Sustained effort network for treatment of status epilepticus/European academy of neurology registry on adult refractory status epilepticus (SENSE-II/AROUSE).

BACKGROUND: Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. METHODS: Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. DISCUSSION: The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. TRIAL REGISTRATION: NCT number: NCT05839418.

Feasibility of non-invasive neuromonitoring in general intensive care patients using a multi-parameter transcranial Doppler approach.

PURPOSE: To assess the feasibility of Transcranial Doppler ultrasonography (TCD) neuromonitoring in a general intensive care environment, in the prognosis and outcome prediction of patients who are in coma due to a variety of critical conditions. METHODS: The prospective trial was performed between March 2017 and March 2019 Addenbrooke's Hospital, Cambridge, UK. Forty adult patients who failed to awake appropriately after resuscitation from cardiac arrest or were in coma due to conditions such as meningitis, seizures, sepsis, metabolic encephalopathies, overdose, multiorgan failure or transplant were eligible for inclusion. Gathered data included admission diagnosis, duration of ventilation, length of stay in the ICU, length of stay in hospital, discharge status using Cerebral Performance Categories (CPC). All patients received intermittent extended TCD monitoring following inclusion in the study. Parameters of interest included TCD-based indices of cerebral autoregulation, non-invasive intracranial pressure, autonomic system parameters (based on heart rate variability), critical closing pressure, the cerebrovascular time constant and indices describing the shape of the TCD pulse waveform. RESULTS: Thirty-seven patients were included in the final analysis, with 21 patients classified as good outcome (CPC 1-2) and 16 as poor neurological outcomes (CPC 3-5). Three patients were excluded due to inadequacies identified in the TCD acquisition. The results indicated that irrespective of the primary diagnosis, non-survivors had significantly disturbed cerebral autoregulation, a shorter cerebrovascular time constant and a more distorted TCD pulse waveform (all p<0.05). CONCLUSIONS: Preliminary results from the trial indicate that multi-parameter TCD neuromonitoring increases outcome-predictive power and TCD-based indices can be applied to general intensive care monitoring.

Neuromuscular monitoring devices - where to go next?

PURPOSE OF REVIEW: This paper reviews the clinical applications, technology, and evidence supporting the use of telemedicine devices and telehealth in neuromuscular disease. RECENT FINDINGS: The COVID-19 pandemic interrupted standard multidisciplinary care of patients with neuromuscular disease and created a need to adapt to remote care. Telemedicine applications were rapidly introduced and have rapidly proved an important tool in maintaining specialist care. This review presents the current data being gathered identifying the patients who benefit from telehealth applications, the appropriate type of telemedicine approach to specific conditions, the conditions needed to optimise telehealth approaches, and potential pitfalls and limitations in their use. SUMMARY: Telemedicine is an important tool in providing robust remote care for patients with neuromuscular disorders, but further investigation is needed to optimise applications.

The clinical management of neuromuscular disorders in intensive care.

Life-threatening neuromuscular disorders affect a small, but growing group of patients in the intensive care unit who present special management problems, as well as great therapeutic opportunities. In inflammatory conditions, a cure is often possible, and for chronic, genetic or degenerative conditions, achieving the previous level of function is the target. Neuromuscular experts and intensivists need to cooperate closely to achieve the best possible outcomes. They need to acquire a very specific set of skills, including both a thorough understanding of the mechanics of ventilation as well as familiarity with the diagnostic categories of genetic and of autoimmune diseases. This review of the clinical management of adult neuromuscular disease in the ICU aims to provide an overview of the most important conditions encountered in the ICU and a practical approach to their diagnosis, monitoring, and treatment.

Trismus caused by paraneoplastic brainstem encephalitis.

We discuss the assessment and differential diagnoses of a middle-aged man who presented with trismus, double vision and behavioural problems. MRI scan of the brain was initially normal, but a month later showed high signal in the hippocampal region on fluid attenuated inversion recovery sequence (FLAIR) imaging. We suspected a paraneoplastic brainstem encephalitis because of his smoking history, rapidly progressive symptoms and abnormal brainstem signs. A positron emission tomography-CT scan identified abnormal subcarinal nodes, shown on biopsy to be metastatic small cell lung cancer. He is currently undergoing treatment with chemotherapy and radiotherapy.

Probable Catastrophic Antiphospholipid Syndrome with Intracerebral Hemorrhage Secondary to Epstein-Barr Viral Infection.

BACKGROUND: Catastrophic antiphospholipid syndrome (CAPS) is a rare, severe variant of antiphospholipid syndrome with a high mortality rate. We report a unique case of CAPS secondary to Epstein-Barr viral (EBV) infection complicated by pulmonary and intracerebral hemorrhage. A review of the CAPS literature relevant to intensive care practice is used to outline a rational approach to diagnosis and management. METHODS: All data are from a single patient admitted to the Neurosciences Critical Care Unit in Addenbrooke's Hospital, Cambridge, in March 2016. Medline, Web of Science, PubMed, and the Cochrane Library were searched through September 2016 without restrictions for cases of CAPS, management of CAPS in the intensive care unit, and hemorrhage complicating CAPS. The patient gave express written consent to access and publish these data. RESULTS: This is only the second reported case of probable CAPS secondary to EBV infection. Furthermore, pulmonary and intracerebral hemorrhage is rare manifestations of this multisystem prothrombotic state which provided unique challenges to the management. CONCLUSIONS: While rare, CAPS should be considered in any patient presenting with rapidly progressive multiorgan failure, evidence of thrombotic microangiopathy, and antiphospholipid antibodies. A high index of suspicion is required as early, aggressive, multimodal treatment with anticoagulation, and immunosuppression improves outcomes.

Neuromuscular problems in the ICU.

PURPOSE OF REVIEW: Patients with acute life-threatening neuromuscular disease require close cooperation between neuromuscular and intensive care specialists to achieve the best possible outcomes. The problems encountered by these patients are different from those in traditional neuromuscular practice, and neurologists consulting in the ICU need a specific skill set to provide useful guidance. However, outcomes can be very good if treatment is instituted effectively. This review aims to provide an overview of the most important neuromuscular conditions encountered in the ICU and enable a practical approach to patient management. RECENT FINDINGS: New research has provided improved knowledge of the impact of acute neuromuscular failure on the mechanics of respiration, on the categories of neuromuscular disease in the ICU, and on the main factors influencing outcomes. Pitfalls and risks in ICU treatment are better understood. SUMMARY: Evidence-based algorithms for monitoring and treatment have been developed. These advances enhance the role of the neuromuscular specialist in acute care. The principles of best practice are discussed in this review.

Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the evidence and make evidence-based recommendations for acute interventions to reduce brain injury in adult patients who are comatose after successful cardiopulmonary resuscitation. METHODS: Published literature from 1966 to August 29, 2016, was reviewed with evidence-based classification of relevant articles. RESULTS AND RECOMMENDATIONS: For patients who are comatose in whom the initial cardiac rhythm is either pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF) after out-of-hospital cardiac arrest (OHCA), therapeutic hypothermia (TH; 32-34°C for 24 hours) is highly likely to be effective in improving functional neurologic outcome and survival compared with non-TH and should be offered (Level A). For patients who are comatose in whom the initial cardiac rhythm is either VT/VF or asystole/pulseless electrical activity (PEA) after OHCA, targeted temperature management (36°C for 24 hours, followed by 8 hours of rewarming to 37°C, and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH and is an acceptable alternative (Level B). For patients who are comatose with an initial rhythm of PEA/asystole, TH possibly improves survival and functional neurologic outcome at discharge vs standard care and may be offered (Level C). Prehospital cooling as an adjunct to TH is highly likely to be ineffective in further improving neurologic outcome and survival and should not be offered (Level A). Other pharmacologic and nonpharmacologic strategies (applied with or without concomitant TH) are also reviewed.

Prospective Study on Noninvasive Assessment of Intracranial Pressure in Traumatic Brain-Injured Patients: Comparison of Four Methods.

Elevation of intracranial pressure (ICP) may occur in many diseases, and therefore the ability to measure it noninvasively would be useful. Flow velocity signals from transcranial Doppler (TCD) have been used to estimate ICP; however, the relative accuracy of these methods is unclear. This study aimed to compare four previously described TCD-based methods with directly measured ICP in a prospective cohort of traumatic brain-injured patients. Noninvasive ICP (nICP) was obtained using the following methods: 1) a mathematical "black-box" model based on interaction between TCD and arterial blood pressure (nICP_BB); 2) based on diastolic flow velocity (nICP_FVd); 3) based on critical closing pressure (nICP_CrCP); and 4) based on TCD-derived pulsatility index (nICP_PI). In time domain, for recordings including spontaneous changes in ICP greater than 7 mm Hg, nICP_PI showed the best correlation with measured ICP (R = 0.61). Considering every TCD recording as an independent event, nICP_BB generally showed to be the best estimator of measured ICP (R = 0.39; p < 0.05; 95% confidence interval [CI] = 9.94 mm Hg; area under the curve [AUC] = 0.66; p < 0.05). For nICP_FVd, although it presented similar correlation coefficient to nICP_BB and marginally better AUC (0.70; p < 0.05), it demonstrated a greater 95% CI for prediction of ICP (14.62 mm Hg). nICP_CrCP presented a moderate correlation coefficient (R = 0.35; p < 0.05) and similar 95% CI to nICP_BB (9.19 mm Hg), but failed to distinguish between normal and raised ICP (AUC = 0.64; p > 0.05). nICP_PI was not related to measured ICP using any of the above statistical indicators. We also introduced a new estimator (nICP_Av) based on the average of three methods (nICP_BB, nICP_FVd, and nICP_CrCP), which overall presented improved statistical indicators (R = 0.47; p < 0.05; 95% CI = 9.17 mm Hg; AUC = 0.73; p < 0.05). nICP_PI appeared to reflect changes in ICP in time most accurately. nICP_BB was the best estimator for ICP "as a number." nICP_Av demonstrated to improve the accuracy of measured ICP estimation.

Hereditary myopathy with early respiratory failure: occurrence in various populations.

OBJECTIVE: Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort. METHODS: DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations. RESULTS: All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin. CONCLUSIONS: We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.

The role of neurosciences intensive care in neurological conditions.

The neurosciences intensive care unit provides specialized medical and nursing care to both the neurosurgical and neurological patient. This second of two articles describes the role it plays in the management of patients with neurological conditions.

The effect of secular trends and specialist neurocritical care on mortality for patients with intracerebral haemorrhage, myasthenia gravis and Guillain-Barré syndrome admitted to critical care : an analysis of the Intensive Care National Audit & Research Centre (ICNARC) national United Kingdom database.

PURPOSE: To analyse mortality for spontaneous intracerebral haemorrhage (ICH), myasthenia gravis (MG) and Guillain-Barré syndrome (GBS) from 1996 to 2009 in UK intensive care units (ICUs). METHODS: We used the Intensive Care National Audit & Research Centre (ICNARC) database. We identified specialised neurosciences critical care units (NCCUs) (n = 16), general ICUs with full neurological support (n = 48) and general ICUs with limited neurological support (n = 138) and undertook descriptive analyses for each condition. Poisson regression was used to identify trends in admission rates, median regression to identify trends in lengths of stay (LOS), and logistic regression (Wald test) to analyse interaction between unit type and time period; odds ratios were calculated for hospital mortality associated with unit types. RESULTS: For ICH (n = 10,313 cases), overall ICU mortality was 42.4 %, and acute hospital mortality 62.1 %. In NCCU, LOS was longer, but mortality lower, and over time, mortality from ICH decreased faster. For MG (n = 1,064 cases) and GBS (n = 1,906 cases), overall mortality was relatively high (MG: 8.7 % ICU mortality and 22 % acute hospital mortality; GBS: 7.7 and 16.7 %, respectively); overall mortality did not decrease over time. CONCLUSIONS: This first large-scale analysis of outcomes in acute neurological disease in the UK demonstrates real-life mortality higher than published series. NCCU care is associated with increased survival in conditions requiring highly specialised intensive care techniques, but high-quality step-down care is pivotal in others. Strategies that truly improve outcomes must integrate emergency department management, ICU admission criteria, NCCU treatment, high-quality step-down care and neurorehabilitation.

Clinical and myopathological characteristics of desminopathy caused by a mutation in desmin tail domain.

BACKGROUND: Most of the previously described pathogenic mutations in desmin are located in highly conserved α-helical domains that play an important role in intermediate filament assembly. The role of the C-terminus non-α-helical 'tail' domain is much less investigated and until recently mutations in this domain have been implicated in only a few patients. The majority of reported desminopathy cases caused by the tail mutations were sporadic, creating a representation bias regarding the disease frequency and phenotypic characteristics. METHODS: We performed detailed genotype-phenotype analysis of autosomal dominant desminopathy associated with tail domain mutations in a four-generation autosomal dominant family with 16 members affected by a progressive cardiac and/or skeletal myopathy caused by a c.1346A>C (p.Lys449Thr) mutation located in the tail domain of desmin. RESULTS: Phenotypic features in patients with tail domain mutations are similar to those in patients with mutations localized in the 1B and 2B α-helical domains. CONCLUSION: We recommend that the tail domain is searched for mutations as intensely as desmin coil domains which until recently were considered to be more 'functional'.

Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies.

Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential.

Decreased ubiquinone availability and impaired mitochondrial cytochrome oxidase activity associated with statin treatment.

In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity.

In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.