Abstract
Faciobrachial Dystonic Seizures: The Influence of Immunotherapy on Seizure Control and Prevention of Cognitive Impairment in a Broadening Phenotype
Irani SR, Stagg CJ, Schott JM, Rosenthal CR, Schneider SA, Pettingill P, Waters P, Thomas A, Voets NL, Cardoso MJ, Cash DM, Manning EN, Lang B, Smith SJM, Vincent A, Johnson MR. Brain 2013:136;3151–3162.
Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346–4515pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11–200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immuno-therapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross- sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n=13) (P<0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.
Commentary
The occurrence of symptomatic seizures in the setting of underlying neurologic and systemic medical conditions that have their own specific therapies apart from AEDs often raises clinical questions with regard to the choice and timing of treatments. In cases of autoimmune epilepsy associated with antineuronal antibodies, for example, these questions concern the relative importance and sequence of immunomodulatory therapies (corticosteroids, intravenous immunoglobulin [IVIg], and plasma exchange) as compared with AEDs.
A distinctive form of autoimmune epilepsy is now known to be associated with antibodies directed against the voltage-gated potassium channel complex (VGKC), and in particular the leucine-rich glioma inactivated 1 (LGI1) protein component of this complex (1). Frequent, brief episodes of posturing, usually involving a unilateral hemiface and ipsilateral upper extremity, termed faciobrachial dystonic seizures, have been described as a characteristic, and often presenting, feature of the limbic encephalitis associated with VGKC/LGI1 antibodies (2). In the article discussed here, Irani et al. report on a prospective study of 10 patients with this form of epilepsy (3), who were followed systematically for seizures, cognitive dysfunction, and serum antibody titers, while the treatments chosen by their physicians were tracked. After the acute phase of the illness, most patients underwent a brain MRI with volumetric analysis. The results of this study are striking and suggest important factors for clinicians to consider in the treatment of VGKC/LGI1 antibody–associated seizures and, perhaps, the broader array of autoimmune epilepsies.
The three most prominent findings from this study are:
The phenotype of VGKC/LGI1 antibody–associated encephalitis is somewhat broader than previously recognized. The patients described here are very similar in characteristics to a previous cohort with retrospectively identified facio-brachial dystonic seizures (2). However, the current series spanned a slightly wider age range of presentation (28–92 years, median 68), and their seizure semiologies included more varied manifestations than previously suggested, including bilateral movements in six cases and durations longer than 10 seconds in four cases, as well as automatisms, auras, and postictal symptoms and signs. Many of the cases were misdiagnosed as movement disorders initially, which becomes quite understandable when one reviews the video recordings of these events available as supplementary material. Finally, although cognitive impairment in the setting of normal conventional brain imaging had been a recognized feature of the VGKC/LGI1 antibody–associated syndrome, the authors here report significantly smaller whole brain and hippocampal fractional volumes in their cases compared with a cohort of control individuals. It was only after the introduction of immunotherapy (in all cases subsequent to the initiation of AED therapy) that patients experienced a resolution of faciobrachial dystonic seizures. Indeed, AEDs alone had almost no impact on the frequency of these seizures, while the addition of immunomodulatory therapy rendered nine patients completely seizure-free after they had been refractory to AEDs for anywhere between 11 and 200 days (median 29.5). Immunotherapy consisted of corticosteroids for all patients, while four also received IVIg and one also received plasma exchange. Furthermore, seizure relapses, seen in four cases, occurred while patients were off or in the process of tapering corticosteroids, and resolved quickly in response to an increase in corticosteroid dosage without a change in AED therapy. The time to institution of immunotherapy was significantly correlated with the time to recovery of baseline function (although a similar nonsignificant trend was seen for time to institution of AED therapy), and all patients who developed cognitive impairment did so before being given immunotherapy.
There are a number of important clinical lessons to be drawn from this study. Although the authors are careful about speculating too broadly beyond what is supported by their data, a strong argument can be made for immunotherapy to be initiated early in the course of any patient with documented VGKC/LGI1 antibodies and a consistent clinical presentation. It would seem reasonable, for example, to start corticosteroids in patients whose seizures do not immediately respond to standard AED therapy, which, if we extrapolate from the experience described in this article, would be essentially all of them. While these patients can certainly develop acute adverse effects to immunomodulatory therapy, they seem particularly prone to do so in response to AED therapy (as noted in this article and prior work (2)) and the prospects of potentially preventing cognitive impairment and shortening the time to overall recovery are likely to be quite precious benefits for most patients when weighing the potential risks.
The two biggest limitations of this investigation are the small sample size and the observational, uncontrolled nature of the study with regard to treatment results. As we know from countless examples of observational treatment studies that have been later followed up by randomized-controlled trials, the fact that treating clinicians chose the type, sequence, and timing of treatments in each of these patients leaves us unable to infer, with absolute confidence, whether the clinical outcomes would have been different if immunotherapy had been started earlier, or indeed what role the therapies played, if any, in altering what would be the natural course of the illness.
Other questions, provocative but not new, remain: given the brief, odd semiology of the abnormal movements, the lack of scalp electrographic correlate for most of them, the quite striking lack of responsiveness to AED therapy and their apparent sensitivity to corticosteroid initiation and withdrawal, are faciobrachial dystonic seizures actually epileptic in origin (4)? Are AEDs necessary early on in this condition, given that 50% of the patients in this series developed an adverse skin reaction to AEDs and 90% showed essentially no seizure frequency reduction whatsoever to AEDs alone? The data in this article provide supportive evidence that for now, the answer to both of these questions is probably yes, as some of the longer clinical events did show ictal electrographic correlate, subclinical electrographic seizures were detected frequently in one patient, and some patients eventually develop other semiologies characteristic of limbic encephalitis, including temporal lobe seizures and generalized tonic-clonic events.
For general neurologists and even epileptologists whose focus is not on autoimmune encephalopathies, perhaps the most critical lesson from this article (and other recent research updates in this field (5)) is the need to remain aware of the specific but varied manifestations of these disorders and to recognize when to have a high index of suspicion for them; after all, decisions about the right timing of therapies may only become relevant once the correct diagnosis has been made.