Search

A number of disease-modifying therapies have been recently approved for the treatment of multiple sclerosis (MS). These molecules which prevent relapses and new central nervous system lesions are more efficient than the "old" first line therapies and/or more convenient, especially with oral agents. Their usefulness in treating active MS is undeniable, but we have to be aware of their potentially extremely severe side effects. The treatment algorithm in MS is constantly evolving according to the long term safety profile of these new treatments. A better knowledge of fundamental pathophysiology is associated with the development of new molecules targeting the immunological cascade of the disease as well as the mechanisms promoting remyelination and repair., (© 2013 médecine/sciences – Inserm.)

Multiple sclerosis is an inflammatory disease of the central nervous system associated with demyelination and axonal damage. It is the leading cause of acquired non traumatic disability in young adults. Current treatments include immunomodulators (interferon beta glatiramer acetate), immunosuppressants (mitoxantrone) and natalizumab, a monoclonal antibody that prevents activated lymphocyte transmigration in the central nervous system. Many candidate drugs are being evaluated in relapsing-remitting forms. Their efficacy is encouraging but is offset by toxicity, including severe infections. None of these new treatments has proven effective in the progressive phase of the disease, in which axonal damage is prominent and partly independent of the inflammatory component.

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., (Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.)

Multiple sclerosis is the main source of significant disability in young adults and is associated with inflammation, demyelinisation and neurodegeneration. Several trials in the past ten years have tested b interfons and other immunomodulators, with some success. Recently, Natalizumab (Tysabri), a monoclonal antibody which targets the a4-integrin expressed by immune effectors, thus preventing their migration from the circulation into the brain tissue, has demonstrated previously unseen efficacy in preventing relapses and disease progression in patients with remitting multiple sclerosis. However, this enthusiasm has been tempered by observed cases of opportunistic infection and especially progressive multifocal leucoencephalopathy, which led to its restricted use to a precise subgroup of patients. This example underlines the difficult evaluation of the benefit/risk ratio experienced by the pratician with these new and often very efficient innovative therapeutics.

Disability in multiple sclerosis is related to demyelination and axonal injury. Remyelination has been shown to occur in the different forms of the disease. In addition to restoring nerve conduction, myelin repair has a major role in preventing neurodegeneration. However, although sometimes extensive, remyelination is usually insufficient. Our understanding of the cellular and molecular mechanisms underlying the success or failure of myelin repair has benefited from lesion analysis in multiple sclerosis, and from in vivo and in vitro models of myelination and remyelination. This also provides potential targets for therapeutic intervention aimed at promoting endogenous remyelination.

Although consistent progress has been made over the last decade in the treatment of the inflammatory component of multiple sclerosis, these strategies have only partial efficacy. Numerous innovative therapeutic perspectives are emerging: currently, monoclonal antibody induced inhibition of entry of activated lymphocytes into the central nervous system is promising, but the benefit/risk ratio has still to be evaluated. In parallel, combination strategies with immunomodulators and/or immunosuppressants, and specific immunotherapy are investigated. In addition, in the longer-term, there is active development of experimental strategies aimed at repairing damaged tissue--both axon and myelin. These strategies are still at the preclinical stage. Therapeutic optimisation may come from an association between anti-inflammatory treatments acting upstream on the immune response, and neuroprotective and myelin repair strategies acting downstream, directed at the lesions.

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.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Available treatments (immuno-modulators, immuno-suppressants) limit central nervous system inflammation and are only partially effective. Remyelination of naked axons becomes insufficient in most cases as the disease progresses. The reason for this repair deficit are many, including oligodendroglial, axonal and environmental factors. Understanding why remyelination fails is crucial for devising effective methods by which to enhance it.

Disease-modifying treatments in multiple sclerosis emerged during the last few years, concerning mainly relapsing-remitting forms of the disease. They are essentially represented by beta-interferons. beta-interferons reduce relapse rate, achieving about 30 p. cent, and have an effect on brain lesions detected on MRI. They are indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis characterized by at least 2 attacks of neurological dysfunction over the preceding 2 (or 3)-year period. Questions and controversies still remain concerning dose-response effect, early initiation and duration of treatment. Copolymer, which has a different mechanism of action, also decreases frequency of relapses, and the magnitude of the clinical effect is similar to beta-interferon. Copolymer is indicated for use in patients with relapsing-remitting multiple sclerosis, having either an intolerance or a contra-indication to beta-interferon.

Orbital myositis is a rare disorder considered as a subgroup of inflammatory orbital pseudotumors. The pathophysiology is still unknown. Patients typically present with orbital pain exacerbated by eye movement and diplopia. Response to steroids is dramatic. We report a case of idiopathic myositis of the right inferior muscle, which recovered after steroid therapy.

The myelination of the axons of the central nervous system (CNS) is assumed by the oligodendrocytes, which depend at least in part on signals of axonal origin. The axonal influence on myelination seems to consist of the sum of positive and negative factors, which can either act on the axon or on the oligodendrocyte, allowing the neuron to decide when and where myelinization is initiated. The induction factors appear to be mediated, in some cases, by electrical activity. Among the negative factors, certain factors such as the adhesion molecule PSA-NCAM seem to act by inhibiting the adhesion between the axon and the oligodendrocytic extension. Others, such as the inhibitory signalling pathway, jagged1/Notch1, appear to trigger an inhibitory oligodendroglial signalling, therapy preventing maturation and myelination. The recent determination of the role of these axonal signals has provided a new approach to the mechanisms of normal myelination. These results could be extrapolated to the process of remyelination in human demyelinating pathologies such as multiple sclerosis, and open up new therapeutic research possibilities aimed at neuronal protection.

The various clinical courses of multiple sclerosis (relapsing-remitting, primary progressive, secondary progressive, progressive-relapsing) are likely related to different severity or distribution of the main lesions that constitute the plaques (inflammation, demyelination, axonal injury and loss, necrosis). They might lead to different therapeutic approaches. Some cases of the other clinico-radiological or clinico-pathological variants (pseudo-tumoral, concentric sclerosis of Baló, acute disseminate encephalomyelitis, Devic's neuromyelitis optica) obviously share similar mechanisms with multiple sclerosis. Other cases are, on the contrary, linked to different diseases. Do the variants of multiple sclerosis could be the consequence of different diseases? This is, today, a highly speculative conjecture. The prevalent hypothesis suggests that the clinico-pathological heterogeneity of multiple sclerosis is linked to the variability of the reaction of the nervous tissue to an initial injury. This different vulnerability, that depends on unknown factors, would explain the variants of the disease.

HIV-associated neurocognitive disorders are mainly reported during the late stages of the disease, in deeply immunosuppressed patients Clinically, they present as a subcortical cognitive impairment, dominated by reduced psychomotor speed and memory deficit. Encephalic magnetic resonance imaging shows in most cases a diffuse leucoencephalopathy, and there is often a poor correlation between clinical status and neuroradiological findings. The diagnostic and prognostic value of HIV load in blood and cerebrospinal fluid is currently under investigation. Finally, the efficacy of new antiretroviral drugs on HIV dementia remains uncertain.

We evaluated prospectively the HIV-1 RNA level in CSF as a marker of HIV encephalitis diagnosis. 110 HIV-1 infected patients (mean age: 39 years; sex-ratio M/F: 94/16) were tested for HIV-1 RNA in plasma and CSF. Lumbar punctures were performed to explore cognitive deficit, seizure or fever. HIV encephalitis was diagnosed in 15 patients (14%), other CNS disease in 34 (31%), and fever without CNS disease in 61 (55%). HIV-1 RNA was detectable in 93% of the plasma and in 62% of the CSF. No significant difference was observed in CSF HIV-1 RNA between patients with or without HIV encephalitis. CSF HIV-1 RNA was correlated with plasma HIV-1 RNA (p < 0.01), CSF protein (p < 0.01) and CSF white cell counts (p < 0.01). The absence of any significant difference between patients with or without HIV encephalitis, suggests that the CSF HIV-1 RNA level is not a good marker for its diagnosis.

AIDS dementia complex is a severe complication related to HIV infection of the central nervous system. It has been estimated to affect about 7% of AIDS patients, with an increased frequency in very young and old patients. In most cases, it appears in severely immuno-deficient patients. Typically, AIDS dementia presents as a subcortical dementia with cognitive, behavioural and motor decline. The mechanism of the dementia remains unclear; the neuronal loss is controversial and a neurotoxicity due to NMDA receptor activation is likely. No treatment proved to be efficient. Beneficial effect of anti-NMDA receptor antagonists are under investigation.

Anti-Yo is the most frequent antibody associated with pure paraneoplastic cerebellar degeneration. Cerebellar degeneration may be associated with anti-Hu antibody but other signs of nervous system involvement occur during the course of the disease. We report the case of a 69-year old man presenting with a severe acute cerebellar dysfunction of sudden onset. High titers of anti-Hu antibodies were detected in serum and cerebrospinal fluid by immunohistochemistry and western blot. No other neurological symptom was found after a follow-up of 18 months. Biopsy of a mediastinal lymph node revealed a poorly differentiated carcinoma. We suggest that the course of the anti-Hu syndrome may rarely be similar to the anti-Yo syndrome.

Oligodendrocytes are the myelin-forming cells of the central nervous system. Despite close relationship between oligodendrocyte and neuron, little is known about the exact role and nature of oligodendrocyte/axons interactions. We used an in vitro myelinating system to study axonal signals involved in myelination and showed: i) that only axons are myelinated, suggesting the existence of an axonal recognition signal and ii) that electrical activity seems necessary for myelination to proceed, as nerve influx blockade by tetrodotoxin strongly inhibits myelination. Moreover, myelinating oligodendrocyte appears to modulate axonal neurofilament phosphorylation. Knowledge of these reciprocal interactions may modify our physiopathological and therapeutical conceptions in human demyelinating diseases like multiple sclerosis.

Multiple sclerosis is a frequent and often disabling neurological disease. Its aetiology and treatment remain to be discovered. It has been demonstrated in multiple sclerosis brains that remyelination can occur after the myelin damage. This myelin repair is achieved by oligodendrocytes, which are the myelinating cells of the central nervous system or by oligodendrocytes precursors still present in adult central nervous system. Several recently discovered growth factors can stimulate oligodendrocytes precursors migration and proliferation, or act as survival factors for mature oligodendrocytes. These glial growth factors may represent a new therapeutic approach in multiple sclerosis, aiming at the stimulation of the endogenous capacities of remyelination.

We report axial myoclonic jerks causing flexion of the trunk, neck, left shoulder, hips and knees in a 28-years-old HIV positive patient. The clinical and electromyographic features of the jerks were consistent with a spinal origin and corresponded to the new concept of propriospinal myoclonus. No structural lesion was identified in this patient. Neurological examination was otherwise normal. HIV specific antibodies were detected in CSF, suggesting central nervous system infection. Spinal myoclonus should be considered an unusual and early manifestation of central nervous system HIV infection.

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.

A cerebellar glioblastoma was discovered in a 28 year old woman, 5 years after a focal 50 grays brain irradiation for meningioma of the clivus. This case fulfilled the accepted criteria for radiation-induced neoplasms of the central nervous system, namely a second histologically-proven tumor different from the first lesion, a location within the irradiated area and a long latent period.

Oligodendrocytes are the myelin forming cells of the central nervous system. They are derived from a precursor cell, named O-2A. This precursor cell is bipotential, and can differentiate in vitro into either an oligodendrocyte or a certain type of astrocyte, named type 2 astrocyte, depending on the presence or absence of extracellular factors. The chronology of glial differentiation is now better understood. Some factors influencing the choice of the differentiation pathway have been described. Most of these factors seem to be secreted in vitro by an other type of astrocyte, type 1 astrocyte. The succession of events leading to myelination can now be analyzed at molecular level. These very recent results have mostly been obtained in vitro. Their significance in vivo has now to be ascertained.