High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

BACKGROUND: No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. OBJECTIVES: The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. STUDY DESIGN: Uncontrolled, non-blinded proof of concept study METHODS: 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. RESULTS: In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. CONCLUSIONS: These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going.

POLG mutations associated with remitting/relapsing neurological events.

Recent experimental data underline the relationship between mitochondria and immune function. Clinical reports of patients presenting with mitochondrial dysfunction associated with dysimmune responses in the central nervous system reinforce this new concept. We describe the first case of a woman presenting with symptoms related to a novel compound heterozygous mutation of the mitochondrial polymerase γ (POLG) gene, associated with neurological events suggestive of a demyelinating process. Clinical examination revealed bilateral ptosis, progressive external ophthalmoplegia and axonal sensitive polyneuropathy suggestive of a mitochondrial disease. In line with this, muscle biopsy showed ragged red fibers, and sequencing of POLG revealed two heterozygous mutations. In addition, the patient exhibited relapsing neurological symptoms, and cerebral and spinal MRI mimicking multiple sclerosis. This patient stresses the relationship between mitochondrial dysfunction and inflammation. Recent studies suggest that targeting mitochondrial dysfunction could provide benefits in treating some inflammatory diseases.

Portosystemic shunts: an underdiagnosed but treatable cause of neurological and psychiatric disorders.

Portosystemic shunts (PSS) remain an unrecognized cause of neurological or psychiatric disorders. Here we report 5 patients with neuropsychiatric presentations of PSS. Main presentations encompassed progressive Parkinsonism, organic psychosis, recurrent coma, recurrent delusion, cognitive decline and posterior cortical atrophy. None of our patients had a known history of liver disease and laboratory analyses of liver function were normal or only slightly perturbed. Only 16 similar cases of PSS revealed by neurological or psychiatric symptoms were found in the English literature. Clinical presentations were similar to our patients but asterixis, cerebellar symptoms and spastic paraparesis were noticed in some cases. EEG could be normal or could show non specific slow waves or even, rarely, triphasic slow waves. The most frequent and specific diagnostic features included hyperammonemia, abnormal brain magnetic resonance spectroscopy and visualization of the shunts by ultrasonography or abdominal imaging techniques. Therefore, in otherwise unexplained neuropsychiatric disturbances, ammonia should be routinely measured and, if elevated, a dedicated gastroenterologist or an expert radiologist should be consulted for potential PSS examination. Treatment of the shunts or of the hyperammonemia resulted in marked neurological or psychiatric improvement in all cases.

Unilateral thalamic deep brain stimulation for disabling kinetic tremor in multiple sclerosis.

BACKGROUND: Surgical options of multiple sclerosis (MS) tremor treatment are limited and narrowed to thalamotomy or deep brain stimulation of the thalamic nucleus ventralis intermedius. Lack of qualification protocol frequently results in poor outcome. OBJECTIVE: To determine prospectively the efficacy and safety of unilateral ventralis intermedius deep brain stimulation as a tool to control disabling kinetic arm tremor related to MS. METHODS: Neurological and neuropsychological evaluations were performed 1 month and 1 day before surgery and 1, 3, and 6 months after surgery. The evaluation included measurement of tremor and dexterity, Extended Disability Status Scale, Mini Mental State Examination, and quality-of-life assessment. Nine consecutive patients were enrolled in the group. Mean age at the time of surgery was 38.9 ± 9 years; median Extended Disability Status Scale at baseline was 7.1. Mean MS duration was 11.7 years, and mean tremor duration was 6.11 years. Mean postural and kinetic scores and hand capacity were measured. RESULTS: One month after surgery, median scores off and on stimulation were 12 and 6 for postural tremor, 12 and 10.5 for kinetic tremor score, 12 and 7.5 for manual capacity, and 22 and 20 for functional handicap, respectively. Similar results were 10 and 4, respectively, at the 3-month follow-up. Six months after surgery, median scores off and on stimulation were 10.4 and 4 for postural tremor and 12 and 7.8 for kinetic tremor, respectively. CONCLUSION: This prospective study confirms the value and safety of ventralis intermedius deep brain stimulation for treatment of kinetic tremor related to MS. Accurate and precise presurgical qualification plays a key role in successful treatment.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Guillain-Barre syndrome, influenzalike illnesses, and influenza vaccination during seasons with and without circulating A/H1N1 viruses.

The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barré syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination.

Spinal cord sarcoidosis: clinical and laboratory profile and outcome of 31 patients in a case-control study.

Sarcoidosis is a granulomatous disorder of unknown cause that affects the spinal cord in fewer than 1% of patients who suffer from it. We conducted a retrospective case-control study of 31 patients with spinal cord sarcoidosis and compared them to 30 patients with myelopathies of other causes to analyze their clinical, laboratory, and magnetic resonance imaging (MRI) profiles and to assess their long-term prognoses. Thirty-one patients presented with clinical signs of myelopathy and were diagnosed with sarcoidosis. Twenty-two of these patients had biopsy-proven noncaseating granulomas. In 9 patients, sarcoidosis involved only a neurologic localization. Patients in the control group were mainly diagnosed with multiple sclerosis or optic neuromyelitis. Patients with sarcoidosis were more likely to have elevated levels of C-reactive protein (CRP), elevated lactate dehydrogenase (LDH), and hypergammaglobulinemia in serum, as well as a higher protein content and white blood cell count in cerebrospinal fluid. Spinal cord MRIs performed in 26 patients with spinal cord sarcoidosis revealed T2-hyperintensities that were extensive and heterogeneous with a central distribution in axial slides. Twenty-six patients with spinal cord sarcoidosis presented neurologic sequelae after follow-up (mean, 64 +/- 8 mo), although 2 patients completely recovered. Neurologic sequelae correlated with cerebrospinal fluid white blood cell counts. One-third of the patients had a monophasic course of the disease, another third had a relapsing-remitting course, and the remaining third had a progressive course. Four patients had pulmonary embolism during follow-up. Spinal cord sarcoidosis remains a diagnostic dilemma since neurologic localization is frequently the only manifestation. Because treatment for spinal cord sarcoidosis is far different from treatment for other myelopathies, such as multiple sclerosis and optic neuromyelitis, diagnosis of sarcoidosis remains an important challenge. Here, we show that spinal cord MRI and blood and cerebrospinal markers may be useful tools in the diagnosis of spinal cord sarcoidosis. We suggest that accessory salivary gland biopsies, chest X-rays, protein electrophoresis, and blood levels of CRP and LDH should be obtained for each patient with subacute myelopathy. We also recommend paying careful attention to thromboembolism in patients with spinal cord sarcoidosis because of systemic disease and their decreased mobility.

Cerebrotendinous xanthomatosis presenting with severe externalized disorder: improvement after one year of treatment with chenodeoxycholic Acid.

Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation. We describe two siblings with an early psychiatric presentation of CTX-associated attention-deficit/hyperactivity disorder and oppositional defiant disorder, also associated with a mild intellectual disability and major behavioral impairments. In both cases, treatment with chenodeoxycholic acid improved externalized symptoms and a partial recovery of cognitive impairments was observed. This suggests that CTX is potentially reversible, demonstrating the need for early diagnosis and treatment of this disorder before irreversible neurological lesions can occur.

[Current treatment for multiple sclerosis]. / Traitements actuels de la sclérose en plaques.

Several drugs are now available to treat multiple sclerosis. MS treatment has included immunomodulatory agents for 15 years; monoclonal antibody therapies have recently been added. IFN beta and Glatiramer acetate are effective in reducing relapses and lesions visible on magnetic resonance imaging (MRI) in patients with MS. Natalizumab, a monoclonal antibody, reduces the short-term risk of increasing disability and the rate of clinical relapse in patients with relapsing MS. Clinical trials are currently underway to assess the efficacy of other monoclonal antibodies and immunosuppressors. In the future, remyelinating and neuroprotective approach offers new perpectives.

Creutzfeldt-Jakob disease in a patient treated by etanercept for rheumatoid arthritis (RA): just a coincidence?

We describe a patient in whom sporadic Creutzfeldt-Jakob disease (sCJD) occurred one year after the onset of etanercept therapy for rheumatoid arthritis (RA). This association could be a chance occurrence. However, TNF-alpha has been implicated in the pathogenesis of neurodegeneration in sCJD and etanercept might worsen the disease. Such an aggravation has been observed in multiple sclerosis, in which TNF-alpha is the key mediator of demyelination. It may be of interest studying the impact of treatment with TNF-alpha antagonists on prevalence and incidence of those neurodegenerative diseases involving TNF-alpha mediation, such as Alzheimer disease.

Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations.

OBJECTIVE: To report the first 2 European cases of biotin-responsive basal ganglia disease and novel SLC19A3 mutations. DESIGN: Case reports. SETTING: University hospital. Patients A 33-year-old man and his 29-year-old sister, both of Portuguese ancestry, presented with recurrent episodes of encephalopathy. Between episodes patients exhibited generalized dystonia, epilepsy, and bilateral hyperintensities of the caudate and putamen. MAIN OUTCOME MEASURES: Clinical and radiologic findings. RESULTS: Administration of high doses of biotin or of a combination of biotin and thiamine during encephalopathies resulted in spectacular clinical and radiologic improvement in both patients. Sequencing of the SLC19A3 disclosed 2 novel mutations, both of which created premature stop codons in the protein sequence of hTHTR2. CONCLUSION: This study demonstrates that biotin-responsive basal ganglia disease is a panethnic condition. A therapeutic trial with high doses of biotin and thiamine seems mandatory in every unexplained encephalopathy with bilateral lesions of putamen and caudate nuclei.

Rapid onset frontal leukodystrophy with decreased diffusion coefficient and neuroaxonal spheroids.

Adult leukodystrophies with neuroaxonal spheroids (LNS) constitute a heterogeneous group of genetic diseases. Herein, we report on two unrelated patients with LNS characterized by rapid onset, predominant involvement of the frontal white matter, and areas of decreased apparent diffusion coefficient on diffusion-weighted imaging. We found similar cases in the literature and propose that they represent a distinct entity within the group of LNS. Further studies will be required to identify its molecular basis.

Intravenous immunoglobulins-induced eczematous eruption: a long-term follow-up study.

BACKGROUND: High-dose intravenous immunoglobulins have emerged as an important therapy for various diseases. Vesicular eczematous eruption has recently been described as an intravenous immunoglobulins adverse effect. Little is known about patients' characteristics, administration regimens and long-term outcomes. METHODS: We retrospectively examined a series of 9 patients which had been notified to the Regional Pharmacovigilance Center for an eczematous skin reaction after intravenous immunoglobulins infusion. RESULTS: There were 8 men and 1 woman. Mean age was 56.4 years. Seven patients were treated with intravenous immunoglobulins for neurological disease. Eruption was mostly localized to palms and soles. All patients improved, either spontaneously or with systemic or topical steroid treatment. Rash recurred in 4 out of 5 patients in which immunoglobulins were readministered. Eruption did not relapse in 3 patients when immunoglobulins preparation was switched for another one. CONCLUSIONS: Eczematous eruption due to infusion of immunoglobulins is rare although mostly benign side effect. Treatment withdrawal is usually not required if there is a major clinical benefit. Switching the type of IVIg is often a useful strategy.

Eating disorder and metabolism in narcoleptic patients.

STUDY OBJECTIVE: To evaluate eating behavior and energy balance as a cause of increased body mass index (BMI) in narcolepsy. DESIGN: Case controlled pilot study. SETTINGS: University hospital. PARTICIPANTS: 13 patients with narcolepsy (7 "typical" patients, with HLA DQB1*0602 and clear cut cataplexy, with suspected hypocretin deficiency; and 6 "atypical" narcoleptics, i.e., HLA negative or without cataplexy), and 9 healthy controls matched for age, gender, and ethnicity. INTERVENTION: Energy balance was evaluated by measuring BMI, rest energy expenditure with calorimetry, daily food and water intake, and plasma hormone levels. Eating behavior was evaluated using psychometric tests (EAT-40, EDI2, CIDI-2, MADRS). RESULTS: Patients with narcolepsy (whether typical or not) tended to be overweight and to have a lower basal metabolism than controls. Only patients with typical narcolepsy tended to eat less than controls. Narcoleptic patients who were overweight ate half as much as others, indicating caloric restriction. Plasma glucose, cortisol, thyroid, and sex hormones levels did not differ between groups, while prolactin levels were twice as high in patients with narcolepsy as in controls. Narcoleptic patients had higher EAT-40 scores and more frequent features of bulimia nervosa (independent of depressive mood) than controls, suggesting a mild eating disorder, classified as "Eating Disorder Not Other Specified." DISCUSSION: Both lower basal metabolism and subtle changes in eating behavior (rather than in calorie intake) could explain the positive energy balance leading to overweight in narcolepsy. Eating behavior changes may be a strategy to control weight or to avoid daytime sleepiness.

Interferons in multiple sclerosis: ten years' experience.

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFN beta in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFN beta are now approved in Europe and North America: chronologically IFN beta-1b (Berlex/Schering), IFN beta-1a given intramuscularly (Biogen), and IFN beta-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.

Intact subliminal processing and delayed conscious access in multiple sclerosis.

Periventricular white matter damage affecting large bundles connecting distant cortical areas may constitute the main neuronal mechanism for the deficit of controlled information processing observed in patients with early multiple sclerosis (MS). Visual backward masking has been demonstrated to affect late stages of conscious perception involving long-range interactions between visual perceptual areas and higher level integrative cortices while leaving intact early feed-forward visual processing and even complex processing such as object recognition or semantic processing. We therefore hypothesized that patients with early MS would have an elevated masking threshold, because of an impairment of conscious perception whereas subliminal processing of masked stimuli would be preserved. Twenty-two patients with early MS and 22 normal controls performed two backward-masking experiments. We used Arabic digits as stimuli and varied quasi-continuously the temporal interval with a subsequent mask, thus allowing us to progressively "unmask" the stimuli. We finely quantified the visibility of the masked stimuli using both objective and subjective measures, thus obtaining accurate estimates of the threshold duration for access to consciousness. We also studied the priming effect caused by the variably masked numbers on a comparison task performed on a subsequently presented and highly visible target number. The threshold for access to consciousness of masked stimuli was elevated in MS patients compared to controls, whereas non-conscious processing of these stimuli, as measured by priming, was preserved. These findings suggest that conscious access to masked stimuli depends on the integrity of large-scale cortical integrative processes, which involve long-distance white matter projections, and are impaired due to diffuse demyelinating injury in patients with early MS.

Therapy insight: inborn errors of metabolism in adult neurology--a clinical approach focused on treatable diseases.

Inborn errors of metabolism (IEMs) are genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism. In most cases, IEMs involve the nervous system. The first clinical symptoms of IEMs usually present in infancy, but in an unknown proportion of cases they can appear in adolescence or adulthood. In this Review, we focus on treatable IEMs, presenting acutely or chronically, that can be diagnosed in an adult neurology department. To make our presentation readily usable by clinicians, the Review is subdivided into eight sections according to the main clinical presentations: emergencies (acute encephalopathies and strokes), movement disorders, peripheral neuropathies, spastic paraparesis, cerebellar ataxia, psychiatric disorders, epilepsy and leukoencephalopathies. Our aim is to present simple guidelines to enable neurologists to avoid overlooking a treatable metabolic disease.

The adult form of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids and other molecules but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Based upon a comprehensive study of 13 unrelated adult patients diagnosed in France over the past 20 years as well as the analysis of the 55 other cases published since 1969, we have attempted to delineate the major clinical, radiological, biochemical and genotypic characteristics of adult NPC. Overall, mean age at onset (+/-SD) of neuropsychiatric symptoms was 25 +/- 9.7 years. The diagnosis of NPC was established after a mean delay of 6.2 +/- 6.4 years and the mean age at death (calculated from 20 cases) was 38 +/- 10.2 years. Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). Less frequent signs were epilepsy and cataplexy. During the course of the disease, clinical features could be subdivided into (i) visceral signs (hepatomegaly or splenomegaly), (ii) cortical signs (psychiatric cognitive disorders and epilepsy); and (iii) deep brain signs (VSO, ataxia, movement disorders, dysarthria, dysphagia, cataplexy) which exhibited different evolution patterns. Asymptomatic and non-evolutive visceral signs were often noticed since early childhood (38.5% of our patients), followed by mild cortical signs in childhood (learning difficulties) and early adulthood (62% of cases among which 38% were psychiatric disorders). Deep brain signs were observed in 96% of patients and were usually responsible for death. In general, there was a good correlation between clinical signs and the localization of brain atrophy on MRI. The 'variant' biochemical phenotype characterized by mild abnormalities of the cellular trafficking of endocytosed cholesterol was over-represented in the adult form of NPC and seemed associated with less frequent splenomegaly in childhood and lesser psychiatric signs. Involvement of the NPC1 gene was shown in 33 families and of the NPC2 gene in one. Improving the knowledge of the disease among psychiatrists and neurologists appears essential since emerging treatments should be more efficient at the visceral or cognitive/psychiatric stages of the disease, before the occurrence of widespread deep brain neurological lesions.

Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study.

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.