mild weakness in his neck flexor, bilateral biceps brachii and triceps brachii, and left hip flexor; the grip strength was 29 kg on the right and 13 kg on the left. He complained of dysesthesia in the tips of the fingers of the left hand but sensory examination was objectively intact, including vibration and position sense. The deep tendon reflexes were diminished except the left biceps and triceps jerks, which were normal; the planter response was flexor bilaterally. Coordination was intact in the upper limbs bilaterally but mildly impaired in the left lower limb on heel-shin test. He was not able to walk due to truncal ataxia and severe nausea. The neck was supple.
The blood test results were unremarkable except elevated level of serum CRP (1.12 mg/dL). CSF examination on the day of admission (day 1) revealed 1 white blood cell/µL, with normal protein level (25 mg/dL). A brain MRI did not show abnormal enhancement along the affected cranial nerves. A nerve conduction study and electroencephalogram were unremarkable.
The patient was initially suspected as Miller Fisher syndrome or Guillain-Barré syndrome with ophthalmoplegia and he was started on IVIg (0.4 g/kg/day, 5 days) on day 1. The symptoms including muscle weakness had progressed for 7 days and the right eye became midline fixed; however, after reaching the peak, the symptoms started improving, without additional immunotherapy. The follow-up CSF examination obtained on day 8 revealed 10 white blood cells/µL with elevated protein levels (51 mg/dL). The serum was positive for GQ1b IgG antibodies (1:3200) but negative for other IgG antibodies against GM1, GD1b, GD1a, GT1b, GM2, and GalNAc-GD1a; anti-GT1a antibodies were not examined at that time. He was discharged on day 25, with mild right abduction palsy, which resolved subsequently.
Nine years later, in early March 2013 (at the age of 48 years) the patient was readmitted to our hospital with recurrent similar episode. Twelve days before admission, cough, sore throat, and low-grade fever developed. One day before admission on awakening he noticed diplopia and dysesthesia in the tips of all fingers and toes and preoral area. He was admitted to our hospital.
On examination the temperature was 38.4°C, the blood pressure 114/77 mm Hg, and the pulse 86 beats per minute. Physical examination was otherwise unremarkable. The patient was alert and well oriented. His speech was normal. There was bilateral ptosis (more affected on the right than the left). The pupils were 4.0 mm, equal, and both did not react to light. The eye movements were mildly restricted in all directions bilaterally with monocular nystagmus on the left eye on looking to the left. Muscle power of the orbicularis oculi was weak on both sides. Muscle strength was normal in all limbs. Sensory examination was unremarkable except mild reduction of vibration sense in the legs and subjective tingling sensation in his perioral area and distal parts of all limbs. Coordination was intact on finger-nose tests and heel-shin tests but he was not able to walk without assistance. Romberg sign was negative. The deep tendon reflexes were diminished in all limbs.
The blood test results were unremarkable. CSF examination on admission (day 1) revealed 1 white blood cell/µL, with normal protein level (27 mg/dL), without CSF-restricted oligoclonal band detection. A brain MRI was normal. A nerve conduction study was unremarkable but H-reflex study showed decreased H/M amplitude ratio.
After admission the patient was started on IVIg. Ophthalmoplegia and limb ataxia progressed for 6 days, resulting in total ophthalmoplegia (mid-line fixed on both eyes) but after day 8 dysesthesia and ataxia started improving, followed by gradual improvement in ophthalmoplegia. The patient became able to walk independently on day 13 and he was discharged on day 18. On discharge ophthalmoplegia still persisted but eye movements had almost recovered on the last visit 51 days after the onset of Miller Fisher syndrome; areflexia remained diminished.
In the fourth episode both anti-GQ1b IgG antibodies (1:6400) and anti-GT1a IgG antibodies (1:12,800) were detected but there were no IgG antibodies against GM1, GD1b, GD1a, GT1b, GM2, and GalNAc-GD1a (< 1:100).
In summary, the patient developed 4 similar episodes compatible with a diagnosis of Guillain-Barré syndrome with ophthalmoplegia at the first episode and Miller Fisher syndrome in the subsequent ones, suggesting that Miller Fisher syndrome is a variant of Guillain-Barré syndrome. Although it is rare but recurrent Guillain-Barré syndrome or Miller Fisher syndrome can occur in a single case. In this patient, anti-GQ1b antibodies were detected in 3 of the 3 examined episodes and anti-GT1a antibodies were detected at high titers concurrent with anti-GQ1b antibodies in the fourth episode (but not examined in the other episodes). It is unclear whether IVIg hastened recovery in the last 2 episodes of typical Miller Fisher syndrome, in which spontaneous recovery is the rule, but we used IVIg because the patient had developed bulbar palsy and muscle weakness in the first 2 episodes.
Some authors have argued a central etiology in Miller Fisher syndrome and Bickerstaff brainstem encephalitis (01), suggesting that ophthalmoplegia and ataxia were due to brainstem and cerebellar lesions respectively. However, some Miller Fisher syndrome patients develop limb weakness and progress to Guillain-Barré syndrome during the clinical course of the illness (41). The existence of such overlapping cases, along with the presence of antecedent infection and CSF albuminocytological dissociation, strongly suggest that Miller Fisher syndrome is a variant of Guillain-Barré syndrome, and that the condition is an autoimmune disease triggered by microorganisms. In a study of 62 patients with Bickerstaff brainstem encephalitis diagnosed by the strict criteria of progressive, relatively symmetrical external ophthalmoplegia and ataxia by 4 weeks along, with a disturbance of consciousness or hyperreflexia, the authors described flaccid symmetrical tetraparesis in 60% of patients, suggesting an overlap of Guillain-Barré syndrome with some Bickerstaff brainstem encephalitis cases.
Following the identification of autoantibodies against GQ1b in patients with Miller Fisher syndrome, the authors proposed these anti-GQ1b antibodies as a diagnostic marker of Miller Fisher syndrome (07). Due to the likely differences in methods and cutoff values, serological results differ somewhat among representative laboratories; however, anti-GQ1b antibodies occur in 83% (n=466) (23), 96% (n=24) (05), 85% (n=23) (60), and 100% (n=9) (63) of Miller Fisher syndrome patients. The discovery of the anti-GQ1b IgG antibodies in Bickerstaff brainstem encephalitis supported a common autoimmune mechanism in both Bickerstaff brainstem encephalitis and Miller Fisher syndrome (69). In a further study that investigated the role of antibodies against complexes of GQ1b and GT1a, the presence of complex-enhanced or complex-attenuated anti-GQ1b or anti-GT1a antibodies resulted in different binding affinities to the single ganglioside (GQ1b or GT1a), leading to a range of neurologic features (13). In another study utilizing the glycoarray methodology, antibodies to antigens containing GQ1b were detected in 73% of patients with Guillain-Barré syndrome and ophthalmoplegia, 87% of patients with Miller Fisher syndrome, and 74% of patients with Bickerstaff brainstem encephalitis, whereas GD1b-related antibodies were identified in 49% of patients with Guillain-Barré syndrome and ophthalmoplegia, 29.7% of patients with Miller Fisher syndrome, and 11% of patients with Bickerstaff brainstem encephalitis (64). The authors also found that patients with Guillain-Barré syndrome with ophthalmoplegia that were seropositive for both antibodies had a higher probability of requiring artificial ventilation than patients without the antibodies. These findings suggest that the expression of complexes of GQ1b likely differs within the nervous system, resulting in the clinical spectrum that is seen in the anti-GQ1b antibody syndrome.
A large study of patients with Bickerstaff brainstem encephalitis and Miller Fisher syndrome demonstrated that both conditions had many similarities (23). The peripheral nerves were abnormal (most frequently with an absence of the soleus H reflex) in 3 of 4 patients with Bickerstaff brainstem encephalitis and 74% of 28 patients with Miller Fisher syndrome. Body sway analyses showed abnormalities within the proprioceptive afferent system in 67% of 3 patients with Bickerstaff brainstem encephalitis and 72% of 18 of those with Miller Fisher syndrome. The findings suggested that ataxia in both Bickerstaff brainstem encephalitis and Miller Fisher syndrome is due to lesions within the proprioceptive afferent system rather than cerebellar system. In contrast, brain MRI and EEG recordings were abnormal in Bickerstaff brainstem encephalitis patients (11% and 57%, respectively), as well as some patients with Miller Fisher syndrome (1% and 25%, respectively), suggesting central components can occasionally be affected in both Bickerstaff brainstem encephalitis and Miller Fisher syndrome. Anti-GQ1b antibodies were present in 83% of patients with Miller Fisher syndrome (n=466) and 68% of those with Bickerstaff brainstem encephalitis (n= 53). The same study also described patients who did not fulfill the criteria of either Bickerstaff brainstem encephalitis or Miller Fisher syndrome, but had anti-GQ1b antibodies. This group of patients was seen to have less extensive clinical features and could represent a forme fruste of either Bickerstaff brainstem encephalitis or Miller Fisher syndrome. These cases did share similar clinical and serological profiles, including the presence of antecedent infections. Referring to such cases as part of the anti-GQ1b antibody syndrome would allow clinicians to recognize the likely etiology.
A patient with typical Miller Fisher syndrome or Bickerstaff brainstem encephalitis patients generally presents with an antecedent episode prior to the onset of their neurologic symptoms. Epidemiological associations between Campylobacter jejuni and Haemophilus influenza infections have been established in patients with Miller Fisher syndrome (26), and a study looking at the serological evidence of infection in patients with Bickerstaff brainstem encephalitis or Miller Fisher syndrome found C jejuni and H influenza to be the 2 most common pathogens in this group of patients (23; 24; 55; 56). Molecular mimicry whereby the lipo-oligosaccharides of C jejuni isolated from patients with Miller Fisher syndrome or Bickerstaff brainstem encephalitis mimic the GQ1b has been demonstrated (27; 25). Other mimics include the GQ1b-like lipo-oligosaccharide of H influenza isolated from a Miller Fisher syndrome patient (18). Therefore, it is likely that the infectious agents of patients with Miller Fisher syndrome or Bickerstaff brainstem encephalitis carrying various GQ1b mimics induce the production of anti-GQ1b IgG antibodies, leading to the development of the disease. Following the Zika virus epidemic in Latin America in 2016, there was a rise in the number of patients with Guillain-Barré syndrome. A report of 68 Colombian patients with Zika-associated Guillain-Barré syndrome described 2 cases with clinical features of Miller Fisher syndrome, expanding the possible microbial associations (46; 58).
Immunohistochemical studies show that GQ1b is highly expressed in the extramedullary regions of the human oculomotor, trochlear, and abducens nerves (05) as compared to other cranial nerves or the ventral and dorsal roots of the spinal cord (06). The neuromuscular junctions may be particularly vulnerable to autoantibody attack as they are outside the blood-nerve barrier. Of note, monoclonal anti-GQ1b antibodies were shown to bind to the vast majority of motor endplates of human oculomotor muscles (34). In an animal model of Miller Fisher syndrome, monoclonal anti-GQ1b antibody plus complement was shown to damage nerve terminals, resulting in the production of mitochondrial hydrogen peroxide that in turn activates Schwann cells (48). Using an in vitro cellular model consisting of co-cultured primary neurons and Schwann cells, the authors found that adenosine triphosphate (ATP) was also released by the injured neurons. The neuron-derived ATP acts as an alarm messenger for Schwann cells, inducing the activation of intracellular pathways and promoting nerve regeneration (47).
Postural body sway analysis results suggest that patients with Miller Fisher syndrome also have a dysfunctional proprioceptive afferent system, and the distinctive sensory ataxia is caused by the selective involvement of muscle spindle afferents (30). These muscle spindles contain specialized muscle fibers, which have motor innervations and are enriched with sensory endings. The neural components and intrafusal muscle fibers of these spindles may be important targets in Miller Fisher syndrome because they have also been labelled by monoclonal anti-GQ1b antibodies in humans (34). The staining pattern suggests that the group 1a afferents in muscle spindles contain GQ1b. Another common neurophysiological finding in patients with Miller Fisher syndrome is an abnormal H-reflex, typically recorded over the soleus muscle stimulating the tibial nerve at the knee. This finding cannot be explained by involvement of the muscle spindles alone (31). It is likely that impairment of the group 1a neurons in the dorsal ganglion also contributes to the ataxia and areflexia. In support of this is the finding that GQ1b is also expressed in some large neurons in the human dorsal root ganglia (29). Patients with Miller Fisher syndrome typically show recovery with no sequelae (41); one explanation could be reversible axonopathy of the group 1a fibers due to lengthening of the nodes of Ranvier and myelin splitting with no demyelination features (57).
In Bickerstaff brainstem encephalitis, the characteristic distinguishing clinical feature is altered levels of consciousness that is central in origin. It is postulated that the breakdown of the blood-brain barrier at vulnerable sites, such as the area postrema or blood-nerve barrier at the roots of the oculomotor cranial nuclei, allows access to anti-GQ1b antibodies, which then bind to its related sites within the brainstem reticular formation; however, this course of events has yet to be confirmed. In a study the authors postulated that local and/or distant neurotoxic effects of endocytosed and retrogradely transported antiganglioside antibodies to the reticular activating system, which lies adjacent to oculomotor nerves in the brainstem, may account for the coma seen in Bickerstaff brainstem encephalitis (08).
The possible mechanism underlying the pathogenesis of Miller Fisher syndrome and Bickerstaff brainstem encephalitis is as follows: (i) infection by a microorganism expressing GQ1b epitope triggers the production of anti-GQ1b antibodies, (ii) these antibodies bind to GQ1b, which are highly expressed on the oculomotor nerves, resulting in acute ophthalmoplegia and group 1a muscle spindles, producing acute ataxic neuropathy. Miller Fisher syndrome develops when both oculomotor nerves and group 1a muscle spindles are affected, and (iii) in some patients, these antibodies can also bind to the reticular formation where GQ1b may be expressed, causing Bickerstaff brainstem encephalitis (68).
At present, there is little epidemiological information on anti-GQ1b antibody syndrome from large clinical studies. Most epidemiology data have been gleaned from the description of Miller Fisher syndrome as a variant of Guillain-Barré syndrome epidemiology work. One study in an Italian population estimated the annual incidence of Fisher syndrome as 0.9/100000/year (11). Miller Fisher syndrome is reported to have an incidence of approximately 1% to 5% of Guillain-Barré syndrome in Western countries. In a prospective study of 170 Dutch patients with Guillain-Barré syndrome and variant forms, 23 (14%) patients had Miller Fisher syndrome or Miller Fisher-Guillain-Barré overlap syndrome, and 2 (1%) had Bickerstaff brainstem encephalitis (60). The incidence of Miller Fisher syndrome is appreciably higher in Asian countries such as Taiwan (19%) (36) and Japan (25%) (41). The exact reason for this discrepancy is uncertain, but it raises the possibility that inherent host and environmental factors are likely to play a part.
In a Japanese nationwide survey, the authors estimated an annual incidence of Bickerstaff brainstem encephalitis as 0.078 per 100,000 population, representing 7% of the patients with Guillain-Barré syndrome (28).
Patients with a condition of thiamine deficiency can mimic Bickerstaff brainstem encephalitis, especially when Wernicke encephalopathy develops with ophthalmoplegia, ataxia, and short-term memory loss (which may be interpreted as drowsiness). It is also important to exclude a brainstem stroke in any patient who presents with a fairly acute brainstem syndrome (eg, with ophthalmoplegia, pupillary abnormalities, ataxia, and reduced levels of consciousness). In the acute setting of a stroke, tendon reflexes may appear depressed.
Central demyelinating conditions such as acute disseminated encephalomyelitis and multiple sclerosis can also present with a constellation of brainstem signs that can cause a diagnostic dilemma at first presentation. The presence of ophthalmoplegia along with good recovery of clinical symptoms and signs, including resolution of abnormal lesions on brain imaging, would favor Bickerstaff brainstem encephalitis. In multiple sclerosis, the future course might involve further neurologic symptoms and signs (relapsing remitting form) or a progressive deterioration (primary progressive form).
Neuromuscular junction disorders such as botulism and myasthenia gravis present with ophthalmoplegia. In the former, there is a classic rapid progression from the cranial muscles to the limbs leading to respiratory failure. The presence of prominent autonomic features should also alert one to this diagnosis. Myasthenia gravis can be differentiated by the absence of ataxia, areflexia, or drowsiness.
Brainstem encephalitis associated with glial or neuronal surface antibodies including NMDA receptor antibodies should be included in a differential diagnosis of anti-GQ1b antibody-positive Bickerstaff brainstem encephalitis (Hacohen et al. 2016). It is of interest that 1 of the 3 original cases described by Bickerstaff and Cloake in 1951, a young woman who developed seizures, eye movement disorders, and acute psychosis while awaiting ovarian cystectomy, had features that may be more consistent with anti-NMDA receptor encephalitis (39).
The differential diagnosis also includes other inflammatory brainstem lesions such as neuro-Behçet disease, neurosarcoidosis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), CNS vasculitis, as well as infiltrative disorders such as primary brainstem glioma or CNS lymphoma.
In addition, it should be noted that Miller Fisher syndrome or cranial neuropathies can occur as early neurologic manifestations of COVID-19 disease caused by severe acute respiratory coronavirus 2 (SARS-Cov-2) infection without detection of anti-GQ1b antibodies (10; 15; Llorente et al 2020). It is also reported that Bickerstaff brainstem encephalitis can develop as a neurologic spectrum of COVID-19 disease (32) but no anti-GQ1b antibodies were detected. It is emphasized that COVID-19 can trigger not only Guillain-Barré syndrome but also other autoimmune neurologic diseases (09).
Case reports also suggest that Miller Fisher syndrome may develop associated with immunotherapy or cancer therapy, including ipilimumab and nivolumab (02; 38), cemiplimab (14), or infliximab (66); however, no anti-GQ1b antibodies were detected in these cases. A case of Bickerstaff brainstem encephalitis that developed after autologous stem cell transplant has also been reported (37).
The diagnostic workup should not only look to support the diagnosis of the anti-GQ1b antibody syndrome, but, when appropriate, should address the differential diagnoses discussed above. Patients who present with features suggestive of a central cause of ataxia and drowsiness with ophthalmoplegia will require brain imaging, preferably MRI, to look for evidence of a vascular, infiltrative, or demyelinating disorder. It should be noted that the MRI can be abnormal in a third of patients with Bickerstaff brainstem encephalitis and 1% of patients with Miller Fisher syndrome, showing increased T2/FLAIR signal in the brainstem, thalamus, cerebellum, cerebrum, or cranial nerves (43; 23; 10). CSF analysis can be normal in Miller Fisher syndrome and its incomplete variants, particularly in the first week of illness, but can also show CSF albuminocytological dissociation. In comparison, the CSF albuminocytological dissociation is less frequent in Bickerstaff brainstem encephalitis (between 35% to 46%) due to a higher frequency of CSF pleocytosis (between 32% to 37%) (43; 23). Electrophysiology in anti-GQ1b antibody syndrome can be normal or show a sensory axonal pattern of neuropathy. In a study, sensory abnormalities were frequently detected in patients, occurring in 94% of patients (53), whereas another group found that an abnormal H-reflex was the most common finding in their patient cohort (51). Electroencephalogram can show slow waves in both Bickerstaff brainstem encephalitis and Miller Fisher syndrome, but it is not likely to be helpful in discriminating them from other encephalopathies.
The most important test that will distinguish this syndrome from other possible diagnoses, as stated above, is the presence of anti-GQ1b IgG antibodies, which are highly specific for any of the disease phenotypes.
There have been no randomized clinical trials of treatment in anti-GQ1b antibody syndrome, including Miller Fisher syndrome or Bickerstaff brainstem encephalitis specifically (45). The decision to treat will depend on the level of disability experienced by patients. Both IVIg and plasma exchange have been used. Although IVIg slightly hastened recovery in Miller Fisher syndrome, the final outcome remained unchanged (40). Bickerstaff brainstem encephalitis also generally has a good prognosis; however, reports of mortality would justify treatment with either IVIg or plasma exchange. In cases where there are also clinical features resembling Guillain-Barré syndrome, treatment with either plasma exchange or IVIg is recommended as randomized controlled trials have established the efficacy of both treatments in Guillain-Barré syndrome (19; 21). The role of steroids in Bickerstaff brainstem encephalitis is less clear, although there have been reports of clinical improvement with steroid administration (49). In Guillain-Barré syndrome, steroids administered on their own were associated with clinical deterioration when compared to no treatment (20); however, the combination of steroids and IVIg may hasten recovery, even if the final outcome has not been shown to be significantly altered (59). Therefore, it is likely that steroids have a role when given with IVIg in the treatment of Bickerstaff brainstem encephalitis and of Miller Fisher syndrome/Guillain-Barré syndrome overlap condition.
Along with immunotherapy, supportive treatment such as ventilatory support, tube feeding in patients with swallowing difficulties, prophylaxis against thromboembolic events in patients not able to ambulate, and early rehabilitation are also important.
In Miller Fisher syndrome, patients tend to make a spontaneous recovery. Improvement in ataxia is reported to occur 3 to 41 days after onset, followed closely by improvement in ophthalmoplegia (between 3 and 46 days) (41). The median periods of complete resolution take 32 days in ataxia and 88 days in ophthalmoplegia, respectively (41).
In 13 patients with Miller Fisher syndrome, 2 out of 5 (40%) patients treated with intravenous immunoglobulin had residual deficits at 6 months compared to 5 out of 8 (63%) patients who were left untreated (60).
In Bickerstaff brainstem encephalitis, most patients achieve complete remission by 6 months but symptoms of dysesthesia, diplopia, or ataxia may persist in a few patients (43).
There have been few reports on a case of Miller Fisher syndrome or Bickerstaff brainstem encephalitis in pregnancy. A 26-year-old woman who developed Miller Fisher syndrome at 11 weeks of gestation was reported to have achieved a spontaneous recovery without intervention of any immunotherapy (44).
No specific precautions are required, and there is no information to suggest added risk of adverse reactions with anaesthetic agents.
Takahiro Iizuka MD
Dr. Iizuka of Kitasato University School of Medicine has no relevant financial relationships to disclose.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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