Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

This corrects the article DOI: 10.1038/leu.2017.177.

Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.

[Nitrous oxide-induced polyneuropathy]. / Lachgasgeïnduceerde polyneuropathie.

Nitrous oxide, laughing gas, is used as a party drug to achieve a euphoric effect. It has been gaining popularity in recent years and is considered a relatively innocent substance. Nitrous oxide is known to cause subacute degeneration of the spinal cord by inactivation of active vitamin B12. Vitamin B12 plays an essential role in the synthesis of myelin. Hence, vitamin B12 deficiency can lead to degeneration of the dorsal and lateral columns of the spinal cord. Polyneuropathy is a less known complication. We present a 17-year-old woman and a 19-year-old man with subacute axonal polyneuropathy caused by laughing gas abuse. Abstinence of laughing gas and treatment with intramuscular and oral vitamin B12 suppletion respectively have led to improvement of their symptoms. Our cases demonstrate a less-known but treatable complication of laughing gas.

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy--a review of the literature.

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo-echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.

Neuromuscular manifestations in hereditary haemochromatosis.

Involvement of peripheral nerves and skeletal muscles has been reported in the course of hereditary haemochromatosis (HH) but a systematic study is lacking. However, patients with HH report symptoms suggesting a possible polyneuropathy or myopathy. In this study patients with DNA proven HH were recruited from a large general teaching hospital. First, all patients were clinically examined using a structured interview and neurological exam. After reviewing these data an expert panel reached consensus about the presence of a possible neuropathy or myopathy and made recommendations for ancillary investigations (nerve conduction studies, electromyography, thermal threshold tests, laboratory tests). After a second meeting consensus was reached about the final diagnosis. Patients who had a neuropathy or myopathy of which the origin was still unclear were referred to an independent neurologist for further evaluation. Ultimately, of 46 patients included, 25 had no myopathy or neuropathy, 5 an axonal sensory motor polyneuropathy of which the cause was found (diabetes in 2, combination of diabetes and chemotherapy in 1, Charcot Marie Tooth type 2 in 1, Morbus Sjögren in 1), 9 an idiopathic axonal sensory motor polyneuropathy, 3 an idiopathic small fiber polyneuropathy and 4 a carpal tunnel syndrome. There were no cases of proven myopathy. We conclude that an idiopathic polyneuropathy was diagnosed in a relative large number of patients with HH (26%), but the causal relationship needs to be confirmed in larger (case-control) series.

The diagnostic value of provocative clinical tests in ulnar neuropathy at the elbow is marginal.

BACKGROUND: Provocative clinical tests are often performed in the diagnosis of ulnar neuropathy at the elbow (UNE) although the evidence for the usefulness of these tests is limited. The aim of this study was to determine the diagnostic value of provocative clinical tests in the diagnosis of UNE in a relevant spectrum of patients and controls. METHODS: A prospective cohort study was performed in consecutive patients clinically suspected of having UNE. All patients underwent a neurological examination and four commonly used provocative clinical tests (Tinel's test, flexion compression test, palpating for local ulnar nerve tenderness and nerve thickening). Subsequently, in all patients a reference standard test comprising electrophysiological studies and neurosonography was independently assessed. RESULTS: 192 eligible patients completed the study protocol. UNE was diagnosed in 137 and an alternative diagnosis was made in 55 patients. The sensitivity, specificity, and positive and negative predictive values were as follows: Tinel's test 62%, 53%, 77% and 30%; flexion compression test 61%, 40%, 72% and 29%; palpating for nerve thickening 28%, 87%, 84% and 33%; and palpating for nerve tenderness 32%, 80%, 80% and 32%. Logistic regression and receiver operating characteristic curves showed that the added value of one or more provocative tests over routine clinical examination is minimal. CONCLUSION: The diagnostic value of provocative clinical tests in UNE is poor.

[Reversible posterior leucoencephalopathy due to hypercalcaemia]. / Reversibele posterieure leuko-encefalopathie bij hypercalciëmie.

A 60-year-old woman presented with changes in behaviour, cognition, cortical blindness and headache. These symptoms were caused by a reversible posterior leucoencephalopathy syndrome due to hypercalcaemia caused by a multiple myeloma, type IgD wavelength. She was treated with isotonic saline and pamidronate; the serum calcium levels normalised and the radiological brain abnormalities disappeared as did the clinical neurological abnormalities. Hypercalcaemia probably affects cerebral perfusion and has direct neurotoxic effects which can lead to cerebral oedema. This case history illustrates a rare cause of a syndrome that can be easily treated and is completely reversible.

Ultrasonography shows extensive nerve enlargements in multifocal motor neuropathy.

Using ultrasonography we found multiple sites with nerve enlargement along the course of the brachial plexus, median, ulnar, and radial nerves in the majority of 21 patients with multifocal motor neuropathy. Sonography and electrophysiologic studies showed more abnormalities than expected on purely clinical grounds. Moreover, sonography revealed nerve enlargement without clinical or electrophysiologic abnormalities.

Ulnar neuropathy at the elbow: follow-up and prognostic factors determining outcome.

OBJECTIVE: To determine the outcome in patients with ulnar neuropathy at the elbow (UNE) treated surgically or conservatively, and the prognostic value of clinical, sonographic, and electrophysiologic features. METHODS: After a median follow-up of 14 months, 69 of 84 patients initially included in a prospective blinded study on the diagnostic value of sonography in UNE were re-evaluated. The patients underwent renewed systematic clinical and sonographic examination. Patients were scored as having a poor (stable or progressive symptoms) or favorable (complete remission of symptoms or improvement) outcome. RESULTS: Of the 74 initially affected arms, 12 (16%) had a complete remission, 21 (28%) improved, 25 (34%) remained stable, and 16 (22%) had progression. Surgically treated patients (28 arms) had a more favorable outcome than those treated conservatively (p = 0.03). After surgery, the mean ulnar nerve diameter decreased from 3.2 to 2.9 mm (p = 0.03), while this was not seen after conservative treatment. Multiple logistic regression analysis showed that more outspoken nerve enlargement found during sonography at the time of the diagnosis was associated with a poor outcome (OR: 2.9, p = 0.009). Furthermore, the presence of a motor conduction block (OR: 0.2, p = 0.03) and motor velocity slowing across the elbow (OR: 0.1, p = 0.01) were associated with a favorable outcome. CONCLUSION: More pronounced ulnar nerve thickening at the time of the diagnosis is associated with poor outcome at follow-up, especially in conservatively treated cases, while electrodiagnostic signs of demyelination on testing indicate favorable outcome.

Blade consolidation of multiple atrial septal defects: a novel approach to transcatheter closure.

The Amplatzer atrial septal defect occlusion device has gained popularity for the nonoperative closure of secundum-type defects. We describe a case of multiple atrial septal defects that were "consolidated" into a single defect using blade atrial septostomy for successful closure with single Amplatzer device.

High-resolution sonography of the peripheral nervous system -- a review of the literature.

High-resolution sonography is capable of depicting peripheral nerves and the brachial plexus. In this study we review the literature on this subject. Normal peripheral nerves have a characteristic echotexture. Most nerves are readily visualized, although this is not always the case with the nerves of the lower extremity. The main pathological changes that can be demonstrated are nerve enlargement and increased hypoechogenicity. In order to demonstrate nerve enlargement, measurements should be performed and compared with a set of reference values. Several neuropathies have been studied by means of ultrasonography. However, many studies concern case reports and show methodological shortcomings. The best studied peripheral neuropathy is the carpal tunnel syndrome in which ultrasonography seems to have an additional value when combined with nerve conduction studies. Nerve enlargement has also been demonstrated in radial neuropathy at the humerus and in ulnar neuropathy at the elbow. The role of sonography in various hereditary and inflammatory neuropathies is uncertain although diffuse nerve thickening could be demonstrated. Further systematic studies are needed to determine the role of sonography in the diagnostic process of the various neuropathies. It would be important to study the subcategories of patients in whom electrodiagnostic studies are normal or show equivocal findings.

Diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow.

OBJECTIVE: To determine the diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow (UNE). METHODS: Sonographic ulnar nerve diameter measurement was compared at three levels around the medial epicondyle with a criterion standard including clinical and electrophysiologic characteristics in a cohort of 123 patients presenting with clinical signs of UNE. UNE or probable UNE was diagnosed in 84 patients and a different condition in 39 patient controls. Reference values were obtained in 56 healthy volunteers. RESULTS: One hundred thirty-six affected arms were studied in 123 patients (UNE in 82, probable UNE in 9, and a different condition in 45 affected arms). Patients with UNE had a larger ulnar nerve diameter than patient controls (p < 0.0001). The sensitivity of sonography was 80%, specificity 91%, positive likelihood ratio 9, and negative likelihood ratio 0.2. The highest diagnostic yield was found in patients in whom electrodiagnostic studies showed signs of ulnar neuropathy but could not localize the lesion (17/20 cases, 86%) and in patients who had motor conduction velocity slowing across the elbow without conduction block (32/37 cases, 86%). CONCLUSIONS: High-resolution sonography is an accurate and easily applied test for the diagnosis of UNE. The authors recommend its use in addition to electrodiagnostic studies because it improves the reliability of the diagnosis of UNE.

A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS.

BACKGROUND: Some patients with multiple sclerosis (MS) do not show a clear improvement of acute relapses after treatment with intravenous methylprednisolone (IVMP). We compared the efficacy of the combination of intravenous immunoglobulins (IVIg) and IVMP with the standard treatment of IVMP alone in promoting recovery from moderate to severe acute relapses in MS. METHODS: Patients with clinically definite MS having a relapse with at least a one point increase in Kurtzke's expanded disability status scale (EDSS) in comparison to the preattack EDSS were randomized to IVMP-IVIg or IVMP-placebo treatment. The primary outcome criterion was the EDSS grade at four weeks. A preplanned interim analysis was performed after inclusion of 19 consecutive MS patients to evaluate the sample size necessary for a larger trial. FINDINGS: Both groups had improved one point on the EDSS four weeks after start of treatment (P = 0.81) and one of the stopping rules of the interim analysis was fulfilled. There were also no differences in secondary outcomes: EDSS at eight and 12 weeks, time to improve > or = 1 EDSS points, difference in Scripps score and ambulation index. Five patients in the IVMP-IVIg group and two in the IVMP group had a new relapse in the six month follow-up. INTERPRETATION: Our study could not show superiority of IVMP-IVIg in the treatment of moderate to severe acute relapses in MS.

Cost-effectiveness of coarctation repair strategies: endovascular stenting versus surgery.

The cost-effectiveness of stent (ST) implantation for the repair of coarctation of the aorta (CoA) is not documented in the medical literature. Inflation-adjusted hospital costs for ST implantation and for surgical (SU) repair were obtained using the HBOC Cost Accounting System software and evaluated for all patients 5 years of age or older who underwent elective treatment of CoA between July 1997 and June 2001. The average age of the ST group (n = 10) to 9.5 +/- 3.5 years for the SU group (n = 12) (p > 0.10). The ST group had one failure due to inability to cross the CoA (failure rate, 10%). Successful repair was accomplished in all other ST cases and in all SU cases, with no residual systolic gradients at 1-year follow-up. Hospital length of stay for the ST group was 0.8 +/- 1.2 days compared to 3.5 +/- 0.5 days for the SU group (p < 0.001). The mean inflation-adjusted cost for the ST group was dollar 7,148 +/- 2,984 versus dollar 11,769 +/- 3,702 for the SU group (p < 0.005). By intention to treat analysis, the cost of repair in the ST-first group was dollar 8,325 +/- 3,354 given the 10% failure rate (p < 0.04 vs the SU only group). Sensitivity analysis demonstrates that cost of repair is lower with the ST-first strategy compared to SU only until the failure rate of ST implantation exceeds 39%. Repair of CoA using an endovascular stent strategy is cost-effective compared to conventional surgical repair.

Subcutaneous fat necrosis of the newborn: hypercalcaemia with hepatic and atrial myocardial calcification.

Subcutaneous fat necrosis of the newborn (SCFN) is a very rare disorder, which can be complicated by hypercalcaemia and thrombocytopenia. The case is presented of an infant with SCFN and symptomatic hypercalcaemia, who developed calcifications in the liver, the inferior vena cava, and the atrial septum of the heart. The hypercalcaemia was treated with hyperhydration, frusemide, glucocorticoids, and a diet low in calcium and vitamin D. Clinical features, diagnosis, complications, and treatment of this rare condition are discussed.

[Good results after closure of a arterial septal defect during heart catheterisation instead of surgery]. / Gunstige resultaten van atriumseptumdefectsluiting tijdens hartkatheterisatie in plaats van operatie.

OBJECTIVE: Evaluation of the first results in the Netherlands of percutaneous and transvenous closure of an ASD II in children with an Amplatzer Septal Occluder (ASO). DESIGN: Prospective. METHOD: Data were collected from children with an ASD II prior to, during and up to 24 months after the insertion of an ASO during heart catheterisation in Leiden University Hospital, the Netherlands. RESULTS: Between 1 January 1998 and 29 February 2000, 28 patients (12 girls, 16 boys; mean age: 74 months (range: 15-198 months)) underwent heart catheterisation to close an ASD II with an ASO. In 26 patients an ASO could be placed without significant complications. The size of the device varied from 9-34 mm (median 16 mm). In one patient ASD closure was not attempted because of multiple ASDs. In another patient the procedure was stopped after air embolism into the coronary arteries had occurred during preparation of ASO implantation. In 23/26 patients with an implanted ASO, no residual shunt was present after 24 hours. One child, in whom the defect was found to be closed after 24 hours and after three weeks, returned abroad and was lost to follow-up. After one year all defects (n = 22) were completely closed. CONCLUSION: Percutaneous transvenous closure of an ASD II with an ASO was possible, was not associated with any significant complications and had a high success rate, even in relatively young children with large defects.

Unrecognized pulmonary venous desaturation early after Norwood palliation confounds Gp:Gs assessment and compromises oxygen delivery.

BACKGROUND: Hemodynamic stability after Norwood palliation often requires manipulation of pulmonary vascular resistance to alter the pulmonary-to-systemic blood flow ratio (Qp:Qs). Qp:Qs is often estimated from arterial saturation (SaO2), a practice based on 2 untested assumptions: constant systemic arteriovenous O2 difference and normal pulmonary venous saturation. METHODS AND RESULTS: In 12 patients early (

Migraine with aura after intracranial endovascular procedures.

OBJECTIVE: To describe three cases of migraine (two with aura) after an intracranial endovascular procedure. Method.-Retrospective. RESULTS: One patient had an attack of migraine with prolonged aura after embolization of a dural arteriovenous fistula. Another patient had an attack of migraine with aura (and hemiparesis) after a diagnostic angiogram. The third patient already suffered from migraine with aura and had a migraine attack after embolization of an occipital arteriovenous malformation. A quadrantanopia persisted in this patient. Outcome of the other two patients was good. CONCLUSION: Intracranial endovascular procedures can induce migraine with aura. We could not identify the underlying pathophysiological mechanism, but mechanical, chemical, immunological, or hemodynamic factors could be involved.

Unique echocardiographic features associated with deployment of the Amplatzer atrial septal defect device.

The purpose of this study was to describe the unique echocardiographic findings associated with deployment of the Amplatzer atrial septal defect (ASD) device. Thirty-five patients (2 to 40 years old; 23 female and 12 male patients) underwent echocardiography during attempted ASD closure with the Amplatzer device. Transesophageal and transthoracic echocardiograms were performed during the placement and follow-up of the device, respectively. In 5 patients, the device was not deployed because of transesophageal echocardiography (TEE) findings (an exceedingly large defect in 3 patients, partial obstruction of the upper right pulmonary vein by the device in 1, and complex atrial septal anatomy in 1). In the remaining 30 patients, after deployment but before release, the device distorted the atrial septum from the normal vertical orientation to an oblique transverse orientation. Excessive septal distortion (i.e., > or =90 degrees in 1 patient) was associated with device embolization upon release. In other patients, TEE also identified mild splaying of the device on the aortic wall, mild abutment of the device upon the mitral valve, and temporary partial obstruction of pulmonary vein flow. Color Doppler revealed residual shunts in 21 of 29 patients immediately after release, but in none of 15 patients at 1-year follow-up. Transesophageal echocardiography is essential to ensure proper Amplatzer device placement. Distortion of the atrial septum and Amplatzer device orientation occur before release but resolve on release from the delivery cable. Small residual shunts are common early, but they resolve in 6 to 12 months.