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Biomedical subjects

Andreas J Steck

Publications and source records attributed to Andreas J Steck.

At least 19 recordsLinked to original sources
PubMed2006

Contribution of nerve biopsy to unclassified neuropathy.

OBJECTIVES: To evaluate the diagnostic yield of nerve biopsy in patients with peripheral neuropathy of undetermined cause despite extensive diagnostic workup. METHODS: From November 2001 through January 2004, 38 patients underwent nerve biopsy because of unclassified neuropathy. RESULTS: The etiology of the neuropathies could be defined in 14 patients (37%), i.e. in 15% of chronic symmetric, 30% of chronic asymmetric, 50% of subacute symmetric and 62.5% of subacute asymmetric neuropathies. The biopsy was diagnostic in 6 patients (16%), where it showed a vasculitis, and supportive in 8 patients (21%). CONCLUSIONS: The contribution of nerve biopsy to the diagnosis of peripheral neuropathy was highest in acute and subacute asymmetric forms of neuropathy and lowest in chronic symmetric forms. The main indication for nerve biopsy remains the diagnosis of vasculitic neuropathy, a potentially treatable disorder.

Aged↗
PubMed2006

Unraveling the differential expression of the two isoforms of myelin-associated glycoprotein in a mouse expressing GFP-tagged S-MAG specifically regulated and targeted into the different myelin compartments.

The two myelin-associated glycoprotein (MAG) isoforms are cell adhesion molecules that differ only in their cytoplasmic domains, but their specific roles are not well understood. In this study, we present a transgenic mouse line that specifically expresses GFP-tagged S-MAG correctly regulated and targeted into the myelin sheath allowing the specific discrimination of L- and S-MAG on the subcellular level. Here, we describe the differential expression pattern and spatial distribution of L- and S-MAG during development as well as in the adult central and peripheral nervous system. In peripheral nerves, where S-MAG is the sole isoform, we observed S-MAG concentrated in different ring-like structures such as periaxonal and abaxonal rings, and discs spanning through the compact myelin sheath perpendicular to the axon. In summary, our data provide new insight in the subcellular distribution of the two isoforms fundamental for the understanding of their specific functions in myelin formation and maintenance.

Animals↗
PubMed2006

Anti-myelin-associated glycoprotein neuropathy.

PURPOSE OF REVIEW: The anti-myelin-associated glycoprotein (MAG) neuropathy is an antibody-mediated demyelinating neuropathy. The clinical picture is characterized by a distal and symmetric, mostly sensory neuropathy. Monoclonal immunoglobulin M anti-MAG antibodies are uniquely found in this condition and are believed to be pathogenic. This review focuses on recent progress in understanding the mechanisms of this neuropathy and discusses new therapeutic advances. RECENT FINDINGS: Different electrophysiological parameters have been demonstrated to distinguish the anti-MAG-associated polyneuropathy from chronic inflammatory demyelinating polyneuropathy. The electrophysiological findings generally indicate a predominantly demyelinating neuropathy with a distal accentuation of conduction slowing. Analyses of pathology in nerve tissue from anti-MAG patients using classical nerve biopsy or skin biopsy tissue demonstrated immunoglobulin M deposits at the site of MAG localization, demyelination and axonal degeneration. MAG is a Schwann cell-based glycoprotein and has been implicated as a mediator of an outside-in signaling cascade influencing the cytoskeletal integrity of axons. SUMMARY: Therapy in patients with anti-MAG neuropathy is directed at reducing the antibody concentration, blocking the effector mechanisms and depleting the monoclonal B cells. The recent availability of rituximab, a monoclonal antibody suppressing B-cell clones, which is not myelosuppressive and does not cause secondary malignancies, allows for early targeted intervention.

Animals↗
PubMed2006

Normal expression of myelin protein zero with frame-shift mutation correlates with mild phenotype.

Mutations in the gene encoding for myelin protein zero (MPZ) cause inherited demyelinating peripheral neuropathies of different severity. The molecular and cellular mechanisms by which the MPZ mutations cause neuropathy are incompletely understood. We investigated MPZ, myelin basic protein, and peripheral myelin protein 22 (PMP22) protein expression levels in a nerve biopsy of a Charcot-Marie-Tooth type 1B patient heterozygous for the Val 102 frame-shift mutation. We demonstrate by quantitative immunohistochemical as well as by Western blot analyses that MPZ expression levels were not reduced in myelin membranes, a finding that is in accordance with the mild phenotype of this patient. Our data show that heterozygous 'loss-of-function' of MPZ may not necessarily lead to reduced protein levels. In conclusion, we demonstrate that careful analysis of protein expression levels in peripheral nerve tissues provides important information with respect to the understanding of the molecular basis of these neuropathies.

Adult↗
PubMed2005

[Use of intravenous immunoglobulin in neurological disorders].

The use of intravenous immunglobulin in the treatment of Guillain-Barré-Syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathies is well established. Other conditions, such as dysglobulinemic neuropathy, myasthenia gravis, multiple sclerosis and inclusion body myositis may also benefit from the administration of intravenous immunoglobulins.

Humans↗
PubMed2005

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti-MAG neuropathy. Skin biopsies were performed in 14 patients with anti-MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti-MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti-MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti-MAG neuropathy, both large- and small-diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers.

Biopsy↗
PubMed2004

Rituximab stabilizes multifocal motor neuropathy increasingly less responsive to IVIg.

The authors report a patient with anti-GM(1) antibody-negative multifocal motor neuropathy (MMN) who was increasingly less responsive to IV immunoglobulins (IVIgs). Five yearly courses of the monoclonal anti-CD20 antibody rituximab were well tolerated and extended the interval of IVIg administration from 7 to 12 days (corresponding to 42% reduction of IVIg) during this period. Rituximab may be a benefit for patients with MMN.

Aged↗
PubMed2004

Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies).

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders (Sjögren's syndrome, SS; Miller Fisher syndrome; and Bickerstaff's brainstem encephalitis, BBE), with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non-length-dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes. This review focuses on recent advances in defining the mechanisms involved in sensory ganglionopathies. Specific topics include a summary of their clinical features, pathological findings, and immunopathology. In SSN, early diagnosis by the detection of anti-Hu antibodies and early treatment of the cancer gives the best chance of stabilizing the disorder. In SS sensory ganglionitis, response to treatment has been disappointing, but immunomodulating treatments are emerging. The immunological profile common to BBE and Fisher syndrome supports a common pathogenesis. In toxic sensory neuronopathy, no treatment is available. The differential diagnosis involves separating sensory ganglionopathies from other ataxic polyneuropathies, such as infectious neuropathies, sensory neuropathies with various autoantibodies, and the neuropathies seen in celiac disease.

Animals↗
PubMed2004

Immune mediated neuropathies--an update on therapeutic strategies.

This paper reviews recent treatment strategies of immune mediated neuropathies, in particular it includes data regarding Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), neuropathy with IgM monoclonal gammopathy and other dysglobulinemic neuropathies. In the treatment of Guillain- Barré syndrome, there is no significant difference between IVIg, plasma exchange or plasma exchange followed by IVIg. However, for reasons of convenience and safety, IVIg is used as standard treatment in most centers. There is so far insufficient evidence for the use of corticosteroids in the therapy of GBS. In treating CIDP corticosteroids, intravenous immunoglobulin and plasma exchange seem to be equally effective. However, the high costs and relative lack of availability of IVIg, the only short-term benefit and the invasive nature of the plasma exchange procedure, and on the other hand serious long-term side effects of corticosteroids are the most important disadvantages of these treatments and have to be taken into consideration before a decision about therapy can be made. In multifocal motor neuropathy the intravenous immunoglobulin therapy is the only treatment that has been shown to be effective in controlled trials. However, inadequate response in a proportion of patients, high cost and variable availability of IVIg show the need for the search of adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may improve after treatment with chemotherapeutic agents, though the long-term effects are not known. In addition, such treatment modalities may be associated with serious side effect and even severe toxicity. Recent data support the use of a new promising drug: Rituximab, a monoclonal antibody directed against the B cell surface membrane marker CD 20.

Adrenal Cortex Hormones↗
PubMed2003

Microheterogeneity of anti-myelin-associated glycoprotein antibodies.

Antibodies to the myelin-associated glycoprotein (MAG) are implicated in the pathogenesis of an acquired demyelinating polyneuropathy. We studied IgM affinity to MAG in 18 patients with anti-MAG antibodies. Binding of sera was tested for anti-MAG immunoreactivity in central nervous system (CNS) by ELISA and in CNS and peripheral nervous system (PNS) by Western blot analysis. Furthermore, immunohistochemical characterization of IgM binding on sural nerve tissue was investigated using the indirect peroxidase method. Western blot analysis revealed that all sera detected MAG in central myelin, but only eight in peripheral myelin. Anti-MAG-IgM-ELISA-titers correlated significantly (p<0.0001) with PNS-Western blot results. By indirect immunoperoxidase immunohistochemistry, 12 sera stained myelin sheaths, while 6 sera showed no staining. These results demonstrate considerable variations in antibody binding strength to MAG between PNS myelin and CNS myelin. The relevance of these differences for the pathogenesis of the neuropathy and clinical impairment remains to be demonstrated.

Adult↗
PubMed2003

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.

No causative or curative therapy exists for the polyneuropathy associated with antibodies to myelin-associated glycoprotein (anti-MAG). Rituximab is a mouse-human chimeric antibody that specifically eliminates B-cells and B-cell precursors. Preliminary results suggest a beneficial effect on antibody-dependent autoimmune diseases. Nine patients with an anti-MAG-associated IgM polyneuropathy received rituximab once weekly for 4 weeks. In all patients, the number of B-cells in the peripheral blood declined below levels of detection, and the IgM levels decreased between 35% and 82% (median, 58%). In eight patients, lowering of the anti-MAG antibody titers of more than 52% was observed. Clinical status improved in six patients, remained stable in two, and worsened in one. The motor nerve conduction velocity improved by at least 10% in one ulnar nerve in seven patients and worsened in two. Rituximab was well tolerated and is a promising new drug in the treatment of patients with anti-MAG-associated polyneuropathy.

Aged↗
PubMed2003

Distal motor latency and residual latency as sensitive markers of anti-MAG polyneuropathy.

There is debate whether the terminal latency index (TLI) is a sensitive marker for polyneuropathy with anti-myelin-associated-glycoprotein antibodies (anti-MAGP). We examined 6 patients with an anti-MAGP and 6 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP). The electroneurographic features studied were: distal compound motor action potential (CMAP), distal motor latency (DML), motor conduction velocity (MCV) elbow to wrist (distal MCV), MCV axilla to elbow (proximal MCV), MCV distal/proximal, terminal latency index (TLI), residual latency (RL), F-wave, and modified F ratio. We found significant differences between anti-MAGP and CIDP for DML and for RL. No significant differences were found for TLI and the other measures. The TLI values were not significant probably because our patients had a longer duration of disease,which supports the hypothesis of a distal to proximal progression of conduction slowing over time. We propose that a residual latency >4.0 and a distal motor latency >7.0 are strongly suggestive for an anti- MAGP.

Action Potentials↗
PubMed2003

Immune-mediated neuropathies: etiology and pathogenic relationship to aging processes.

Immune-mediated peripheral neuropathies are more frequent in aged populations. Equally, underlying diseases such as vasculitis and paraproteinemia are more prevalent in the elderly. Accumulating evidence is linking the aging process of the immune system, immunosenescence, to the susceptibility of older individuals for paraproteinemic, vasculitic and inflammatory demyelinating neuropathies. Why an individual develops a particular disease is likely due to a number of factors. These include mutations in neural tissue-specific B and T cells, decreased central tolerance, increased proinflammatory environment due to cytokine shifts and higher functional capacity of innate immune cells.

Aging↗
PubMed2003

Bilateral vertebral artery occlusion resulting from giant cell arteritis: report of 3 cases and review of the literature.

Giant cell arteritis (GCA) is known to affect the extracranial part of the vertebral arteries. Bilateral vertebral artery occlusion (BVAO) is a rare but serious neurologic condition. We report 3 patients with autopsy-proven (2 patients) or clinically diagnosed (1 patient) GCA causing BVAO. A review of the literature concerning BVAO revealed 5 other cases of BVAO resulting from GCA and 110 cases with underlying arteriosclerotic disease. Our 3 patients (mean age, 66 yr; range, 60-78 yr) with BVAO resulting from GCA all had initial severe headache followed by the onset of stepwise progressive, partly side-alternating neurologic deficits due to bilateral infarctions in the vertebrobasilar circulation territory. This course, more accelerated in BVAO due to GCA than in BVAO of arteriosclerotic origin, seems to be a typical, if not particular, clinical syndrome. BVAO was the first clinical manifestation of GCA in 1 of our patients and in 1 published case. From a clinical view, BVAO resulting from GCA differs from BVAO of arteriosclerotic origin by the much higher mortality rate (75% versus 19%, respectively), the presence of headache (100% versus 22%), fever (50% versus 0%), and elevated erythrocyte sedimentation rate (ESR in all GCA cases >45 mm/h; no data in the arteriosclerotic patient group), but not by the neurologic signs themselves. Therapy of BVAO resulting from GCA is purely empiric. In view of the serious prognosis, we propose treatment with intravenous high-dose glucocorticoids and additional immunosuppression with cyclophosphamide; the use of anticoagulation depends on the individual patient's estimated risk-benefit profile. Although BVAO due to GCA is rare, physicians and especially rheumatologists or neurologists should be aware of this entity because of its high mortality in patients without immediate introduction of a high-dose immunosuppressive therapy. Suspicion of GCA should arise in a patient aged over 50 years with no other vascular risk factors suffering from bilateral symptoms of ischemia in the vertebrobasilar territory, with a quickly progressing stepwise course and with headache, fever, or history of myalgia. ESR and temporal artery biopsy should be performed without delay. Early diagnosis of GCA is necessary for immediate initiation of intensive antiinflammatory and immunosuppressive treatment, without which progressive deterioration and systemic involvement are likely to be fatal.

Aged↗
PubMed2003

Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult.

Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the gene-expression pattern of 12 samples of normal appearing white matter from 10 post-mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF-1alpha and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.

Aged↗