The natural history of epilepsy and nonepileptic seizures in Sturge-Weber syndrome: A retrospective case-note review.

OBJECTIVE: Patients with Sturge-Weber Syndrome (SWS) experience varying degrees of neurological problems - including epilepsy, hemiparesis, learning disability (LD), and stroke-like episodes. While the range of clinical problems experienced by children with SWS is well recognized, the spectrum of clinical presentation and its treatment during adulthood has been relatively neglected in the literature to date. This study explored the natural history of epileptic and nonepileptic seizures into adulthood in patients with SWS, and their treatment, and investigated whether any clinical factors predict which symptoms a patient will experience during adulthood. METHODS: A retrospective case-note review of a cohort of 26 adults with SWS at the National Hospital for Neurology and Neurosurgery (NHNN). Childhood data were also recorded, where available, to enable review of change/development of symptoms over time. RESULTS: The course of epilepsy showed some improvement in adulthood - seventeen adults continued to have seizures, while six patients gained seizure freedom, and no one had adult-onset seizures. However, seizures did worsen for some patients. Although no factors reached statistical significance regarding predicting continued epilepsy in adulthood, being male, more severe LD, having required epilepsy surgery, and bilateral cortical involvement may be important. Nonepileptic seizures (NES) also began during adulthood for four patients. SIGNIFICANCE: By adulthood, there is some degree of improvement in epilepsy overall; while NES may occur for the first time. While the majority of the results did not survive adjustments for multiple comparisons, some interesting trends appeared, which require further investigation in a multicenter national audit. Patients with more neurologically severe presentations during childhood may continue to experience seizures. Careful monitoring and screening are needed during adulthood, to detect changes and newly developing symptoms such as NES, and target treatment promptly.

Evaluation and Treatment in Urology for Nocturia Caused by Nonurological Mechanisms: Guidance from the PLANET Study.

Patients with nocturia are commonly referred to urology clinics, including many for whom a nonurological medical condition is responsible for their symptoms. The PLanning Appropriate Nocturia Evaluation and Treatment (PLANET) study was established to develop practical approaches to equip healthcare practitioners to deal with the diverse causes of nocturia, based on systematic reviews and expert consensus. Initial assessment and therapy need to consider the possibility of one or more medical conditions falling into the "SCREeN" areas of Sleep medicine (insomnia, periodic limb movements of sleep, parasomnias, and obstructive sleep apnoea), Cardiovascular (hypertension and congestive heart failure), Renal (chronic kidney disease), Endocrine (diabetes mellitus, thyroid disease, pregnancy/menopause, and diabetes insipidus), and Neurology. Medical and medication causes of xerostomia should also be considered. Some key indicators for these conditions can be identified in urology clinics, working in partnership with the primary care provider. Therapy of the medical condition in some circumstances lessens the severity of nocturia. However, in many cases there is a conflict between the two, in which case the medical condition generally takes priority on safety grounds. It is important to provide patients with a realistic expectation of therapy and awareness of limitations of current therapeutic options for nocturia. PATIENT SUMMARY: Nocturia is the symptom of waking at night to pass urine. Commonly, this problem is referred to urology clinics. However, in some cases, the patient does not have a urological condition but actually a condition from a different speciality of medicine. This article describes how best the urologist and the primary care doctor can work together to assess the situation and make sensible and safe treatment suggestions. Unfortunately, there is sometimes no safe or effective treatment choice for nocturia, and treatment needs to focus instead on supportive management of symptoms.

Association of Sleep Disorders with Nocturia: A Systematic Review and Nominal Group Technique Consensus on Primary Care Assessment and Treatment.

CONTEXT: Sleep disorders affect responsiveness to sensory information and can cause nocturnal polyuria and reduced sleep depth; hence, these are potentially influential in understanding the mechanism of nocturia. OBJECTIVE: To report the systematic review (SR) and expert consensus for primary care management of nocturia in sleep disorders. EVIDENCE ACQUISITION: Four databases were searched from January to April 2020. A total of 1658 titles and abstracts were screened, and 23 studies potentially applicable were included for full-text screening. The nominal group technique (NGT) was used to derive a consensus on recommendations for management using an expert panel with public involvement. EVIDENCE SYNTHESIS: Thirteen studies met the SR inclusion criteria, all of which studied obstructive sleep apnoea (OSA), with ten evaluating the effect of continuous positive airway pressure. The NGT consensus discussed the assessment of OSA with other key sleep disorders, notably insomnia, restless legs syndrome/periodic limb movements of sleep, and parasomnias, including non-rapid eye movement (non-REM) parasomnias and REM sleep behaviour disorder (RBD). The NGT considered that the use of screening questions to reach a clinical diagnosis is a sufficient basis for offering conservative therapy within primary care. Reasons for referral to a sleep clinic are suspected sleep disorder with substantially impaired daytime function despite conservative treatment. Suspected RBD should be referred, and if confirmed, neurology opinion is indicated. Referrals should follow local guidelines. Persisting nocturia is not currently considered an indication for referral to a sleep clinic. CONCLUSIONS: Sleep disorders are potentially highly influential in nocturia, but are often overlooked. PATIENT SUMMARY: People with sleep disorders can experience nocturia due to easy waking or increased bladder filling. We looked at published research, and information was limited to one form of sleep disturbance-obstructive sleep apnoea. We assembled a group of experts, to develop practical approaches for assessing and treating nocturia in the potentially relevant sleep disorders.

Expert Opinion: Managing sleep disturbances in people with epilepsy.

Poor sleep and daytime sleepiness are common in people with epilepsy. Sleep disorders can disrupt seizure control and in turn sleep and vigilance problems can be exacerbated by seizures and by antiepileptic treatments. Nevertheless, these aspects are frequently overlooked in clinical practice and a clear agreement on the evidence-based guidelines for managing common sleep disorders in people with epilepsy is lacking. Recently, recommendations to standardize the diagnostic pathway for evaluating patients with sleep-related epilepsies and comorbid sleep disorders have been presented. To build on these, we adopted the Delphi method to establish a consensus within a group of experts and we provide practical recommendations for identifying and managing poor night-time sleep and daytime sleepiness in people with epilepsy. We recommend that a comprehensive clinical history of sleep habits and sleep hygiene should be always obtained from all people with epilepsy and their bed partners. A psychoeducational approach to inform patients about habits or practices that may negatively influence their sleep or their vigilance levels should be used, and strategies for avoiding these should be applied. In case of a suspected comorbid sleep disorder an appropriate diagnostic investigation should be performed. Moreover, the possible presence of sleep fragmentation induced by sleep-related seizures should be ruled out. Finally, the dose and timing of antiepileptic medications and other co-medications should be optimized to improve nocturnal sleep and avoid daytime sedation.

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer's disease: A proof-of-principle behavioural study.

Sleep disruption is a key clinical issue in the dementias but the sleep phenotypes of these diseases remain poorly characterised. Here we addressed this issue in a proof-of-principle study of 67 patients representing major syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD), in relation to 25 healthy older individuals. We collected reports on clinically-relevant sleep characteristics - time spent overnight in bed, sleep quality, excessive daytime somnolence and disruptive sleep events. Difficulty falling or staying asleep at night and excessive daytime somnolence were significantly more frequently reported for patients with both FTD and AD than healthy controls. On average, patients with FTD and AD retired earlier and patients with AD spent significantly longer in bed overnight than did healthy controls. Excessive daytime somnolence was significantly more frequent in the FTD group than the AD group; AD syndromic subgroups showed similar sleep symptom profiles while FTD subgroups showed more variable profiles. Sleep disturbance is a significant clinical issue in major FTD and AD variant syndromes and may be even more salient in FTD than AD. These preliminary findings warrant further systematic investigation with electrophysiological and neuroanatomical correlation in major proteinopathies.

Increasing the accuracy of 3D EEG implantations.

OBJECTIVEThe accuracy of stereoelectroencephalography (SEEG) electrode implantation is an important factor in maximizing its safety. The authors established a quality assurance (QA) process to aid advances in implantation accuracy.METHODSThe accuracy of three consecutive modifications of a frameless implantation technique was quantified in three cohorts comprising 22, 8, and 23 consecutive patients. The modifications of the technique aimed to increase accuracy of the bolt placement.RESULTSThe lateral shift of the axis of the implanted bolt at the level of the planned entry point was reduced from a mean of 3.0 ± 1.6 mm to 1.4 ± 0.8 mm. The lateral shift of the axis of the implanted bolt at the level of the planned target point was reduced from a mean of 3.8 ± 2.5 mm to 1.6 ± 0.9 mm.CONCLUSIONSThis QA framework helped to isolate and quantify the factors introducing inaccuracy in SEEG implantation, and to monitor ongoing accuracy and the effect of technique modifications.

Circadian rhythm and epilepsy.

Advances in diagnostic technology, including chronic intracranial EEG recordings, have confirmed the clinical observation of different temporal patterns of epileptic activity and seizure occurrence over a 24-h period. The rhythmic patterns in epileptic activity and seizure occurrence are probably related to vigilance states and circadian variation in excitatory and inhibitory balance. Core circadian genes BMAL1 and CLOCK, which code for transcription factors, have been shown to influence excitability and seizure threshold. Despite uncertainties about the relative contribution of vigilance states versus circadian rhythmicity, including circadian factors such as seizure timing improves sensitivity of seizure prediction algorithms in individual patients. Improved prediction of seizure occurrence opens the possibility for personalised antiepileptic drug-dosing regimens timed to particular phases of the circadian cycle to improve seizure control and to reduce side-effects and risks associated with seizures. Further studies are needed to clarify the pathways through which rhythmic patterns of epileptic activity are generated, because this might also inform future treatment options.

Oculomotor apraxia and disrupted sleep with nocturnal ballistic bouts in ADCY5-related disease.

OBJECTIVE: To characterise the distinctive eye movement disorder and the sleep-related dyskinesia in Adenylate cyclase 5 (ADCY5) related disease. METHODS: Formal eye movement examination and video-polysomnography in a cohort of patients with ADCY5 mutations. RESULTS: All three patients had an eye movement disorder characterised by oculomotor apraxia with gaze limitation most prominently in the vertical plane. All patients had disrupted sleep architecture with reduced sleep efficiency due to frequent and prolonged arousals and awakenings in the context of dyskinesia, which could arise from any sleep stage. The nocturnal movements could last up to 30 min and be more severe than those seen during day-time. CONCLUSION: Nocturnal exacerbations of dyskinesia ("ballistic bouts") seem to be a characteristic feature of the disease, affect the quality of life of patients and therefore require awareness and symptomatic treatment approaches. Apraxia of eye movements, with predominant difficulties in the vertical plane, was a common finding in our patients with ADCY5 mutations. These features may prompt the diagnosis and help to distinguish ADCY5-related disease from other childhood-onset hyperkinetic movement disorders.

The utility of polysomnography for the diagnosis of NREM parasomnias: an observational study over 4 years of clinical practice.

Polysomnography (PSG) is considered the gold standard for diagnosis of non-rapid eye movement (NREM) parasomnias, however its diagnostic yield has been rarely reported. We aimed to assess the diagnostic value of polysomnography in different categories of patients with suspected NREM parasomnia and define variables that can affect the outcome. 124 adults referred for polysomnography for suspected NREM parasomnia were retrospectively identified and divided into clinical categories based on their history. Each polysomnography was analysed for features of NREM parasomnia or different sleep disorders and for presence of potential precipitants. The impact on the outcome of number of recording nights and concomitant consumption of benzodiazepines and antidepressants was assessed. Overall, PSG confirmed NREM parasomnias in 60.5 % patients and showed a different sleep disorder in another 16 %. Precipitants were found in 21 % of the 124 patients. However, PSG showed limited value when the NREM parasomnia was clinically uncomplicated, since it rarely revealed a different diagnosis or unsuspected precipitants (5 % respectively), but became essential for people with unusual features in the history where different or overlapping diagnoses (18 %) or unsuspected precipitants (24 %) were commonly identified. Taking benzodiazepines or antidepressants during the PSG reduced the diagnostic yield. PSG has a high diagnostic yield in patients with suspected NREM parasomnia, and can reveal a different diagnosis or precipitants in over 40 % of people with complicated or atypical presentation or those with a history of epilepsy. We suggest that PSG should be performed for one night in the first instance, with leg electrodes and respiratory measurements and after benzodiazepine and antidepressant withdrawal.

High-throughput, automated quantification of white matter neurons in mild malformation of cortical development in epilepsy.

INTRODUCTION: In epilepsy, the diagnosis of mild Malformation of Cortical Development type II (mMCD II) predominantly relies on the histopathological assessment of heterotopic neurons in the white matter. The exact diagnostic criteria for mMCD II are still ill-defined, mainly because findings from previous studies were contradictory due to small sample size, and the use of different stains and quantitative systems. Advance in technology leading to the development of whole slide imaging with high-throughput, automated quantitative analysis (WSA) may overcome these differences, and may provide objective, rapid, and reliable quantitation of white matter neurons in epilepsy. This study quantified the density of NeuN immunopositive neurons in the white matter of up to 142 epilepsy and control cases using WSA. Quantitative data from WSA was compared to two other systems, semi-automated quantitation, and the widely accepted method of stereology, to assess the reliability and quality of results from WSA. RESULTS: All quantitative systems showed a higher density of white matter neurons in epilepsy cases compared to controls (P = 0.002). We found that, in particular, WSA with user-defined region of interest (manual) was superior in terms of larger sampled size, ease of use, time consumption, and accuracy in region selection and cell recognition compared to other methods. Using results from WSA manual, we proposed a threshold value for the classification of mMCD II, where 78% of patients now classified with mMCD II were seizure-free at the second post-operatively follow up. CONCLUSION: This study confirms the potential role of WSA in future quantitative diagnostic histology, especially for the histopathological diagnosis of mMCD.

The effect of posterior hypothalamus region deep brain stimulation on sleep.

BACKGROUND: Early observations by von Economo showed that the posterior part of the hypothalamus (PH) plays a prominent role in sleep-wake regulation. The PH is a candidate area involved in cluster headaches and other trigeminal autonomic cephalalgias (TACs) and is targeted for deep brain stimulation (DBS). CASE REPORTS: Sleep studies in two men, 69- and 39-years-old, with pre-existing sleep disorders, before and after PH-DBS for pharamacoresistant cluster headache and SUNCT syndrome showed that PH-DBS led to a dramatic alteration of the patients' sleep patterns. This coincided with an improvement of the predominantly diurnal TACs, suggesting a PH-DBS-induced change in sleep patterns. Hypnograms after DBS demonstrated disrupted sleep and a prolonged period of wakefulness after midnight in both patients, which was reproduced the second night. CONCLUSIONS: PH-DBS, a promising treatment for severe refractory TACs, affects sleep quality and pre-existing sleep disorders. This needs to be considered when treating patients with PH-DBS.

Loss of rapid eye movement sleep atonia in patients with REM sleep behavioral disorder, narcolepsy, and isolated loss of REM atonia.

STUDY OBJECTIVES: To compare the amounts of REM sleep without atonia (RSWA) between patients with REM sleep behavior disorder (RBD), "isolated loss of REM atonia," narcolepsy, and control subjects and determine if there were threshold values for the amount of RSWA that differentiate each group from controls. METHODS: Retrospective analyses of polysomnography (PSG) records were used employing strict quantitative criteria for the measurement of phasic and tonic EMG activity during REM sleep. The PSG recordings of 47 individuals were analyzed (RBD 16, isolated loss of REM atonia 11, narcolepsy 10, control 10). RESULTS: Patients with the diagnosis of isolated loss of REM atonia had significantly lower levels of EMG activity during REM sleep than those with RBD but higher than control subjects. RSWA was higher in narcolepsy than in loss of REM atonia but lower than for RBD patients. Receiver operating characteristic (ROC) curves provided threshold values with high specificity and sensitivity in all patient groups with a cutoff value ≥ 1.22% (100% correctly classified) for phasic and ≥ 3.17% for tonic (92% correctly classified) EMG activity in RBD. CONCLUSION: Quantification of REM sleep EMG activity can successfully differentiate RBD and isolated loss of REM atonia patients from controls. The consistently increased amount of RSWA in patients with narcolepsy indicates that this can be an additional marker for a diagnosis of narcolepsy. Longitudinal studies of patients with isolated loss of REM atonia are needed to evaluate if these patients are at risk of developing RBD or neurodegenerative disorders.

Adult-onset NREM parasomnia with hypnopompic hallucinatory pain: a case report.

We report the case of a 43-year-old woman presenting with nocturnal episodes of pain and screaming during sleep starting at age 30. There was no childhood or family history of parasomnia. The events had gradually become more frequent over the years, occurring in the first half of the night within 2 h of sleep onset. There were no triggers, and she had partial amnesia for the events. A diagnosis of adult-onset sleep terrors was made on clinical grounds and supported polysomnographically. Seizures and periodic limb movements were excluded as triggering factors. There was some mild sleep disordered breathing (predominantly non-desaturating hypopnea with a propensity for REM sleep of debatable significance). Imaging of the brain and spine and neurophysiological investigations ruled out lesions, entrapments, or neuropathies as possible causes of pain. Treatment (clonazepam, paroxetine, or gabapentin) was poorly tolerated and made no difference to the nocturnal episodes, while trazodone worsened them. This is the first report of hypnopompic psychic pain in association with a NREM parasomnia. We hypothesize that the pain may represent a sensory hallucination analogous to the more commonly recognized visual NREM parasomnia-associated hypnopompic visual hallucinations and that, as such, it may arise during arousal of the sensory neocortex as confabulatory response.

Imaging the interaction: epileptic discharges, working memory, and behavior.

Interictal generalized epileptiform discharges may impair cognition. We used simultaneous video-electroencephalography and functional imaging to quantify changes, induced by epileptiform discharges, in the task-related activations during a spatial working-memory paradigm. The number of epileptiform discharges increased during the task with its level of complexity, but were not significantly associated with wrong responses during the task. We observed hemodynamic responses in working-memory related frontal-lobe-network, motor-cortex, precuneus, and parietal lobes in the absence of epileptiform discharges. In the presence of epileptiform discharges during the task, task-related hemodynamic changes were seen only in motor-cortex, precuneus, and parietal lobes. These findings suggest that generalized epileptiform discharges during a high demanding working memory task may change the working memory-related hemodynamic responses in frontal-lobe-network.

Correlating 3T MRI and histopathology in patients undergoing epilepsy surgery.

PURPOSE: To investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRI scan appeared normal. These MRI techniques have the potential to visualise subtle structural abnormalities currently undetected on conventional MRI; but correlation between pre-operative in vivo MRI and histopathology is needed to understand the basis of these MRI abnormalities. Predicting subtle histopathology with semi-quantitative MRI techniques could contribute to pre-surgical evaluation of epilepsy patients. MATERIALS AND METHODS: MRI techniques: normalised FLAIR signal intensity (nFSI), grey matter probability and diffusion tensor imaging (DTI) were correlated with quantitative histopathological measures: NeuN (neuronal nuclear antigen); GFAP (glial fibrillary acidic protein) and MBP (myelin basic protein) field fractions and stereological neuronal densities obtained in grey and white matter regions in twenty-four patients who underwent anterior temporal lobe resections. RESULTS: There were no significant correlations between the histopathological measurements and MRI values in grey or white matter in macroscopically normal appearing tissue. CONCLUSION: Findings suggest that in macroscopically normal appearing tissue, the studied semiquantitative MRI measurements are not significantly related to the measures of gliosis, neuronal loss/gain and myelin used in the current study. Studies of macroscopically abnormal tissue as well as improvements to the MRI techniques may increase the sensitivity of future correlative studies to improve our understanding of the histopathological basis of MRI signal characteristics.

Epilepsy and sleep.

PURPOSE OF REVIEW: There is a complex relationship between epilepsy, sleep and sleep disorders. Recent studies have provided new insights into the links between the disorders that may facilitate differential diagnosis and treatment but may also improve our understanding of underlying pathophysiological mechanisms. RECENT FINDINGS: Sleep and sleep deprivation have long been recognized to influence interictal epileptiform discharges and seizures. More recent studies have shown that primary sleep disorders such as obstructive sleep apnoea may worsen epilepsy and treatment of these sleep disorders can lead to improved seizure control. Seizures may interfere with night-time sleep structure and cause excessive day-time somnolence (EDS). Antiepileptic drugs may also cause EDS or influence sleep. Despite more frequent use of video-electroencephalographic telemetry and polysomnography, the differential diagnostic challenges between nonrapid eye movement parasomnia and nocturnal frontal lobe epilepsy remain. There is also ongoing debate regarding the possibility of a common pathogenic background for parasomnias and nocturnal seizures that is summarized in the review. SUMMARY: Accurate identification and diagnosis of sleep disorders as well as epilepsy is clinically important to ensure optimal treatment of both epilepsy and sleep disorders. Further studies of these nocturnal events may advance our understanding of underlying pathological mechanisms and the complex relationship between sleep and epilepsy.

Cortical neuronal loss and hippocampal sclerosis are not detected by voxel-based morphometry in individual epilepsy surgery patients.

Voxel-based morphometry (VBM) has detected differences between brains of groups of patients with epilepsy and controls, but the sensitivity for detecting subtle pathological changes in single subjects has not been established. The aim of the study was to test the sensitivity of VBM using statistical parametric mapping (SPM5) to detect hippocampal sclerosis (HS) and cortical neuronal loss in individual patients. T1-weighted volumetric 1.5 T MR images from 13 patients with HS and laminar cortical neuronal loss were segmented, normalised and smoothed using SPM5. Both modulated and non-modulated analyses were performed. Comparisons of one control subject against the rest (n = 23) were first performed to ascertain the smoothing level with the lowest number of SPM changes in controls. Each patient was then compared against the whole control group. The lowest number of SPM changes in control subjects was found at a smoothing level of 10 mm full width half maximum for modulated and non-modulated data. In the patient group, no SPM abnormalities were found in the affected temporal lobe or hippocampus at this smoothing level. At lower smoothing levels there were numerous SPM findings in controls and patients. VBM did not detect any abnormalities associated with either laminar cortical neuronal loss or HS. This may be due to normalisation and smoothing of images and low statistical power in areas with larger inter-individual differences. This suggests that the methodology may currently not be suitable to detect particular occult abnormalities possibly associated with seizure onset zone in individual epilepsy patients with unremarkable standard structural MRI.

PROPELLER MRI visualizes detailed pathology of hippocampal sclerosis.

PURPOSE: Hippocampal sclerosis (HS) is the most common cause of refractory temporal lobe epilepsy. Histopathologically, HS is characterized by neuron loss and gliosis. HS can be identified on MRI by signal increase on T(2)-weighted images and volume loss on T(1)-weighted volume images. The Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction ("PROPELLER") sequence has excellent contrast between grey and white matter and compensates for subjects moving during the scan. The aim of the current report was to explore PROPELLER image quality of the hippocampus compared to routine sequences. METHODS: Routine sequences (T(1) volume, T(2)-weighted, PD and FLAIR images) and PROPELLER images were acquired in four presurgical patients with HS using a GE 3T Excite HD scanner (General Electric). Resected tissue was stained with LFB, and for GFAP, NeuN and dynorphin immunohistochemistry. Hippocampal sections were compared with PROPELLER images. RESULTS: PROPELLER images were T(2)-weighted and had superior tissue contrast compared to routine sequences. PROPELLER images showed the internal hippocampal structures and tissue changes associated with HS. This corresponded to changes seen on histopathological sections confirming that the sequence could distinguish between different strata and subfields of the hippocampus. DISCUSSION: The PROPELLER sequence shows promise for detailed in vivo imaging of the hippocampus in patients who did not move overtly, negating the inevitable subtle movements during scans. More detailed in vivo studies of the hippocampal formation, investigating subtle abnormalities such as end folium sclerosis, and the neocortex are now possible and may increase the diagnostic yield of MRI.