Differential Target Multiplexed Spinal Cord Stimulation for the Treatment of Chronic Intractable Upper Limb Pain: 12-Month Results From a Prospective, Multicenter Study.

OBJECTIVES: This prospective, open-label, single-arm, multicenter study evaluated the use of differential target multiplexed (DTM) spinal cord stimulation (SCS) therapy for chronic upper limb pain (ULP). MATERIALS AND METHODS: A total of 58 candidates for SCS who had chronic ULP were enrolled at 11 sites in the USA. The safety and effectiveness of DTM SCS for treating chronic intractable ULP were evaluated over 12 months. The primary end point was the percentage of responders (≥50% ULP relief versus baseline) to treatment at three months after device activation. This study also evaluated the extent of disability, patient satisfaction, and patient global impression of change with DTM SCS therapy. RESULTS: The mean baseline pain score (10-cm visual analog scale [VAS-10]) for ULP was 7.2 cm, with a mean age of 56 years and mean ULP duration of ten years; 47 subjects were assessed at the primary end point. The percentage of ULP responders was 92% at three months, which was consistent at six (91%) and 12 months (86%). Significant ULP relief (81% reduction in VAS-10) was observed at the primary end point and sustained throughout the study duration. Significant improvements in disability in addition to high levels (>95%) of satisfaction and feelings of improvement were reported. Frequency of study-related anticipated adverse events was in line with expectations of SCS therapy. CONCLUSION: In this patient population with difficult-to-treat conditions with limited clinical evidence of the effectiveness of SCS, subjects reported significant reduction in chronic ULP in response to treatment with DTM SCS.

Evoked compound action potentials during spinal cord stimulation: effects of posture and pulse width on signal features and neural activation within the spinal cord.

Objective.Evoked compound action potential (ECAP) recordings have emerged as a quantitative measure of the neural response during spinal cord stimulation (SCS) to treat pain. However, utilization of ECAP recordings to optimize stimulation efficacy requires an understanding of the factors influencing these recordings and their relationship to the underlying neural activation.Approach.We acquired a library of ECAP recordings from 56 patients over a wide assortment of postures and stimulation parameters, and then processed these signals to quantify several aspects of these recordings (e.g., ECAP threshold (ET), amplitude, latency, growth rate). We compared our experimental findings against a computational model that examined the effect of variable distances between the spinal cord and the SCS electrodes.Main results.Postural shifts strongly influenced the experimental ECAP recordings, with a 65.7% lower ET and 178.5% higher growth rate when supine versus seated. The computational model exhibited similar trends, with a 71.9% lower ET and 231.5% higher growth rate for a 2.0 mm cerebrospinal fluid (CSF) layer (representing a supine posture) versus a 4.4 mm CSF layer (representing a prone posture). Furthermore, the computational model demonstrated that constant ECAP amplitudes may not equate to a constant degree of neural activation.Significance.These results demonstrate large variability across all ECAP metrics and the inability of a constant ECAP amplitude to provide constant neural activation. These results are critical to improve the delivery, efficacy, and robustness of clinical SCS technologies utilizing these ECAP recordings to provide closed-loop stimulation.

A Clinical Feasibility Study of Spinal Evoked Compound Action Potential Estimation Methods.

OBJECTIVES: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. Recently, SCS has been enhanced further with evoked compound action potential (ECAP) sensing. Characteristics of the ECAP, if appropriately isolated from concurrent stimulation artifact (SA), may be used to control, and aid in the programming of, SCS systems. Here, we characterize the sensitivity of the ECAP growth curve slope (S) to both neural response (|Sresp|) and SA contamination (|Sart|) for four spinal ECAP estimation methods with a novel performance measure (|Sresp/Sart|). MATERIALS AND METHODS: We collected a library of 112 ECAP and associated artifact recordings with swept stimulation amplitudes from 14 human subjects. We processed the signals to reduce SA from these recordings by applying one of three schemes: a simple high-pass (HP) filter, subtracting an artifact model (AM) consisting of decaying exponential and linear components, or applying a template correlation method consisting of a triangularly weighted sinusoid. We compared these against each other and to P2-N1, a standard method of measuring ECAP amplitude. We then fit the ECAP estimates from each method with a function representing the growth curve and calculated the Sresp and Sart parameters following the fit. RESULTS: Any SA reduction scheme selected may result in under- or overestimation of neural activation or misclassification of SA as ECAP. In these experiments, the ratio of neural signal preservation to SA misclassification (|Sresp/Sart|) on the ECAP estimate was superior (p < 0.05) with the HP and AM schemes relative to the others. CONCLUSIONS: This work represents the first comprehensive assessment of spinal ECAP estimation schemes. Understanding the clinically relevant sensitivities of these schemes is increasingly important, particularly with closed-loop SCS systems using ECAP as a feedback control variable where misclassification of artifact as neural signal may lead to suboptimal therapy adjustments.

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control.

OBJECTIVES: Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms - both sub- and supra-threshold - are programmed relative to the patient's perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems. METHODS: ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed. RESULTS: ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT (r = 0.93; p < 0.0001) and DT (r = 0.93; p < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture. CONCLUSION: We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.

High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.

A New Direction for Closed-Loop Spinal Cord Stimulation: Combining Contemporary Therapy Paradigms with Evoked Compound Action Potential Sensing.

Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electrodes placed on the dorsal side of the spinal cord, typically to treat chronic pain. The first clinical use of SCS involved the delivery of paresthesia inducing, low-frequency waveforms to the neural targets corresponding to the painful areas. Contemporary SCS therapies now leverage novel therapeutic pathways to limit paresthesia and deliver superior clinical outcomes. Historically, SCS has largely been delivered with fixed stimulation parameters. This approach, referred to as open-loop (OL) SCS, does not account for the fluctuations in spacing-driven by postural changes and activity-between the electrodes and the cord. These fluctuations result in variability in the delivered dose and the volume of tissue activation (VTA) that manifests with each stimulation pulse. Inconsistent dosing may lead to suboptimal therapeutic efficacy and durability. To address this clinical need, closed-loop (CL) SCS systems have been developed to automatically adjust stimulation parameters to compensate for this variability. The evoked compound action potential (ECAP), a biopotential generated by the synchronous activation of dorsal column fibers, is indicative of the VTA resulting from the stimulation pulse. The ECAP may be utilized as a control signal in CL SCS systems to adjust stimulation parameters to reduce variability in the ECAP, and in turn, variability in the VTA. While investigational CL SCS systems with ECAP sensing have so far focused solely on managing paresthesia-based SCS, such systems must also incorporate the stimulation approaches that now define the contemporary clinical practice of SCS. Accordingly, we describe here a flexible, next-generation framework for neural responsive SCS that blends science-based methodologies for pain management with real-time CL control for biophysical variation. We conclude with a clinical example of such a system and the associated performance characteristics.

A decade of excellent transplant survival in children with inherited metabolic diseases: A report from a single metabolic transplant centre in Europe.

Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the overall survival (OS) and engrafted survival (ES) of children with IMDs, who received first HCT at Royal Manchester Children's hospital from 1985 to 2016. A total of 137 children with IMDs were included in this analysis (historical cohort [1985-2006], n＝65; current cohort [2007-2016], n＝72). Primary diagnoses included mucopolysaccharidoses (81%), X-linked adrenoleukodystrophy (6%), metachromatic leukodystrophy (4%), mannosidosis (3%), Wolman disease (2%), and other conditions (4%). The five-year OS has increased from 65% (95% confidence interval [CI], 52%-76%) in the historical cohort to 91% (95% CI, 81%-96%) in the current cohort (P<0.001). Moreover, the five-year ES, which was 64% (95 CI%, 56%-72%) for the entire cohort, has doubled from 41% (95% CI, 29%-53%) in the historical cohort to 85% (95% CI, 75%-92%) in the current cohort (P<0.001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P<0.001). In patients who received a second transplant, 13 out of 20 patients (65%) in the historical cohort and all four in the current cohort were alive and engrafted. Of 82 survivors followed-up at Manchester, 80% and 20% had full and mixed chimerism, respectively. Although this study was restricted to a single center, our findings show that HCT is an increasingly safe procedure and provides long-lasting endogenous enzyme replacement therapy for children with IMDs in the modern era of HCT.

How we treat the platelet glycoprotein defects; Glanzmann thrombasthenia and Bernard Soulier syndrome in children and adults.

The inherited platelet glycoprotein deficiencies, Glanzmann thrombasthenia (GT) and Bernard Soulier syndrome (BSS) are rare but important long-term bleeding disorders. Once diagnosed, affected patients should be referred to a specialist centre for bleeding disorders for general advice and ongoing management. Patients do not require prophylactic treatment and so the management of GT and BSS focuses around prophylactic treatment prior to high risk procedures and treatment in response to non-surgical bleeding events and, in women, the management of menorrhagia and pregnancy. There is no consistent approach to the treatment or prevention of bleeding complications. Management must be tailored for each individual and the approach may not be the same for different events, even for the same patient, depending on the type of accident or invasive procedure, the extent of bleeding and the presence or not of platelet refractoriness.

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging.

OBJECTIVE: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features. METHODS: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined. RESULTS: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC). CONCLUSION: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making. ADVANCES IN KNOWLEDGE: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.

Neonatal haemostasis and the management of neonatal thrombosis.

Two detailed reviews of the management of neonatal thrombosis were published in 2012; one was an up-dated version of guidance first issued in 2004 and the other was a comprehensive review. Both of these publications gave very similar advice regarding the practical aspects of the indications, dosage and management of antithrombotic therapy. The authors stated that the evidence supporting most of their recommendations for anti-thrombotic therapy in neonates remained weak and so the therapy for a neonate with a thrombosis has to be based on an individualized assessment of estimated risk versus potential benefit. The aim of this present review is to give the treating physician an outline of the unique physiology of neonatal coagulation and how this affects the monitoring, dosing and even the choice of therapeutic strategy for the management of thrombosis in the neonate.

Newborn bloodspot results: predictive value of screen positive test for thalassaemia major.

AIM: There are limited published data on the performance of the percentage of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period. This paper aims to analyse data derived from a national newborn bloodspot screening programme for sickle cell disease on the performance of haemoglobin A (Hb A) as a screening test for beta thalassaemia major in the newborn period. METHODS: Newborn bloodspot sickle cell screening data from 2,288,008 babies were analysed. Data reported to the NHS Sickle Cell and Thalassaemia Screening Programme in England for the period 2005 to 2012 were also reviewed to identify any missed cases (4,599,849 babies). RESULTS: Within the cohort of 2,288,008 births, 170 babies were identified as screen positive for beta thalassaemia major using a cut-point of 1.5% HbA. There were 51 identified through look-back methods and 119 prospectively identified from 4 screening laboratories. Among 119 babies with prospective data, 7 were lost to follow up and 15 were false positive results. Using a cut-off value of 1.5% Hb A as a percentage of the total haemoglobin as a screening test for beta thalassaemia major in the newborn provides an estimated sensitivity of 99% (from the look back arm of the study) with a positive predictive value of 87% (from the prospective arm of the study). Excluding infants born before 32 weeks gestation, the positive predictive value rose to 95%. CONCLUSION: A haemoglobin A value of less than 1.5% is a reliable screening test for beta thalassaemia major in the newborn period.

Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma.

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue.

The clinical management of tumour lysis syndrome in haematological malignancies.

Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent.

Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency.

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.