A prospective study on 132 cases of ocular palsy.

OBJECTIVES: In this prospective study, we used one diagnostic protocol to establish an early diagnosis in patients with ocular palsies in absence of other neurological findings. MATERIALS AND METHODS: The study was performed on a consecutive series of 132 patients who visited our Neurological Department for ptosis and/or diplopia in absence of other neurological signs, using the same diagnostic protocol. RESULTS: An etiological diagnosis was made in 74% of cases during a mean time of 17 ± 23 months from symptom onset. Myasthenia gravis was the most common diagnosis (n = 60, 45.5%). Thirty-four cases (26%) remained undiagnosed in spite of a follow-up lasting 32 ± 33 months on average. CONCLUSIONS: Identifying the cause of an isolated ocular palsy can be difficult, and an extended follow-up time does not aid in further establishment of the diagnosis.

Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation.

Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain, and it is increasingly used in experimental and clinical settings. Recent studies suggest that the after-effects of tDCS are related to molecular mechanisms of activity-dependent synaptic plasticity. Here we investigated the effect of DCS on the induction of one of the most studied N-methyl-d-aspartate receptor-dependent forms of long-term potentiation (LTP) of synaptic activity at CA3-CA1 synapses in the hippocampus. We show that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Immediate early genes, such as c-fos and zif268 (egr1/NGFI-A/krox24), are rapidly induced following neuronal activation, and a specific role of zif268 in the induction and maintenance of LTP has been demonstrated. We found that both anodal and cathodal DCS produce a marked subregion-specific increase in the expression of zif268 protein in the cornus ammonis (CA) region, whereas the same protocols of stimulation produce a less pronounced increase in c-fos protein expression in the CA and in dentate gyrus regions of the hippocampus. Brain-derived neurotrophic factor expression was also investigated, and it was found to be reduced in cathodal-stimulated slices. The present data demonstrate that it is possible to modulate LTP by using DCS and provide the rationale for the use of DCS in neurological diseases to promote the adaptive and suppress the maladaptive forms of brain plasticity.

Epstein-Barr virus antibodies in serum and cerebrospinal fluid from multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy and amyotrophic lateral sclerosis.

Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS.

Light chain deposition in peripheral nerve as a cause of mononeuritis multiplex in Waldenström's macroglobulinaemia.

Waldenström's macroglobulinaemia is a form of monoclonal IgM gammopathy associated with a rare B-cell lympho-plasmacytic lymphoma, characterized by the involvement of bone marrow, lymph nodes and spleen. Neurological complications involving peripheral nerves are common and different pathogenic mechanisms have been reported. We describe a patient with severe multineuropathy associated with Waldenström's macroglobulinaemia. Nerve biopsy revealed copious light chain deposition which subverted the normal architecture of the endoneurium and epineurium resulting in massive fascicular hyalinosis and epineural arteries disruption, respectively. This report confirms that massive immunoglobulin deposition is one of the several mechanisms of nerve damage in IgM-related neuropathy. Since their recognition has important therapeutical consequences, nerve biopsy is an essential diagnostic tool in patients with an unusual clinical presentation of IgM-related neuropathies.

Multiple sclerosis attacks triggered by hyperprolactinemia.

Multiple sclerosis (MS) is a T-cell autoimmune disease of the central nervous system (CNS). Predominance of women in autoimmune diseases suggests that sex hormones may play a role in disease susceptibility. A possible role for prolactin, a neuroendocrine peptide with powerful immunomodulatory properties, is suggested in MS. We describe the case of a 32-year-old man affected by relapsing-remitting MS who experienced the first MS clinical event during the development of a prolactin-secreting adenoma and the only two MS relapses during adenoma recurrence. Prolactin may have facilitated the inflammatory process and triggered MS clinical attacks, suggesting a role of prolactin in immunomodulation and therefore in autoimmune disease course.

Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.

The aim of this study was to investigate the role of Brain Derived Neurotrophic Factor (BDNF) and inflammatory factors in the development of cognitive dysfunctions in Multiple Sclerosis (MS). We correlated peripheral blood mononuclear cell (PBMC) production of BDNF, Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin (IL)-6 and IL-10 with performances on specific neuropsychological tasks in a selected series of MS patients. We studied a sample of 30 patients with relapsing-remitting (RR)MS, segregated by gender and matched for age, education, disease duration, type of immunomodulating therapy, degree of disability and overall cognitive status. We found that low BDNF levels were correlated with increased time of execution on a divided attention and visual scanning task whereas high levels of IL-6 were correlated with low Mini Mental State Examination scores. We did not observe any significant correlations between IL-10, TNF-alpha levels and cognitive performances in our patients. In conclusion our study shows a correlation between low BDNF and high IL-6 production by PBMCs and poorer performances in cognitive tasks in RRMS patients suggesting a possible role of these factors in cognitive impairment in MS.

T-bet and pSTAT-1 expression in PBMC from coeliac disease patients: new markers of disease activity.

Coeliac disease (CD) is considered a T cell-mediated autoimmune disease, and up-regulation of T-bet and phosphorylated signal transducers and activators of transcription (pSTAT)1, key transcription factors for the development of T helper type 1 (Th1) cells, has been described in the mucosa of patients with untreated CD. Using transcription factor analysis, we investigated whether T-bet and pSTAT1 expressions are up-regulated in the peripheral blood of CD patients and correlate with disease activity. Using flow cytometry, we analysed T-bet, pSTAT1 and pSTAT3 expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes from peripheral blood of 15 untreated and 15 treated CD patients and 30 controls, and longitudinally in five coeliac patients before and after dietary treatment. We evaluated using enzyme-linked immunosorbent assay (ELISA), interferon (FN)-gamma, interleukin (IL)-17 and IL-10 production by peripheral blood mononuclear cell (PBMC) cultures. T-bet expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes and IFN-gamma production by PBMC was higher in untreated than in treated CD patients and controls. pSTAT1 expression was higher in CD4(+)T cells, B cells and monocytes from untreated than from treated CD patients and controls. pSTAT3 was increased only in monocytes from untreated patients compared with CD-treated patients and controls. The data obtained from the longitudinal evaluation of transcription factors confirmed these results. Flow cytometric analysis of pSTAT1 and T-bet protein expression in peripheral blood mononuclear cells could be useful and sensible markers in the follow-up of CD patients to evaluate disease activity and response to dietary treatment.

Tourettism in multiple sclerosis: a case report.

The term Tourettism refers to Tourette Syndrome (TS)-like symptoms which appear secondary to a variety of both acquired and congenital neurological and neuropsychiatric disorders or following an exposure to several drugs. The association between Tourettism and Multiple Sclerosis (MS) is very rare. Only two cases of patients affected by MS who also showed a simple phonic tic and complex vocal tics respectively have been reported. The case here described reports of a 30 year-old woman affected by secondary-progressive MS who developed, 7 years after the onset of the disease, TS-like symptoms which were responsive to quetiapine. At that time her brain MRI, when compared with the previous scan, showed an increased lesion burden and an increased atrophy in the regions around Sylvian fissures. Considering recent findings on TS, the increased atrophy in these strategic brain regions could be responsible for the tics onset in our patient. At the same time, the diffuse involvement of the white matter and the progressive brain atrophy which we observed could have impaired the cortico-striato-thalamo-cortical circuits consistently implicated in the pathogenesis of TS. In conclusion, we can hypothesize that in our case Tourettism and MS could be considered causal related more than coincidentally associated.

T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis.

In pregnant women affected by multiple sclerosis (MS) we observed increased percentages of CD4(+)CD25(+)Foxp3(+) T regulatory cells at the 1st and the 2nd trimester of gestation that was associated with a decreased T-bet expression in CD4(+) T cells. In women showing clinical relapse and/or new lesions at MRI after delivery we found, a higher expression of T-bet, pSTAT1 and pSTAT3 in CD4(+), CD8(+) T cells and CD14(+) cells, associated with an increase of IFNgamma and IL17 production by PBMC at the 3rd trimester of gestation and after delivery. Our data suggest that the expansion of circulating CD4(+)CD25(+)Foxp3(+) regulatory T cells and the lower expression of T-bet in CD4(+) T cells may account for the decreased MS activity during pregnancy. The expression of T-bet, pSTAT1 and pSTAT3 in peripheral blood CD4(+) and CD8(+) T cells and monocytes could be useful to identify MS patients who will develop a relapse after delivery.

Movement disorders in multiple sclerosis: Causal or coincidental association?

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.

Neurotrophic factors and clinical recovery in relapsing-remitting multiple sclerosis.

Pathogenic autoimmune cells are demonstrated to be able to produce neurotrophic factors during acute phase of multiple sclerosis (MS). In this study, we determined the production of various neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4)] and some pro-inflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] by unstimulated peripheral blood mononuclear cells (PBMC) in 21 relapsing-remitting MS patients during different phases of disease (stable, relapse and post-relapse). During acute phase of disease, we detected a considerable increase of BDNF, TNF-alpha and IFN-gamma production, while significantly higher levels of GDNF, NGF, NT3 and NT4 were found in post-relapse phase. When neurotrophin production was correlated with clinical outcome (complete or partial recovery from new symptoms), we found a significantly higher BDNF production in relapse phase followed by increased GDNF, NGF, NT3 and NT4 levels during post-relapse phase in subjects with complete remission only. During relapse phase, we detected a significant increase of pro-inflammatory cytokines, that was more evident in patients with partial recovery. The neuroprotective potential of immune cells seems to be inversely correlated with disease duration and with the age of patients.

Clinical characteristics, course and prognosis of spinal multiple sclerosis.

STUDY DESIGN: Retrospective examination. OBJECTIVE: To define the clinical characteristics and response to therapy of spinal multiple sclerosis (MS). SETTING: Italy. METHODS: Retrospective review was performed on 563 patients with clinical definite MS. Selection criteria were two or more spinal cord lesions in the presence of normal magnetic resonance imaging of the brain. RESULTS: Spinal MS was diagnosed in 13 patients (2.3%) out of 563 with clinical definite MS. There were seven female and six male patients; nine had a relapsing-remitting (RR) and four, a primary progressive (PP) course. All patients were treated with immunosoppressive or immunomodulatory therapy. Mean disease duration in patients with RR-MS was 13.1+/-10.1 years with a mean age at onset of 29.5+/-14.3 years; the mean Expanded Disability Status Scale (EDSS) at the time of the study was 3.5+/-2.5 with a progression index of 0.28. Mean disease duration in patients with PP course was 7+/-6.2 years with a mean age at onset of 56.7+/-10.4 years; the mean EDSS at the time of the study was 6.2+/-2.0 with a progression index of 1.48. CONCLUSIONS: Patients with spinal RR-MS are characterised by an early disease onset with minimal or moderate disability progression; patients with spinal PP-MS show a late disease onset and more rapid disability progression. In our series of spinal MS patients, disability progression seems to be mainly due to the disease course and age at onset rather than to the site of lesion.

Relapsing-remitting autoimmune agrypnia.

A woman affected by multiple cranial nerve palsy developed several episodes of total insomnia and respiratory crises resulting from central breathing depression associated with dysautonomic symptoms. Oligoclonal IgG bands were present in her cerebrospinal fluid, and immunohistochemistry showed increased binding of serum and cerebrospinal fluid on gamma-aminobutyric acid-ergic, synapse-rich neuronal cells. Immunosuppressive treatment and plasma exchange were followed by clinical improvement, with restoration of sleep architecture and disappearance of respiratory crises, suggesting autoimmune pathogenesis of the syndrome.