Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome.

Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3 years.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.

OBJECTIVE: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI. METHODS: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans. RESULTS: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability. CONCLUSION: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.

Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome.

We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF-restricted IgMOB predicted a relapse within one year.

Isolated progressive cognitive impairment and depression in a patient with neuroradiological features suggestive of multiple sclerosis.

We report the case of a woman who started complaining of depression, attention and memory problems at the age of 49. Over the following 6 years, serial neuropsychological assessments showed fluctuating, but overall progressively worsening, performances in tests exploring attention, working memory, language and executive functions. Cerebrospinal fluid (CSF) examination showed identical IgG oligoclonal bands in serum and CSF. Neurological examination, to date, only reveals minimal pyramidal and cerebellar signs. Although typical clinical and laboratory evidence indicating a diagnosis of multiple sclerosis (MS) in this patient is lacking, an extensive diagnostic work-up ruled out many other causes of leukoencephalopathy and neuroradiological features strongly suggest this diagnosis. Multiple sclerosis may present with cognitive or neuropsychiatric symptoms; this should be kept in mind, especially in younger patients, even in the absence of "classical" physical symptoms.

Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM.

BACKGROUND: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing-remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). OBJECTIVE: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. METHODS: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. RESULTS: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. CONCLUSION: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.

A multifactorial prognostic index in multiple sclerosis. Cerebrospinal fluid IgM oligoclonal bands and clinical features to predict the evolution of the disease.

BACKGROUND: The ability to predict the future progression of MS represents a key issue for the neurologist. The aim of the study was to create a multifactorial prognostic index (MPI) providing the probability of a severe MS course at diagnosis based on clinical and immunological CSF parameters. METHODS: 64 clinically definite relapsing-remitting (RR)MS patients (38 benign, 26 severe MS) followed up for at least 10 years were included. Clinical and demographic details, EDSS after 5 and 10 years, progression index, relapse number and rate, time to a second relapse were assessed. CSF and serum samples collected at diagnosis were examined for CSF IgM and IgG oligoclonal bands (OB) and quantitative IgM and IgG determination. RESULTS: Kaplan-Meier analysis showed that the probability of reaching an EDSS score of 3 or 4 was significantly influenced by the presence of IgMOB (p<0.01 and p<0.01, log-rank test) and by the symptoms at onset (p=0.04 and p=0.03, log-rank test). These results were confirmed at multivariate analysis (Cox model). Univariate logistic analysis showed that IgMOB presence predicted a severe MS course (OR=9.33, CI=2.92- 29.88), whereas sensory symptoms at onset predicted a benign MS course (OR=0.12, CI=0.02-0.56). Using multivariate logistic regression the factors found to be significant were: presence/absence of IgMOB (p<0.01), onset with sensory (p<0.01) and pyramidal symptoms (p=0.01), and first inter-attack interval (p=0.03). The individual probability of a severe evolution was thus estimated by a simple formula comprising clinical and biological markers of prognosis available at diagnosis (pyramidal and sensory symptoms, months to the 2nd episode, and IgMOB presence/absence), giving the probability of developing a severe MS course. Applied to the same patient cohort this formula showed a global error of 6/64 (9.37%). We then used another independent series of 65 RRMS patients to validate this model. In this second patient cohort, 4/45 BMS and 4/20 SMS patients were found to have been incorrectly classified (based on the formula), with a global error of 8/65 (12.31%). CONCLUSION: For the first time we created a MPI, using clinical and biological markers to predict the clinical course of MS at diagnosis. This index can support the clinician in patient counselling, therapeutic choices, as well as in patient selection criteria for clinical trials.

Do flavan-3-ols from green tea reach the human brain?

Following acute ingestion of green tea by six human subjects, HPLC-MS2 analysis revealed that flavan-3-ol methyl, glucuronide and sulfate metabolites appeared in the bloodstream but did not pass through the blood-cerebrospinal fluid barrier. These observations emphasize the discrepancies between in vitro and in vivo evidence on the neuroprotective role of these compounds. If, as has been proposed, green tea exerts neuroprotective effects, this finding indicates that the active components are not flavan-3-ols or their metabolites. Alternatively, a systemic action may be hypothesised whereby dietary flavan-3-ols up-regulate antioxidant defences and/or reduce inflammation, the benefit of which may be effective throughout the body.

Total antioxidant capacity of cerebrospinal fluid is decreased in patients with motor neuron disease.

Oxidative stress has been associated with motor neuron disease (MND). The human body has several antioxidant defense systems to repair the damage caused by oxidative stress. The activity of these systems is thought to be reduced in neurodegenerative diseases, which may increase the level of oxidative damage and be a contributing factor to motor neuron death. In the present study, we compared the total antioxidant capacity (TAC) of human serum and cerebrospinal fluid (CSF) of MND patients with that of a control group including patients with migraine, tension headache and psychiatric disorders. Within-subject serum and CSF TAC were strongly correlated (r=0.639; p=0.000), and CSF TAC was significantly lower in MND patients as compared to controls after adjustment for known influencing factors (112.7 micromol Fe/L+/-11.7 versus 135.2 micromol Fe/L+/-19.7; p=0.012). No differences in serum or CSF TAC were observed among the clinical forms of MND considered in this work. In conclusion, the CSF TAC was strongly correlated with serum TAC, and a decrease in CSF TAC was demonstrated in MND patients compared to controls that was not independent from serum antioxidants, this translating in a systemic (but prevailing in the CNS) oxidative damage in this pathology.

Clinical characteristics, course and prognosis of relapsing Devic's Neuromyelitis Optica.

OBJECTIVES: To evaluate the clinical characteristics, course and prognosis of Devic's neuromyelitis optica (DNO), to evaluate the prognostic role of demographic and clinical features, to evaluate the current DNO diagnostic criteria. METHODS: Demographic, clinical, CSF and MRI data of patients affected by DNO were collected from fifteen Italian MS centres. Inclusion criteria were: 1) two or more acute episodes of neurological dysfunction indicating involvement of the optic nerve and spinal cord, in a simultaneous or subsequent temporal relationship; 2) no evidence of lesions beyond the optic nerve or the spinal cord; 3) brain MRI at onset negative or non-specific for multiple sclerosis (MS) (white matter lesions < or = 2). Disability was scored by means of Kurtzke's Expanded Disability Status Scale (EDSS). RESULTS: 46 patients with relapsing DNO were included, 37 females and 9 males, with mean age at onset of 40.1 +/- 16.3 years (range 12-77 years). The follow up duration was 8.8 +/- 3.5 years, the mean annualised relapse rate was 1.3 +/- 1.2. After 5, 10 and 15 years EDSS 3.0 was reached respectively by 65%, 82 % and 86% of cases, EDSS 6.0 respectively by 42%, 53 % and 69% of cases, EDSS 10 respectively by 8%, 12% and 23% of cases. The probability of reaching EDSS 3 was statistically correlated with age at onset, interval between the first and 2(nd) attack, and relapse rate. The probability of reaching EDSS 6.0 was correlated with the residual EDSS at onset and to relapse rate. During the follow up, brain white matter lesions appeared in 8 subjects. Spinal cord MRI showed lesions extending across 3 or more segments in 39 subjects, only 1 lesion involving 1 segment in 4 subjects, and was normal in 3 subjects. One or more CSF abnormalities were found at least once in 29/44 patients (65.9 %), the most frequent findings being pleocytosis (38.6 %), oligoclonal bands (34.1 %), high protein level (25 %), and high albumin ratio (20.5 %). CONCLUSIONS: DNO has a poor prognosis in most cases. Compared with MS, DNO patients have a higher age at onset, females are more frequently affected, the course is more severe. Brain and spinal cord MRI permit the differentiation of DNO from MS. CSF supports the probability of DNO if it shows increased cells and proteins.

Necrotizing skin lesions and NABs development in a multiple sclerosis patient treated with IFNbeta 1b.

A case of a severe necrotizing vasculopathic skin lesions occurred in a 43 year old women affected by multiple sclerosis (MS) submitted to IFNbeta-1b has been described. After two months of therapy the patient presented, in injection sites of the abdomen, arms and legs, numerous ulcers. A biopsy of the lesions was performed and evidenced confluent necrosis of the superficial and deep skin tissue with mild infiltration by inflammatory cells and thrombosis in deep blood vessels. The IFNbeta-1b was immediately discontinued and therapy with corticosteroids was started. After 12 months from the onset of the adverse reaction, the skin vasculopathic lesions cicatrised leaving sclerotic areas on the abdomen. Neutralizing antibodies against IFNbeta-1b (NABs) were strongly positive at the onset of the skin ulcers and slowly decreased until the recovery. A possible role of NABs in the development of the skin lesions has been considered.

The epidemiology of ALS in Modena, Italy.

OBJECTIVE: To determine the incidence, prevalence, and mortality rates of ALS in the province of Modena, Northern Italy, from 1990 through 1999. METHODS: A retrospective epidemiologic study was conducted, ascertaining cases from all neurologic centers and hospitals of the province, death certificates, and the Italian ALS Association, section of Modena. All clinical records were reviewed, and only patients fulfilling the El Escorial revised diagnostic criteria were included. RESULTS: During the period considered (1990 to 1999), 143 residents (67 men and 76 women) entered the study. The average annual incidence was 2.16 per 100,000, with a peak in the age class of 75 to 79 years. Mean prevalence rate was 4.02 per 100,000, and mean mortality rate was 1.69 per 100,000. The incidence rate remained constant over time, whereas the prevalence and mortality rates increased owing to a rise in survival time (ALS mean duration was 17.38 months in 1990, 43.18 months in 1999). In the mountainous areas, where agricultural work is more common, the incidence, prevalence, and mortality rates were higher than in urban areas and the disease onset occurred 10 years later. Of the risk factors examined, only agricultural work and rural residence were significant. CONCLUSIONS: The incidence, prevalence, and mortality rates agree with those in recent Italian surveys and with most international studies, but the distribution of cases varied with higher rates in mountainous areas. Further prospective studies are required.

New insights into the viral theory of amyotrophic lateral sclerosis: study on the possible role of Kaposi's sarcoma-associated virus/human herpesvirus 8.

In the last few years, three new herpesviruses, HHV-6, -7 and -8, have been discovered, which share interesting biological characteristics for a possible role in the development of both neurological and lymphoproliferative diseases. In particular HHV-8, besides being strongly associated with Kaposi's sarcoma, is related with several lymphoproliferative diseases. More recently, specific viral sequences belonging to HHV-8 have been detected in autoptic brain specimens from multiple sclerosis patients and controls, suggesting that, similarly to HHV-6, this novel herpesvirus is strongly neurotropic. HHV-8 is an unusual herpesvirus in that it is able to produce homologues of several human gene products, resulting in alterations in cell cycle, in apoptosis and cell-mediated immune responses. To verify a possible relationship between HHV-8 and the development of amyotrophic lateral sclerosis (ALS), we investigated the presence of signs of HHV-8 infection, by both nested polymerase chain reaction (nPCR) and indirect immune fluorescence analysis in ALS patients. Both PCR and serological data did not suggest a clear role of this virus in originating ALS. Nevertheless, new insights into the mechanisms by which viruses may interact with the host cell genome and with the human immune system make the viral hypothesis of ALS still worthy of further studies.