Citations

AbstractThe spectrum of presentation of neuromyelitis optica (NMO) is now recognized as being more diverse than defined by current diagnostic criteria, and includes limited forms of optic neuritis and transverse myelitis, as well as other brain syndromes. Discovery of a specific biomarker, autoantibodies targeting aquaporin‐4, facilitated the recognition of this broader spectrum of disease. Brain magnetic resonance imaging lesions in NMO might be relatively specific or entirely non‐specific. The most specific lesions are lesions of the area postrema or hypothalamus, longitudinally extensive corpus callosum lesions, and long corticospinal tract lesions in the corona radiata and brainstem. Although the full spectrum of aquaporin‐4‐associated disease based on population‐based serological studies remains undefined, studies from service testing laboratories show that the vast majority of patients have had optic neuritis and myelitis or one of the now well‐accepted signature syndromes of NMO, such as intractable vomiting or hiccough, although ascertainment bias undoubtedly influences this conclusion. New diagnostic criteria based on deliberations of an international panel of experts are anticipated shortly. Almost certainly, new criteria will allow for diagnosis of NMO based on a single episode of a “signature” syndrome of NMO. Nevertheless, in the face of a syndrome that is less characteristic and less well associated with NMO, especially if associated with other disease entities, caution is necessary.

AbstractBackground & AimsNon‐ischaemic cardiomyopathy (NIC) is an early complication of liver transplantation (LT). Our aims were to define the prevalence, associated clinical factors, and prognosis of this condition.MethodsA retrospective study was performed on patients undergoingLTat our institution from January 2005 to December 2012. Patients who developedNICwere identified. Data collected included demographic and clinical data.ResultsA total 1460 transplants were performed in this period and seventeen patients developedNIC. Pretransplant medianQTc interval was 459 (range, 405–530), and median E/A ratio was 1 (range, 0.71–1.67). Fourteen patients (82%) were severely malnourished and required nutritional support. Thirteen patients (76%) had renal insufficiency. Median time to onset was 2 days post‐transplant (range, 0–20). Echocardiograms showed global left ventricular hypokinesis and a decrease in ejection fraction (EF) from a median of 65% (range, 50–81) pretransplant to a median of 21% (range, 15–32). Median raw model for end‐stage liver disease (MELD) score was 29 in patients withNICvs. 18 in patients without cardiomyopathy (P = 0.01). There was no significant difference between recipients withNICvs. recipients without cardiomyopathy regarding donor age, donor risk index, and cold and warm ischaemia time. Recovery of cardiac function occurred in 16 patients, with a medianEFof 44% (range, 25–65%) at the time of discharge. The last echocardiogram available showed a medianEFof 59% (range, 49–73%). One‐year survival of NIC patients was 94.1%.ConclusionNon‐ischaemic cardiomyopathy is a rare complication afterLT. Patients withNICare critically ill, with highMELDscore, and severe malnutrition.

IntroductionAdjudication of thousands of implantable cardioverter defibrillator (ICD)‐treated arrhythmia episodes is labor intensive and, as a result, is most often left undone. The objective of this study was to evaluate an automatic classification algorithm for adjudication of ICD‐treated arrhythmia episodes.MethodsThe algorithm uses a machine learning algorithm and was developed using 776 arrhythmia episodes. The algorithm was validated on 131 dual‐chamber ICD shock episodes from 127 patients adjudicated by seven electrophysiologists (EPs). Episodes were classified by panel consensus as ventricular tachycardia/ventricular fibrillation (VT/VF) or non‐VT/VF, with the resulting classifications used as the reference. Subsequently, each episode electrogram (EGM) data was randomly assigned to three EPs without the atrial lead information, and to three EPs with the atrial lead information. Those episodes were also classified by the automatic algorithm with and without atrial information. Agreement with the reference was compared between the three EPs consensus group and the algorithm.ResultsThe overall agreement with the reference was similar between three‐EP consensus and the algorithm for both with atrial EGM (94% vs 95%, P = 0.87) and without atrial EGM (90% vs 91%, P = 0.91). The odds of accurate adjudication, after adjusting for covariates, did not significantly differ between the algorithm and EP consensus (odds ratio 1.02, 95% confidence interval: 0.97–1.06).ConclusionsThis algorithm performs at a level comparable to an EP panel in the adjudication of arrhythmia episodes treated by both dual‐ and single‐chamber ICDs. This type of algorithm has the potential for automated analysis of clinical ICD episodes, and adjudication of EGMs for research studies and quality analyses.

Aims Citalopram ( CT ) and escitalopram ( S ‐ CT ) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder ( MDD ). We applied a genome‐wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S ‐ CT and their metabolites in MDD patients treated with CT or S ‐ CT . Methods Our genome‐wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within‐subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single‐nucleotide polymorphisms ( SNPs ) were modelled as additive allelic effects. Results Genome‐wide significant associations were observed for S ‐ CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10 −9 ) and with S ‐didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10 −16 ), supporting the important role of these cytochrome P450 ( CYP ) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. Conclusions In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome‐wide association study performed in MDD patients treated with CT or S ‐ CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.

Background The study aims to compare methods of determining headache directionality (imploding, exploding, and/or ocular headaches) in women with migraine, investigate the concordance between physician assignment and patient self‐assignment of pain directionality, and evaluate whether patients assigned their headaches to the same direction when queried using different methods. Directionality of migraine headache pain (imploding, exploding, or ocular) may reflect differences in the underlying pathogenesis of individual migraine attacks among and within individuals. Emerging evidence suggests that directionality of pain in migraine sufferers may predict response to onabotulinumtoxin A . The best method of determining headache directionality in migraine sufferers has not been systematically explored. Methods We conducted a prospective cross‐sectional survey study of 198 female patients with migraine presenting to a W omen's H ealth C linic. Patients determined the directionality (imploding, exploding, and/or ocular) of their own migraine pain by choosing among 3 pictures graphically representing directionality and also by responding to a written question regarding directionality. Clinicians then classified directionality of migraine pain using structured interviews. Concordance between clinician assignment of directionality and patient self‐assignment was determined with K appa coefficients. Results Subjects were females between the ages of 18 and 77 years (mean 48 years). According to patient selection of representative pictures, 62 (31.6%) had imploding headaches with or without ocular pain, 36 (18.4%) had exploding headaches with or without ocular pain, 78 (39.8%) had ocular pain only, and 20 (10.2%) had imploding and exploding headaches with or without ocular pain. Two subjects did not respond. According to patient responses to a written question, 80 (41.0%) had imploding headaches with or without ocular pain, 53 (27.2%) had exploding headaches with or without ocular pain, 46 (23.6%) had ocular pain only, and 16 (8.2%) had imploding and exploding headaches with or without ocular pain. Three subjects did not respond. For physician assignment, 69 (34.9%) subjects had imploding headaches with or without ocular pain, 89 (45%) had exploding headaches with or without ocular pain, 14 (7.1%) had ocular pain only, and 26 (13.1%) had imploding and exploding headaches with or without ocular pain. The concordance ( K appa coefficient) between physician assignment of headache directionality with patient response to the written question was 0.33 (weak agreement), between physician assignment and patient assignment via selection of representative pictures was 0.35 (weak agreement), and between patient assignment via written question and via selection of representative pictures was 0.35 (weak agreement). Conclusions The assignment of headache directionality varied substantially depending upon the method of determination. The concordance between clinician assignment, patient‐self assignment via answering a written question, and patient self‐assignment via choosing a representative picture was weak. Improved methods of determining pain directionality are needed.

ABSTRACT There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls ( Δ 0.02; 95% confidence interval [CI]: −0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: −0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss. © 2014 International Parkinson and Movement Disorder Society

Disease overview: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome.Diagnosis: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria.Risk stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the PCD is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy.Risk‐adapted therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3–6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti‐VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. Am. J. Hematol. 89:214–223, 2014. © 2014 Wiley Periodicals, Inc.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.