Autoimmune Disorders of the Nervous System: Pathophysiology, Clinical Features, and Therapy.

Remarkable discoveries over the last two decades have elucidated the autoimmune basis of several, previously poorly understood, neurological disorders. Autoimmune disorders of the nervous system may affect any part of the nervous system, including the brain and spinal cord (central nervous system, CNS) and also the peripheral nerves, neuromuscular junction and skeletal muscle (peripheral nervous system, PNS). This comprehensive overview of this rapidly evolving field presents the factors which may trigger breakdown of self-tolerance and development of autoimmune disease in some individuals. Then the pathophysiological basis and clinical features of autoimmune diseases of the nervous system are outlined, with an emphasis on the features which are important to recognize for accurate clinical diagnosis. Finally the latest therapies for autoimmune CNS and PNS disorders and their mechanisms of action and the most promising research avenues for targeted immunotherapy are discussed.

Stem cell therapy: challenges ahead.

Stem cells have generated great interest for their potential therapeutic use because of their capacity to self-renew indefinitely and to generate all cell lineages (pluripotency). Many diseases such as neurodegenerative disorders or diabetes are caused by loss of functionality or deficiency of a particular cell type. Stem cells differentiated into a specific cell type such as pancreatic ß-cells or neurons, for example, thus hold great promise for regenerative medicine. However, many challenges have to be overcome before stem cell therapy can become a viable clinical approach.

Frequent hemorrhagic lesions in cerebral toxoplasmosis in AIDS patients.

Cerebral toxoplasmosis is a frequent complication in immunosuppressed patients such as AIDS (acquired immunodeficiency syndrome). Frequently, lesions are located deep in the brain which are inaccessible for biopsy making rapid diagnosis dependent on accurate interpretation of neuroimaging findings. The commonest cranial CT findings reported in toxoplasmosis are ring enhancing hypodense lesions in basal ganglia or cortical gray matter. Hemorrhage has only rarely been described and is usually seen following antitoxoplasma treatment. We reviewed the records of 11 AIDS patients with cerebral toxoplasmosis and found multiple hemorrhagic cerebral, cerebellar, or brain stem lesions in 7 of 11 patients. Six patients had hemorrhage at the time of initial clinical presentation and one developed hemorrhage following 2 weeks of antitoxoplasma treatment. We conclude that hemorrhagic lesions are frequently found on cranial MRI scans in cerebral toxoplasmosis. AIDS patients presenting with hemorrhagic cerebral lesions should be considered for a trial of presumptive antitoxoplasma treatment.

The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy.

We report the detailed clinical, electrophysiological and molecular analysis of a patient with Charcot-Marie-Tooth (CMT) disease. DNA sequencing of the coding sequences of the neurofilament light chain polypeptide (NEFL) gene revealed a c.64C>T heterozygous, missense mutation resulting in a Pro22Ser amino acid substitution. Clinical and electrophysiological studies revealed a mixed axonal and demyelinating neuropathy, with widespread demyelination involving both proximal and distal nerve segments. Mutations at this site in the NEFL gene have been previously linked to an axonal neuropathy or distal nerve demyelination. Our results emphasize the complexity of genotype-phenotype correlations in CMT and underline the possible importance of host factors and gene interactions in the development of clinical phenotypes.

Stem cell based therapy for skeletal muscle diseases.

The use of stem cells to repair and replace damaged skeletal muscle cells in chronic, debilitating muscle diseases such as the muscular dystrophies holds great promise. Different stem cell populations, both of embryonic and adult origin display the potential to generate skeletal muscle cells and have been studied in animal models of muscular dystrophy. These include muscle derived satellite cells; bone marrow derived mesenchymal stem cells, muscle or bone marrow side population cells, circulating CD133+ cells and cells derived from blood vessel walls such as mesoangioblasts or pericytes. The design of effective stem cell based therapies requires a detailed understanding of the molecules and signaling pathways which determine myogenic lineage commitment and differentiation. We discuss the great strides that have been made in delineating these pathways and how a better understanding of muscle stem cell biology has the potential to lead to more effective stem cell based therapies for skeletal muscle regeneration for devastating muscle diseases.

Hypertensive encephalopathy presenting with isolated brain stem and cerebellar edema.

Hypertensive encephalopathy typically presents with headache and confusion and bilateral parietooccipital vasogenic edema. Brain stem and cerebellar edema in hypertensive encephalopathy usually occurs in association with these typical supratentorial changes and is usually asymptomatic. We report here an uncommon hypertensive patient with isolated, severe, and symptomatic brain stem and cerebellar edema with fourth ventricular obstruction and mild hydrocephalus. Rapid treatment of hypertension resulted in clinical and radiological improvement. Prompt recognition of the cause and aggressive treatment of hypertension in such patients are crucial to relieve edema and prevent life-threatening progression.

RNAi inhibition of Pax3/7 expression leads to markedly decreased expression of muscle determination genes.

Skeletal muscle regeneration by cell transplantation for the treatment of muscle diseases requires the identification and isolation of well-defined, early skeletal muscle progenitor cells. It is known that myogenesis is governed by the sequential and compound activation of the muscle determination genes, the myogenic regulatory factors (MRFs). Recently it has been proposed that the transcription factors Pax3 and Pax7 trigger the expression of the MRFs and thereby specify a novel population of cells destined to enter the myogenic program. We directly tested this hypothesis using RNA interference methodology to reduce the levels of Pax3 and Pax7 RNA in mouse embryoid bodies developing in vitro. We found that decreasing the levels of Pax3/Pax7 RNA leads to a marked and selective decrease in Myf5, MyoD and Desmin expression. Pax3 and Pax7 expressing cells from developing embryos may thus serve as the earliest known skeletal muscle progenitor cells potentially useful for cell transplantation studies.

Generation of skeletal muscle from transplanted embryonic stem cells in dystrophic mice.

Embryonic stem (ES) cells have great therapeutic potential because of their capacity to proliferate extensively and to form any fully differentiated cell of the body, including skeletal muscle cells. Successful generation of skeletal muscle in vivo, however, requires selective induction of the skeletal muscle lineage in cultures of ES cells and following transplantation, integration of appropriately differentiated skeletal muscle cells with recipient muscle. Duchenne muscular dystrophy (DMD), a severe progressive muscle wasting disease due to a mutation in the dystrophin gene and the mdx mouse, an animal model for DMD, are characterized by the absence of the muscle membrane associated protein, dystrophin. Here, we show that co-culturing mouse ES cells with a preparation from mouse muscle enriched for myogenic stem and precursor cells, followed by injection into mdx mice, results occasionally in the formation of normal, vascularized skeletal muscle derived from the transplanted ES cells. Study of this phenomenon should provide valuable insights into skeletal muscle development in vivo from transplanted ES cells.

Isolation and enrichment of skeletal muscle progenitor cells from mouse bone marrow.

There is great interest in the therapeutic potential of non-hematopoietic stem cells obtained from bone marrow called mesenchymal stem cells (MSCs). Rare myogenic progenitor cells in MSC cultures have been shown to convert into skeletal muscle cells in vitro and also in vivo after transplantation of bone marrow into mice. To be clinically useful, however, isolation and expansion of myogenic progenitor cells is important to improve the efficacy of cell transplantation in generating normal skeletal muscle cells. We introduced into MSCs obtained from mouse bone marrow, a plasmid vector in which an antibiotic (Zeocin) resistance gene is driven by MyoD and Myf5 enhancer elements, which are selectively active in skeletal muscle progenitor cells. Myogenic precursor cells were then isolated by antibiotic selection, expanded in culture, and shown to differentiate appropriately into multinucleate myotubes in vitro. Our results show that using a genetic selection strategy, an enriched population of myogenic progenitor cells, which will be useful for cell transplantation therapies, can be isolated from MSCs.