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An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Objective We evaluated pain in leucine-rich glioma inactivated1(LGI1) and contactin-associated protein2(CASPR2)-antibody positive(Ab+) patients, to evaluate clinical associations and pathophysiology of treatable pain syndromes. Methods 108 LGI-Ab+, 33 CASPR2-Ab+, and 6 LGI1/CASPR-Ab+patients were phenotyped. Pain questionnaires were undertaken to identify neuropathic pain using the Douleur Neuropathique(DN4), patient reported outcome measurement information system(PROMIS), and quality of life(EQ5D). Skin biopsies, and serum binding to cell-based assays, sensory neuronal cocultures, and dorsal root ganglion(DRG) cultures were undertaken. Results 39/147 patients described pain, including 17/33 CASPR2-Ab+(52%), 20/108 LGI1-Ab+(19%), and 2 LGI/CASPR2-Ab+patients. Questionnaires completed in 23/39(59%) revealed comparable DN4 scores(p=0.319) with 58% of LGI1-Ab+ and 67% of CASPR2-Ab+patients having neuropathic pain. Patients rated >50% response in 8/30(27%) analgesia trials, versus 20/40(55%) immunotherapy trials(p=0.045). PROMIS ratings were similar between LGI1-Ab+ and CASPR2-Ab+patients at nadir(p=0.662), but showed more improvement following immunotherapy in LGI1-Ab+(p=0.008) than CASPR2-Ab+patients(p=0.125). At follow-up(median 57 months) CASPR2-Ab+patients showed more impairment in mobility(p=0.014), daily activities(p=0.019), and anxiety/depression(p=0.043); and lower overall health(p=0.019) on the EQ5D compared to LGI1-Ab+patients. Intraepidermal nerve fibre density was reduced in 2 LGI1-Ab+ and 1 CASPR2-Ab+patients. Serum immunoglobulin G(IgG) from 6/16 CASPR2-Ab+patients bound to sensory neuronal cocultures compared to 0/14 LGI1-Ab+patients(p=0.019) and 0/12 healthy controls. Serum IgG from 10/16 CASPR2-Ab+patients bound to DRG cultures compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab+ and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

BackgroundPathognomonic clinical signs are increasingly well recognised across the autoim- mune encephalitides. Faciobrachial dystonic seizures (FBDS) are exclusively present in patients with LGI1-autoantibodies. Owing to their recent description and rarity, however, the wider clinical phenotypes remain less well-defined.AimsTo describe novel clinical features in a large cohort of patients with LGI1-autoantibodies.MethodsPatients were recruited for clinical research following either direct referral to the Oxford Autoim- mune Neurology Service, or via notification to the national Association of British Neurologists Rare Disease Ascertainment and Recruitment (RaDaR) Surveillance Unit. Novel clinical signs were identified through clinical assessment of 107 LGI1-autoantibody patients. We use video footage to present the phenotypes.Results5/104* (5%) of patients with LGI1-autoantibodies displayed highly unusual manual stereotypies which we have termed ‘complex motor behaviours’. These behaviours consisted of the patients acting out intricate manual behaviours using imaginary objects, for example drinking from a cup, writing, and imitation of winding a piece of string around the fingers. They typically occurred during sleep or periods of relaxed wakefulness, were of short duration (30-60 seconds), and were associated with loss of awareness. All patients had multiple seizure semiologies (3-5) and associated visual hallucinations and sleep disorder.ConclusionsComplex motor behaviours were observed in 5% of patients with LGI1-autoantibodies and may represent either a novel seizure semiology or the sleep disorder agrypnia excitata. These findings expand the clinical phenotypes of LGI1-autoantibody encephalitis.

Initiation of anti-epileptic drugs is increasingly relevant to daily neurosurgical practice. Intracranial pathologies ranging from brain tumours to subarachnoid haemorrhage and traumatic brain injury are commonly associated with the subsequent development of seizures. The scope and range of anti-epileptic drugs available has increased dramatically in recent years and understanding the evidence base behind this class of drugs in addition to their interaction/side effect profiles is essential. In this review we aim to generate a practical guide for neurosurgeons regarding the use of different anti-epileptic medications in common neurosurgical conditions, including considerations for their use in pregnancy.

Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan’s syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities (‘double-negative’) are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.

See Zekeridou and Pittock (doi:10.1093/brain/awaa153) for a scientific commentary on this article. Ramberger et al. generate patient-derived monoclonal antibodies against LGI1 and describe their epitopes and sequences, plus their pathogenic potential in vitro and in vivo. They find that binding characteristics of these antibodies inform the molecular mechanisms and relative pathogenicity within polyclonal specificities., Autoantibodies against leucine-rich glioma inactivated 1 (LGI1) are found in patients with limbic encephalitis and focal seizures. Here, we generate patient-derived monoclonal antibodies (mAbs) against LGI1. We explore their sequences and binding characteristics, plus their pathogenic potential using transfected HEK293T cells, rodent neuronal preparations, and behavioural and electrophysiological assessments in vivo after mAb injections into the rodent hippocampus. In live cell-based assays, LGI1 epitope recognition was examined with patient sera (n = 31), CSFs (n = 11), longitudinal serum samples (n = 15), and using mAbs (n = 14) generated from peripheral B cells of two patients. All sera and 9/11 CSFs bound both the leucine-rich repeat (LRR) and the epitempin repeat (EPTP) domains of LGI1, with stable ratios of LRR:EPTP antibody levels over time. By contrast, the mAbs derived from both patients recognized either the LRR or EPTP domain. mAbs against both domain specificities showed varied binding strengths, and marked genetic heterogeneity, with high mutation frequencies. LRR-specific mAbs recognized LGI1 docked to its interaction partners, ADAM22 and ADAM23, bound to rodent brain sections, and induced internalization of the LGI1-ADAM22/23 complex in both HEK293T cells and live hippocampal neurons. By contrast, few EPTP-specific mAbs bound to rodent brain sections or ADAM22/23-docked LGI1, but all inhibited the docking of LGI1 to ADAM22/23. After intrahippocampal injection, and by contrast to the LRR-directed mAbs, the EPTP-directed mAbs showed far less avid binding to brain tissue and were consistently detected in the serum. Post-injection, both domain-specific mAbs abrogated long-term potentiation induction, and LRR-directed antibodies with higher binding strengths induced memory impairment. Taken together, two largely dichotomous populations of LGI1 mAbs with distinct domain binding characteristics exist in the affinity matured peripheral autoantigen-specific memory pools of individuals, both of which have pathogenic potential. In human autoantibody-mediated diseases, the detailed characterization of patient mAbs provides a valuable method to dissect the molecular mechanisms within polyclonal populations.

CXCL13 triggers B-cell homing to germinal-centres (GCs). Plasma CXCL13 levels are a marker of GC activity, and CSF CXCL13 levels are elevated in MS, NMDA-R-antibody encephalitis, and NMO. Our objectives were to examine CXCL13 concentrations in LGI1-antibody patients, and the concept of GC-reactions in these patients. Additionally, we explored patient serum binding patterns to two LGI1 domains: LRR and EPTP.End-titrations against full-length LGI1, LRR and EPTP were quantified by live-CBA for 100 sera from 38 LGI1-antibody patients. Serum CXCL13 levels were determined by ELISA in 86 samples from 19 LGI1-antibody patients and HCs (n=20), and evaluated with Mann-Whitney and Spearman’s correlation.98% sera bound both EPTP and LRR, with tight correlation in end-titres (r 0.9257;pLGI1-antibody patients showed high CXCL13 levels with dynamic longitudinal fluctuations. Autoantibodies with reactivity to both EPTP- and LRR-LGI1 domains were detected in equal proportions throughout disease, indicating their ongoing production. Overall, these findings suggest that sustained, ongoing GC-reactions may act as a dominant mechanism of autoantibody production in LGI1-antibody syndromes.

Vitamin E deficiency is known to result mainly in a spinocerebellar syndrome and involvement of the peripheral nervous system occurs less commonly. Most cases of vitamin E-deficient ataxic neuropathy reported relate to a genetically-mediated cause through mutation of the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13 [1]. Severe subacute adult-onset rapidly disabling neuropathy due to vitamin E deficiency is not to our knowledge reported. Cognitive dysfunction is uncommon in this setting. Occurrence of isolated ymptomatic vitamin E deficiency due to pancreatic exocrine insufficiency (PEI) appears exceptional.

This chapter presents a recollection of the events that occurred in Cyprus during and after the two-week period (15–28 March 2013) when the country was left with no banking system, subsisting solely on ATMs and payment cards. It examines the role of local bankers and key institutions, such as the International Monetary Fund (IMF), European Central Bank (ECB), and Eurogroup, in the light of corporate legitimacy; and appraises the transformation of the Cypriot society three years from the levy imposed on depositors. This work suggests that Automated Teller Machines (ATMs) and payment cards played a political role, securing peace through controlled circulation of money and transactions with restrictions. In addition, we argue that the new deal has sunk the real economy and pushed people towards practices and activities in the unrecorded sphere.

Contributions to this edited book evolve around the central role banks have in retail payments (see Fig. 33.1 below). This analysis takes a long-term view all the way to the present while, in some cases, points to the future. Contributions come from different fields in academia, combined with others from active industry participants.

A 31 year old lady was admitted with worsening of right sided hemiparesis, on a background five month history of mild right upper limb weakness, and upper limb sensory ataxia. MRI revealed a longitudinally enhancing intrinsic cord lesion from C2-C7 with severe cord expansion, raising initial suspicion for ependymoma. Inflammatory aetiology was considered due to multiple areas of involvement, with T2-weighted signal change within the cervical and thoracic spine, and brain. CSF revealed 4 mononuclear cells, normal protein, normal CSF-serum glucose ratio, T lymphocyte predominance on histology, and no neoplastic cells on flow cytometry. Testing for tuberculosis was negative, including CSF, and extensive imaging did not reveal malignancy. Aquaporin-4 antibodies were positive, and the patient showed marked improvement to intravenous steroids and oral taper, with significant radiological resolution at two months. This case highlights an unusual presentation of NMO, with progressive history over five months, and unusual radiological findings, including severe cord expansion. Positive aquaporin-4 antibody and excellent clinical and radiological response to immunosuppressive therapy confirmed the diagnosis. We took this opportunity to review the clinical presentation and MRI findings in 31 of our five year NMO patient cohort (26 aquaporin-4 antibody positive, 3 anti-MOG positive and 2 seronegative).