Cortico-muscular and cortico-cortical coherence changes resulting from Perampanel treatment in patients with cortical myoclonus.

OBJECTIVE: To investigate the mechanisms by which Perampanel (PER) reduces the severity of action myoclonus, we studied on MEG signals the changes occurring in cortico-muscular coherence (CMC) and cortico-cortical connectivity in patients with progressive myoclonus epilepsies. METHODS: The subjects performed an isometric extension of the hand; CMC and cortico-cortical connectivity were assessed using autoregressive models and generalized partial-directed coherence. The contralateral (Co) sensors showing average CMC values >0.7 of the maximum (set to 1) were grouped as central (C) regions of interest (ROI), while adjacent sensors showing CMC values >0.3 were grouped as Surrounding (Sr) ROIs. RESULTS: Under PER treatment, CMC decreased on Co C and Sr ROIs, but also on homologous ipsilateral (Ip) ROIs; out-degrees and betweenness centrality increased in Co ROIs and decreased in Ip ROIs. The flow from Ip to Co ROIs and from activated muscles to Ip C ROI decreased. CONCLUSION: The improvement of myoclonus corresponded to decreased CMC and recovered leadership of the cortical regions directly involved in the motor task, with a reduced interference of ipsilateral areas. SIGNIFICANCE: Our study highlights on mechanisms suitable to treating myoclonus and suggests the role of a reduced local synchronization together a better control of distant synaptic effects.

Different patterns of movement-related cortical oscillations in patients with myoclonus and in patients with spinocerebellar ataxia.

OBJECTIVE: To assess whether different patterns of EEG rhythms during a Go/No-go motor task characterize patients with cortical myoclonus (EPM1) or with spinocerebellar ataxia (SCA). METHODS: We analyzed event-related desynchronization (ERD) and synchronization (ERS) in the alpha and beta-bands during visually cued Go/No-go task in 22 patients (11 with EPM1, 11 with SCA) and 11 controls. RESULTS: In the Go condition, the only significant difference was a reduced contralateral beta-ERS in the EPM1 patients compared with controls; in the No-go condition, the EPM1 patients showed prolonged alpha-ERD in comparison with both controls and SCA patients, and reduced or delayed alpha- and beta-ERS in comparison with controls. In both conditions, the SCA patients, unlike EPM1 patients and controls, showed minimal or absent lateralization of alpha- and beta-ERD. CONCLUSIONS: EPM1 patients showed abnormal ERD/ERS dynamics, whereas SCA patients mainly showed defective ERD lateralization. SIGNIFICANCE: A different behavior of ERS/ERD distinguished the two patient groups: the pattern observed in EPM1 suggests a prominent defect of inhibition occurring in motor cortex contralateral to activated segment, whereas the pattern observed in SCA suggested a defective lateralization attributable to the damage of cerebello-cortical network, which is instead marginal in patients with cortical myoclonus.

Early effect of dalfampridine in patients with MS: A multi-instrumental approach to better investigate responsiveness.

BACKGROUND: 4-aminopyridine (4-AP) is a potassium-channel blocker able to enhance walking speed in MS improving the action potentials of demyelinated axons on which internodal potassium channels are exposed. OBJECTIVE: to study early 4-AP effect with clinical, subjective, neurophysiological and neuroradiological tools. METHODS: Clinical (Timed 25-Foot Walk - T25FW, Timed Up-And-Go - TUG), subjective (MS Walking Scale-12 - MSWS-12), neurophysiological (Motor Evoked Potentials - MEPs) and imaging (Diffusion Tensor Imaging - DTI) evaluations were performed before (T0) and after (T1) 14days of 4-AP treatment. MEPs were recorded from Abductor Hallucis of both legs. A Tract-Based-Spatial-Statistics (TBSS) was performed on DTI. RESULTS: We found a significant difference between T0 and T1 for T25FW, TUG, MSWS-12 (p≤0.001) in the whole patients' sample (23 subjects, median EDSS 6.0) and decrease of Central Motor Conduction Time and increase of mean Amplitude (Amp) at T1 (p=0.008 and p=0.006). We also recorded a significant difference of T25FW, TUG, MSWS-12 and Amp in clinical responder (CR) patients (CR: amelioration >20% at T25FW). TBSS showed a significant Mean and Radial Diffusivity reduction in the corticospinal tracts (p<0.05) of the whole group of patients; this reduction was also found in the CR subgroup. CONCLUSION: Neurophysiological and neuroradiological parameters were modified in MS patients treated with 4-AP, and most of them reported a subjective improvement of their motor performances after treatment. The use of clinical, subjective, neurophysiological and neuroradiological tools could help to better explore MS patients responsiveness to 4-AP.

The impact of chorionicity and type of conception on maternal-neonatal outcome in twin pregnancies.

PURPOSE OF INVESTIGATION: To evaluate the maternal and neonatal outcomes in twin pregnancies according to chorionicity (monochorionic (MC) versus dichorionic (DC) and type of conception [spontaneously conceived (SC) versus assisted reproduction technology (ART)]. MATERIALS AND METHODS: A retrospective study of 196 twin pregnancies admitted to the Department of Gynecology, Obstetrics and Urology of the University of Rome Sapienza, from January 2008 to April 2013. RESULTS: There were 55 MC and 141 DC twin pregnancies (82 SC and 59 ART). MC twin pregnancies had a higher incidence of preterm birth (p < 0.008), twin-twin transfusion syndrome (TTTS) (p < 0.021), and intrauterine growth restriction (IUGR) (p < 0.05). MC pregnancies had lower neonatal birth weight (p < 0.05), and lower Apgar score. ART DC pregnancies had a higher incidence of preterm delivery (p < 0.05). CONCLUSIONS: MC twin pregnancy is associated with higher risk of adverse maternal and perinatal outcomes. In the DC subgroup, ART is associated to a higher incidence of preterm delivery.

Histologic transformation in marginal zone lymphomas†.

BACKGROUND: Histologic transformation (HT) is a poorly understood event in patients with marginal zone lymphoma (MZL). The aim of this study was to analyze incidence and risk factors for HT in a large series of MZL patients. PATIENTS AND METHODS: The studied cohort included 340 MZL patients diagnosed and treated between 1995 and 2012: 157 extranodal MZLs [mucosa-associated lymphoid tissue (MALT) lymphoma, 46%], 85 splenic MZLs (SMZLs, 25%) and 37 nodal MZLs (NMZLs, 11%). Sixty-one patients (18%) had bone marrow infiltration at presentation, with or without detectable involvement of peripheral blood, but without other involved sites; they were considered clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ). RESULTS: With a median follow-up of 4.8 years, the median overall survival and progression-free survival of the whole population were 14.5 and 5 years, respectively. HT was observed in 13 cases [3.8%, 95% confidence interval (95% CI) 2%-6.5%]. Elevated lactate dehydrogenase (LDH) at diagnosis was associated with the risk of HT (P = 0.019). HT occurred in 5% of SMZLs, 4% of MALT lymphomas, 3% of NMZLs and 3% of CBL-MZ (P = 0.974). The risk of HT was 5% (95% CI 3-9%) at 5 and 10 years after diagnosis and 10% (95% CI 5%-20%) at 12 years. At the time of HT, most patients had high LDH and B symptoms. At a median follow-up of 12 months after HT, 4 of 13 patients died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 57% (95% CI 13%-86%). CONCLUSIONS: In this large retrospective series, the risk of HT across all MZL types appeared lower than the one reported for follicular lymphoma.

Life expectancy of young adults with follicular lymphoma.

BACKGROUND: This study was aimed at investigating the clinical features and outcomes of follicular lymphoma (FL) patients younger than 40 years, which have not been extensively investigated yet. PATIENTS AND METHODS: One hundred and fifty-five patients younger than 40 years were retrospectively studied from a series of 1002 FL patients diagnosed in four different European Oncology Centres (Barcelona, Spain; Bellinzona, Switzerland; London, UK; Novara, Italy) from 1985 to 2010. RESULTS: Patients younger than 40 had a lower incidence of elevated LDH, high beta2-microglobulin, and a high-risk Follicular Lymphoma International Prognostic Index (FLIPI) score, whereas bone marrow involvement and bulky and disseminated lymphadenopathy were more frequent. At a median follow-up of 10 years, younger patients, in comparison with those older than 40, had significantly better overall (OS), cause-specific survival (CSS), and progression-free survival (PFS), with 10-year OS rate of 81% versus 51% (P < 0.0001), 10-year CSS rate of 82% versus 60% (P < 0.0001), and 10-year PFS of 39% versus 24% (P = 0.0098). However, there were no significant CSS and PFS differences in comparison with the patients aged 40-60. In multivariate analysis, having the lymphoma diagnosed in the last two decades and a favourable FLIPI score were associated with a significantly longer PFS and CSS in younger patients, whereas only FLIPI retained statistical significance for OS. CONCLUSIONS: In our series, FL patients younger than 40 have a median OS of 24 years and their outcome seems to be improving over time. However, they still have a significantly shorter life expectancy than that of an age-matched general healthy population.

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study.

Multimodal human brain mapping has been proposed as an integrated approach capable of improving the recognition of the cortical correlates of specific neurological functions. We used simultaneous EEG-fMRI (functional magnetic resonance imaging) and EEG-TD-fNIRS (time domain functional near-infrared spectroscopy) recordings to compare different hemodynamic methods with changes in EEG in ten patients with progressive myoclonic epilepsy and 12 healthy controls. We evaluated O2Hb, HHb and Blood oxygen level-dependent (BOLD) changes and event-related desynchronization/synchronization (ERD/ERS) in the α and ß bands of all of the subjects while they performed a simple motor task. The general linear model was used to obtain comparable fMRI and TD-fNIRS activation maps. We also analyzed cortical thickness in order to evaluate any structural changes. In the patients, the TD-NIRS and fMRI data significantly correlated and showed a significant lessening of the increase in O2Hb and the decrease in BOLD. The post-movement ß rebound was minimal or absent in patients. Cortical thickness was moderately reduced in the motor area of the patients and correlated with the reduction in the hemodynamic signals. The fMRI and TD-NIRS results were consistent, significantly correlated and showed smaller hemodynamic changes in the patients. This finding may be partially attributable to mild cortical thickening. However, cortical hyperexcitability, which is known to generate myoclonic jerks and probably accounts for the lack of EEG ß-ERS, did not reflect any increased energy requirement. We hypothesize that this is due to a loss of inhibitory neuronal components that typically fire at high frequencies.

Significance of multiple neurophysiological measures in patients with chronic disorders of consciousness.

OBJECTIVE: The aim of this study was to verify the value of multiple neurophysiological tests in classifying disorders of consciousness (DOCs) in patients in a chronic vegetative or minimal consciousness state categorised on the basis of the Coma Recovery Scale (CRS). METHODS: The study included 142 patients, all of whom underwent long (18h) EEG-polygraphic recordings including one night. The EEG was scored using the Synek scale and sleep patterns using an arbitrary scale. Absolute total power and relative EEG power were evaluated in different frequency bands. Multimodal evoked potentials (EPs), including auditory event-related potentials, were also evaluated and scored. RESULTS: The most information came from the combined multimodal EPs and sleep EEG scores. A two-step cluster analysis based on the collected information allowed a satisfactory evaluation of DOC severity. Spectral EEG properties seemed to be significantly related to DOC classes and CRS scores, but did not seem to make any significant additional contribution to DOC classification. CONCLUSIONS: Multiple electrophysiological evaluations based on EEG, sleep polygraphic recordings and multimodal EPs are helpful in assessing DOC severity and residual functioning in patients with chronic DOCs. SIGNIFICANCE: Simple electrophysiological measures that can be easily applied at patients' bedsides can significantly contribute to the recognition of DOC severity in chronic patients surviving a severe brain injury.

Management of hydrosalpinx before IVF: a literature review.

Hydrosalpinx has a detrimental effect on the outcome of in vitro fertilization (IVF). Surgical intervention such as salpingectomy or tubal occlusion before IVF improves the outcome of IVF, but these procedures are often contraindicated in women with dense pelvic adhesions. Thus, it is worthwhile to search minimally invasive alternative therapies. The main objective of this review is to assess and compare the value of all the therapeutic options for hydrosalpinx before IVF. The results of the following procedures were compared: the laparoscopic treatments (salpingectomy/proximal tubal occlusion), the hysteroscopic insertion of device achieving tubal occlusion, the tuberous sclerosis and the aspiration of hydrosalpingeal fluid at the time of IVF procedure. Laparoscopic surgical treatment should be considered for all women with hydrosalpinx before IVF. Whenever laparoscopy is not recommended, hysteroscopic insertion of device seems the most effective option for management of hydrosalpinx before IVF.

The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL).

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

Giant SEPs and SEP-recovery function in Unverricht-Lundborg disease.

OBJECTIVE: To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht-Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800. METHODS: We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600 ms in 25 patients and 20 controls. The SEPs were considered "giant" if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD. RESULTS: During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100 ms) wave pertaining to the S1 response. CONCLUSIONS: The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli. SIGNIFICANCE: The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R.

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion.

BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.

Music and emotion: an EEG connectivity study in patients with disorders of consciousness.

Human emotion perception is a topic of great interest for both cognitive and clinical neuroscience, but its electrophysiological correlates are still poorly understood. The present study is aimed at evaluating if measures of synchronization and indexes based on graph-theory are a tool suitable to study and quantify electrophysiological changes due to emotional stimuli perception. In particular, our study is aimed at evaluating if different EEG connectivity patterns can be induced by pleasant (consonant) or unpleasant (dissonant) music, in a population of healthy subjects, and in patients with severe disorders of consciousness (DOCs), namely vegetative state (VS) patients. In the control group, pleasant music induced an increase in network number of connections, compared with the resting condition, while no changes were caused by the unpleasant stimuli. However, clustering coefficient and path length, two indexes derived from graph theory, able to characterise segregation and integration properties of a network, were not affected by the stimuli, neither pleasant nor unpleasant. In the VS group, changes were found only in those patients with the less severe consciousness impairment, according to the clinical assessment. In these patients a stronger synchronization was found during the unpleasant condition; moreover we observed changes in the network topology, with decreased values of clustering coefficient and path length during both musical stimuli.Our results show that measures of synchronization can provide new insights into the study of the electro physiological correlates of emotion perception, indicating that these tools can be used to study patients with DOCs, in whom the issue of objective measures and quantification of the degree of impairment is still an open and unsolved question.

Abnormal ERD/ERS but unaffected BOLD response in patients with Unverricht-Lundborg disease during index extension: a simultaneous EEG-fMRI study.

Electrophysiological studies indicate that Unverricht-Lundborg's disease (ULD), the most common form of progressive myoclonus epilepsy in Europe, is characterized by the involvement of multiple cortical regions in degenerative changes that lead to enhanced excitation and deficient inhibition. We searched for the haemodynamic correlates of these effects using functional MRI (fMRI) of self-paced index extensions, a well-accepted task highlighting significant differences. EEG and fMRI were simultaneously acquired in 11 ULD patients and 16 controls, performing the index extensions individually (event-related task) as well as repetitively (block task). ERD/ERS analysis was performed for the EEG data in the alpha and beta bands. fMRI time-series were analyzed using the traditional general linear model, as well as with an assumption-free approach, and by means of cross-region correlations representing functional connectivity. In line with the existing literature, ULD patients had enhanced desynchronization in the alpha band and reduced post-movement synchronization in the beta band. By contrast, fMRI did not reveal any difference between the two groups; there were no activation intensity, latency or extent effects, no significant engagement of additional regions, and no changes to functional connectivity. We conclude that, so long as the patients are executing a task which does not induce obvious action myoclonus, the hypothesized abnormalities in pyramidal neuron and interneuron dynamics are relatively subtle, embodied in processes which are not metabolically-demanding and take place at a time-scale invisible to fMRI.

Event-related potential (ERP) markers of melodic processing: The N2 component is modulated by structural complexity, not by melodic 'meaningfulness'.

Previous studies have demonstrated that the event-related potential (ERP) evoked by a note shows substantial differences depending on whether the note is part of a melodic context or presented in an unstructured repetition. In particular, the N2 component has been found to have considerably increased latency and a more frontal topography for notes presented in a melody. An open question is whether such effect is related to the 'meaningfulness' of a note sequence, that is due to the formation of abstract melodic entities, rather than more simply an indicator of cognitive load associated with processing a structurally-complex sequence as opposed to an unstructured repetition. In this study, we addressed this issue by recording ERPs from 10 healthy non-musicians listening to eight one-part unfamiliar tonal melodies and eight sequences of random notes. The two stimuli were matched for distribution of pitch, intervals and note duration as well as for entropy of the time-series of pitch and duration. While tonal melodies were rated more meaningful (p<0.001) and pleasant (p<0.001) by all participants, no effects were found for the N2 component amplitude (p> or =0.8) and latency (p=0.2). Combined with previous findings, this indicates that the N2 evoked by each individual note responds to the structural complexity of the note sequence, i.e., to the presence of pitch and duration changes, but not to higher-level processing related to the formation of abstract melodic entities. In contrast, we found that the amplitude of the P2 component was marginally (p=0.04) elevated for random notes as compared to tonal melodies. This may be related to attentional modulation, or more specifically to associative components of auditory processing.

Photosensitive epilepsy: spectral and coherence analyses of EEG using 14Hz intermittent photic stimulation.

OBJECTIVE: To evaluate the EEG recorded in photosensitive idiopathic generalised epilepsy (IGE) patients at rest and during 14Hz IPS, frequency capable of inducing photoparoxysmal responses (PPRs). METHODS: Power spectrum density and coherence profiles were estimated using a block autoregressive parametric model (AR) in 28 patients and 22 controls. RESULTS: At rest, the intra- and inter-hemispheric coherence spectra showed a significantly larger number of coherence peaks in the gamma band in patients with respect to controls. During intermittent photic stimulation (IPS), coherent gamma activity is mainly presented as IPS frequency harmonics; moreover, the patients' mean coherence values significantly increased. In six patients re-evaluated with IPS after putting on glasses with Z1 blue lens (which counteracts PPR) the spectral and coherence profiles tended to return to the resting ones. CONCLUSIONS: Patients are endowed with inherited EEG hyper-synchrony as shown by the large number of coherence peaks detectable under resting conditions, whereas IPS enhances intra- and inter-hemispheric mean coherence values in the gamma band. The persistence of alpha activity peaks during IPS in most controls but not in patients suggests that the alpha generating network plays a significant role in counteracting PPR. SIGNIFICANCE: Both gamma and alpha EEG generators are involved in the PPR generation and in the widespread synchronisation characterising the IGE-associated photosensitivity.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21.

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.

Progressive myoclonic ataxia with intrathecal immune activation in six patients.

In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2-6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients' disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia.

Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls.

Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.