This retrospective study assessed long‐term effectiveness of add‐on perampanel (PER) in patients with Lennox–Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse ...in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure‐free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty‐seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty‐six patients (41.4%) were responders during a median follow‐up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow‐up. This study provides real‐world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.
The clinical, electroencephalographic, and genetic findings are reported for three pairs of monozygotic twins who developed infantile spasms in their first year. In all three pairs, the spasms ...started on the same day in each member of the pair. Neither sequencing of the ARX and CDKL5 (alias STK9 ) genes nor array comparative genomic hybridization assessment revealed any abnormalities. The long-term outcome was poor in all twins, although with different severity in individual pairs. These findings suggest that genes other than those currently known likely play a role in predisposition to infantile spasms, and that genetic susceptibility is linked to a variable phenotypic expression, ranging from quite benign to very severe, in monozygotic twins with no other apparent risk factors.
In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical ...management.
We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES.
We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project.
Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ± 19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ± 7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project.
Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.
Using two specific and sensitive fluorometric/HPLC methods and a GC‐MS method, alone and in combination with D‐aspartate oxidase, we have demonstrated for the first time that N‐methyl‐D‐aspartate ...(NMDA), in addition to D‐aspartate (D‐Asp), is endogenously present as a natural molecule in rat nervous system and endocrine glands. Both of these amino acids are mostly concentrated at nmol/g levels in the adenohypophysis, hypothalamus, brain, and testis. The adenohypophysis maximally showed the ability to accumulate D‐Asp when the latter is exogenously administered. In vivo experiments, consisting of the i.p. injection of D‐Asp, showed that D‐Asp induced both growth hormone and luteinizing hormone (LH) release. However, in vitro experiments showed that D‐Asp was able to induce LH release from adenohypophysis only when this gland was co‐incubated with the hypothalamus. This is because D‐Asp also induces the release of GnRH from the hypothalamus, which in turn is directly responsible for the D‐Asp‐induced LH secretion from the pituitary gland. Compared to D‐Asp, NMDA elicits its hormone release action at concentrations ~100‐fold lower than D‐Asp. D‐AP5, a specific NMDA receptor antagonist, inhibited D‐Asp and NMDA hormonal activity, demonstrating that these actions are mediated by NMDA receptors. NMDA is biosynthesized from D‐Asp by an S‐adeno‐sylmethionine‐dependent enzyme, which we tentatively denominated as NMDA synthase.—D‧Aniello, A., Di Fiore, M. M., Fisher, G. H., Milone, A., Seleni, A., D'Aniello, S., Perna, A. F., Ingrosso, D. Occurrence of D‐aspartic acid and N‐methyl‐D‐aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release. FASEB J. 14, 699–714 (2000)
Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative ...neoplasm (MPN) observed in the adhering centers.
Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades.
Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005.
Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II).
The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p <0.001; clonality tests (JAK2 and/or others): 80% vs 9%, p<0.001; cytogenetic evaluation: 55% vs 57%, p 0.58; abdominal echography: 46% vs 41%, p 0.016.
The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p <0.001; age >60 years in 50% vs 45% of cases, p <0.01); a similar rate of prior thrombosis (19% vs 19%), prior hemorrhage (3% vs 4%), CVRFs 69% vs 66%), splenomegaly (25% vs 25%), and hepatomegaly (22% vs 24%); a lower rate of disease-related symptoms (36% vs 40%, p 0.04); a higher rate of comorbidities (55% vs 51%, p 0.03).
Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p <0.001; <600 x 109/L in 22% vs 14% of cases, p <0.001); a similar white blood cell (WBC) count (median 8.6 vs 8.5 x 109/L; >10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004.
In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p<0.001): AntiPLT 29% vs 24%, CYT 13% vs 16%, CYT+AntiPLT 49% vs 46%, CYT ± AntiPLT 62% vs 62%, AntiPLT ± CYT 78% vs 69%.
The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively.
The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age (>60 and 40-60 vs <40 years, p <0.001), higher PLT count (>1000 and 700-1000 vs <700 x 109/L, p <0.001), prior thrombosis (p <0.001), symptoms (p <0.001). Noteworthy, no relationship was found with JAK2 mutation, and WHO diagnosis.
Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%).
The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count >700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs.
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Gugliotta:SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.
Background: The relationship between prior trauma and primary adult-onset dystonia is not well understood. Previous uncontrolled observations and exploratory case–control studies have yielded ...contradictory results. Objective: To analyse the association between cranial dystonia and prior head trauma. Methods: An ad hoc multicentre case–control study was performed using a semistructured interview to collect detailed information on the history of head trauma before disease onset in five Italian tertiary referral centres for movement disorders. The presence of a history of head trauma and of post-traumatic sequelae (loss of consciousness, bone fractures, scalp/facial wounds) before disease onset was recorded from 177 patients with primary adult-onset cranial dystonia and from 217 controls with primary hemifacial spasm matched by age strata and sex. Differences between groups were assessed by Mann–Whitney U test and Fisher’s exact test, and the relationship between prior head trauma and case/control status was analysed by multivariate logistic regression models. Results: No association was found between vault/maxillofacial trauma and cranial dystonia. Most reported traumas occurred several years before disease onset. None of the main post-traumatic sequelae altered the chance of developing cranial dystonia compared with patients with primary hemifacial spasm, nor did head trauma modify the age at onset of cranial dystonia. Conclusions: These results do not support prior head trauma as a possible environmental factor modifying the risk of developing late-onset cranial dystonia. The lack of association may have pathogenetic and medical–forensic implications.
Gene rearrangements activating the RET proto-oncogene are frequently associated with human thyroid carcinomas belonging to the papillary subtype. These arrangements cause the fusion of the ...tyrosine-kinase domain of RET to the 5'-terminal region of different genes creating the RET/PTC chimeric oncogenes. Here we report the generation of transgenic mice lines expressing the RET/PTC1 oncogene under the control of the thyroid-specific rat thyroglobulin promoter. RET/PTC1-transgenic mice developed thyroid tumors displaying the histological aspect of papillary carcinomas. These tumors were slowly progressive and did not cause premature death of the animals. Two additional mice developed areas of thyroid hyperplasia. Immunohistochemical and reverse-transcriptase polymerase chain reaction analyses confirmed the thyroid-specific expression of the transgene. Given the frequency of activating rearrangements of RET in human papillary thyroid carcinomas we conclude that this animal system could be a good model for studying the neoplastic progression of thyroid carcinomas.
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