A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Aseptic meningitis and ischaemic stroke in Fabry disease.

BACKGROUND: Fabry disease (OMIM 301 500) is an X-linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients. METHODS: Clinical analysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analysed in three cases of meningitis associated with Fabry disease. FINDINGS: Mean age at meningitis onset was 26.6 (24-28) years. Headache was present in all cases and fever in two cases. Meningitis was always diagnosed before Fabry disease. A familial history of Fabry disease was present in two cases. Non-neurological symptoms caused by Fabry disease were present in all cases. All patients also suffered stroke and sensorineural hearing loss. Cerebrospinal fluid (CSF) analysis showed pleocytosis (mean, 36; range: 8-76 cells/mm(3)) and a high protein level (mean, 63; range, 47-70 mg/dl). C-reactive protein blood levels and erythrocyte sedimentation rate were raised. Diagnosis was assessed by low alpha-galactosidase A dosage and/or gene mutation analysis in all cases. All patients were treated with enzyme replacement therapy (ERT). In two cases, lumbar puncture was repeatedly performed and there was no normalisation of CSF under ERT alone, at 9 and 24 months of follow-up, respectively. One patient who suffered intracranial hypertension was treated efficiently with steroids, associated with azathioprine. The fact that Fabry disease could be an auto-inflammatory disorder is discussed. INTERPRETATION: Fabry disease may cause aseptic meningitis.

[Use of mitoxantrone in early multiple sclerosis with malignant disease course. Observational study in 30 patients with clinical and MRI outcomes after one year]. / Utilisation de la mitoxantrone dans les formes malignes inaugurales de sclérose en plaques. Etude observationnelle de 30cas. Evaluations cliniques et IRM à un an.

INTRODUCTION: In an observational multicenter study, we analyzed retrospectively 30 patients with malignant form of multiple sclerosis (MS) treated with mitoxantrone the year following the first neurological event. METHODS: The 30 patients were selected according to Weinshenker criteria of malignant MS (either a "catastrophic" relapse or a quickly aggressive form). We compared clinical and MRI findings the year before with the year following mitoxantrone onset treatment: annualized relapse rates (ARR), EDSS score and percentage of patients with gadolinium enhancing lesions on MRI. RESULTS: A total of 87 relapses were observed in the 5.7 months before and 10 during the year following onset of mitoxantrone treatment. The ARR decreased by 95% (6.0+/-2 before and 0.3+/-0.7 after). Twenty-four patients (80%) were relapse-free one year after onset of mitoxantrone treatment. The EDSS score improved in 87% of MS patients and the mean EDSS decreased by 1.9. Ninety-seven percent had at least gadolinium enhancing lesions before the start of mitoxantrone treatment as compared to 17% after. CONCLUSION: In our experience, mitoxantrone had a rapid and strong impact on the malignant forms of MS with a short disease duration. In this MS subgroup, mitoxantrone should be considered as an early treatment option.

Quantification of neutralizing antibodies to human type I interferons using division-arrested frozen cells carrying an interferon-regulated reporter-gene.

Development of neutralizing antibodies (NAbs) to interferons (IFNs) can reduce the clinical response to IFN therapy. As current cell-based assays for quantifying NAbs have limitations, a highly sensitive and reproducible assay was developed, using division-arrested frozen human U937 cells transfected with the luciferase reportergene controlled by an IFN-responsive chimeric promoter, which allows IFN activity to be determined with precision within hours. Assay-ready PIL5 cells can be stored frozen for >3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting <1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from <1.0 to 100 IU/mL and able to measure different IFN subtypes and their pegylated variants. The use of this assay has shown that NAbs from patients treated with IFN-alpha2 exhibited markedly lower titers against 10 LU/mL of low specific activity IFNs, namely, IFN-alpha1, PEG-Intron(TM) (Schering-Plough, Levallois-Perret,France), or Pegasys(TM) (Hoffmann-La Roche, Neuilly-sur-Seine, France, than against 10 LU/mL IFN-alpha2. Similarly, NAbs from patients treated with IFN-beta1a exhibit lower titers against 10 LU/mL of low specific activity IFN-beta1b than against IFN-beta1a. The combination of the use of division-arrested, IFN-responsive human cells transfected with the luciferase reporter-gene makes the rapid PIL5 assay for NAbs highly advantageous.

Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile.

The concept of preclinical multiple sclerosis is now well recognised, and a diagnosis of silent brain T2 lesions is frequent because of the ease of performing MRI. Nevertheless, patients with incidental brain MRI fulfilling Barkhof- Tintoré criteria are more rare. We report a descriptive retrospective study of clinical and 5 year MRI follow-up in patients with subclinical demyelinating lesions fulfilling MRI Barkhof-Tintoré criteria with a normal neurological examination. 30 patients were identified and the first brain MRI was performed for various medical events: headaches (n = 14), migraine with (n = 2) or without (n = 4) aura, craniocerebral trauma (n = 3), depression (n = 3), dysmenorrhoea (n = 2), epilepsy (n = 1) and cognitive changes (n = 1). Mean time for the second brain MRI was 6 months (range 3-30). 23 patients had temporospatial dissemination (eight with gadolinium enhancement). 11 patients had clinical conversion: optic neuritis (n = 5), brainstem (n = 3), sensitive symptoms (n = 2) and cognitive deterioration (n = 1). Eight (72%) already had criteria of dissemination to space and time before the clinical event. Mean time between the first brain MRI and clinically isolated syndrome (CIS) was 2.3 years. To our knowledge, this is the first cohort of CIS with preclinical follow-up. Early treatment should be discussed in view of the predictive value on conversion of the MRI burden of the disease.

Evolution of previous sarcoidosis under type 1 interferons given for severe associated disease.

Sarcoidosis is a granulomatous disorder with a well-known T helper (Th) type 1 cell commitment and a key pathogenic role of interferon (IFN)-gamma. However, little is known about the influence of type 1 IFNs, such as IFN-alpha and IFN-beta, on the course of previous sarcoidosis. The aim of this study was to determine whether type 1 IFNs can safely be used in patients with sarcoidosis for severe associated disease. The present study examined a series of four patients with sarcoidosis, treated by IFN-alpha or IFN-beta for viral hepatitis (three cases) or multiple sclerosis (one case). IFN was initiated soon after apparent recovery (three cases) or during a worsening phase of sarcoidosis (one case). Hydroxychloroquine was added in the case with active disease. Patients received interferon for 6-24 months and had close monitoring during and after IFN therapy. Interestingly, no recurrence or exacerbation of sarcoidosis had occurred at 4 yrs of follow up. Two patients were cured from viral hepatitis, whilst treatment for another failed. No neurological progression was observed in the remaining patient. This series suggests that, despite the T helper type 1 phenotype of sarcoid granulomatous reaction, type 1 interferons do not exacerbate sarcoidosis in remission and this makes their use possible if indicated. However, their effect in persistent forms of the disease needs further evaluation.

Anticardiolipin antibodies in patients with multiple sclerosis do not represent a subgroup of patients according to clinical, familial, and biological characteristics.

BACKGROUND: In multiple sclerosis (MS), case control studies have shown that anticardiolipin antibodies (aCL Ab) are more frequent than in the general population and that aCL Ab positivity may be associated with specific clinical characteristics. OBJECTIVES: To determine whether patients with MS who are positive for aCL Ab have specific characteristics. METHODS: 285 consecutive patients with MS were tested for aCL Ab positivity. Patients also underwent complete autoimmune screening and were systematically evaluated for clinical characteristics and individual or family history of autoimmune disease. RESULTS: aCL Ab positivity was found in 42 patients (15%). The main isotype was aCL IgM (32 patients, 11%). Demographics and clinical characteristics including sex, age at onset, course of the disease, expanded disability status scale score, and progression index were not different between aCL Ab positive and aCL Ab negative patients. Clinical systems involved at onset or during the course of the disease were not different from what is usually observed in MS. aCL Ab positivity was not associated with an increased frequency of autoimmune disease and was not predictive of a family history of autoimmune disease. Patients positive for aCL IgM were more frequently positive for the presence of non-organ specific antibodies (53% v 39%, respectively, p = 0.02). CONCLUSIONS: These results do not support the hypothesis that patients with MS with aCL Ab constitute a subgroup of MS according to demographic clinical and familial characteristics. The greater frequency of other antibodies in aCL Ab positive patients suggests that they only reflect a more general autoimmune activation in MS.

[Clinical evaluation of follow-up and disease course]. / Evaluation clinique du suivi et de l'évolution.

The clinical assessment of the evolution of Multiple Sclerosis (MS) is based on international criteria. For the definition of relapse and progression, the so-called Schumacher criteria (1965) may be chosen. For the definition of clinical subtypes (relapsing-remitting, secondary progressive, primary progressive, and progressive-relapsing), the criteria issued from a survey conducted by the group of Lublin (1996) are mandatory. One may be cautious to apply such research-driven sets of criteria to clinical practice. Many scales have been elaborated for the evaluation of the handicap caused by MS (i.e. neurological deficit, impairment, and "handicap"). None is perfect, but the Expanded Disability Status Scale (EDSS, Kurtzke, 1983) is widely used. Recent development in the elaboration process of scales ("scalology") may soon lead to the validation of new composite outcome measures.

Multiple sclerosis and antecedent infections: a case-control study.

OBJECTIVES: To determine whether there is an excess of respiratory tract infections in the 5-week, 3-month, and 12-month periods before MS symptom onset and if there is an association between MS and a history of infectious mononucleosis (IM). BACKGROUND: The etiology of MS remains unknown, but infection is frequently suggested as a putative etiologic agent. Epidemiologic studies have produced inconsistent evidence for an etiologic role of respiratory tract infections (RTI) and IM in MS. METHODS: The authors performed a case-control study using the General Practice Research Database from the United Kingdom. There were 225 subjects with definite or probable MS, and 900 controls matched for age, sex, and physician practice. Using computerized patient records, the authors compared the mean rates of RTI per patient in the 5-week, 3-month, and 12-month periods before the date of onset of the first symptoms compatible with MS (index date). They also compared histories of IM. RESULTS: In all periods, an increased frequency of RTI was associated with a significantly increased risk of MS. A history of IM was associated with greater than five times the risk of MS (OR = 5.5 [95% CI 1.5 to 19.7]). CONCLUSIONS: These results support an association between a history of IM and subsequent MS. Respiratory tract infections may precipitate disease onset.

[Familial multiple sclerosis: study of 357 consecutive patients]. / Sclérose en plaques familiale: étude de 357 patients consécutifs.

The empiric recurrence risk of multiple sclerosis (MS) of relatives of French MS patients is not known. Using a standardized interview, we collected the family histones of 357 consecutive patients followed at our MS clinic; adequate information was obtained on 4784 relatives up to the third degree. Thirty-five patients (9.8%) had a relative with MS. The risk-curve for relatives was the same as in other studies conducted with a similar methodology in Canada. England and Flanders. but the crude overall MS recurrence risk for relatives was lower in France. The genetic burden of MS may be lower in France than in areas of higher MS prevalence.

Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis. A puzzle illustrated by a new case.

We report a case of amyotrophic lateral sclerosis in a patient with rheumatoid arthritis. Only three similar cases have been reported. Our case illustrates the diagnostic difficulties raised by early amyotrophic lateral sclerosis responsible for localized or unusual manifestations. Occurrence of the two diseases in the same patient is probably due to chance alone.

Autoimmune diseases in families of French patients with multiple sclerosis.

Multiple sclerosis (MS) is associated with autoimmune disorders (AIDs) in individual patients, and limited data suggest a possible familial association of MS and AIDs; however, no systematic study has been conducted on the occurrence of AIDs in the families of MS patients. Using a standardized interview focused on AIDs, we obtained the family histories of 357 consecutive patients from our MS clinic. Adequate information was obtained on 1971 first-degree relatives. Fifty-five patients (15.4%) had first-degree relatives with MS (n=22, 6.2%) another AID (n = 30, 8.4%), or both (n = 3, 0.8%). In 16 families (4.5%), at least 3 first-degree relatives had MS or another AID. MS, Grave's disease, rheumatoid arthritis, vitiligo, type 1 insulin-dependent diabetes mellitus, and uveitis, were the most common AIDs in these families. Such multiplex families (families with MS plus AID) are appropriate for identifying susceptibility genes that may be common to MS and other AIDs.

[Towards a reliable prognosis for multiple sclerosis]. / Vers un pronostic fiable de la sclérose en plaques.

Although the general course of multiple sclerosis is well known from natural history studies, the determination of a detailed prognosis in a given individual is almost an insurmountable task. Cerebral magnetic resonance imaging is the best predictor of conversion to definite multiple sclerosis after a first demyelinating event. The main factors indicative of long-term bad prognosis are: onset after the age of 40, initial pyramidal or cerebellar signs, high relapse rate during the first two years, and onset of the progressive phase. Altogether, up to 20% of patients have a benign course.

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Opportunistic infections of the central nervous system during HIV-1 infection (emphasis on cytomegalovirus disease).

Toxoplasma encephalitis, cryptococcal meningitis, progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) encephalitis are the most common opportunistic infections of the central nervous system (CNS) in HIV-infected patients. They occur at variable degrees of immunosuppression, and their diagnosis is based on a systematic evaluation with includes, in a definite order, ongoing prophylactic therapies, extraneurological signs, neuroimaging and CSF studies, and an anti-Toxoplasma therapeutic trial. Concurrent neurological HIV-CNS disease (such as the AIDS dementia complex) is frequent. The development of reliable molecular biology techniques such as the polymerase chain reaction and their application to the CSF have made the diagnosis of virus-related opportunistic infections much easier and has limited the need for cerebral biopsy. The incidence of opportunistic infections has decreased since the introduction of recent antiretroviral therapeutic strategies.

Multiple sclerosis associated with uveitis in two large clinic-based series.

The authors reviewed records from consecutive patients in an MS clinic (n = 1,098) and in a uveitis clinic (n = 1,530) to select patients with "definite MS" and uveitis. A total of 28 of 2,628 patients (1%) were identified: 12 from the MS clinic (12 of 1,098; 1.1%) and 16 from the uveitis clinic (16 of 1,530; 1%). Pars planitis and panuveitis were most commonly encountered. The delay between the onset of neurologic and ocular symptoms (mean, 9 years) emphasizes the importance of a sequential diagnostic search throughout the patient's course.

[Childhood multiple sclerosis]. / La sclérose en plaques chez l'enfant.

Multiple sclerosis begins before the age of 17 years in 0.4 to 0.5% of the cases, but the diagnosis is exceptionally made before the age of 10 years. Female predominance is more marked in early onset multiple sclerosis. The general features of the disease (clinical expression, progression, prognostic) and the findings of complementary explorations are comparable with those found when the disease begins in adulthood although acute onset and signs of brain stem involvement have been reported. The diagnosis must be made with prudence, especially when progression is slow from the beginning. An analysis of the influence of infective environmental factors and puberty has not provided new insight. Corticosteroids can be used in case of flare-ups. Management requires a multidisciplinary approach to maintain appropriate educational activities.