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Background Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. Objective To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes. Methods We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 μmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia. Results We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment. Conclusions Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes.

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings.

Hippocampal theta oscillations have been implicated in spatial memory function in both rodents and humans. What is less clear is how hippocampal theta interacts with higher frequency oscillations to support long‐term memory. Here we asked 10 presurgical epilepsy patients undergoing intracranial EEG recording to perform a long‐term spatial memory task in desktop virtual reality and found that increased theta power in two discrete bands (“low” 2‐5 Hz and “high” 6‐11 Hz) during cued retrieval was associated with improved task performance. Similarly, increased coupling between “low” theta phase and gamma amplitude during the same period was associated with improved task performance. Finally, low and high gamma amplitude appeared to peak at different phases of the theta cycle; providing a novel connection between human hippocampal function and rodent data. These results help to elucidate the role of theta oscillations and theta‐gamma phase‐amplitude coupling in human long‐term memory.

Our aim was to demonstrate the first use of Optically Pumped Magnetoencephalography (OP-MEG) in an epilepsy patient with unrestricted head movement. Current clinical MEG uses a traditional SQUID system for recording MEG signal, where sensors are cryogenically cooled and housed in a helmet in which the patient’s head is fixed. Here we use a different type of sensor (OPM), which operates at room temperature and can be placed directly on the patient’s scalp, permitting free head movement. We performed two 30 minute OP-MEG recording sessions in a patient with refractory focal epilepsy and compared these with clinical scalp EEG performed earlier. OP-MEG was able to identify analogous interictal activity to scalp EEG, and source localise this activity to an appropriate brain region. This is the first application of OP-MEG in human epilepsy. Future directions include simultaneous EEG/OP-MEG recording and prolonged OP-MEG telemetry.

Anhedonia, the impaired ability to experience pleasure, is a core feature of major depressive disorder, one of the most common comorbidities in epilepsy. It is also reported as a clinical feature independent of depression in a number of other neurological conditions. This study aimed to establish the prevalence of anhedonia in a sample of people with epilepsy, with and without a diagnosis of depression, and to examine the clinical and demographic characteristics of those who present with this symptom.A consecutive sample of 211 people (118 female, 93 male, mean age 38.09 years) completed the Snaith-Hamilton Pleasure Scale (SHAPS) to determine the presence of anhedonia and the Hospital Anxiety and Depression Scale to determine levels of anxiety and depression. The majority of patients had focal epilepsy (n = 165), and the remaining patients had generalized epilepsy (n = 22), or unclassified epilepsy (n = 24). Sixteen percent of the sample had a clinical diagnosis of depression at the time of the study.Over one in three of the sample (35%) reported significant anhedonia on the SHAPS. While these patients were more likely to have a diagnosis of depression (p 0.01), 30% of people without a diagnosis of depression also reported significant anhedonia. Difficulties gaining pleasure on 12 of the 14 items on the SHAPS were associated with cognitive difficulties, with those reporting an inability to feel pleasure on the item scoring significantly lower on tests of cognitive function than those who were able to gain pleasure. Of the three cognitive domains examined (overall intellectual ability, verbal memory, and processing speed), a poor memory had the strongest relationship; with lower memory function associated with an impaired ability to experience pleasure on 9 of the 14 items.While anhedonia is well recognized as a feature of depression, our data suggests that it can be present in up to a third of people with epilepsy who do not have a diagnosis of depression. Cognitive difficulties, particularly impaired memory function may mediate some features of anhedonia. The implications of these findings for the clinical management of anhedonia in people with epilepsy are discussed.

Optically Pumped Magnetometer based Magnetoencephalography (OP-MEG) has significant potential for clinical use in pre-surgical planning in epilepsy. Unlike current clinical MEG, the sensors do not require cryogenic cooling and so can be placed directly on the patient’s head. This allows the patient to move during the recording and means that the sensor positions can be chosen to suit the patient’s head shape and suspected epileptogenic focus. However, OP-MEG is a new technology, and more work is needed to demonstrate this potential. We present OP-MEG recordings from a patient (male in their 30s) with a radiologically identifiable focal cortical dysplasia (FCD) in the right superior frontal sulcus approximately 1.9 cm3 in volume. Previous scalp EEG studies and prolonged video-EEG telemetry did not identify any interictal epileptiform abnormalities. We recorded 30 minutes of OP-MEG with 62-channel, whole-head sensor coverage. During the experiment, the patient’s head was unconstrained. We localised interictal epileptiform discharges (IEDs) from this recording with a beamformer and by fitting a dipole to the averaged IED data. Both the beamformer peak and dipole fit locations were within 2.3 cm of the MRI lesion boundary. This single subject, proof-of-concept recording provides further evidence that OP-MEG can be a useful and minimally invasive tool in the clinical evaluation of epilepsy.

This prospective open-label feasibility study aimed to evaluate acceptability, tolerability and compliance with dietary intervention with K.Vita, a medical food containing a unique ratio of decanoic acid to octanoic acid, in individuals with drug-resistant epilepsy. Adults and children aged 3–18 years with drug-resistant epilepsy took K.Vita daily whilst limiting high-refined sugar food and beverages. K.Vita was introduced incrementally with the aim of achieving ≤35% energy requirements for children or 240 ml for adults. Primary outcome measures were assessed by study completion, participant diary, acceptability questionnaire and K.Vita intake. Reduction in seizures or paroxysmal events was a secondary outcome. 23/35 (66%) children and 18/26 (69%) adults completed the study; completion rates were higher when K.Vita was introduced more gradually. Gastrointestinal disturbances were the primary reason for discontinuation, but symptoms were similar to those reported from ketogenic diets and incidence decreased over time. At least three-quarters of participants/caregivers reported favourably on sensory attributes of K.Vita, such as taste, texture and appearance, and ease of use. Adults achieved a median intake of 240 ml K.Vita, and children 120 ml (19% daily energy). Three children and one adult had ß-hydroxybutyrate >1 mmol/l. There was 50% (95% CI 39–61%) reduction in mean frequency of seizures/events. Reduction in seizures or paroxysmal events correlated significantly with blood concentrations of medium chain fatty acids (C10 and C8) but not ß-hydroxybutyrate. K.Vita was well accepted and tolerated. Side effects were mild and resolved with dietetic support. Individuals who completed the study complied with K.Vita and additional dietary modifications. Dietary intervention had a beneficial effect on frequency of seizures or paroxysmal events, despite absent or very low levels of ketosis. We suggest that K.Vita may be valuable to those with drug-resistant epilepsy, particularly those who cannot tolerate or do not have access to ketogenic diets, and may allow for more liberal dietary intake compared to ketogenic diets, with mechanisms of action perhaps unrelated to ketosis. Further studies of effectiveness of K.Vita are warranted., See Auvin (https://doi.org/10.1093/braincomms/fcab234) for a scientific commentary on this article. Schoeler et al. report that K.Vita, a decanoic acid-rich medical food, was well-tolerated when introduced gradually and flexibly to individuals with epilepsy. Seizures or paroxysmal events reduced by 50% (95% CI 39–61%). Only 4/61 (7%) patients had ß-hydroxybutyrate levels >1 mmol/l. K.Vita may be valuable for individuals with drug-resistant epilepsy., Graphical Abstract Graphical Abstract

Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physiological function. It is unclear whether more common forms of epilepsy share this particular feature. By measuring interictal spikes in patients with a range of epilepsies, we show that 2 tasks known to specifically engage the hippocampus and temporal neocortex promoted increased interictal spiking within these regions, whereas a nonhippocampal dependent task did not. This indicates that interictal spike frequency may reflect the processing demands being placed on specific functional-anatomical networks in epilepsy. ANN NEUROL 2019;86:304-309.

Introduction Respiratory failure is one of the most common causes of mortality in myotonic dystrophy type 1 (DM1). The variation in the DM1 phenotype causes difficulty in clinically predicting the severity of respiratory involvement, and variables such as daytime somnolence are insensitive for identifying patients who require continuous or bilevel nocturnal positive airway pressure (NPAP). Methods We retrospectively analyzed a cohort of 126 adult onset patients with DM1 at the point of their first respiratory assessment to identify significant factors in predicting ventilator requirement. Results Triplet repeat years score and Muscle Impairment Rating Scale were significantly linearly related to NPAP and, thus, formed the model. Discussion We devised a simple model to aid clinicians in predicting at first visit those patients with DM1 who are likely to require NPAP. We also describe the causes of failure to tolerate NPAP in DM1. Muscle Nerve 59:683-687, 2019.

Both magnetoencephalography and stereo-electroencephalography are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether simultaneous stereo-electroencephalography–magnetoencephalography recording confers an advantage over both individual modalities, in particular whether magnetoencephalography can provide spatial context to epileptiform activity seen on stereo-electroencephalography. Twenty-four adult and paediatric patients who underwent stereo-electroencephalography study for pre-surgical evaluation of drug-resistant focal epilepsy, were recorded using simultaneous stereo-electroencephalography–magnetoencephalography, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with detected superficial (n = 7) and deep (n = 7) brain interictal activity. Interictal spikes were independently identified in stereo-electroencephalography and magnetoencephalography. Magnetoencephalography dipoles were derived using a distributed inverse method. There was no significant difference between stereo-electroencephalography and magnetoencephalography in detecting superficial spikes (P = 0.135) and stereo-electroencephalography was significantly better at detecting deep spikes (P = 0.002). Mean distance across patients between stereo-electroencephalography channel with highest average spike amplitude and magnetoencephalography dipole was 20.7 ± 4.4 mm. for superficial sources, and 17.8 ± 3.7 mm. for deep sources, even though for some of the latter (n = 4) no magnetoencephalography spikes were detected and magnetoencephalography dipole was fitted to a stereo-electroencephalography interictal activity triggered average. Removal of magnetoencephalography dipole was associated with 1 year seizure freedom in 6/7 patients with superficial source, and 5/6 patients with deep source. Although stereo-electroencephalography has greater sensitivity in identifying interictal activity from deeper sources, a magnetoencephalography source can be localized using stereo-electroencephalography information, thereby providing useful whole brain context to stereo-electroencephalography and potential role in epilepsy surgery planning., In the largest case series to date, Vivekananda et al. perform simultaneous magnetoencephalography and stereo-electroencephalography in refractory focal epilepsy patients. They demonstrate that for deep brain epileptogenic foci, magnetoencephalography dipoles could be derived from average stereo-electroencephalography data, thereby overcoming a traditional limitation of magnetoencephalography of reduced sensitivity for deep sources.

Highlights • We applied Hidden Markov Model (HMM) to concurrent MEG and intracranial EEG (iEEG). • Epilepsy cohort HMM analysis yielded states similar to those of healthy subjects. • iEEG power correlated with the time course of HMM states. • Functional clusters of iEEG electrodes agreed with those based on spatial location. • Our pipeline can be used for group analysis of concurrent MEG and invasive data., Background Intracranial electroencephalography (iEEG) recordings are used for clinical evaluation prior to surgical resection of the focus of epileptic seizures and also provide a window into normal brain function. A major difficulty with interpreting iEEG results at the group level is inconsistent placement of electrodes between subjects making it difficult to select contacts that correspond to the same functional areas. Recent work using time delay embedded hidden Markov model (HMM) applied to magnetoencephalography (MEG) resting data revealed a distinct set of brain states with each state engaging a specific set of cortical regions. Here we use a rare group dataset with simultaneously acquired resting iEEG and MEG to test whether there is correspondence between HMM states and iEEG power changes that would allow classifying iEEG contacts into functional clusters. Methods Simultaneous MEG-iEEG recordings were performed at rest on 11 patients with epilepsy whose intracranial electrodes were implanted for pre-surgical evaluation. Pre-processed MEG sensor data was projected to source space. Time delay embedded HMM was then applied to MEG time series. At the same time, iEEG time series were analyzed with time-frequency decomposition to obtain spectral power changes with time. To relate MEG and iEEG results, correlations were computed between HMM probability time courses of state activation and iEEG power time course from the mid contact pair for each electrode in equally spaced frequency bins and presented as correlation spectra for the respective states and iEEG channels. Association of iEEG electrodes with HMM states based on significant correlations was compared to that based on the distance to peaks in subject-specific state topographies. Results Five HMM states were inferred from MEG. Two of them corresponded to the left and the right temporal activations and had a spectral signature primarily in the theta/alpha frequency band. All the electrodes had significant correlations with at least one of the states (p

ObjectivesBoth Magnetoencephalography (MEG) and stereo-electroencephalography (SEEG) are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether combined recording using both modalities can maintain inherent advantages whilst overcoming these limitations e.g. recording from deep brain sources whilst preserving good spatial resolution.Methods24 adult and paediatric patients who underwent SEEG study for pre-surgical evaluation of focal drug-resistant epilepsy, were recorded using simultaneous SEEG-MEG, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with presumed superficial (n=7) and deep (n=7) brain interictal activity.ResultsThere was no significant difference between SEEG and MEG in identifying superficial spikes (p=0.135) and SEEG was significantly better at detecting deep spikes (p=0.002). Mean distance across patients between SEEG channel with highest average spike amplitude and MEG dipole was 26.6+/-3.6 mm for superficial sources, and 21.5 +/- 2.04 mm for deep sources, even though for some of the latter (n=4) no MEG spikes were detected and MEG dipole was fitted to a SEEG interictal activity triggered average. Removal of MEG dipole was associated with 1 year seizure freedom in 5/6 patients with superficial source, and 4/6 patients with deep source.ConclusionsAlthough SEEG has greater sensitivity in identifying interictal activity from deeper sources, an MEG source can be localised using SEEG information, thereby providing useful whole brain context to SEEG and potential role in epilepsy surgery planning.

Highlights • Primary neuronal cultures from cryopreserved tissue retain functional neuronal properties. • Cryopreservation of brain tissue allows long-distance collaborations. • Exchange of cryopreserved tissue can reduce the need to maintain multiple colonies of mutant mice., Background Dissociated primary neuronal cultures are widely used as a model system to investigate the cellular and molecular properties of diverse neuronal populations and mechanisms of action potential generation and synaptic transmission. Typically, rodent primary neuronal cultures are obtained from freshly-dissociated embryonic or postnatal brain tissue, which often requires intense animal husbandry. This can strain resources when working with genetically modified mice. New method Here we describe an experimental protocol for frozen storage of mouse hippocampi, which allows fully functional dissociated primary neuronal cultures to be prepared from cryopreserved tissue. Results We show that thawed hippocampal neurons have functional properties similar to those of freshly dissociated neurons, including neuronal morphology, excitability, action potential waveform and synaptic neurotransmitter release, even after cryopreservation for several years. Comparison to the existing methods In contrast to the existing methods, the protocol described here allows for efficient long-term storage of samples, allowing researchers to perform functional experiments on neuronal cultures from brain tissue collected in other laboratories. Conclusions We anticipate that this method will facilitate collaborations among laboratories based at distant locations and will thus optimise the use of genetically modified mouse models, in line with the 3Rs (Replacement, Reduction and Refinement) recommended for scientific use of animals in research.

Hippocampal theta oscillations have been implicated in spatial memory function in both rodents and humans. What is less clear is how hippocampal theta interacts with higher frequency oscillations during spatial memory function, and how this relates to subsequent behaviour. Here we asked ten human epilepsy patients undergoing intracranial EEG recording to perform a desk-top virtual reality spatial memory task, and found that increased theta power in two discrete bands (‘low’ 2-5Hz and ‘high’ 6-9Hz) during cued retrieval was associated with improved task performance. Similarly, increased coupling between ‘low’ theta phase and gamma amplitude during the same period was associated with improved task performance. These results support a role of theta oscillations and theta-gamma phase-amplitude coupling in human spatial memory function.

St George's Hospital hyperacute neurology service (HANS) is a comprehensive, consultant-delivered service set in a teaching hospital regional neuroscience centre. The service addresses deficiencies in acute neurological care previously highlighted by the Royal College of Physicians and the Association of British Neurologists. HANS adopts a disease-agnostic approach to acute neurology, prioritising the emergency department (ED) management of both stroke and stroke mimics alike alongside proactive daily support to the acute medical unit and acute medical take. Rapid access clinics provide a means to assess ambulatory patients, providing an outlet to reduce the burden of referral from primary care to acute medicine. This paper reports the results from the first year of the service. Admission was avoided in 25% of the cases reviewed in the ED. Compared to historic data, there was a significant improvement in the length of stay for non-stroke disorders while the occupancy of stroke beds by non-stroke cases reduced by 50%. The configuration of this service is replicable in other neuroscience centres and provides a framework to reduce the barriers facing patients who present with acute neurological symptoms.

Hyperammonaemia is often encountered in acute neurology and can be the cause of acute or chronic neurological symptoms. Patients with hyperammonaemia may present with seizures or encephalopathy, or may be entirely asymptomatic. The underlying causes are diverse but often straightforward to diagnose, although sometimes require specialist investigations. Haemodialysis or haemo(dia)filtration is the first-line treatment for acute severe hyperammonaemia (of any cause) in an adult. Here we discuss our approach to adult patients with hyperammonaemia identified by a neurologist.

The myotonic dystrophies type 1 and type 2 are the most frequently inherited neuromuscular diseases of adult life. They are progressive multisystem disorders and predominantly affect the conduction system of the heart. Tachy and bradyarrhythmias are the predominant cardiac manifestation and are associated with up to 30% of all cause mortality in DM. Routine cardiac screening is recommended in all patients with a minimum of a yearly ECG, ECHO and 24 h Holter monitoring. In our practice we recommend electrophysiological studies when there are any abnormalities on the ECG. Future work will aim to define criteria for implantation of pacemakers and implantable cardioverter defibrillators.

Although action potentials propagate along axons in an all-or-none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog–digital modulation is depolarization-mediated inactivation of presynaptic Kv1-family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization. We recorded instead from small boutons supplied by intact axons identified with scanning ion conductance microscopy in primary hippocampal cultures and asked how distinct potassium channels interact in determining the basal spike width and its modulation by subthreshold somatic depolarization. Pharmacological or genetic deletion of Kv1.1 broadened presynaptic spikes without preventing further prolongation by brief depolarizing somatic prepulses. A heterozygous mouse model of episodic ataxia type 1 harboring a dominant Kv1.1 mutation had a similar broadening effect on basal spike shape as deletion of Kv1.1; however, spike modulation by somatic prepulses was abolished. These results argue that the Kv1.1 subunit is not necessary for subthreshold modulation of spike width. However, a disease-associated mutant subunit prevents the interplay of analog and digital transmission, possibly by disrupting the normal stoichiometry of presynaptic potassium channels.

An 18-year-old girl presented with inability to smell from birth. She had no symptoms to suggest an endocrine disturbance. Anosmia was confirmed on bedside testing. A diagnosis of congenital anosmia was made. A 3T MRI scan (figure) of this patient revealed no olfactory bulbs but developed olfactory sulci. The rest of the brain including corpus callosum was normal. The differential diagnosis for congenital anosmia is Kallman syndrome. However, in Kallman syndrome, the olfactory sulci would also be absent.

Emery Dreifuss Muscular dystrophy (EDMD) is an X-linked recessive condition although female carriers may be mildly affected. This case illustrates the cardinal features observed in EDMD; namely slowly progressive muscle weakness in a humeroperoneal distribution first affecting the distal leg muscles followed by proximal arm muscles. The early development of contractures is common and dilated cardiomyopathy may occur. Diagnosis is confirmed by mutation analysis of the emerin gene and/or the loss of emerin on immunocytochemmistry of muscle tissue.

A case of intermediate phenotype of dystrophinopathy is presented with a good clinical reponse to steroids. Dystrophinoapthy is discussed including the role of steroids in the treatment plan.

This chapter summarizes our increasing knowledge of the antibody-mediated encephalitides since the first diagnosis made in 1968. It focuses on anti-NMDA-receptor-mediated encephalitis (ANMDARE), and describes the diverse neurological manifestations that can be expected, its stereotypical progression, and the possible pathophysiological processes underlying the condition. It reviews recent ANMDARE case series including typical MRI, EEG, and CSF features seen on diagnostics, associated neoplasms to investigate, and a suggested pathway for treatment. It discusses other forms of antibody-mediated encephalitis, including paraneoplastic limbic encephalitis, limbic encephalitis associated with voltage-gated potassium-channel antibodies, stiff person syndrome (SPS) and its variants, and more recently found causative antibodies to AMPA and GABA receptors.

The cause of ALS remains largely unknown for the 90% with no known family history, but spontaneous mutation to risk alleles of as yet unidentified genes is possible. It has long been recognized that genetic diseases may be more likely to occur in the last born children of a sibship because increased paternal age is associated with an increased spontaneous point mutation rate in sperm. To test the hypothesis that such a mechanism is responsible for sporadic ALS, we have performed a retrospective analysis of birth order position. We have analyzed sibships of size greater than four using a binomial test for birth position. The 478 pedigrees studied show no birth order effect, suggesting that any genetic contributions to sporadic ALS are more likely to be through deletion in large genes or interactions of common polymorphisms, rather than frequent spontaneous point mutation. This is encouraging for the prospect of finding sporadic ALS susceptibility genes using genome-wide association mapping.

We describe a 33 year old man with a severe vasculitis causng a profound axonal neuropathy and brainstem syndrome. The atient became unresponsive and lost all movement and braintem reflexes. The EEG showed poorly reactive rhythms suggesting lobal cortical dysfunction. The clinical signs were compatible with rainstem death except that an irreversible cause had not been emonstrated. The patient was treated and subsequently made a ood recovery.

Respiratory failure is the commonest cause of mortality in myotonic dystrophy type 1 (DM1). The variation in the DM1 phenotype causes difficulty in clinically predicting the severity of respiratory involvement. Parameters, such as daytime somnolence, are insensitive in highlighting DM1 patients who require non-invasive ventilation and are at risk of life threatening respiratory compromise. We have retrospectively analysed a cohort of 118 DM1 patients at the point of their first respiratory assessment and provide a multivariate model for predicting ventilator requirement based on the patient’s triplet repeat years score (derived from a semi-quantitative analysis of triplet repeat size and age of patient) and Muscle Impairment Rating Scale (MIRS). We also describe the causes of failure to tolerate NIV in DM1.

Summary Direct electrical access to presynaptic ion channels has hitherto been limited to large specialized terminals such as the calyx of Held or hippocampal mossy fiber bouton. The electrophysiology and ion-channel complement of far more abundant small synaptic terminals (≤1 μm) remain poorly understood. Here we report a method based on superresolution scanning ion conductance imaging of small synapses in culture at approximately 100–150 nm 3D resolution, which allows presynaptic patch-clamp recordings in all four configurations (cell-attached, inside-out, outside-out, and whole-cell). Using this technique, we report presynaptic recordings of K+, Na+, Cl−, and Ca2+ channels. This semiautomated approach allows direct investigation of the distribution and properties of presynaptic ion channels at small central synapses. Video Abstract, Highlights • Topographic imaging of live synaptic boutons at nanoscale resolution • Cell-attached patch-clamp recordings of ion channels in small central synapses • Whole-cell small presynaptic bouton recordings, Novak and colleagues have developed a method for nanoscale-targeted patch-clamp presynaptic recordings in submicrometer central synapses identified using superresolution scanning ion conductance microscopy. This semiautomated approach opens a new window on the physiology of small presynaptic terminals.

Background Type 1 episodic ataxia is a disorder characterised by paroxysmal cerebellar incoordination and interictal myokymia. It is caused by dominant negative mutations of KCNA1 , which encodes the presynaptic and axonal potassium channel subunit Kv1.1. Mutations in the disorder increase neuronal excitability and neurotransmitter release in neuronal cultures. Our hypothesis is that type 1 episodic ataxia prolongs the action potential at presynaptic terminals thus causing increased neurotransmitter release. We aimed to test this hypothesis in mouse models of type 1 episodic ataxia. Methods We used two mouse models, one with a knockout of the KCNA1 mutation ( KCNA1a –/–) and one with a knockin of the mutation KCNA1a (V408A/+). We used scanning ion conductance microscopy to acquire super-resolution images of very small synaptic boutons (∼1 μm diameter) in mouse hippocampal neuronal cultures and achieved direct electrophysiological recording from these boutons. We compared wild-type, KCNA1a –/–, and KCNA1a (V408A/+) mice. Action potentials were either elicited by injection of a depolarising current at the bouton or via a second pipette at the cell body. Findings Presynaptic action potential half width was larger in KCNA1a –/– mice than in their wild-type littermates when directly elicited at the bouton (mean 1·43 ms [SE 0·12] vs 0·86 [0·068]) and when elicited by depolarising the cell body (1·44 [0·089] vs 1·17 [0·055]), and was also larger in KCNA1a (V408A/+) mice (1·14 [0·063] vs 0·91 [0·065] and 1·38 [0·063] vs 1·11 [0·048], respectively). In separate prepulse experiments, wild-type mice showed an increase in bouton action potential half width when moving from hyperpolarising to depolarising subthreshold prepulse steps. KCNA1a –/– mice also showed increasing action potential half widths with the steps. However, in KCNA1a (V408A/+) mice this positive correlation was abolished. Interpretation A prolonged presynaptic action potential in type 1 episodic ataxia might cause the increase in neurotransmitter release. Progressive presynaptic depolarisation in KCNA1a (V408A/+) mice has no effect on Kv1.1 inactivation, which in turn might affect the digital-analogue facilitation of synaptic transmission in hippocampal synapses. Since Kv1.1 is abundantly expressed in cerebellar basket cells, it could lead to added inhibition of cerebellar Purkinje cells and ataxia. Funding Wellcome Trust.

BACKGROUND The aetiology of apparently sporadic amyotrophic lateral sclerosis (ALS) is unknown, but prenatal factors are known to influence disease development. In both men and women, motor neurons require testosterone for survival and axonal regeneration after injury, and androgen insensitivity leads to a form of motor neuron degeneration in men. Reduction in the ratio of index to ring finger length (2D:4D ratio) is considered a surrogate marker for high prenatal testosterone levels in both men and women. The authors therefore tested the hypothesis that prenatal testosterone irrespective of gender is an independent risk factor for the development of ALS later in life, and that this would be reflected in a lower 2D:4D ratio in both men and women with ALS. METHODS Patients and unrelated control individuals attending a specialist tertiary referral centre for ALS were studied. A digital camera was used to photograph hands. Finger lengths were measured by four independent scorers blind to case-control status, and the mean 2D:4D ratio derived. Analysis was by linear regression and receiver-operator-curve analysis. RESULTS Controlling for differences in sex ratio between groups, the 2D:4D ratio was lower for people with ALS (n=47) than for controls (n=63) (r=-0.25, two-tailed p=0.009). CONCLUSIONS Patients with ALS have a lower 2D:4D ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor-neuron vulnerability in later life.