We report a case of a patient with anti-GABAB-R and anti-Hu limbic encephalitis, presenting with progressive seizures and behavioral disturbance, as well as cardiac dysrhythmias. While much of his phenotype was classic of GABAB-R encephalitis, phenotypic overlap is rare and an association with cardiac dysrhythmias has not previously been described. The first paraneoplastic antibodies were to intracellular targets (e.g., anti-Hu, -Ma2, -CRMP5, -amphiphysin). Anti-GABAB-R antibodies join the family of the more recently discovered antibodies against cell surface targets, such as anti-NMDAR, -AMPAR, -GlyR, -Caspr2, and -LGI1 . All of the GABAB-R-positive patients described by Lancaster et al.  presented with early or prominent seizures, with the majority showing limbic dysfunction in the form of confusion, memory disturbance, and behavioral changes. This is thought to be due to the inhibitory action of GABAB-R with high density in the hippocampus [3, 4]. Further case series and case reports have broadened the scope of anti-GABAB-R syndromes [1–7]. Half were associated with SCLC, (27/53), two were associated with other cancer (thymus carcinoid, melanoma), while the remainder were not paraneoplastic. The majority were associated with seizures (46/53), however atypical phenotypes have been reported including cerebellar ataxia, opsoclonus myoclonus, brainstem encephalitis, and status epilepticus. Cerebellar ataxia and opsoclonus myoclonus may be related to high GABAB-R density in the cerebellum [3, 4]. MRI changes involve high signal in limbic regions on T2/FLAIR images, however MRI was normal in 32% of patients. Outcomes varied, but the majority showed some improvement with immunotherapies and oncological treatment where tumor was present. Patients with SCLC have poorer survival compared to those without tumor .
The presence of dual autoantibodies in our patient (anti-GABAB-R and anti-Hu) is notable. Only three patients have previously been described with this combination [4, 5]. Classically, anti-Hu antibodies confer a poor prognosis and are associated with sensory or sensorimotor neuropathy, however they are not always pathogenic [4, 8]. Our patient also displays phenotypic overlap. The presence of dysarthria (prominent in our patient) in GABAB-R encephalitis has been described only in the setting of cerebellar ataxia phenotype [3, 5] or brainstem phenotype . To the best of our knowledge, dysarthria has not been described in combination with the prominent seizures and behavioral changes of classic limbic encephalitis. This overlap may be due to either anatomically extensive GABAB-R encephalitis (possibly with limbic and cerebellar involvement) or ‘silent’ anti-Hu antibodies, or due to anti-Hu antibodies modifying a more classical GABAB-R phenotype.
Two controls in a previous study  had low titer GABAB-R antibodies and high titer GAD-65 antibodies, and phenotypically resembled a GAD-65 encephalopathy with progressive cerebellar ataxia, rigidity, myoclonus, and gait instability. Similarly, Hoftberger et al.  reported a patient with GABAB-R and amphiphysin autoantibodies with a mixed phenotype of limbic encephalitis, diffuse encephalomyelitis and gait ataxia. The significance of antibody titers is still under investigation. Although Lancaster et al.  showed no correlation between titer and disease severity, Mundiyanapurath et al.  showed a steady decline in titer mapping treatment response. The clinical manifestation of GABAA-R autoimmune encephalitis is dependent on titer. High titers cause encephalitis while low titers invoke seizures, stiff-person syndrome and opsoclonus myoclonus . Thus, while different individuals may have different disease thresholds, titer may help to determine symptomatology when multiple competing antibodies are present.
Our patient’s motor vehicle accident was initially thought to be a primary cardiac event, with subsequent asystole and pauses consistent with sick sinus syndrome. If this was the case, then two distinct cardiac events (in addition to other arrhythmias) preceded the development of seizure activity. It is known that elevated levels of S100B, a dimeric calcium-binding protein in brain astrocytes, has been associated with conditions of hypoxia, such as high altitude and obstructive sleep apnoea [10, 11]. S100B is also believed to be a marker of blood brain barrier (BBB) dysfunction . In addition to hypoxia, acute stress, and epinephrine have also been shown to alter BBB permeability . If the hypoxia or acute stress from cardiac arrest preceded neurological symptoms, it is conceivable that this BBB disruption may have granted serum GABAB-R autoantibodies access to cerebral tissue. This would also allow translocation of activated memory B cells into the central nervous system , mediating subsequent intrathecal production of autoantibodies similar to the mechanism proposed in multiple sclerosis . However, the fact that our patient’s first documented seizure occurred 1 week after his accident casts doubt over this hypothesis, requiring a very rapid humoral response within the central nervous system. It also fails to identify a cause for his sinus dysfunction. Our patient had no history or family history of cardiac disease or sudden death. He had suffered no previous episodes of palpitations, chest pain, or syncope. Aside from a mildly dilated left atrium, there were no other cardiac abnormalities detected on routine workup, and no underlying precipitant for his sick-sinus syndrome was found.
In retrospect, we believe our patient’s initial motor vehicle accident to instead be secondary to a seizure. That he was found in the passenger seat raises the possibility of convulsions, and if the force of impact alone were enough to throw him into the passenger seat, we would expect further injuries to be seen on his secondary survey. His agitation and confusion at the scene are consistent with a post-ictal phase. An ictal or post-ictal asystolic event would explain the non-palpable pulses and unrecordable blood pressure at the time of his motor vehicle accident, as well as the sinus pauses on telemetry associated with seizure activity. Ictal and post-ictal conduction abnormalities are rare but well-described complications of seizures, with asystole, bradycardia, and other arrhythmias potentially involved in the pathogenesis of sudden unexplained death in epilepsy patients (SUDEP) [13–15]. In asystole, it is thought that seizure activity disrupts temporal and insular connections with the brainstem and hypothalamus, causing a transient excess of vagal tone [13, 14]. Ictal asystole is classically brief (90% lasting less than 30 seconds) and is always associated with a focal seizure, with or without secondary generalization. Progression to GTCS is associated with prolonged ictal asystole (up to 96 seconds has been reported) . In post-ictal asystole from generalized seizures, the greatest reported delay between seizure and onset of asystole was 158 seconds, asystole duration was 7–60 seconds, and more than half died from probable SUDEP . However, the patient’s in-hospital asystolic cardiac arrest would be atypical for ictal asystole, lasting more than twice as long as those previously described and lacking preceding seizure activity.
Thus, while it is possible that isolated cardiac dysrhythmias precipitated neurological symptoms, we believe this mechanism to be less likely due to the events surrounding his initial motor vehicle accident, its time course, and the absence of other cardiac abnormalities as a cause. His asystolic arrest is also insufficiently explained purely by a post-ictal mechanism, and as a result we propose a link between our patient’s underlying GABAB-R encephalitis and his cardiac dysrhythmias and asystole. Other encephalitides have been associated with asystole and cardiac arrhythmias, including N-methyl-D-aspartate receptor (NMDA-R) autoimmune limbic encephalitis [16, 17] and viral encephalitis . In one series of 100 patients more than 1/3 of patients with NMDA-R encephalitis had cardiac dysrhythmias in addition to the classical symptoms of psychiatric and behavioral disturbance – 7% had prolonged pauses and 4% required pacemaker insertion . In this series, it is unclear whether these were associated with seizures or not. A smaller series  identified 80% of NMDA-R encephalitis patients with tachycardias, 60% with sinus bradycardias and 40% with sinus arrests. The authors suggest that NMDA-R dysfunction within the nodose vagal nuclei and the nucleus of solitary tract (NTS) lead to abnormal vagal responses capable of tachyarrhythmias, bradycardias, and asystole. GABAB-Rs have been shown to populate similar areas of the brain including the NTS and vagal nuclei [19–21]. They have similarly been implicated in modulating vagal cardiorespiratory reflexes in animal models [20, 22, 23]. It is possible that in our patient, a similar disruption of vagal reflexes by GABAB-R antibodies may account for his sinus node dysfunction, pauses, and asystolic arrest. Interestingly, Nazif noted a progressive bradycardia and subsequent arrest in vagally mediated NMDA-R asystole, and a similar progression was seen in our patient . However, it is unclear whether a significant vagal stimulus was present prior or not. This mechanism of autonomic dysregulation and vagal disturbance has also been proposed to explain ictal asystole, and may represent a common pathway in these patients [13, 14]. Thus we propose an association between GABAB-R limbic encephalitis and cardiac dysrhythmias, which has not previously been described.
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