New anti-seizure medication for elderly epilepsy patients - a critical narrative review.

Introduction: The number of elderly patients with epilepsy is growing in resource rich countries due to demographic changes and increased longevity. Management in these patients is challenging as underlying etiology, co-morbidities, polypharmacy, age-related pharmacokinetic and pharmacodynamic changes need to be considered.Areas covered: Lacosamide, eslicarbazepine acetate, brivaracetam, and perampanel have been approved in the USA and Europe for monotherapy and/or adjunctive treatment of seizures in the last few years. The authors review the pharmacological properties and safety profile of these drugs and provide recommendations for their use in in the elderly.Expert opinion: There are only limited data available on more recent antiseizure medications (ASMs). Drugs with a low risk of interaction (lacosamide, brivaracetam) are preferred choices. Once daily formulations (perampanel and eslicarbazepine acetate) have the advantage of increased compliance. Intravenous formulations (brivaracetam and lacosamide) are useful in emergency situations and in patients who have difficulties to swallow. Dose adjustments are necessary for all ASMs used in the elderly with slow titration and lower target doses than in the regulatory trials. The adverse event profile does not significantly differ from that found in the general adult population.

HMPAO-SPECT Can Discriminate between Patients with Subjective Cognitive Complaints with and without Cognitive Deficits and those with Mild Cognitive Impairment.

BACKGROUND: Growing evidence suggests that pathological processes leading to Alzheimer's disease occurs gradually and begins to develop decades before the earliest clinical symptoms occur. The use of biomarkers has been proposed to detect evidence of preclinical Alzheimer's pathologic change in asymptomatic subjects. Subjective cognitive complaints (SCC) i.e. self-reported cognitive decline with normal cognition have been reported as an indicator of future cognitive decline, however, this condition is unspecific. OBJECTIVE: In the present study we used the regional brain perfusion measured by HMPAO-SPECT as Biomarker of neurodegeneration to compare the regional brain perfusion of patient with subjective cognitive complaints with and without minimal cognitive dysfunction (SCC+ and SCC- respectively) in respect to patients with mild cognitive impairment (MCI). METHODS: We retrospectively examined 736 Patients who referred to our Memory Clinic because of suspected cognitive dysfunction. After exclusion of patients with overt dementia, automated, quantitatively assessed relative cerebral blood flow of 10 forebrain regions (thalamus, parietotemporal, medial temporal, posterior temporal, posterior cingulate gyrus, each region left hemispheric and right hemispheric) and neuropsychological assessment of 64 SCC (32 SCC+; 32 SCC-) and 28 MCI subjects were analysed. RESULTS: .The most relevant differences between groups in cognitive performance concerned verbal memory. Left hemispheric medial temporal region could significantly discriminate between all three groups, with a progressive decrease n perfusion from SCC towards MCI. Area under the curve of left medial temporal region showed a sensitivity of 0,61 and a specificity of 0,78 for discriminating MCI from SCC. CONCLUSION: Automated analysis of HMPAO-SPECT data of MCI and SCC+ patients showed significant perfusion differences in medial temporal region and impaired verbal memory, both of which are known features of Alzheimer's disease. Perfusion patterns and verbal memory performance in SCC+ are more similar to MCI than SCC-. Thus, SPECT analysis could distinguish those subjects whose perfusion pattern resembles that of an MCI from those who do not. In our opinion, this could identify two populations with a different risk of progression to AD, with SCC+ subjects needing further diagnostic examination and repeated follow-up.

Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival.

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study).

It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer's Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

Neurosyphilis manifesting with rapidly progressive dementia: report of three cases.

Neurosyphilis is rather an unusual cause of dementia characterized by a rapidly progressive course and psychiatric symptoms. Diagnosis of neurosyphilis should be suspected in the presence of a global cognitive impairment consisting in disorientation, amnesia and severe impairment of speech and judgement and psychiatric symptoms such as depression, mania and psychosis, with a subacute onset. More commonly, clinical manifestations of neurosyphilis include general PARESIS (involvement of Personality, Affect, Reflexes, Eye, Sensorium, Intellect and Speech). Upon clinical suspicion, diagnosis of neurosyphilis is confirmed by a reactive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory. Here we report three Human Immunodeficiency Virus (HIV)-negative male patients presenting with psychiatric symptoms and a rapidly evolving dementia. Although magnetic resonance imaging did not address to diagnosis, CSF examination was mandatory in neurosyphilis diagnosis. Other diagnostic tools such as neuropsychology and single-photon emission computed tomography resulted supportive in the diagnosis. We showed that a prompt antibiotic treatment might stop disease progression. Therefore, neurosyphilis should be always considered even in HIV-negative patients in the presence of unexpected psychiatric symptoms accompanied by a rapidly evolving cognitive decline.

Fixation-off sensitivity.

Fixation-off sensitivity (FOS) is a phenomenon induced by elimination of central vision/fixation, and may either manifest clinically with seizures or only represent an EEG abnormality. FOS is characterized by posterior or generalized epileptiform discharges that consistently occur after closing of the eyes and last as long as the eyes are closed. It is most commonly encountered in patients with idiopathic childhood occipital epilepsies, but may also be observed in cases of symptomatic or cryptogenic focal and generalized epilepsies, as well as in asymptomatic non-epileptic individuals. FOS should be differentiated from pure forms of scotosensitivity, in which EEG discharges or epileptic seizures are elicited by darkness, and from epileptiform discharges triggered by eye closure, which refer to eye closure sensitivity. Although FOS is probably associated with occipital hyperexcitability its intrinsic epileptogenic potential is presumed to be low.

Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy.

Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM) patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to collect a minimum of 4 × 10(6) CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7 × 10(6) CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous transplantation in 91% of newly diagnosed patients.

Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).

The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in Italy during the European Confederation of Medical Mycology of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin B (L-AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.

The colorectal malignant polyp: scoping a dilemma.

Colorectal adenomas containing invasive carcinoma represent the majority of early colorectal cancers. The malignant polyp carries a significant risk of lympho-haematic metastasis and mortality due to the penetration of cancerous cells into the submucosal layer. The therapeutic dilemma is whether to perform endoscopic or surgical resection. A thorough assessment of the endoscopic, histological and clinical variables is needed to unravel the best treatment for each patient. In particular, a unique staging of such lesions, based on certain histopathological features, has been deeply implicated in the therapeutic choice. Aim of this article is to review the main endoscopic, histological and clinical features of the malignant polyp in order to propose a systematic management of this lesion.

Endoscopic follow-up after colorectal cancer resection: an Italian multicentre study.

BACKGROUND: Endoscopic follow-up is advised in patients operated for colorectal cancer due to a high risk for both metachronous colorectal cancer and adenomas. Such issue has been scarcely addressed in Italy. This study aimed to evaluate the incidence of neoplastic lesions at a scheduled endoscopic follow-up and to identify the patients at higher risk of recurrence. METHODS: Colorectal cancer patients diagnosed in the three participating hospitals (one North, one Centre and one South Italy) were scheduled for colonoscopies at 1, 3 and 5 years after surgery. Incidence of adenomas, advanced adenomas and colorectal cancer was assessed in all patients. Neoplastic incidence in patients with and without synchronous lesions at entry was also compared. RESULTS: Overall, 318 consecutive patients were prospectively enrolled including 108 (34%, group A) with a synchronous lesion and 210 (group B) without it. A cumulative neoplastic incidence of 20.1, 32.4 and 44% was observed at 1, 3 and 5 years of follow-up, respectively. The cumulative incidence of all the lesions was 70% in group A and 30.2% in group B at 5-year follow-up, being 39.5 and 15.5% after excluding the lesions detected at 1-year examination. A neoplastic lesion was detected more frequently in group A at 1year (30.5% versus 14.7%; p = 0.0013), 3 years (21.4% versus 7.6%; p = 0.0008) and at 5years (18.1% versus 7.8%; p = 0.02). CONCLUSIONS: Our data showed that the incidence of adenomas in patients operated for colorectal cancer is fairly high. Colorectal cancer patients with synchronous lesions are at higher risk of neoplastic recurrence at follow-up as compared to those without them.

Clinical identification and long-term surveillance of 22 hereditary non-polyposis colon cancer Italian families.

OBJECTIVE: To assess the efficacy of a hereditary non-polyposis colon cancer (HNPCC) identification and surveillance policy. METHODS: Familial clustering of colorectal cancer (CRC) and extracolonic cancers (ECs) was investigated in 1520 consecutive CRC patients and relatives. HNPCC was identified by Amsterdam criteria, and individuals at risk were offered biennial colonoscopy and other examinations, starting from age 25 years. RESULTS: Twenty-two HNPCC families were identified. The CRC prevalence was 27.8% (121/435), decreasing from 59.4% in the first generation to 24.4% and 8% in the second and third generation, respectively. Twenty-nine patients had multiple CRC and 34 patients (in 12 families) had ECs.A total of 199/331 at-risk individuals accepted surveillance. The mean follow-up was 48+/-32 months. CRCs were detected at first surveillance in four out of 199 surveilled individuals (2%); in two surveilled individuals (1%), three CRCs developed during follow-up. The overall CRC incidence was 7/199 (3.5%) in surveilled individuals and 5/132 (3.7%) in unsurveilled individuals. CRCs were less advanced in surveilled than in unsurveilled patients. Eleven individuals had 22 adenomas (one with high-grade dysplasia). Three individuals had adenomas at first surveillance; two of them and eight more individuals during surveillance. Seven surveilled individuals and six unsurveilled individuals, all belonging to families with a history of EC, had EC during the study period. All patients with CRC detected by surveillance are alive. One of the unsurveilled patients who had CRC died 18 months after the diagnosis. CONCLUSIONS: Data confirm the importance of the family history collected in each patient with CRC for identification of HNPCC and support the efficacy of repeated colonoscopies for early diagnosis and prevention of CRC in at-risk members. Reasons for surveillance failure could be an accelerated progression of small adenomas and a lesion missing at colonoscopy. Longer follow-up is required to assess the efficacy of surveillance for EC.

Cytomegalovirus infection after autologous stem cell transplantation: incidence and outcome in a group of patients undergoing a surveillance program.

This study was performed to evaluate the incidence, risk factors, and outcome of cytomegalovirus (CMV) infection in autologous stem cell transplantation (ASCT), with the aim of performing preemptive therapy in patients with antigenemia. Starting from 2001, 171 consecutive ASCTs were performed in 136 patients; 102 of these patients were seropositive for CMV at the onset of hematological disease. In all these patients, a CMV pp65 antigenemia assay was determined weekly, starting from the day when the absolute neutrophil count went above 500/microL, and until day 60 after ASCT; subsequently, antigenemia was determined only when a CMV infection was suspected. Among the 136 transplanted patients, 40 (29.4%) presented a positive antigenemia; all of them were seropositive for CMV before ASCT; and no cases of primary infection were seen. The incidence of CMV infection in the seropositive population was 40/102 (39.3%); 6 patients (5 with multiple myeloma and 1 with non-Hodgkin's lymphoma) who received 2 ASCTs developed CMV infections after both transplantations, so that positive antigenemia developed after 46/171 (26.9%) transplantations. First positive antigenemia presented a median of 32 days (range 7-57) after stem cell reinfusion. The median antigenemia level at the first appearance was 2/200,000 (range 1-1000). No significant prognostic factors could be shown. Enteritis was present in 5 patients; 2 of them also had fever, and 1 of them also had thrombocytopenia. In 5 patients fever without any other clinical signs or symptoms was present; 30 patients were asymptomatic. Fourteen patients were treated with anti-CMV drugs. CMV reactivation was successfully treated in all patients, and no patient died from CMV disease.

Gastric metaplasia and small bowel ulcerogenesis in a case of ulcerative jejunitis not related to celiac disease.

The possible relationship between gastric metaplasia and ulcerative lesions in an unusual case of ulcerative jejunitis not related to celiac disease and with extensive gastric metaplasia is discussed. Previous studies have described gastric metaplasia in duodenal ulcers on the basis of endoscopic data, and some authors maintain that acid secretion in metaplastic mucosa could represent a pathogenetic factor of ulcerogenesis, with a self-amplifying mechanism. In the absence of functional evidence, we could provide data, in a case of ulcerative jejunitis, about morphologic signs of acid secretion in gastric metaplastic epithelium using an antibody against HMFG-1, a good marker of acid-secreting fundic cells. Metaplastic areas demonstrated a focal positivity for HMFG-1, and these finding are suggestive of local acid secretion.

Multiple myeloma: comparison of two dose-intensive melphalan regimens (100 vs 200 mg/m(2)).

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.

Infliximab for treatment of steroid-refractory ulcerative colitis.

BACKGROUND: Success achieved in two subtypes of Crohn's disease has persuaded a few investigators to experiment the monoclonal anti-tumour necrosis factor antibody infliximab in the treatment of ulcerative colitis. So far, however, the results (achieved in some 30 steroid-refractory patients included in two independent full-papers) indicate a rate of initial response of 50% and of remission of 25%. AIMS: To analyse data of an open trial conducted on consecutive steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS AND METHODS: In 9 months, infliximab was given to 8 patients (4 male, 4 female aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non-responders to parenteral steroids. All received the first infliximab dose as an intravenous infusion of 5 mg/kg. RESULTS: Of the 8, 4 (50%) did not respond to the first injection and were submitted to urgent colectomy; the other four responded clinically. Two have maintained clinical remission for 7 months, without the need for steroids; both have received daily azathioprine at 2 mg/kg, and only one has received two further infliximab injections. Of the other two, one received a second injection at week 5, despite this relapsed, and underwent elective colectomy at that time; the other relapsed at 6 months and showed a partial response to a repeat infliximab infusion. Thus, the rate of sustained response is 2/8 (25%) in this study. CONCLUSION: These results, achieved in an open uncontrolled fashion, seem to reflect those of other independent studies. In our opinion, these findings warrant an in-depth reappraisal of the indication to use infliximab as rescue treatment for refractory ulcerative colitis.

Cancer surveillance in ulcerative colitis: critical analysis of long-term prospective programme.

BACKGROUND: Patients with longstanding ulcerative colitis are at increased risk of colorectal cancer. In the literature, no agreement has yet been reached regarding prevention strategies. Our report sums up a prospective study started in 1980. METHODS: A total of 65 patients affected by ulcerative colitis for more than seven years were admitted to a regular colonoscopic and biopsy follow-up programme. RESULTS: Some 20 years after the beginning of the study, 23 (35.3%) patients have been operated upon, 2 patients have died but not from cancer 29 (44.66%) patients have abandoned the programme. Only 11 (16.9%) patients have remained under colonoscopic surveillance. CONCLUSION: These results cast some doubts on the significance of such a programme and on its long-term feasibility.

Two novel mutations and a new STK11/LKB1 gene isoform in Peutz-Jeghers patients.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disorder with variable expression and incomplete penetrance characterized by mucocutaneous pigmentation, predisposition to hamartomatous intestinal polyposis, and various other neoplasms. It occurs in approximately 1 in 8,300 to 29,000 live births. In nearly 50% of patients PJS is caused by germ line mutations in the STK11/LKB1 serine/threonine kinase gene, the only kinase gene currently known to act as a tumor suppressor. We have performed a mutation search in the STK11/LKB1 gene in 8 sporadic cases and 3 PJS families using a combination of different screening techniques. We have identified four mutations, two of which I177N and the IVS2+1A->G, were previously unreported. We have also evaluated the presence of cDNA alterations by means of RT-PCR analysis and direct cDNA sequencing and have found two aberrant transcripts in a single PJS case despite the lack of any apparent genomic alteration. Finally, we report the presence of a novel STK11/LKB1 cDNA isoform observed in all the normal subjects studied as well as in the majority of the PJS patients.

Small-bowel endoscopy.

During the last year, promising results with the first clinical applications of capsule endoscopy have been reported; this is a new, revolutionary diagnostic method for endoscopic study of the small bowel. The method has chiefly been used in patients with obscure gastrointestinal bleeding, and in some cases has allowed additional diagnoses to be made in comparison with push enteroscopy, with a positive influence on patient management. New therapeutic possibilities have also been developed in push enteroscopy, emphasizing the role of this technique as an essential component of gastrointestinal endoscopy. Important innovations in enteroscopy technique have been described, aimed at increasing the depth of examination, and these will probably make it possible to extend endoscopic treatments to include the entire small bowel. Finally, numerous articles are still being published concerning intraoperative enteroscopy. It is to be hoped that, in future, the use of this invasive procedure will be based on data acquired by capsule endoscopy.