Bethan Lang

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes.

Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

To describe a distinctive seizure semiology that closely associates with voltage‐gated potassium channel (VGKC)‐complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE).

Morvan syndrome: clinical and serological observations in 29 cases.

A study was undertaken to describe the clinical spectrum, voltage‐gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS).

An improved diagnostic assay for Lambert-Eaton myasthenic syndrome.

A new immunoprecipitation assay has been established for detecting antibodies to voltage-gated calcium channels (VGCCs) in Lambert-Eaton myasthenic syndrome (LEMS), using 125I-omega-conotoxin MVIIC, which binds to P-type VGCCs, to label extracts of human cerebellum. Fifty six of 66 serum samples (85%) from patients with clinically and electrophysiologically definite LEMS were positive for the presence of VGCC antibodies, defined as a titre > 3 SD above the mean for the healthy controls (n = 10). All disease controls (n = 40) were negative. This sensitive immunoassay should prove valuable in the diagnosis of LEMS.

Serum antibodies in epilepsy and seizure-associated disorders

Objective: To investigate whether autoantibodies to ion channels and other neural antigens are present in the sera of patients with epilepsy and seizure-related diseases. Methods: Sera were obtained from 139 patients, including 26 with preexisting autoimmune disease, 46 in whom an autoimmune basis was suspected, and 67 with drug-resistant epilepsy. The sera were assayed for antibodies to voltage-gated potassium (VGKC) and calcium (VGCC) channels, glutamic acid decarboxylase (GAD), gangliosides, glutamate receptor type 3, cardiolipins, DNA, and nuclear antigens; the results were compared with results from a large cohort of healthy and disease controls. Results: Increased titers of VGKC antibodies (>100 pM) were detected in 16 of 139 (11%) patients with seizures but only 1 control (0.5%). Eight VGKC-positive patients presented with an acute/subacute illness, and 5 of these had the highest VGKC antibodies; 3 patients improved spontaneously, another 5 patients responded well to immunomodulatory therapy. The other VGKC-positive patients had longer disease duration (>6 years) and intermediate levels of antibodies; immunotherapies have not been tested in this group. Very high levels of GAD antibodies (>1,000 U) were found in an additional 3 patients (2.1%) with long-standing drug-resistant epilepsy. Conclusions: The presence of autoantibodies to voltage-gated potassium channels and glutamic acid decarboxylase suggests that the immune system may contribute to certain forms of epilepsy or seizure-associated disorders. Further studies are needed to determine whether the antibodies are pathogenic.

P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer.

Abstract—Raised levels of P/Q type voltage-gated calcium-channel (VGCC) antibodies were found in 16 (41%) of 39 patients with paraneoplastic cerebellar degeneration (PCD) and Hu antibodies were found in nine (23%). Seven of the 16 VGCC antibody-positive patients had Lambert–Eaton myasthenic syndrome (LEMS). Seven of 15 CSF samples had VGCC antibodies, with evidence of intrathecal synthesis in four. VGCC antibodies should be looked for in PCD, even if there are no symptoms of LEMS, and may be related to the cerebellar dysfunction.

Autoimmune aetiology for acquired neuromyotonia (Isaacs' syndrome)

Neuromyotonia is a rare disorder of unknown cause in which hyperexcitability of peripheral motor nerves leads to incapacitating muscle twitching, cramps, and weakness. We investigated an antibody-mediated mechanism for neuromyotonia in a 24-year-old man with a 7-year history of severe disease unresponsive to pharmacological treatment. Two periods of plasma exchange each produced almost complete disappearance of symptoms for 2-3 weeks, and a highly significant decrease in recorded neuromyotonic discharges. Injection of the patients plasma or purified IgG into mice significantly enhanced in-vitro resistance to d-tubocurarine at the neuromuscular junction of phrenic nerve-diaphragm preparations. This finding suggests that an increase in neurotransmitter release might result from an antibody-mediated reduction in the number of functional potassium channels that normally regulate nerve excitability. The demonstration of pathogenic IgG autoantibodies in acquired neuromyotonia suggests that immunosuppressive treatment may be helpful in severe cases.

Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype.

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 (346-4515 pM): 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 immunotherapy 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.

N-Methyl-D-Aspartate Receptor Antibodies in Pediatric Dyskinetic Encephalitis Lethargica

Encephalitis lethargica (EL) describes an encephalitis with psychiatric, sleep, and extrapyramidal movement disorders. Dyskinetic and Parkinsonian forms have been described. EL shares clinical features with the anti–N‐methyl‐D‐aspartate receptor (NMDAR‐Ab) encephalitis. We studied 20 sera from pediatric patients with contemporary EL. Ten sera (from 2 males and 8 females, aged 1.3–13 years) and 6/6 cerebrospinal fluid samples were positive for NMDAR‐Ab. NMDAR‐Ab–positive patients had dyskinesias, agitation, seizures, and insomnia, whereas Parkinsonism and somnolence dominated in the NMDAR‐Ab–negative children. We were unable to identify any tumors. The dyskinetic form of EL is an NMDAR‐Ab encephalitis and can affect very young children. Ann Neurol 2009;66:704–709