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Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the α subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis.We did a randomised, double-blind, placebo-controlled trial at 76 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1), via a central interactive voice response system, to subcutaneous injections of daclizumab HYP 150 mg or 300 mg, or placebo, every 4 weeks for 52 weeks. Patients and study personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug for injection, but had no interaction with the patient. The primary endpoint was annualised relapse rate. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00390221.204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0·21, 95% CI 0·16-0·29; 54% reduction, 95% CI 33-68%; p0·0001) or 300 mg (0·23, 0·17-0·31, 50% reduction, 28-65%; p=0·00015) than for those given placebo (0·46, 0·37-0·57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p0·0001 in the 150 mg group and p=0·0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess.Subcutaneous daclizumab HYP administered every 4 weeks led to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. Our findings support the potential for daclizumab HYP to offer an additional treatment option for relapsing-remitting disease.Biogen Idec and AbbVie Biotherapeutics Inc.

Resumen Las complicaciones neurologicas del embarazo suelen ser benignas y pueden beneficiar de un tratamiento sintomatico. Algunas de estas complicaciones son mas graves y pueden poner en peligro el pronostico vital de la madre. Es por eso que deben ser detectadas precozmente y tratadas eficazmente. Las pacientes afectadas de enfermedades neurologicas que desean quedar embarazadas deben recibir una informacion completa acerca de los riesgos potenciales de la enfermedad sobre el embarazo y de la repercusion del mismo sobre la enfermedad. En consecuencia, ciertas terapeuticas deben ser interrumpidas y otras adaptadas.

Using a new ELISA method we have measured the IgM concentration in the serum and the cerebrospinal fluid CSF from 110 neurological patients. Among there, 41 had multiple sclerosis (MS), 48 other inflammatory diseases (OID), including 30 AIDS, and 21 non-inflammatory neurological diseases (NID). A highly significant correlation was established between results with native IgM and the dithiothreitol reduced IgM. An intrathecal synthesis (ITS) of IgM was detected using the CSF IgM/CSF albumin ratio, the IgM index and a quantitative formula in 33 patients: nine MS, 23 OID (including 18 AIDS) and one NID. The frequency of IgM ITS was 22% in MS patients, 48% in the OID (60% in AIDS) and 5% in the NID groups. This ITS was not impaired by an increase in serum IgM concentration or by a blood-CSF barrier damage. These facts confirm that intrathecal immunity is not a "steady-state" related to the general immunity but a specific response restricted to the central nervous system. Conversely, CSF IgM increase and IgM ITS were closely related (p < 10(-6) ). In addition, IgM ITS and IgG ITS were found to be highly correlated in OID, especially in AIDS patients: such correlation was not observed in the MS group. No significant correlations were observed between IgM ITS and any of the clinical parameters in MS patients. These results suggest the probable specificity of IgM ITS in MS patients.

BACKGROUND--The prevalence of hepatitis C virus (HCV) infection has been estimated at 43 to 84% in patients with essential mixed cryoglobulinaemia in recent large series. Some of these cases have been successfully treated with interferon-alpha. The objective was to evaluate the prevalence and the possible role of HCV infection in essential mixed cryoglobulinaemia. METHODS--Fifteen patients (eight men and seven women; mean age: 61.2 (SD 16.5) years) with peripheral neuropathy (10 polyneuropathies and five multifocal mononeuropathies) and essential mixed cryoglobulinaemia were tested for serum anti-HCV antibodies. RESULTS--Antibodies were found in 10 of 15 patients involving either polyneuropathies (seven patients) or multifocal mononeuropathies (three patients). Electrophysiological studies and teased nerve fibre studies (in seven patients) allowed neuropathies to be classified as predominantly sensory axonopathies. Compared with HCV-negative (HCV -) patients, HCV-positive (HCV +) patients had a more pronounced and more widespread motor deficit; motor nerve conduction velocities in peroneal and median nerves were more impaired in HCV + patients, although significance was not reached except for the mean value of the amplitude of the compound muscle action potentials of the median nerves (P < 0.05); necrotising vasculitis was found in two of nine nerve biopsies from the HCV + patients studied and in none of the three HCV - patients. In addition, HCV + patients had more frequent cryoglobulin related cutaneous signs, higher aminotransferase and serum cryoglobulin concentrations, lower total haemolytic complement concentrations, and more frequent presence of rheumatoid factor. A liver biopsy performed in eight HCV + patients disclosed a range of lesions, from chronic active hepatitis (six patients) to persistent hepatitis (two patients). Lastly, treatment with interferon-alpha conducted over six months in two patients seemed to improve the peripheral neuropathy. CONCLUSIONS--Patients with peripheral neuropathy and essential mixed cryoglobulinaemia should be tested for anti-HCV antibodies to determine the appropriate treatment.

We review here the epidemiologic and clinical aspects of tropical spastic paraparesis, human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy (TSP/HAM) as observed in Europe and in Africa. Europe is not an endemic region for HTLV-I (seroprevalence in blood donors, < 0.03%), and TSP/HAM is thus rarely observed in European countries. Most of the few patients suffering from TSP/HAM are first- or second-generation immigrants from HTLV-I endemic areas (mostly the West Indies), and the clinicoepidemiologic aspects of these patients are similar to those seen in endemic areas. However, rare cases occur in European-born subjects with or without risk factors for HTLV-I infection, which raises the possibility of limited foci areas in Europe. Although Africa is considered as a primary HTLV-I endemic area, with at least a few million infected inhabitants, epidemiologic data on the situation of TSP/HAM in Africa remain scarce. Relatively few cases of patients with TSP/HAM have been reported in Africa, including some clusters in Zaire (prevalence, 50/100,000) and in South Africa and sporadically in the main cities of some Western, Central, and Eastern African countries. The paucity of clinical and epidemiologic data on TSP/HAM may be linked to several factors, including the paucity of neurologists, the lack of laboratory and radiologic facilities, and the chronicity of the disease, along with the limited number of field epidemiologic studies performed on this topic and the wide diversity of causes (toxic, nutritional, and infectious) of chronic myelopathies as seen on the African continent.

Summary Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain recently mapped to chromosome 19. We studied 148 subjects belonging to seven families by magnetic resonance imaging and genetic linkage analysis. 45 family members (23 males and 22 females) were clinically affected. Frequent signs were recurrent subcortical ischaemic events (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%). All symptomatic subjects had prominent signal abnormalities on MRI with hyperintense lesions on T2-weighted images in the subcortical white-matter and basal ganglia which were also present in 19 asymptomatic subjects. The age at onset of symptoms was mean 45 (SD [10·6]) years, with attacks of migraine with aura occurring earlier in life (38·1 [8·03] years) than ischaemic events (49·3 [10·7] years). The mean age at death was 64·5 (10·6) years. On the basis of MRI data, the penetrance of the disease appears complete between 30 and 40 years of age. Genetic analysis showed strong linkage to the CADASIL locus for all seven families, suggesting genetic homogeneity. CADASIL is a hereditary cause of stroke, migraine with aura, mood disorders and dementia. The diagnosis should be considered not only in patients with recurrent small subcortical infarcts leading to dementia, but also in patients with transient ischaemic attacks, migraine with aura or severe mood disturbances, whenever MRI reveals prominent signal abnormalities in the subcortical white-matter and basal ganglia. Clinical and MRI investigations of family members are then crucial for the diagnosis which can be confirmed by genetic linkage analysis. The disease is probably largely undiagnosed.

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 for3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from1.0 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.

MRI is one of the most important tools for the investigation of white matter diseases of the central nervous system. Other techniques based on the magnetic resonance phenomena (magnetization transfer imaging, diffusion imaging, magnetic resonance spectroscopy) have joined MRI to better caracterize certain diseases, understand their pathophysiology and follow their evolution.

Hereditary metabolic diseases may appear during adolescence or young adulthood, revealed by an apparently unexplained neurological or psychiatric disorder. Certain metabolic diseases respond to specific treatments and should be identified early, particularly in emergency situations where rapid introduction of a treatment can avoid fatal outcome or irreversible neurological damage. The main diseases leading to an acute neurological syndrome in the adult are urea cycle disorders, homocysteine metabolisms disorders and porphyria. More rarely, Wilson's disease, aminoacid diseases, organic aciduria, or pyruvate dehydrogenase deficiency, beta-oxidation disordes or biotin metabolism may be involved. Most emergency situations can be screen correctly with simple tests (serum ammonia, homocysteine, lactate, urinary prophyrines, acylcarnitine pattern, amino acid and organic acid chromatography). For chronic situations, the main treatable diseases are Wilson's disease, homocysteine, cerebrotendinous xanthomatosis, Refsum's disease, vitamin E deficiency, Gaucher's disease, Fabry's disease, and neurotransmitter metabolism disorders. We present treatable metabolic disorders as a function of the different clinical situations observed in adults.

In clinical practice, the term "genetic leukoencephalopathy" refers to a group of genetic diseases whose common point is to give an aspect of diffuse leukoencephalopathy on MRI. With progress in diagnostic techniques including radiology, biochemistry or genetics, a large number of hereditary diseases causing leukoencephalopathy have been identified. Although generally beginning in childhood, these diseases often have more insidious clinical forms which can begin in adulthood. These forms remain poorly known. Some are accessible to treatment so their diagnosis appears essential. The diagnostic steps must be guided by clinical examination (neurological, ophthalmological and systemic), electromyography and MRI. The purpose of this review is to propose a classification of the genetic leukoencephalopathies and to give a progress report applicable in neurological practice.

A 60-year-old woman who had experienced isolated ptosis for two years was seen when it had been fixed for one year. She had a personal and familial history of stromal corneal dystrophy. The diagnosis of mitochondrial cytopathy was made on the basis of clinical, electrophysiological, biological and histological findings. Surgical repair of the ptosis allowed visual recovery. The relationship between ptosis, corneal dystrophy and mitochondrial cytopathy is discussed.

Demyelination events or multiple sclerosis following hepatitis B virus (HBV) vaccination have been reported. We therefore compared the T-cell response to HBsAg in patients with CNS demyelination following HBV vaccination and in HBV-vaccinated healthy individuals. Our data showed no differences in terms of T-cell proliferation or cytokine production between these groups and may help to allay concerns that HBV vaccination might trigger a deleterious immune response.

Das Tagebuch, das Sir August Frederick d’Este (1794-1847) seit 1822 fuhrte, enthalt wahrscheinlich die erste autobiographische Beschreibung einer multiplen Sklerose (MS). Die Symptomatik begann mit ophthalmologischen Storungen (1822). Nach einer Phase sukzessiver Schube, die bis 1843 dauerte (Diplopie, Storungen der Motorik der Beine, Funktionsstorungen des Blasenschliesmuskels, Sensibilitatsstorungen und sexuelle Storungen), schien ab 1845 eine progrediente Phase einzusetzen, die bis zum Tod 1847 anhielt. 1844 diagnostizierten die damaligen Arzte „eine Paraplegie passiver Art, deren Ubergang vom funktionellen in einen organischen Zustand noch nicht gesichert werden konnte“. Zur gleichen Zeit gaben Cruveilhier [1] und Carswell [2] die ersten anatomischen Beschreibungen der MS unter dem Begriff „Paraplegie infolge grauer Degeneration der Ruckenmarksbahnen”. Es dauerte jedoch noch bis 1868, bis Charcot und Vulpian die erste ausfuhrliche klinische und anatomische Beobachtung der Krankheit veroffentlichten [3]. In der Tat stellte Charcot in einem „Fall einer generalisierten multiplen Sklerose des Gehirns und des Ruckenmarks“ die diagnostischen Kriterien der Krankheit auf und zeichnete ein sehr prazises Bild dieser Krankheit, indem er an mehreren verstorbenen Patienten in der Salpetriere die histologischen Untersuchungen wieder aufnahm. Er meinte, dass es sich bei der Erstlasion um eine Zerstorung der Markscheiden handele, wobei die Nerven selbst unversehrt blieben, und beschrieb die perivaskularen entzundlichen Reaktionen und die durch alte Lasionen entstandenen Narben.

Die Definition der multiplen Sklerose (MS) ist eine anatomische [1]. MS ist eine Erkrankung, die zur Bildung multipler, deutlich umschriebener Lasionen innerhalb der weisen Substanz des zentralen Nervensystems fuhrt. Diese Lasionen, die so genannten „Plaques“, bilden sich aus einem entzundlichen Infiltrat, das sich um die Venolen entwickelt. Die Zerstorung des Myelins ist elektiv, zumindest am Beginn der Erkrankung verschont sie die Axone. Fur die klinische Praxis ist das Kriterium der anatomischen Definition der MS untauglich: Die Autopsie und die Gehirnbiopsie sind zwar mogliche, aber ganz ausergewohnliche Umstande fur die Diagnose einer MS. Die anatomischen Untersuchungen haben gezeigt, dass bei ein und demselben Patienten Plaques unterschiedlichen Alters vorhanden sind. Mittels MRT lasst sich der naturliche Verlauf einer MS in vivo prazisieren. Die MRT bildet Lasionen in der weisen Substanz des zentralen Nervensystems ab, deren Aussehen sich mit der Zeit andert und die bei sukzessiven Untersuchungen sichtbar werden und wieder verschwinden konnen. Bei den remittierenden Formen der MS gibt es mindestens zwanzigfach mehr radiologische als klinische Ereignisse. Die Plaques sind fur klinische Symptome verantwortlich, sofern sie „klinisch sprechende“ Areale im zentralen Nervensystem befallen. Im Verlauf der MS mit Schuben und Remissionen spiegelt sich die Geschichte der Plaque, die fur die objektiven und subjektiven Zeichen beim Patienten verantwortlich ist.

Eine kanadische Studie berichtet, dass 125 Patienten von 4000 untersuchten Fallen bei Krankheitsbeginn junger als 16 Jahre waren (3 Prozent) [1]. Von diesen jungen Patienten gehorten 75 Prozent dem weiblichen Geschlecht an. Die Anfangssymptomatik unterscheidet sich nicht von der des Erwachsenen, allerdings steht meistens ein einziges Symptom im Vordergrund. Dem Beginn der Krankheit geht bei der Halfte der Betroffenen ein unspezifischer Infekt, in der Regel einer der Atemwege voraus. Besonders haufig sind Storungen der Sensibilitat und des Sehvermogens (Optikusneuritis). Manchmal fallt anfangs das klinische Bild einer akuten Enzephalopathie auf, die auf eine Virusenzephalitis oder einen Hirntumor schliesen lasst. Die Ergebnisse der Zusatzuntersuchungen gleichen denen, die man beim Erwachsen gewinnt. Bei einem enzephalitischen Beginn kann der Zellgehalt im Liquor beachtlich (bis zu 900 Zellen/µl) steigen und der Eiweisgehalt erhoht sein (>1 g/1) [2].

The diagnosis of inflammatory optic neuritis remains essentially clinical, and may be improved by complementary investigations. The prognosis is related to the evolution of visual acuity and the risk of development of multiple sclerosis. The treatment of acute episodes is better precised but remains a matter of debate. Long term treatment has benefited from the results of recent MRI studies.

The objective of this study was to evaluate the risk of visual outcome after acute optic neuritis (ON) in relation to clinical and MRI findings. Fifty cases of acute ON within one month were retrospectively studied. MRI with Short Tau Inversion Recovery (STIR) sequence of the optic nerve were obtained with a median time onset of 9 days after ON. Mean age of patients was 32.8 years, mean initial visual acuity was 3/10 and orbital pain was present in 86 percent100 of patients. The STIR sequence revealed lesion in 88 percent 100 of acutely symptomatic optic nerves. An initial low visual acuity (less than 2/10), the absence of orbital pain and involvement of the intracanalicular portion of the optic nerve on STIR sequence were statistically correlated with a poorer visual outcome (respectively p=0.0041, p=0.035 and p=0.011).

Andermann syndrome or Agenesis of the Corpus Callosum with Polyneuropathy (MIM 218000) is an autosomal recessive disease almost exclusively found in Québec. Only few cases have been reported in other populations. The locus for Andermann syndrome was assigned to chromosome 15q13-q15 in French Canadian families. We performed a haplotype analysis with two markers of this chromosomal region in an Algerian consanguineous family with two affected sibs. The children were homozygous for both markers, suggesting genetic homogeneity in Andermann syndrome.

GENERAL DATA: The clinical manifestations and neuropathological signs of multiple sclerosis have been recognized for more than one hundred years, but the cause remains unknown.Multiple sclerosis is not evenly distributed throughout the world. There is an important north-south gradient in the northern hemisphere and inversely in the southern hemisphere; multiple sclerosis is more frequent in the higher altitudes. For a given latitude, there is a difference by ethnic origin. These observations indicate that multiple sclerosis is a multifactorial condition determined by both genetic and environmental factors.Progress in our knowledge of the human genome and statistical analysis techniques have made it possible to search for genetic factors in multiple sclerosis using two complementary approaches. The first is by anonymous screening and the second is to search for a candidate gene. The HLA locus is the only one with an identified predisposing effect for multiple sclerosis. It only accounts for 10 to 20% of the genetic predisposition for multiple sclerosis and many factors remain to be discovered.

Magnetic resonance imaging (MRI) is very sensitive in depicting multiple sclerosis (MS) lesions, but its specificity is poor. New sequences such as fast spin echo and FLAIR (fluid attenuated inversion recovery) improve the detection of lesions. The exploration of the whole central nervous system, brain, optic nerves and spinal cord improves sensitivity and specificity. The existence of lesions at different ages responds to temporal dissemination. MRI has also allowed to better understand the natural history of MS, showing 5 to 10 times more radiological than clinical activity. In case of isolated demyelinating syndrome, MRI is the best predictor of the occurrence of definite MS and of the severity of disability in the subsequent 10 years. However, the diagnosis of MS remains clinical, and systematic control MRI are not useful in clinical practice.

MRI is the most powerful imaging technique in managing patients with suspected or confirmed multiple sclerosis (MS). However, conventional MRI variables show nonspecific abnormalities weakly correlated with clinical progression of the disease. New techniques, now routinely available, offer better characterisation of the pathophysiology. We combined conventional MRI, including lesion load, contrast enhancement and "black holes" with magnetisation transfer and diffusion-weighted imaging and localised proton MR spectroscopy (MRS) to study their relationship with disability, course and duration of MS. The variables that were the most significantly linked to the course of the disease (relapsing remitting versus secondary progressive) were lesion load, mean overall magnetisation transfer ratio and apparent diffusion coefficient (MGADC), the percentage of ADC in (PADCIMD), and out of (PAD-COMD) modal distribution, and the ratio N-acetylaspartate and creatine-containing compounds on MRS of the centrum semiovale. MGADC and PADCIMD were the independent factors most related to disability and duration of disease. Combining MRI techniques is clinically relevant and feasible for studies of MS and may be applied to other diseases of the central nervous system.

We report a case of a mitochondrial cytopathy (MERRF) with a late diagnosis because of the absence of Ragged-Red Fibers (RRF) in the first muscular biopsy performed in childhood. Eight years after the onset of the disease the familial history and the clinical manifestations were very suggestive of a mitochondrial cytopathy and a second biopsy was performed confirming the diagnosis of MERRF. The authors discuss several hypotheses to explain the negativity of the first muscular biopsy. The absence of ragged-red fibers does not exclude the diagnosis of a mitochondrial cytopathy and other investigations are justified such as the biochemical study of the respiratory chain and the molecular analysis of mitochondrial DNA.

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.

Magnetic resonance spectroscopy allows in vivo neurochemical exploration of multiple sclerosis (MS) lesions and normal appearing white matter on MRI. It gives insights into pathophysiology: inflammation (increase of choline), recent demyelination (increase in lipids and choline), axonal dysfunction (decrease of NAA), gliosis (increase of myoinositol). The spectroscopic profile of lesions is not specific to MS. Therefore MRI remains the first investigation to perform when MS is suspected. However, spectroscopy is a sensitive, reproducible, non invasive tool which may provide an index of activity. In the future, spectroscopy may contribute in homogenizing patient selection for clinical trials and might be used, in association with MRI, to evaluate therapeutic efficiency. Spectroscopy might also influence therapeutic choices by identifying the prevailing lesional mechanism: inflammation, demyelination, axonal destruction, or gliosis.

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

The interobserver variability of the expanded disability status scale (EDSS) was studied in 59 patients with multiple sclerosis (MS). Interrater agreement was measured by the kappa coefficient. Agreement was low in patients with mild disability (EDSS less than 5); it was higher in patients with EDSS equal to or greater than 5. The difference between ratings of 2 independent examiners was equal to at least 1 point in 34% of the MS cases. This variability must be taken into consideration in designing clinical trials in MS.

Cognitive evaluation of 6 cases of adult adrenoleukodystrophy (ALD) included in a brain magnetic resonance (MR) study are reported: 2 males with adrenomyeloneuropathy and 4 women heterozygous for ALD. Cognition was normal in 4 and MR scan in 2 of them. In the 2 others, there were mild modifications of the white matter. One patient suffered of visual retention disturbances with abnormalities of the white matter in MR scan. In the last, cognitive decline was observed; MR scan showed atrophy of cortex and corpus callosum and periventricular high signal areas. Comparison with leukoaraiosis in healthy adults and with multiple sclerosis suggests that there is probably a relationship between cognition and extension of brain MR abnormalities. Time of appearance and frequency of cognitive dysfunction might be explained by the natural history of each of these diseases.

We investigated neurochemical abnormalities in the normal-appearing white matter (NAWM) on MRI of patients with optic neuritis (ON) and compared them to those of patients with multiple sclerosis (MS). Patients with ON (42) were classified into three groups according to abnormalities on brain MRI. Patients with MS (55) were devided in two groups: relapsing remitting MS (RRMS) and secondary progressive MS (SPMS). All patients underwent MRI of the brain and localised proton magnetic resonance spectroscopy (MRS) of NAWM. The results were compared to those of 15 controls. Patients with MS had significant abnormalities compared with controls and with patients with ON. Patients with RRMS and those with ON had comparable MRS parameters, while patients with SPMS had significant spectroscopic abnormalities in comparison with controls, but also with patients with RRMS. These changes consisted of a decrease in N -acetylaspartate, a neuronal marker, which may reflect axonal dysfunction and/or loss. MRS abnormalities were detected in 14 patients with ON (27 %). The main abnormalities consisted of a decrease in N -acetylaspartate, an increase in choline-containing compounds at long echo times, and the presence of free lipid peaks at short echo times. MRS of the NAWM on MRI may prove useful for detecting neurochemical brain abnormalities in ON not visible on MRI.

Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease.To determine the contribution of familial factors to the clinical expression of MS.The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features).The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03).This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis.Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS.Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA.Negative results were obtained for all candidate genes. The lower limits of the relative risk (Xs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFbeta3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA.Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFbeta3, the only gene highlighted by this study, deserves further analysis.

Sneddon syndrome is characterized by the association of livedo reticularis and cerebrovascular ischemic events. Clinical and MRI aspects are described in 26 patients with Sneddon syndrome. MRI features were classified in 6 groups according to the aspect and topography of the lesions. No correlation was found between the presence of vascular risk factors, valvulopathy or antiphospholipid antibodies and the presence of dementia or MRI lesions. There was a significant correlation between MRI extension of the lesions and clinical disability. Clinical course and MRI findings are presented according to the treatment.

We report a 73-year-old man who presented with Vernet9s syndrome (involvement of the IXth, Xth, and XIth cranial nerves) as a first manifestation of giant cell arteritis.

Fifty six patients among whom 39 had white matter diseases had MRI of the brain comparing FLAIR sequence to a conventional proton density sequence. Flair sequence allowed to detect 18 additional hypersignal (HS) that were not present on T2 sequence. These HS were located in the periventricular areas for 5 of them, near the cortical sulci in 10, and in the centrum semi-ovale for 3. FLAIR sequence permitted analyze 41 other lesions that were not obvious on proton density sequences. Thirty five of them were thus confirmed to be HS : 31 in the paracortical areas, 3 in the paraventricular regions and one in the internal capsule, whereas the remaining 6 were normal sulci of the brain. FLAIR sequence increases the sensitivity of MRI in white matter diseases.

We used a rapid long TE proton magnetic resonance spectroscopic (MRS) sequence in the normal appearing white matter of 11 patients with definite multiple sclerosis (MS) localizing the volume of interest in the centrum semi-ovale. The metabolic changes were compared to the same area in 11 normal brains. We found a significant decrease in NAA/Cr ratios and a borderline significance of increase in Cho/Cr ratios in patients with MS. A discriminant analysis was performed on these data. This allowed to obtain a simple ratio, NAA/(Cho+Myo), which discriminated MS patients from controls. Our results indicate that normal appearing white matter on MRI is biochemically abnormal in patients with MS. In addition MRS could be routinely used after a standard MRI examination in patients with MS for clinical correlations, total load of the disease assessment and monitoring clinical trials.

The authors describe a 28-year-old woman with histopathologically confirmed early onset Alzheimer disease characterized by severe frontal lobe involvement associated with a de novo mutation in the presenilin 1 gene (PSEN1).

Adult adrenoleukodystrophy is a X-linked peroxisomal disease associated with the accumulation of very long chain fatty acids (VLCFA) in tissues and body fluids. The diagnosis is established on the demonstration of elevated VLCFA in blood and cultured skin fibroblasts. Women are affected in nearly 15% of cases and neurological symptoms and/or signs develop in 53% of them. Identifying these women is important because of genetic counseling and a possible therapeutic approach. Ten cases of symptomatic heterozygous adult adrenoleukodystrophy are reported. Mean age at the time of diagnosis was 44.6 +/- 9.3 years. All patients presented with spastic paraparesis with inconstant and mild sensory or bladder disturbances. Cognitive impairment was present in 1 case. Cerebrospinal fluid was normal. Adrenal function in response to tetracosactide injection was abnormal in 1/7 cases. Electromyography detected a peripheral neuropathy in 1 case. Somatosensory evoked responses were abnormal in all cases, visual and auditory evoked responses in respectively 3/6 cases and 3/4 cases. Brain MRI detected non specific abnormalities in 3/7 cases; spinal cord MRI was normal in 3/3 cases. The familial history was helpful for the diagnosis in 3/10 cases. Examination of pedigrees detected 5 hemizygous and 1 asymptomatic heterozygous cases. All the patients were enrolled in a dietary study which adret with low VLCFA is currently under evaluation.

Numerous immune abnormalities have been described in multiple sclerosis, including dysfunction of humoral, cellular and non specific immunity. The main abnormality probably concerns suppressive T cell function. The decrease of this function could explain the breakdown of immunological tolerance towards myelin antigens. The primary responsibility of these abnormalities in the triggering of the disease has still to be demonstrated. Moreover, the antigenic target of immune dysfunction has not yet been determined. A better understanding of T cell traffic into the central nervous system and of the mechanisms of interactions between the T cells and the antigen on one hand, the T cells and the cells presenting antigen on the other hand, offer encouraging therapeutic possibilities.

We report on a 54-year-old man with a sensory-motor polyneuropathy associated with a biclonal IgM-kappa gammopathy, which reacted with the ganglioside GD1b. Examination of nerve biopsy specimens showed some reduction in the density of myelinated fibers and axonal degeneration with a loss of large fibers and a relative increase in the density of small fibers. Immunodetection on thin-layer chromatography of the glycolipid antigens showed strong reactivity of the patient's serum IgM-kappa with GD1b ganglioside and weak binding to GD1a. biclonal IgM antibodies did not react with GM1, asialo-GM1, GT1b, GD2, or GD3. Indirect immunofluorescence staining showed binding of IgM-kappa mainly in a crescent-like pattern on the internal side of myelin sheaths, which could correspond either to an enlarged periaxonal (adaxonal) space or to the internal mesaxon or to both. The immunostaining was abolished after absorption of the serum with GD1b.