The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation.

BACKGROUND: Docetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists. Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach. METHODS: Using a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model. RESULTS: The transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model. CONCLUSIONS: Our results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.

[The acute renal and cerebral toxicity of lithium: a cerebro-renal syndrome? A case report]. / Tossicità renale e cerebrale acuta da litio:sindrome cerebro-renale? Descrizione di un caso clinico.

This descriptive report describes the case of a 50 year-old woman with bipolar disorder, whose maintenance therapy comprised risperidone, sodium valproato and lithium carbonate without any past occurrence of toxicity. Her past medical history was significant for hypertension, cardiopathy and obesity. She presented with a 1-week history of fever, increasing confusion and slurred speech. At presentation, the patient was somnolent. Laboratory investigations revealed a serum creatinine of 3,6 mg/dl, BUN 45 mg/dl serum lithium 3,0 mEq/L with polyuria defined as more than 3 litres a day. EEG and ECG were abnormal. CT brain scanning and lumbar puncture were negative for brain haemorrage or infection. Lithium toxicity causes impairment of renal concentration and encephalopathy due to lithium recirculation, a mechanism responsible for the so-called cerebro-renal syndrome, where dialysis plays an important role in treatment.The patient was treated with continous veno-venous haemodiafiltration (CVVHDF) over 35 hours with gradual improvement of her general condition and efficacy of renal concentration. Our case highlights a few important points. Lithium nefrotoxicity and neurotoxicity can cause a cerebro-renal syndrome even when serum lithium levels are not particularly raised (2,5-3,5 mEq/L). Haemodialysis is the treatment of choice to reduce the molecular mechanisms of lithium-related changes in urinary concentration and reinstate dopaminergic activity in the brain.

Recurrent partial seizures with ictal yawning as atypical presentation of Hashimoto's encephalopathy (steroid-responsive encephalopathy associated with autoimmune thyroiditis).

Hashimoto's encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare condition whose pathogenesis is unknown, though autoimmune-mediated mechanisms are thought to be involved. The prevalent neurological manifestations of this disorder are epileptic seizures and psychocognitive disorders associated with EEG alterations. High anti-thyroid antibody titers (particularly in cerebrospinal fluid) and the effectiveness of steroid therapy are usually considered to be crucial elements in the diagnostic process. We describe a 19-year-old female patient who had been referred to the psychiatric unit because of behavioral disorders characterized predominantly by delirium with sexual content. She developed recurrent focal seizures characterized by atypical ictal semiology (repetitive forceful yawning) and a rare EEG pattern (recurrent seizures arising from the left temporal region without evident "encephalopathic" activity). The presence of anti-thyroperoxidase antibodies in her cerebrospinal fluid and a good response to steroids confirmed the diagnosis of HE. The atypical presentation in the case we describe appears to widen the electroclinical spectrum of HE and highlights its importance for differential diagnosis purposes in the neuropsychiatric setting.

Differential diagnosis of endodontic-related inferior alveolar nerve paraesthesia with cone beam computed tomography: a case report.

AIM: To discuss the use of cone-beam computed tomography (CBCT) in the differential diagnosis of a case of labiomandibular paraesthesia caused by extrusion of endodontic sealer into the mandibular canal. SUMMARY: A 59-year-old woman suffering from a paraesthesia on the left posterior mandible and numbness on the left side of the lower lip was referred to an endodontic specialist 1 month after multiple root canal treatments. A panoramic radiograph revealed the presence of extruded root filling material beyond the apex of the mesial root of the mandibular left second molar and also beyond the apex of the first premolar. A cone beam computed tomography examination was undertaken, which confirmed the presence of radiopaque root canal filling material in the periapical area of the second molar, and revealed that the material was inside the mandibular canal. No extruded filling material was found inside the mental foramen beyond the apex of the first premolar tooth. KEY LEARNING POINTS: Small field of view CBCT (where possible) can be considered an effective radiographic diagnostic device when endodontic-related inferior alveolar nerve or mental foramen paraesthesia are suspected. CBCT is able to provide detailed three-dimensional images of the tooth, the root canal system and the surrounding tissue.

Intravenous Levetiracetam as first-line treatment of status epilepticus in the elderly.

BACKGROUND: Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. OBJECTIVE: The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. METHODS: We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. RESULTS/CONCLUSIONS: In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly.

Safe implementation of thrombolysis in stroke-monitoring study in Italy.

BACKGROUND AND PURPOSE: The safe implementation of thrombolysis in stroke-monitoring (SITS-MOST) study was an unique opportunity to test in Italy, where only few centres were expert in thrombolytic treatment before, safety and efficacy of i.v. alteplase within 3 h of ischaemic stroke outside the setting of clinical trials. METHODS: In Italy to participate in the study the clinical centres had to possess organizational and structural characteristics certified by Regional Health Authorities. RESULTS: Seventy-one centres were activated, 56 (79%) treated patients of which 41 (73%) had never used thrombolysis before the study. Globally, 586 patients were included. Baseline median National Institute of Health Stroke Scale of Italian patients was 13 vs. 12 in other European centres (P = 0.0001). Symptomatic intracerebral haemorrhage as per the NINDS/Cochrane definition, mortality and independence (modified Rankin Scale 0-2) rates at 3 months occurred respectively in 6.7% (95% CI: 4.8-9.1), 11.7% (9.2-14.6) and 51.6% (47.4-55.7) of Italian patients compared with 7.3% (6.7-8.0) (P = 0.56), 11.2% (10.4-12.1) (P = 0.75) and 55.1% (53.8-56.4) (P = 0.09) in the European patients and in 8.6% (40/65; 6.3-11.6), 17.3% (14.1-21.1) and 50.1% (44.5-54.7) of the patients treated in the pooled randomized controlled trials. CONCLUSIONS: The SITS-MOST study showed that in Italy i.v. alteplase is safe and effective in routine clinical use also in non-expert centres.

[Color-Doppler ultrasound in renal artery stenosis and cardiovascular risk: case report]. / Eco-color-Doppler delle arterie renali nel rischio cardiovascolare: case report.

Renal artery stenosis (RAS) is a common manifestation of generalized atherosclerosis, frequently involving other vascular districts, particularly the coronary tree. Duplex ultrasonography is the diagnostic procedure of choice for screening outpatients for RAS. We report a case of metabolic syndrome in a 63-year-old obese man with atherosclerosis and low-grade RAS that was an important sign of cardiovascular risk. In fact, cardioscintigraphy and coronary arteriography showed severe coronary artery disease. RAS is an independent predictor of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular death. In this case, duplex ultrasonography demonstrated the importance of screening for RAS as the expression of coronary artery disease.

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro.

BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2 cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2 cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2 MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.

Removable Partial Prosthesis (RPP) with acrylic resin flange for the mandibular guidance therapy.

OBJECTIVES: Patients undergoing hemimandibulectomy suffer from mandibular deviation. The purpose of this article is to describe a new therapeutic possibility for the prosthetic management of these patients using only one device both for physiotherapy and eating. METHODS: A 56-year-old man's pre-existing mandibular removable partial prosthesis was modified to use as a partial prosthesis as a device to correct mandibular deviation. In fact, two precision attachments patrix were inserted into buccal surface of partial prosthesis base and corresponding matrix were inserted into a transparent acrylic resin guide-flange. RESULTS: In this way the patient can use only one prosthesis both for physiotherapy and eating simply inserting and removing the guide flange. The transparent resin employ is important for the day by day use. CONCLUSION: This technique permits to use only one device both for mechanical correction of mandibular deviation and masticatory function while literature shows that two different devices are usually used in patients with mandibular deviation to satisfy both these functions.

Autonomic cardiovascular function and baroreflex sensitivity in patients with cervical dystonia receiving treatment with botulinum toxin type A.

OBJECTIVE: To investigate possible changes in autonomic cardiovascular regulation and cardiopulmonary baroreflex sensitivity in patients with primary cervical dystonia receiving chronic treatment with botulinum toxin type A. METHODS: Short-term power spectral analysis of heart rate and systolic blood pressure variability, high-frequency and low-frequency oscillations of heart rate variability, low frequency/high frequency ratio and baroreflex sensitivity (alpha index) were measured in 12 patients with cervical dystonia before and 2-4 weeks after botulinum toxin type A injection and compared with normative data. RESULTS: Before treatment, at rest, patients had significantly lower high frequency power than healthy subjects (p < 0.01), whereas no differences were found in low frequency power. Botulinum toxin injection in patients induced no changes in either power frequency. In patients before treatment and healthy subjects the low frequency oscillatory components increased similarly from rest to tilt (p < 0.01), but tilt induced lower low frequency values in patients than in healthy subjects (p < 0.01). In patients before treatment, the high frequency variations from rest to tilt remained unchanged, whereas in healthy subjects they decreased significantly (p < 0.01). Botulinum toxin type A injection in patients induced no changes in low frequency or high frequency powers. In patients before treatment the low frequency/high frequency ratio increased slightly from rest to tilt, but in healthy subjects increased significantly (p < 0.01). Botulinum toxin type A left the pretreatment low frequency/high frequency ratio unchanged. The alpha-index measured at rest in patients before treatment was lower than in healthy subjects (p<0.05), whereas during tilt was similar in both groups. The alpha-index measured after botulinum toxin injection in patients remained unchanged at rest and during tilt. CONCLUSIONS: Patients with cervical dystonia receiving treatment with botulinum toxin type A have mild, subclinical abnormalities in autonomic cardiovascular regulation and cardiopulmonary baroreflex sensitivity. These changes do not worsen after acute botulinum toxin type A injection.

Status epilepticus in epileptic patients. Related syndromes, precipitating factors, treatment and outcome in a video-EEG population-based study.

INTRODUCTION: Status epilepticus (SE) is frequently observed in epileptic patients. We reviewed a series of video-EEG documented SE to define the characteristics of SE in this population. MATERIALS AND METHODS: Retrospective evaluation of 50 epileptic patients with SE, revision of the electro-clinical data and therapies, and definition of the semeiological subtypes, aetiology, outcome and related epileptic syndromes. RESULTS: We identified 28 convulsive (19 focal and 9 generalized) and 22 non-convulsive (8 focal and 14 generalized) SE patients. In 13 patients, SE was situation-related (poor compliance, AED reduction, worsening seizures). In the remaining 37 patients, SE was related to the natural history of epilepsy (progression of underlying pathologies or intrinsic expression of epileptic syndromes); in these last cases, our results show a higher occurrence in cryptogenic frontal epilepsy (p=0.01). We identified two subgroups according to the duration of the event, i.e. SE lasting <12h and SE lasting >12h. Our results showed a worse response to therapy in SE lasting >12h (p=0.01), a better response to therapy in non-convulsive SE than in convulsive SE (p<0.05) and a relationship at statistical significance limit between a poor response to therapy/worse outcome and symptomatic epileptic syndromes (p=0.06). CONCLUSION: SE in epileptic patients has a wide spectrum of electro-clinical features. It may be related to the withdrawal or reduction of AEDs, or may even be the expression of the evolution of epileptic syndromes. Response to therapy is dependent on early diagnosis and therapy.

Acute and chronic effects of ethanol on cortical excitability.

OBJECTIVE: We designed this study to find out whether 5Hz repetitive transcranial magnetic stimulation (rTMS) would disclose changes in cortical plasticity after acute intake of ethanol and in patients with chronic alcohol consumption. METHODS: Ten stimuli-5Hz-rTMS trains were applied over the primary motor cortex in 10 healthy subjects before and after acute ethanol intake and in 13 patients with chronic ethanol abuse, but negative blood ethanol levels when studied. The motor evoked potential (MEP) amplitude and the cortical silent period (CSP) duration during the course of rTMS trains were measured. Short-interval intracortical inhibition (3ms) and intracortical facilitation (10ms) were studied by paired-pulse TMS in 4 healthy subjects and 4 patients. RESULTS: In healthy subjects before and after acute ethanol intake, 5Hz-rTMS produced a significant increase in the MEP size and CSP duration during rTMS. The first CSP in the train was significantly longer after than before ethanol intake. In patients 5Hz-rTMS failed to produce the normal MEP facilitation but left the CSP increase unchanged. CONCLUSIONS: Acute and chronic ethanol intake alters cortical excitability and short-term plasticity of the primary motor cortex as tested by the MEP size facilitation and CSP lengthening after 5Hz-rTMS. SIGNIFICANCE: This finding suggests that rTMS is a valid tool for investigating the effects of ethanol on cortical plasticity in humans.

Case report of adult-onset Allgrove syndrome.

Allgrove syndrome is a rare autosomal recessive disorder characterised by childhood onset, alacrima, oesophageal achalasia, adrenocortical insufficiency, neurological and occasionally autonomic involvement. Although the disease has been associated with mutations in the ALADIN gene on chromosome 12q13, it is genetically heterogeneous. The case we report is interesting because of its onset in adulthood, long duration of disease and prominent neurological dysfunctions. After the onset of neurological abnormalities the diagnosis went unrecognised for years until the patient presented for evaluation of dysphagia. The presence of achalasia with dysphagia, adrenal insufficiency, reduced tear production, optic atrophy and peripheral motor-sensory neuropathy with axonal loss led us to clinically diagnose Allgrove syndrome even though a genetic study showed no mutations in the ALADIN gene exons. The case we report shares many clinical features with Allgrove syndrome and, even with the limitations of a single case, underlines the variability in this syndrome and the need for appropriate investigations along with a multidisciplinary approach.

[A contrast with good intentions]. / Un contrasto a fin di bene.

A seventy-five-year-old woman with moderate chronic renal failure was admitted to evaluate a complex renal cyst in the frame of acquired cystic kidney disease. Computed tomography (CT) was performed without contrast media due to the risk of radiocontrast-induced nephrotoxicity. Sonographic investigation at our ultrasound unit revealed a hypoechoic lesion measuring 20x20 mm in size by conventional B-mode sonography, confirmed by NTHI. The Hypoechoic lesion was consistent with complex renal cyst or renal tumour. This finding triggered investigation with CEUS.A sulphur hexafluoride-filled microbubble contrast medium was injected intravenously. The focal lesion CES pattern was characterized by intralesional enhancement in the arterial phase. Further diagnostic imaging including CT with contrast media confirmed a lesion consistent with renal tumour. The patient underwent right-sided nephrectomy; histopathological work-up revealed a renal cell carcinoma. Contrast-enhanced sonography could be clinically useful for the differential diagnosis of kidney lesions in patients with chronic renal failure.

[Ultrasound investigation in Apulo-Lucano renal echography study group of the Italian Society of Nephrology: a cognitive report]. / Report conoscitivo sull'esecuzione dell'indagine ecografica del Gruppo di Studio di Ecografia Renale della sezione Apulo-Lucana della SIN.

The number of ultrasonography expert consultant Nephrologists is more and more increasing thanks to the contribution that this methodology has brought in both clinical and treatment fields. Up to now, a database of the ultrasonography benefits, as well as the main criteria for the interpretation of the urinary tract echographic examination has not been compiled, yet. We have therefore drawn up and distributed a questionnaire to the consultant nephrologists of the urinary tract echography study group (Apulo-Lucano division). This questionnaire is made up of 27 ultrasonography application and interpretation issues; it aims mainly at creating a common 'language' to reduce the variety of 'descriptors' currently employed by all different specialists and centres involved. 60 consultant nephrologists participated in the study, from the 29 Nephrology and Dialysis O.U.s of Puglia and Basilicata regions, where there is an active echographic service. Data collected show the key role of ultrasonography investigation for all nephrology patients, as high quality and cost efficient test procedure. Moreover, despite the fact that there are differences in echographic examination performance and interpretation, literature data show clearly that it is fundamental to follow general shared principles. The responsibility and task of those specializing in this discipline should be to allow reproduction and comparison of ultrasonographies, also among different operators and centres, and meta studies, i.e. 'a series of comparative studies', which are still very few in number.

Topiramate and cortical excitability in humans: a study with repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) delivered at 5 Hz frequency and suprathreshold intensity progressively increases the size of muscle evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. The aim of this study was to evaluate the effects of topiramate (TPM) at different doses on cortical excitability variables tested with rTMS. We tested the facilitation of the MEP size and CSP duration evoked by focal rTMS in eight patients before and after treatment with TPM at different doses for chronic neuropathic pain. In each patient, rTMS (5 Hz frequency-120% resting motor threshold) was applied at baseline and during the TPM induction phase (drug intake schedule: week I 25 mg/day, week II 50 mg/day, week III 75 mg/day, week IV 100 mg/day) and total TPM plasma concentrations were measured. The effects on the MEP size of 5 Hz-rTMS delivered over repeated sessions were tested in eight control subjects. TPM had no effect on the resting motor threshold. Antiepileptic treatment at increasing doses abolished the normal rTMS-induced MEP facilitation. ANOVA showed that this was a dose-related effect. Accordingly, in patients receiving TPM at higher doses (75 and 100 mg) rTMS failed to elicit the MEP facilitation. TPM left the progressive lengthening of the CSP during the rTMS train unchanged. In control subjects, rTMS applied over repeated sessions elicited a constant increase in MEP size. Our results suggest that TPM modulates the excitatory intracortical interneurons probably by altering rTMS-induced synaptic potentiation. These drug-induced effects are related to TPM doses and plasma concentrations. In conclusion, rTMS may be useful for quantifying the effectiveness of antiepileptic drugs and for assessing individual responses to different drugs but acting through similar mechanisms, thus combining functional neurophysiological information and laboratory data.

The SITS-MOST registry.

In September 2002 the European Medicines Evaluation Agency (EMEA) approved a licence for alteplase (rt-PA) in the treatment of ischaemic stroke within 3 h of symptom onset. One of the conditions required by the EU regulatory authorities for the official definitive approval of thrombolytic therapy was that treatment safety should be monitored over a period of three years by entering all treated patients in the SITS-ISTR (Safe Implementation of Thrombolysis in Stroke -Thrombolysis Register) web register, in accordance with a study protocol, the SITS Monitoring Study - SITS-MOST. The aims of this study are to evaluate the efficacy (in terms of functional independence for activities of daily living at three months after treatment) and safety (in terms of symptomatic intracerebral haemorrhage and death) of the thrombolytic treatment in real routine clinical practice, outside the ideal conditions of an experimental setting, and to compare the results with a systematic review from the randomised clinical trials.

Expression and heterodimer-binding activity of Ku70 and Ku80 in human non-melanoma skin cancer.

BACKGROUND: Experimental data suggest that exposure to ultraviolet radiation may indirectly induce DNA double-strand breaks. AIM: To investigate the contribution of the non-homologous end-joining repair pathway in basal and squamous cell carcinomas. METHODS: Levels of Ku70 and Ku80 proteins were determined by immunohistochemical analysis and Ku70-Ku80 heterodimer-binding activity by electrophoretic mobility shift assay. Matched pathological normal margins and skin from healthy people were used as controls. RESULTS: A significant increase in Ku70 and Ku80 protein levels was found for both tumour types as compared with normal skin (p<0.001). Squamous cell carcinoma showed increased immunostaining as compared with basal cell tumours (p<0.02). A direct correlation was found between Ku70 and Ku80 protein levels and expression of the proliferation markers Ki-67/MIB-1 (p<0.02 and p<0.002, respectively) in basal cell carcinoma. DNA binding activity was increased in basal cell carcinoma samples as compared with matched skin histopathologically negative for cancer (p<0.006). In squamous cell carcinomas, however, the difference was significant only with normal skin (p<0.02) and not with matched pathologically normal margins. CONCLUSIONS: Overall, an up regulation of the Ku70 and Ku80 protein levels seems to correlate only with tumour proliferation rate. As non-homologous end joining is an error-prone mechanism, its up regulation may ultimately increase genomic instability, contributing to tumour progression.

Use of levetiracetam in treating epilepsy associated with other medical conditions.

OBJECTIVE: This prospective, open-label study was conducted to evaluate the effectiveness, tolerability, and safety of levetiracetam in patients with epilepsy in whom unfavorable metabolism, complex drug interactions, or direct toxic effects of antiepileptic drugs (AEDs) had caused a worsening of comorbid conditions. METHODS: Study design included the introduction of levetiracetam, discontinuation of other AEDs, and a serial assessment comprising electroencephalograms and blood tests at baseline and 2, 6, and 12 months. Of 21 patients, 16 had partial and five generalized epilepsy. Concomitant pathologies were gastroenterological (six), vascular (four), endocrinological (four), or complex conditions including hematological (four) or dermatological (three) disease. A change of regimen was necessitated by drug-drug interactions in four patients, direct real or potential toxic effects of previous AEDs in 13, and a combination of interactions/toxic effects in four. RESULTS: After 12 months, 12 patients were seizure-free, nine had reductions in seizure frequency of 50-75%, and improvement in concomitant medical conditions was observed. No side effects were reported. CONCLUSION: Levetiracetam appears to be effective, well tolerated, and safe in patients with epilepsy and other medical conditions that are difficult to manage because of drug interactions or AED-related side effects.

Altered response to rTMS in patients with Alzheimer's disease.

OBJECTIVE: In this study, we tested the excitability of cortical motor areas in patients with Alzheimer's disease. Because repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability, possibly by inducing a short-term increase in synaptic efficacy, we used rTMS to investigate motor cortex excitability in patients with Alzheimer's disease. METHODS: We tested the changes in the size and threshold of motor evoked potential (MEP) and cortical silent period (CSP) duration evoked by focal rTMS delivered in 10 trains of 10 stimuli at 5Hz frequency and 120% rMth intensity in a group of patients with Alzheimer's disease, and age-matched controls. In a further session, rTMS was also delivered at 1Hz frequency (trains of 10 stimuli, 120% rMth). RESULTS: Whereas in control subjects, 5Hz-rTMS elicited normal MEPs that progressively increased in size during the train, in patients, it elicited MEPs that decreased in size. The increase in the duration of the CSP was similar in patients and healthy controls. One hertz rTMS left the MEP amplitude unchanged in patients and healthy controls. CONCLUSIONS: The lack of MEP facilitation reflects an altered response to 5Hz-rTMS in patients with Alzheimer's disease. SIGNIFICANCE: Our rTMS findings strongly suggest an altered cortical plasticity in excitatory circuits within motor cortex in patients with Alzheimer's disease.