Cortical damage in brains of patients with adult-form of myotonic dystrophy type 1 and no or minimal MRI abnormalities

Objective To evaluate, by using quantitative MRI metrics, subtle cortical changes in brains of patients with the adult form of myotonic dystrophy type I (DM1) who showed no or minimal abnormalities on MRI. Background DM1 is an autosomal dominant multisystem disorder caused by the expansion of CTG repeats in the myotonic dystrophy-protein kinase gene. Mild to severe involvement of the CNS can be part of the clinical features of the disease. Several MRI studies have demonstrated that both focal white matter (WM) lesions and diffuse grey matter atrophy can be found in the brains of DM1 patients. However, whether these two processes are related or may occur independently is not clear. Design/Methods Ten genetically-proven DM1 patients who showed no or minimal abnormalities on MRI underwent a new brain MRI examination to obtain computerized measures of total and regional brain volumes normalized to head size and regional measurements of the magnetization transfer ratio (MTr). Results Normalized brain volumes (NBV) were significantly (p < 0.0001) lower in DM1 subjects than in a group of age- and sex-matched normal controls. Normalized cortical volumes (NCV) also were lower (p = 0.003) in DM1 subjects than in normal controls, whereas normalized WM volumes were not different between the two groups (p = 0.3). In agreement with this, values of MTr in the neocortex (cortical-MTr) were significantly (p = 0.006) lower in DM1 patients than in normal controls and this difference was not found in the WM tissue (p = 0.8). Conclusions Neocortical damage seems to be evident in the absence of visible WM lesions suggesting that a neocortical pathology, unrelated to WM lesion formation, occurs in DM1 brains. Received in revised form: 29 January 2006     

Lennox-Gastaut syndrome with late-onset and prominent reflex seizures in trisomy 21 patients

Purpose:   Lennox-Gastaut syndrome (LGS) is a severe epileptic condition characterized by multiple seizure types including tonic seizures, slow spike-and-wave discharges on electroencephalography (EEG), and cognitive impairment. LGS can occur in apparently healthy subjects or in patients with preexisting brain damage. The onset peaks between 3 and 5 years of age and the prognosis is usually poor. Herein we report 13 subjects with trisomy 21 who developed LGS.
Methods:   We retrospectively reviewed the clinical and EEG data of consecutive patients with LGS and trisomy 21 referred to five epilepsy centers over the last 30 years.
Results:   Data for 13 patients (8 male, 5 female) were collected. The mean age at onset was 9.1 years (range 5–16). The mean age at last follow-up was 23.5 years (range 11–43 years). Seizure onset was after age 8 years in eight (62%) patients and between age 5 and 8 in the other five. In none of the cases did a West syndrome precede the onset of LGS. Nine of 13 patients (69%) had unambiguous reflex seizures, mostly precipitated by sudden unexpected sensory stimulations, usually preceding or accompanying the onset of a full-blown LGS picture. Interictal and ictal EEG findings were typical for LGS. All patients were drug-resistant.
Discussion:   Patients with trisomy 21 may present a peculiar LGS, characterized by late onset and high occurrence of reflex seizures. Mechanisms underlying this particular presentation of LGS may include dendritic rarefaction and decreased interneurons, as well as functional abnormalities leading to overall decreased brain inhibition in these patients.     

Effect of thalidomide on signal transduction pathways and secondary damage in experimental spinal cord trauma

TNF-alpha seems to play a central role in the inflammatory process of spinal cord injury. We tested the neuroprotective effects of thalidomide, an immunomodulatory agent that inhibits TNF-alpha production, which have not been investigated so far. The aim of our study was to evaluate the therapeutic efficacy of thalidomide in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a 4-level T5 to T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production that is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, apoptosis, and disease. Thalidomide treatment significantly reduced the degree of: 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase evaluation); 3) iNOS, nitrotyrosine, lipid peroxidation, and cytokine expression (TNF-alpha and IL-1beta); 4) apoptosis (terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, and Bax and Bcl-2 expression); and 5) nuclear factor-kappaB activation. In a separate set of experiments, we have also clearly demonstrated that thalidomide significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with thalidomide reduces the development of inflammation and tissue injury events associated with spinal cord trauma.     

TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome

The aim of our study was to evaluate in vivo the therapeutic efficacy of genetic inhibition of TNF-alpha using TNF-R1 knockout mice in an experimental model of spinal cord trauma. Spinal cord injury was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. To elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-alpha, we also investigated the effect of infliximab, a TNF-alpha-soluble receptor construct, on spinal cord damage. Pharmacological and genetic TNF-alpha inhibition significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (evaluated by myeloperoxidase activity), (3) cytokine expression (TNF-alpha), (4) and apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and Fas-L expression). In a separate set of experiments, we have also demonstrated that TNF-alpha inhibition significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results demonstrate that inhibition of TNF-alpha reduces the development of inflammation and tissue injury associated with spinal cord trauma, suggesting a possible role of TNF-alpha on the pathogenesis of spinal cord injury.     

Role of chest radiography in the diagnosis of allergic bronchopulmonary aspergillosis in adult patients with cystic fibrosis

PURPOSE: This study aimed to verify the usefulness of chest radiography in the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in adult patients with cystic fibrosis. MATERIALS AND METHODS: Eleven patients (with a total of 14 episodes) affected by ABPA were selected from among subjects attending a Regional Cystic Fibrosis Centre. For each episode, we retrospectively reviewed the baseline chest radiographs obtained before the diagnosis of ABPA, those obtained during the course of ABPA and those obtained during follow-up. Radiographs were assessed for the presence of bronchial wall thickening, bronchiectasis, infiltrates, atelectasis, mucoid impaction, lymphadenopathy, pleural effusion and fluid levels. Radiographic findings that had appeared at the time of ABPA diagnosis and disappeared after treatment were considered related to ABPA and thus useful for a correct diagnosis of the disease. Chest radiograph abnormalities were compared with changes on the respiratory function tests [forced expiratory volume in 1 s (FEV1)] during the different stages of the disease. RESULTS: Radiographic findings at the time of ABPA diagnosis appeared to have deteriorated in 8/14 cases when compared with the baseline films; after treatment, the radiographic findings deteriorated in 6/14 cases and improved in 6/14. The most significant among the radiographic signs considered (infiltrates and mucoid impaction) appeared at the time of ABPA diagnosis in 7/14 and 4/14 cases, respectively, and in some patients, they were also present at baseline and persisted during follow-up. FEV1 values were significantly decreased (>10%) in 9/14 cases at the time of ABPA diagnosis. CONCLUSIONS: Our results demonstrate the limited usefulness of chest radiography in the diagnosis of ABPA in patients with cystic fibrosis. The most significant abnormalities are nonspecific and commonly seen on baseline films in cystic fibrosis without ABPA and persist after treatment in most cases.     

Hallucinations after abrupt withdrawal of oral and intrathecal baclofen

Since 1977 several cases of hallucinations after abrupt withdrawal of oral baclofen have been described. There are no reports of hallucinations after gradual withdrawal of oral baclofen. No one has ever described visual hallucinations after abrupt interruption of intrathecal baclofen therapy. We describe five personally observed cases of visual hallucinations occurring after sudden interruption of baclofen (in two of these cases, intrathecal baclofen) therapy. The patients were immediately submitted to routine EEG, visual evoked potentials and standard brain magnetic resonance imaging (MRI). A few days later they also underwent polysomnography, fundus oculi examination and brain MRI of the temporal lobe. All these examinations were normal. We hypothesise that these symptoms could be due to biochemical and molecular changes, chiefly in glutamatergic n-methyl-d-aspartate, GABA-A, and GABA-B receptor response, leading to increased excitability and spontaneous activity as a result of chronic use of baclofen.     

Gonadotropin-releasing hormone (GnRH) antagonist plus recombinant luteinizing hormone vs. a standard GnRH agonist short protocol in patients at risk for poor ovarian response

Various studies have compared the efficacy of GnRH agonists (GnRH-a) and antagonists (GnRH-ant) for controlled ovarian stimulation (COS) in women undergoing IVF. Nevertheless, few data are available about the use of GnRH-ant in poor responders. Here, a flexible protocol providing a gradual increase in the dose of GnRH-ant in association with recombinant LH (rec-LH) administration is compared with the standard GnRH-a flare-up protocol in 133 women at risk for poor ovarian response. The mean number of metaphase 2 oocytes (primary end point) was significantly higher in the antagonist group (5.73 +/- 3.57 vs. 4.64 +/- 2.23, respectively; P<.05).