[Diagnostics of polyneuropathies]. / Diagnostik bei Polyneuropathien.

The diagnosis of polyneuropathy (PNP) is based on the anamnesis and description of complaints of the patient and clinical findings. The type of distribution as well as known diseases and drug toxic factors can provide indications. Electromyography and electroneurography can be used to differentiate between axonal and demyelinating PNP. The laboratory examinations are initially directed towards frequent and treatable causes. These are then expanded depending on the suspected diagnosis. Analysis of cerebrospinal fluid (CSF) is facultative and should be carried out when there is a suspicion of a certain form of PNP with CSF findings indicative of the diagnosis. Nerve biopsy is indicated when the etiology of a severe or progressive PNP cannot be clarified by less invasive means and can have consequences for the treatment. A genetic investigation can be meaningful with a positive family anamnesis or with typical signs of hereditary PNP. Depending on the neuropathy and context, the diagnostic approach is structured differently. The special diagnostics for small fiber neuropathy and amyloid neuropathy as well as for diabetes and alcohol abuse are dealt with in detail in this article. Numerous cases of polyneuropathy remain unexplained and regularly have a favourable prognosis.

Multiple acyl-CoA-dehydrogenase deficiency (MADD)--a novel mutation of electron-transferring-flavoprotein dehydrogenase ETFDH.

This is the case of a 41 year old man, suffering general weakness and elevated liver enzymes, sensitive to a treatment with riboflavin and coenzyme Q(10). Tandem mass spectroscopy and molecular analysis reveal a multiple acyl-CoA-dehydrogenase deficiency (MADD) with two novel heterozygote missense mutations of the EFTDH gene.

Annexin-1 is no useful surrogate marker of multiple sclerosis - an immunocytochemical study of the cerebrospinal fluid.

OBJECTIVE: Annexin-1 is a calcium-binding protein with anti-inflammatory properties, which has previously been described in MS plaque tissue. We investigated the feasibility and specificity of annexin-1-immuncytochemistry of CSF cells to test its potential as a surrogate marker for MS. MATERIALS AND METHODS: CSF-specimens of 49 MS cases with different courses and 94 control cases were immunocytochemically studied with a monoclonal antibody to annexin-1. RESULTS: The highest level of cytoplasmic immunoreaction was seen in the most acute inflammatory disorders, such as bacterial meningitis and neuroborreliosis. CIS-, RR-MS-, and viral meningoencephalitis cases came next. The lowest annexin-1 expression was observed in neurosyphilis and SP-MS. In PP-MS and non-inflammatory control cases, annexin-1 expression was entirely lacking. CONCLUSION: Immunocytochemical staining of CSF cells with an antibody to annexin-1 is feasible. This may be helpful in further study of its role in the pathophysiology of inflammatory CNS diseases. The expression pattern seems to rather reflect the acuteness of the inflammatory process than specifying a certain underlying pathology. Although differences were observed between diverse disease groups, because of considerable overlap, a certain diagnosis of an individual case cannot be achieved. Thus, at present, we cannot recommend annexin-1 as a reliable surrogate marker of MS.

Chronic vasculitis and polyneuropathy due to infection with Bartonella henselae.

Bartonella henselae, the causative agent of cat scratch disease and bacillary angiomatosis, is associated with an expanding spectrum of diseases. Here, we report on a 40-year-old patient suffering from chronic recurrent painful ulcers of the toes, distal axonal sensomotor polyneuropathy and Raynaud's phenomenon. Biopsy of the sural nerve demonstrated an axonal neuropathy with a neurogenic muscular atrophy. Treatment with high dose corticosteroids had no beneficial effect. A biopsy taken from a recurring ulcer 7 years after the beginning of the disease revealed superficial ulcerated hyperkeratosis with subepithelial proliferation of small vessels compatible with a diagnosis of verruca peruana, however, without detection of microorganism. Serologic analysis revealed an elevated IFT titer of 1:1,024 against B. henselae. Treatment with erythromycin induced healing of the ulcer, remission of the vasculitis and the polyneuropathy, and a decline of the IFT titer. This case illustrates that B. henselae infection should be considered in patients with vasculitis and polyneuropathic syndromes.

The AGE/RAGE/NF-(kappa)B pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT).

Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor nuclear factor kappa B (NF-(kappa)B) and subsequent expression of NF-(kappa)B-regulated cytokines. This has been shown to be a relevant pathomechanism in diabetic polyneuropathies (PNP). To determine whether this pathway may contribute to the pathogenesis of PNP due to impaired glucose tolerance (IGT) we performed a pilot study to demonstrate the presence of the RAGE ligand N (epsilon)-(Carboxymethyl)lysine (CML), the receptor itself and N-(kappa)B in sural nerve biopsies of 4 patients with IGT-related PNP. Biopsies of either 4 patients with diabetic PNP and with Charcot-Marie-Tooth disease (CMT) I and II served as positive and negative controls, respectively. In IGT-related PNP and diabetic PNP, CML, RAGE, and NF-(kappa)B was found in the perineurium, epineurial vessels and in part in endoneurial vessels. CMT patients showed, if any, only weak staining for one or the other antigen. These data suggest that activation of the RAGE pathway may be one of the first steps in the pathogenesis of PNP even before chronic hyperglycemia occurs.

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.

Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

Spinocerebellar ataxia type 2 with glial cell cytoplasmic inclusions.

Glial cell cytoplasmic inclusions were identified in a case of spinocerebellar ataxia type 2. These have not been reported before. The inclusions were found in low frequency in the dentate nucleus, cerebellar white matter, pontine transverse fibres, and the inferior olivary nucleus. They were of variable size and shape and expressed ubiquitin, thus resembling glial cytoplasmic inclusions in multiple system atrophy. However, their immunohistochemical profile was different as they did not show immunoreactivity for either tau protein or alpha-synuclein. There was no evidence of expanded polyglutamine tracts in these inclusions, which also failed to label with silver stains. As in many other neurodegenerative diseases, in spinocerebellar ataxia type 2 there may be pathogenic contributions of glial cells other than the common astrogliotic response to neuronal damage.

[Diagnosis and treatment of polyneuropathy: what can the family doctor do?]. / Polyneuropathie erkennen und behandeln. Mit Fingerspitzengefühl zur richtigen Diagnose.

Polyneuropathies are common disorders of the peripheral nervous system. Early diagnosis and therapy enables to stop the progression of the polyneuropathy and to ameliorate polyneuropathic symptoms in most cases. Clinical examination is sufficient to diagnose polyneuropathy. However, to reveal the etiology of a polyneuropathy additional diagnostic procedures are necessary. The general practitioner should recognize the signs and symptoms of a polyneuropathy and start necessary investigations. If the etiology of the polyneuropathy is revealed specific therapy can be started. Furthermore, polyneuropathic symptoms can be ameliorated independently of the underlying cause.

[Diagnosis and therapy of vasculitic neuropathy. Consensus statement of the German Centers for Neuromuscular Disease]. / Klinik, Diagnostik und Therapie der vaskulitischen Neuropathie. Bundeseinheitliche Konsensuspapiere der Muskelzentren im Auftrag der Deutschen Gesellschaft für Muskelkranke e. V. (DGM).

Vasculitic neuropathies are immune mediated diseases of the peripheral nervous system, in which inflammation of the blood vessels causes damage to the nerves. We distinguish neuropathies associated with primary and secondary systemic vasculitis, with rheumatic diseases, with malignant disorders, drug-induced vasculitis and the non-systemic vasculitic neuropathies (NSVN). The typical clinical picture consists in an asymmetric or multifocal, painful sensorimotor neuropathy with an acute, subacute or chronic course and acute relapses. Neurophysiology reveals an active, asymmetric, axonal sensorimotor neuropathy. The disorders usually respond to immunosuppressive treatment. A diagnosis of definite vasculitis can be made with evidence of vasculitis in a biopsy specimen. The absence of positive morphological evidence, however, does not exclude the diagnosis. There is no single laboratory test that can prove or exclude vasculitis, in NSVN even an elaborate panel of blood tests can show normal findings. Systemic vasculitis has an incidence of 4/100,000 per year and, untreated, has a poor prognosis, which is greatly improved by the use of immunosuppressive treatment. The prognosis of NSVN is generally better, although many patients need long term immunosuppression. Current treatment recommendations for vasculitic neuropathies are presented.

Expression of annexin-1 in multiple sclerosis plaques.

This study describes the distribution and identity of annexin-1 positive cells in the central nervous system in patients with multiple sclerosis (MS). Glucocorticoid-inducible, anti-inflammatory properties have been ascribed to annexin-1, a member of a family of calcium-binding proteins that are referred to collectively as annexins. We have found annexin-1 to be spatially associated with active MS lesions and demonstrated a stage-dependent expression of annexin-1 in MS plaques. All of the most important pathogenetically involved cells of MS lesions showed a strong annexin-1 reactivity. Both correlation analysis and double staining procedures suggested annexin-1 expression in macrophages and perivascular lymphocytes, where a cytoplasmic reactivity was displayed, whereas in activated, gemistocytic astrocytes it was also concentrated close to the plasma membrane. Although the exact roles of annexin-1 in this setting are still to be determined, a possible contribution to anti-inflammatory processes might be suggested.

N(epsilon)-Carboxymethyllysine in diabetic and non-diabetic polyneuropathies.

Increased oxidative stress and advanced glycosylation are important factors in the development of diabetic neuropathy. In non-diabetic neuropathies their influence has not been investigated in detail so far. We studied the localisation of N(epsilon)-carboxymethyllysine (CML) - a biomarker for oxidative stress - by immunohistochemistry in sural nerve biopsies of 31 patients with different polyneuropathies [diabetic polyneuropathy (n=5), alcohol-associated polyneuropathy (n=4), vitamin B12-deficient polyneuropathy (n=6), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=6), vasculitic neuropathy (n=6), Charcot-Marie-Tooth disease type I (CMT I) (n=4)] and 4 normal controls. CML was detected in the perineurium of patients with diabetic, alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. Epineurial, perineurial and endoneurial vessels were CML positive in diabetic, vitamin B12-deficient and vasculitic polyneuropathies. CML was also found in mononuclear inflammatory cells in vasculitic neuropathy. In CIDP and normal controls there was only marginal perineurial CML deposition in 2/6 and 1/4 cases. In CMT I no CML was detected. Immunohistochemical results were confirmed by immunoblot. Our data suggest a role of oxidative stress in the pathogenesis not only of diabetic but also of alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. It may be a minor pathogenetic factor in CIDP and may not be involved in CMT I. Underlying causes for increased oxidative stress may be an elevated production of reactive oxygen species and an impairment of antioxidative defences. Therefore, an antioxidative treatment should be considered in alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathy.

Hyperintense and hypointense MRI signals of the precentral gyrus and corticospinal tract in ALS: a follow-up examination including FLAIR images.

In amyotrophic lateral sclerosis (ALS) patients, hyperintense signals at the subcortical precentral gyrus in brain fluid attenuated inversion recovery (FLAIR) MR images have been found more frequently than in controls. Quantitative analysis has revealed a significant increase of the FLAIR-magnetic resonance imaging (MRI) signal at the subcortical precentral gyrus of ALS patients compared to healthy controls. In addition, hypointense signals at the rim of the precentral gyrus in FLAIR and T2-weighted images have been shown in ALS patients. In 17 ALS patients, we evaluated hyperintense signals in T2-, T1-, proton density-weighted and FLAIR MR images, and hypointense signals in T2-weighted and FLAIR images 15.7+/-3.0 months after the initial examination by visual scoring. In FLAIR images, a quantitative analysis was added. The visual scores of hyperintense signals along the corticospinal tract did not change significantly in all sequences. However, the quantitative evaluation of FLAIR images revealed a significant increase of the signal intensity at the subcortical precentral gyrus (p<0.005). In addition, the frequency of the visually evaluated hypointense signals at the precentral gyrus increased significantly (p<0.05). The change of MR results did not correlate with the change of clinical parameters. In ALS patients, the increase of the quantified MRI signal at the subcortical precentral gyrus in FLAIR images and the increase of hypointense signals at the rim of the precentral gyrus corroborate the hypothesis that these signals are related to the upper motor neuron degeneration in ALS. Their specificity and clinical relevance have to be clarified further.

MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1- and proton-density-weighted images.

In some patients with amyotrophic lateral sclerosis (ALS), T2-weighted and proton-density-weighted magnetic resonance imaging (MRI) shows hyperintense or hypointense signals at the corticospinal tract. Fluid-attenuated inversion recovery (FLAIR) sequences increase the sensitivity of MRI to detect cortical and subcortical tissue changes. In 31 ALS patients and 33 controls, we studied the frequency and the extent of signal abnormalities in FLAIR images compared to T2-, T1- and proton-density-weighted images. Hyperintense signals at the corticospinal tract were significantly more frequent in FLAIR images than in all other tested sequences. In FLAIR images of ALS patients only, distinct hyperintense signals at the subcortical precentral gyrus (five patients), the centrum semiovale (eight patients), the crus cerebri (nine patients) and the pons (four patients) as well as mild hyperintense signals in the medulla oblongata (three patients) were seen. More frequently, but not exclusively in ALS patients, FLAIR images showed mild hyperintense signals at the subcortical precentral gyrus (15 patients vs. 1 control). Quantitative analysis confirmed the significant difference between ALS patients and controls at the subcortical precentral gyrus in FLAIR images. In T1-weighted images, the corticospinal tract at the capsula interna was hypointense in significantly more controls than ALS patients. Also this difference was confirmed in the quantitative analysis. Similar to previous results, MR image alterations did correlate poorly to clinical data of upper motor neuron affliction.MR images of the head, including FLAIR images, provide additional information regarding corticospinal tract involvement in ALS patients. Because of an overlap with physiological findings, they have to be interpreted cautiously, with the exception of hyperintense signals at the subcortical precentral gyrus.

[Survival with artificial respiration at home. An open, prospective study on home ventilation for neuromuscular diseases, in particular, the situation of ALS patients]. / Uberleben mit Heimbeatmung. Eine offene, prospektive Untersuchung zur Heimbeatmung bei neuromuskulären Erkrankungen unter besonderer Berücksichtigung der Situation von ALS-Patienten.

A growing number of patients with neuromuscular disease have been treated with home mechanical ventilation during the past 15 years. We prospectively examined the long-term effects and complications of this method, particularly with regard to noninvasive positive pressure ventilation (NPPV). Thirty-one patients with amyotrophic lateral sclerosis (ALS, n = 20) or other slowly progressive neuromuscular diseases (NMD, n = 11) were observed for 17,517 home ventilation days (almost 48 ventilation years). The mean observed ventilation time was 565 days (min/max: 30/2930). Twenty-five patients were ventilated noninvasively with different masks. The calculated mean survival with NPPV ventilation (criteria: death, tracheostomy, or patient deciding to break off) was 2052 (SE: +/- 317.8) days in the NMD group, 248 days (+/- 35.7) for ALS patients without bulbar symptoms, and 82 days (+/- 27.4) with bulbar paralysis. Complications with the need for intervention were observed six times more frequently with ALS than with NMD. NPPV is effective for years in patients with slowly progressing NMD. Those ALS patients without bulbar symptoms can profit for up to a year from NPPV, while those with bulbar paralysis can have some symptom relief. Complications of every kind are much more frequent in ALS patients.

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).