Leukodystrophies: clinical and therapeutic aspects

This chapter reviews that leukodystrophies is a genetic diseases that occur in early childhood. It is a possibility that leads to screening for leukodystrophy patients with early-onset dementia of unknown origin or atypical psychiatric symptoms. The chapter focuses on genetic cases of white matter involvement presenting with deficits in cognitive functions or dementia. Leukodystrophies are rare causes of dementia in the adult. They may cause a dementia of the frontal type or psychiatric symptoms than can mimic schizophrenia but are rapidly associated with long tract involvement. The presence of other cases in the family is a crucial step in the diagnosis but apparently isolated cases are frequent. Homochrony and homotypy are the rule but with many exceptions they have to be considered for genetic counseling. MRI is also critical, showing abnormal increased signals of the white matter on T2-weighted and FLAIR sequences, with a frontal predominance. Normal MRI imaging, at least at the beginning of the disease, does not rule out the diagnosis. The study of the pathogenetic mechanisms of leukodystrophies has been improved by the development and the analysis of animal models. The chapter states that no curative treatment is yet available. New perspectives have opened with the development of cell and gene therapies, even in adult forms, where the demyelination can at least be stabilized

Ultrastructure du cytosquelette axonal au cours des neuropathies des vascularites nécrosantes

Introduction Au cours des vascularites nécrosantes (VN) les caractéristiques ultrastructurales des altérations du cytosquelette axonal (neurofilaments (NF) et microtubules (MT)) et leurs corrélations immunocytochimiques sont peu connues.   Objectifs Les NF et MT sont étudiés au cours des VN et les résultats comparés à ceux de l’immunocytochimie montrant respectivement une réduction et une augmentation de ceux-ci corrélées à la perte axonale (Fressinaud et al., 2003).   Méthodes Dans les VN (6 cas) la densité par m2 des NF et des MT en fonction du diamètre des fibres myélinisées (10 fibres par classe) du nerf musculocutané étaient comparées à celle de témoins (indemnes de neuropathie, n = 5) d’une banque de biopsies précédemment étudiées. De même la distance inter-NF minimale (dmNF) était mesurée.   Résultats Les altérations concernaient les fibres de tout diamètre et étaient globalement sévères et très variables selon les fibres. A l’exception d’un cas, les NF étaient diminués (de 62% en moyenne), quel que soit le diamètre axonal, de façon globalement parallèle à la perte axonale. La dmNF augmentait en moyenne de 16%, de façon inversement proportionnelle à la densité des NF. Les MT diminuaient de plus de 50%, contrairement aux données de l’immunocytochimie.   Discussion Ces données confirment, pour les NF, celles de l’immunohistochimie, montrant une réduction de l’immunoréactivité proportionnelle à la perte en fibres (Fressinaud et al., 2005). Elles démontrent que la perte en NF correspond à une diminution par fibre et non à la seule réduction du nombre de fibres. La réduction des MT pourrait résulter d’un défaut d’assemblage de tubuline dont la synthèse serait accrue et l’immunoréactivité augmentée.   Conclusion Une dégradation accrue des NF, et une augmentation de la synthèse de tubuline libre (détectée en immunocytochimie et correspondant à la régénération

Neuropathie démyélinisante au cours d’un traitement par anti-TNF alpha et revue de la littérature

Introduction Tumor necrosis factor- (TNF) blockers are efficient in the treatment of autoimmune disorders such as inflammatory bowel disease and rheumatoid arthritis, but can induce CNS adverse effects including retrobulbar optic neuritis or aggravation of multiple sclerosis. Observation We report a case of progressive demyelinating polyneuropathy after initiation of Adalimumab (Humira®). Corticosteroid and intravenous immunoglobulins were ineffective but the neuropathy improved within six months after adalimunab discontinuation. Discussion This case, and other reports recently published suggest that anti-TNF alpha drugs can induce demyelinating neuropathy. Conclusion Clinicians should be on the lookout for signs evocating neuropathy in patients given anti TNF alpha

Syndrome de Garcin révélant un lymphome malin non hodgkinien

INTRODUCTION: R Garcin described progressive unilateral cranial nerve palsy in 1926. Garcin syndrome is characterized by progressive involvement of the cranial nerves culminating in total unilateral paralysis of all cranial nerves. Carcinoma of the skull base or ENT regions is the most common etiology. CASE REPORT: A 74-year-old man developed signs involving the left Vth (V2 and V3) cranial nerve then the VIth, VIIth and VIIIth cranial nerves and finally the IXth and Xth. MRI showed involvement of these cranial nerves with gadolinium uptake and involvement of the pons at the terminal phase. Careful ENT explorations failed to reveal a cause. The lymphocyte count was elevated in the cerebrospinal fluid. The patient died one year after diagnosis and the general autopsy was normal. The neuropathological studies led to the post-mortem diagnosis of type B non-Hodgkin lymphoma. CONCLUSION: In patients with Garcin syndrome, lymphoma is a possible diagnosis when carcinoma of the ENT regions or of the skull bases are not present

Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis

A major cytopathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of axonal spheroids containing abnormally accumulated neurofilaments. The mechanism of their formation, their contribution to the disease, and the possibility of other co-aggregated components are still enigmatic. Here we analyze the composition of such lesions with special reference to stable tubule only polypeptide (STOP), a protein responsible for microtubule cold stabilization. In normal human brain and spinal cord, the distribution of STOP proteins is uniform between the cytoplasm and neurites of neurons. However, all the neurofilament-rich spheroids present in the tissues of affected patients are intensely labeled with 3 different anti-STOP antibodies. Moreover, when neurofilaments and microtubules are isolated from spinal cord and brain, STOP proteins are systematically co-purified with neurofilaments. By SDS-PAGE analysis, no alteration of the migration profile of STOP proteins is observed in pathological samples. Other microtubular proteins, like tubulin or kinesin, are inconstantly present in spheroids, suggesting that a microtubule destabilizing process may be involved in the pathogenesis of ALS. These results indicate that the selective co-aggregation of neurofilament and STOP proteins represent a new cytopathological marker for spheroids

Cytoskeleton abnormalities in axonopathies of unknown aetiology: correlations with morphometry

To determine if specific axonal cytoskeleton abnormalities could be demonstrated in axonopathies without aetiology, nerve biopsies from five controls and nine cases were analyzed by morphometry and immunocytochemistry with anti-neurofilament (NF, subunits L, M, H) and anti-beta tubulin (TUB) antibodies. Morphometry revealed either large fiber atrophy (decrease in large fiber density with increased density in small fibers), degeneration of large fibers (decrease in large fiber density and in total density of fibers) or of all diameter fibers. NF immunostaining density decreased (by 21-89%) only in cases with fiber loss, in parallel to myelinated fiber density as determined by morphometry. On the contrary, the density of fibers labelled for TUB increased significantly in all except two cases by 52-102% over controls. Nevertheless, in these two cases--with a severe loss of fibers--as well as in other cases, the ratio of the density of fibers labelled for TUB and NFL (TUB/NFL) increased by 48-404%. Thus, the total density of myelinated fibers was always inversely correlated with the TUB/NFL ratio. Similar abnormalities have been described only after axotomy; our cases could thus be compared to

Axon cytoskeleton ultrastructure in chronic inflammatory demyelinating polyneuropathy

Introduction: To detail the extent and pattern of axon cytoskeleton alterations in chronic inflammatory demyelinating polyneuropathy (CIDP).Methods: Nerve biopsies from 7 cases of CIDP, including 4 cases with severe fiber loss, were compared with 5 controls by morphometric transmission electron microscopy (TEM).Results: Despite demyelination of single fibers, myelin ultrastructure was otherwise normal. Contrary to immunolabeling, TEM revealed a decrease in neurofilament (NF) density in every case, although there were pronounced variations among fibers even in the same sample. The NF decrease reached the same extent in large- and small-diameter fibers. It was observed in normally myelinated fibers, suggesting they were demyelinated at a distance from the section. Minimal inter-NF distance increased roughly inversely to NF density. Microtubules increased in 3 cases previously characterized by increased growth-associated protein (GAP-43) immunolabeling.Conclusion:These data demonstrate the severity and constancy of axonal lesions, and especially of NF, in residual fibers in our cases of CIDP. Muscle Nerve 44: 332–339, 201

Periodic hypokalemic paralysis disclosing thyrotoxicosis

BACKGROUND: Hypokaliemic periodic paralysis is an uncommon complication of hyperthyroidism occurring sporadically almost exclusively in young Asian men. The clinical presentation is the same as in familial hypokaliemic periodic paralysis. Treatment consists of conventional management for thyrotoxicosis. CASE REPORT: A Laotian man aged 42 years had suffered episodes of pain and fatigue in the lower limbs lasting 2 to 7 days over the last few months. The patient was hospitalized with severe limb pain. Clinical examination found severe motor deficit involving all four limbs. Laboratory findings induced hypokaliemia (1.8 mmol/l) and hyperthyroidism (free thyroxin 36 pmol/l, TSH < 0.005 mlU/l). Thyroid echography revealed multinodular goitre with two heterogeneous nodules. Strong uptake was seen on the scintigram. The motor deficit regressed within 8 hours and the kaliemia was restored with 1.50 g KCl. The patient was discharged with carbimazole (30 mg/d). Three months later he was euthyroid and symptom free. Total thyroidectomy was performed and L-thyroxin prescribed. The patient remains symptom-free at the last follow-up, 5 months after thyroidectomy. DISCUSSION: The pathogenesis of hypokaliemic periodic paralysis involves the ATPase-dependent sodium-potassium pump whose activity is stimulated by thyroid hormones. The reasons for the ethnic and male predominance are poorly elucidated

Chronic inflammatory demyelinating polyneuropathy in Waldenström's macroglobulinemia

Waldenström’s disease (WD) is frequently associated with a predominantly sensory neuropathy with a progressive course due to the monoclonal IgM activity against Myelin Associated Glycoprotein (MAG). However, neurolymphomatosis or chronic demyelinating inflammatory polyneuropathy (CDIP) may occur in some patients with WD.Case report We report a case of Waldenström’s macroglobulinemia in an adult male presenting with cranial nerve palsy and rapidly progressive asymmetric polyneuropathy. Intravenous IgM treatment that provided transient amelioration was followed by a relapse involving tetraparesis. Cerebrospinal fluid analysis, medullar magnetic resonance imaging, and electrophysiological studies led to equivocal findings suggesting the presence of either neurolymphomatosis or CIDP. Finally, sural nerve biopsy results supported the diagnosis of CIDP, which then received appropriate treatment. Conclusion In patients with WD, the possible occurrence of CIDP should be investigated with a neuromuscular biopsy when other investigations are equivocal since the disease calls for a specific treatment