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In 1940, at the age of 84, Marshal Pétain was appointed the head of state and government of France. His health was excellent but he tired easily. He felt unable to learn and his memory was weak. During a crisis situation in 1942, he did not lead, plan and decide and he was replaced as head of government. From 1943 on, he was increasingly apathetic. In 1945/1946 he had difficulty finding words after a short conversation. A parliamentary committee concluded in 1947 that he was senile. His mental condition worsened in the years thereafter. In retrospect, it is clear that the final responsibility for the policies of the French government in the Second World War had rested on a man who was going through a predementia process of cognitive decline., (© 2015 S. Karger AG, Basel.)

The notion of heredity of degenerative constitutions of human beings contributed in the nineteenth century to the fear for deterioration of the human race and in the twentieth century to attempts by several Western Countries, particularly Germany, to improve the inborn qualities of their populations by eugenic measures. In the years following World War II, the term eugenics was eradicated from medicine. The qualification degenerative disappeared from genetics and psychiatry but remained in use to denote decay of tissues and cells. The adjective neurodegenerative came in vogue in neurology and was mostly applied to brain diseases. Definitions in the literature indicate that neurodegenerative diseases are considered as to be age related, incurable, and largely untreatable chronic progressive diseases of the central nervous system. Scrutiny of available data shows that the notion concerns an ill-defined group of genetic and idiopathic disorders. Genetic central nervous system diseases may become manifest at all ages and are accessible for symptomatic treatment. Investigations of animal models suggest that not all neurodegenerative diseases are inherently incurable. Alternatives for the terms neurodegenerative and degenerative are available.

Rembrandt's etching of a beggar with a wooden leg is notable because the two lower limbs of the presumed beggar are present and not deformed. Using the facilities of four specialised Dutch art institutes, we carried out a systematic investigation to find other etchings and engravings of subjects with artificial legs supporting non-amputated limbs, from the period 1500 to 1700 AD. We discovered 28 prints produced by at least 18 artists. Several offered clues to a disorder of a knee, the lower leg or the foot. All individuals were adult males, suggesting the probability of traumatic lesions. We conclude that in this period artificial legs were not only used in the case of absence of part of a lower limb, but also for other reasons, notably disorders of the knee, lower leg or foot. They may also have been used to attract compassion.

Vinken and Bruyn's Handbook of Clinical Neurology (HCN) is best characterized as an encyclopedia. In this paper we describe the origin, production, and reception of HCN. Data were gathered from a literature search, by screening of HCN-volumes, interviewing key-role persons and a study of an HCN-archive. The initiative for HCN was taken by two Excerpta Medica staff members, the one a strategist with expertise in information systems, the other a gifted neurologist with an expert knowledge of who is who in the world of neurological literature. Within a period of 38 years, 2799 authors, 28 volume editors, the two initiators, and a third chief editor for the American continent described the whole of neurology in 1909 chapters on all together 46,025 pages (excluding index volumes). HCN was sold mainly to medical institutes in affluent countries. A digital version of the revised edition was proposed by the editors but refused by the publisher for commercial reasons. HCN was in general well received by book reviewers. The main criticisms concerned the price of the volumes, lack of editorial control, inadequacy of indexes, and lack of cross references. HCN offers unrivalled information on the state of the art of the clinical neurosciences in the second half of the twentieth century. In addition, it contains extensive reviews of the history of neurological diseases in the volumes of the original edition.

This guideline presents recommendations for the diagnosis and treatment of dermatomyositis, polymyositis and sporadic inclusion body myositis (sIBM) according to the best available evidence. Characteristic skin abnormalities can be sufficient for the diagnosis of dermatomyositis. In case of doubt, a skin biopsy is advisable. A muscle biopsy is indicated when other examinations are inconclusive and the musculature is involved. The working group considers screening for cancer to be required in adults with dermatomyositis and presents recommendations for the way that this should be done. At least one-third of all patients with polymyositis has, or will develop, an associated inflammatory connective tissue disease. If a patient with a connective tissue disease develops symmetrical, proximal muscle weakness in the course of weeks or months, this may be assumed to be due to polymyositis. In the absence ofpre-existing connective tissue disease, demonstration of a mononuclear cell infiltrate in muscle tissue is a prerequisite for the diagnosis ofpolymyositis. The histopathology of muscle tissue is used as the gold standard for the diagnosis of sIBM. The practice guideline presents criteria for the concept 'activity' of myositis. Disease activity serves as a guideline for the treatment of polymyositis and dermatomyositis. The treatment of choice for dermatomyositis and polymyositis is high-dose prednisone. Physical activity does not have a negative effect on the course of these diseases. The long-term prognosis ofdermatomyositis and polymyositis is not well known. The clinical course of sIBM is slowly progressive.

We examined the thyroarytenoid muscles of 23 larynges in order to assess function-related characteristics and to discover age-related changes. The neonatal thyroarytenoid muscle differed from limb muscles in the slow maturation of fibre types. In adults, we examined the medial part of the thyroarytenoid muscle. It showed a larger variation in fibre size and more endomysial connective tissue than is common for limb muscles. Structural and histochemical evidence of ageing developed from approximately the 6th decade. It comprised a marked increase of endomysial connective tissue and striking myopathic changes of muscle fibres. Up to 20% of the muscle fibres showed at some places of some sections evidence of mitochondrial accumulations and increased mitochondrial enzyme activity (ragged red fibres). The rise of such ragged red fibres is commonly related to the development of mutations in mitochondrial DNA. Significant myopathic changes including mitochondrial abnormalities develop in the thyrovocalis muscle with age and may play a role in the functional deficit of the larynx in old age.

Patients with amyotrophic lateral sclerosis (ALS) have symptoms of progressive muscle weakness, of disturbed speech and swallowing, and in the terminal phase those of respiratory weakness. Treatment options, in particular those for excessive weight loss and respiratory weakness, should be introduced to the patients and their families when the patient is emotionally capable and before dysarthria severely hampers communication. Special equipment for keeping the patient as mobile as possible should be made available much earlier than in the case of other diseases of the muscles as in ALS progression is much faster. Cramps, pathological crying or laughter, spasms, and spasticity can all be treated by medication. When speech can no longer be understood, adaptive strategies such as sign language, mime, posture and communication apparatus varying from a note pad to advanced computer systems can be used. Sialorrhoea, caused by difficulty swallowing with its accompanying danger of aspiration can be halted by the use of medication, by radiotherapy and by the injection into the salivary glands of botulin A toxin. Weight loss, also a result of dysphagia, can be avoided by eating frequent small meals or if necessary performing a percutaneous endoscopic or radiological gastroscopy. Excess mucus in the respiratory tract can be treated with anticholinergics. Difficulty in coughing up thick and sticky mucus cannot always be adequately helped. Respiratory weakness is treatable by external respiratory supportive therapy using a nasal mask, as well as invasive respiratory support via a trachcostoma and by treating the symptoms of respiratory weakness. The latter form of treatment is palliative and forms part of terminal care. During the terminal phase restlessness, anxiety, pain, and dyspnoea require the most attention. Treatment requires careful multidisciplinary cooperation.

In two patients (men aged 64 and 62 years, respectively) with amyotrophic lateral sclerosis (ALS) tracheostomy ventilation was initiated following (imminent) acute respiratory failure; in one patient this was done because advance directives were lacking, while in the other non-invasive ventilation (NIPPV) was no longer an option. A third ALS patient, a woman aged 36 years, already had chronic respiratory failure when she presented at the local centre for home mechanical ventilation. As a result, the placement of a percutaneous endoscopic gastrostomy (PEG) was impossible. Instead, she had to use a nasopharyngeal feeding tube, which diminished the effectiveness of her NIPPV. The fourth patient, a man aged 60 years, was referred in good time and hence had sufficient time to consider domiciliary ventilation. Following the placement of a PEG he started NIPPV electively. In patients with ALS, domiciliary ventilation should be discussed early in the course of the disease. Advance directives with regard to domiciliary ventilation are important, not only to avoid undesired (invasive) ventilation, but also with respect to the placement of a PEG and the appropriate use of oxygen and morphine.

Objectives: To establish the central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE) as described in the literature and to compare the results with two previously published classifications., Methods: Using PUBMED, a systematic search was performed for publications from 1980 onwards on CNS syndromes of patients with SLE. A distinction was made between CNS syndromes induced by SLE and the CNS autoimmune diseases associated with SLE. Criteria were defined for inclusion of CNS syndromes or diseases as SLE-induced or SLE-associated., Results: The literature search yielded names of 30 syndromes and two diseases, but only 16 syndromes and one disease fulfilled the set of predefined criteria. Two syndromes-depression and anxiety-were predominantly psychological in origin in most patients; other syndromes were biological., Discussion: Strengths and weaknesses of two classifications of CNS syndromes are evaluated. The older of the two is long and has not been accepted fully. Brevity is an advantage of the American College of Rheumatology (ACR) nomenclature system. A disadvantage of this system is the concealment of differences in health risks by the pooling of items. Furthermore, the items of the system do not all belong to the same dimension: one is pathological and the others are clinical. To remedy these drawbacks, we suggest the rephrasing and subdivision of items and that the predominantly psychopathological syndromes should be dealt with separately in epidemiological studies., Conclusions: SLE may induce 16 different clinical syndromes of the CNS and is occasionally associated with one other CNS autoimmune disease. A modification of the ACR nomenclature system is proposed.

Objectives: To identify the pathogenetic mechanisms of central nervous system (CNS) syndromes of systemic lupus erythematosus (SLE) as described in the literature., Methods: Using PUBMED, we performed a systematic search of publications from 1980 onwards. Studies were eligible if they had been performed on patients or material from patients with CNS manifestations and definite SLE and when the CNS manifestations were not secondary. Criteria were formulated for the identification of pathogenetic mechanisms., Results: The single most important cause of the CNS syndromes of SLE is ischaemia due to narrowing or occlusion of small vessels, arteries and veins. Antiphospholipid antibodies and premature atherosclerosis play roles in these processes, but they have not been delineated definitely. Intracranial and intraspinal haemorrhages are much less frequent than ischaemia and are presumably in part due directly to SLE. Vasculitis may cause ischaemia or haemorrhage in the CNS and is involved occasionally, as shown by imaging and histological findings. White matter damage is heterogeneous and ill-understood. It includes white matter degeneration and myelin vacuolation of the spinal cord, and reversible leucoencephalopathy due to oedema. Antibody-induced neuronal dysfunction in the CNS is a realistic hypothesis and may involve anti-ribosomal P antibodies and several other antibodies. Deficiency of psychological reactions forms a separate and entirely different category of mechanisms., Conclusions: Causes have been identified or possible causes have been suggested for most of the CNS syndromes of SLE, thus offering rationales for different forms of prevention and therapy.

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.

Background: Diagnostic criteria for the Guillain-Barré syndrome (GBS) have been available since 1978. Since then, several variants have been described. More recently, a distinction has been made between pure motor forms, severe sensory forms, primary axonal and primary demyelinating varieties. Associations of clinical characteristics, and specific infections and the presence of antiganglioside antibodies have been found. For further studies on GBS, it is therefore necessary to reconsider the available diagnostic criteria and add additional criteria for subclassification., Methods: A panel of (20) experts was formed. The literature representing the recent developments in GBS subclassification was reviewed. Following a consensus protocol, diagnostic and classification criteria were formulated., Results: The diagnosis of GBS can usually be made on clinical characteristics. A schedule for subclassification has been made to cover also the clinical variants in a systematic manner.

Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family with LGMD. This mutation leads to reduction of gamma-sarcoglycan, and gives rise to a childhood-onset, slowly-progressive dystrophy.

Objective: To assess the frequency, nature, and severity of cardiac abnormalities in limb girdle muscular dystrophy, and its relation to age and weakness in various genotypes., Design: In 26 autosomal dominant, 38 autosomal recessive, and 33 sporadic strictly defined patients with limb girdle muscular dystrophy, cardiac evaluation included history, physical examination, chest x ray, electrocardiography, 24 hour ECG Holter monitoring, and echocardiography. In 35 of the 71 autosomal recessive and sporadic cases muscle biopsies were available for sarcoglycan analysis., Main Results: Dilated cardiomyopathy was present in one autosomal dominant case and in three advanced autosomal recessive or sporadic patients, of whom two were found to have alpha sarcoglycan deficiency. Two of these three patients and three other cases showed ECG abnormalities known to be characteristic of the dystrophinopathies. A strong association between the absence of alpha sarcoglycan and the presence of dilated cardiomyopathy was found (p = 0.04). In six autosomal dominant cases there were atrioventricular (AV) conduction disturbances, increasing in severity with age and in concomitant presence of muscle weakness. Pacemaker implantation was necessary in four., Conclusions: 10% of these patients had clinically relevant cardiac abnormalities. In autosomal dominant limb girdle muscular dystrophy one subtype characterised by muscle weakness and AV conduction disturbances is recognised. In the course of autosomal recessive/sporadic limb girdle muscular dystrophy, dilated cardiomyopathy may develop, probably related to deficiency of dystrophin associated proteins.

There is peer review by scientific journals and by fund granting institutions. The former is usually a very thorough procedure with the authors being informed of the reasons for rejection of the article, whereas the latter often leaves the applicants with doubts as to the thoroughness and the fairness of the procedure. It is suggested that grant peer review follow the rules for scientific journal peer review including information of the applicants of the referees' findings and opinions. Moreover there is a need for an ombudsperson to deal with complaints.

In an open prospective study, we analyzed the effect of cyclophosphamide (300 mg/m2 body surface daily for 4 days) combined with prednisone (40 mg/m2 body surface daily for 5 days) at 4-week intervals during 6 months in 16 patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS). Eleven patients had an IgM-MGUS and five an IgG-MGUS. During a follow-up period of 3 years, eight patients had improvement and six patients stabilized, based on quantitative neurologic examination, the Rankin disability scale, and electrophysiologic studies. These 14 patients had neuropathy with demyelinating and axonal features. One patient with a purely axonal neuropathy had deterioration despite therapy. One other patients developed severe leukopenia as side effect of cyclophosphamide, necessitating withdrawal of treatment. A difference in response was not present in patient with IgM- or IgG-MGUS, nor in patients with or without autoantibodies against myelin-associated glycoprotein. Nine patients had a bone marrow biopsy before and 1 year after treatment. In eight patients, the monoclonal lymphoid IgM or plasma cell IgG infiltration decreased, while in four the monoclonality disappeared after treatment. In the patient who had neurologic deterioration, repeated bone marrow biopsy showed deposits of amyloid. In conclusion, short-term treatment with intermittent cyclophosphamide and prednisone may have a long-term favorable effect in patients with demyelinating polyneuropathy associated with MGUS.

A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.

In seven unrelated patients with a demyelinating motor and sensory neuropathy, we found mutations in exons 2 and 3 of the P0 gene. Morphologic examination of sural nerve biopsy specimens showed a demyelinating process with onion bulb formation in all cases. In four patients, ultrastructural examination demonstrated uncompacted myelin in 23 to 68% of the myelinated fibers, which is in agreement with the widely accepted function of P0 as a homophilic adhesion molecule. Three patients showed normal compact myelin, but morphology was dominated by the abundant occurrence of focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene.

Locally applied ciliary neurotrophic factor (CNTF) has a powerful effect on retrograde axonal reaction following facial nerve crush in neonatal rats. We examined whether it also exerts a strong effect on retrograde axonal reaction in young adult rats when administered subcutaneously. The dose was 1 mg/kg body weight, three times a week, similar to that used in a previous experiment in which CNTF was reported to have an effect. We studied changes in the morphology of the motor nerve cell bodies, in the number of perineuronal microglial cells and in the expression of five proteins. It appeared that CNTF prevented swelling of the facial motoneuron cell bodies but it did not influence the swelling of the nucleus nor the shift of the nucleus towards the periphery. In saline-treated rats, facial nerve crush resulted from day two to day six in a marked increase in the number of perineuronal glial cells. This increase was neither diminished nor augmented by CNTF. Following facial nerve crush, the immunoreactivity of the proteins C3bi, GFAP, B-50 and CGRP increased in the glial cells and motoneuron cell bodies, whilst the immunoreactivity of synaptophysin at the membrane of the motoneuron cell bodies decreased. CNTF had no obvious effect on these changes. It was concluded that in young adult rats under the present conditions, CNTF had only a small effect on a specific aspect of the retrograde cell reaction. The small effects might be explained by the minor availability of CNTF to the motoneuron cell bodies. The gain in body weight of rats treated with CNTF was less than that of saline-treated rats.

Charcot-Marie-Tooth disease comprises a heterogeneous group of neurologic disorders that shape peripheral motor and sensory neuropathy. A classification of these disorders was proposed in 1975, defining seven types of hereditary motor and sensory neuropathy. Clinical features of hereditary motor and sensory neuropathy type VI are muscle weakness and atrophy in leg and hand muscles, leading to progressive disability and loss of vision and progressing to blindness due to optic atrophy. Hereditary motor and sensory neuropathy type VI was first reported in 1879 by Vizioli, who described a kinship in which a father and two sons presented with peroneal muscular atrophy in association with optic atrophy. Since then, at least nine similar cases have been reported: three sporadic cases, two pairs of siblings who were offspring of consanguineous parents, and one pair of siblings who were offspring of unrelated parents suggesting autosomal recessive inheritance. Vertical transmission has been reported only by Vizioli. We present a father and two offspring (one boy and one girl) with the above-mentioned characteristic features of hereditary motor and sensory neuropathy type VI. Vizioli's kinship and either an autosomal recessive or autosomal dominant pattern of inheritance.

We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult-onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(-13T --> G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Deterioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of alpha-glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of alpha-glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years.

The effect of high dose intravenous immunoglobulin (IVIg) treatment was studied in six patients with multifocal motor neuropathy (MMN). All patients responded to treatment (0.4 g/kg for five consecutive days) in an open trial. The effect of IVIg treatment was confirmed for each patient in a single patient, double blind, placebo controlled trial. Four patients received two IVIg treatments and two placebo treatments, and two patients received one IVIg and one placebo treatment in a randomised order. Five out of six patients responded to IVIg but not to placebo. One patient responded to IVIg in the same manner as to placebo treatment. Thus IVIg treatment can lead to improvement of muscle strength in patients with MMN.

We have used histological and histochemical techniques at the light microscopical level, and electron microscopy to examine the myopathological changes in rat muscle up to 30 weeks following botulinum toxin injection. Apart from muscle fibre atrophy and related myofibrillar structural changes, the results show a number of striking abnormalities which developed and disappeared at different stages. During the first 4 weeks after toxin injection, vacuoles of variable size were seen in the sarcoplasm near myonuclei, both at and away from endplates. Following this, between 4 and 10 weeks post-injection, progressive degeneration of junctional folds and separation of some nerve terminals from the simplified postsynaptic membranes were observed. At different time points following recovery from the toxin-induced paralysis (evidenced by the increase in muscle fibre size and return of function) a number of abnormalities were still detectable in muscle fibres. These included the appearance within them of multiple arrays of sarcotubular profiles, focal areas lacking myofibrillar organization and mitochondria, abnormal mitochondrial aggregates showing crystalline inclusions, and extension of the postsynaptic densities along the full depth of junctional folds. Furthermore, targetoid-like areas were detected histochemically following recovery from the toxin-induced paralysis. The early extensive vacuolation of the sarcoplasm and the degeneration of junctional folds suggest a myotoxic effect of botulinum toxin. The late changes are likely to be (at least in part) related to the process of recovery following reinnervation.

The present study was undertaken to investigate the effect of Org2766 on the recovery of lesioned motor nerve fibres. The facial nerve of Wistar rats was crush lesioned and the process of recovery was assessed by functional and histological methods. Functional recovery was examined in two experiments and was assessed by quantifying blind the return of eyelid and whisker movements. No difference could be demonstrated between Org2766-treated and saline-treated groups of animals. The histological investigations involved quantifying the number of reinnervated motor endplates in the whisker muscle. On days 10 to 12 in male rats and on days 12 and 13 in female rats, there was no difference in reinnervation between the two treatment groups. It was concluded that with the methods used in this study, no significant effect of Org2766 on the axonal regeneration of motor nerve fibres could be established.

The natural course of polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) is not well known. We therefore studied 32 untreated patients for a period of 5 years. Fifteen patients had an IgM M-protein, 15 an IgG and two an IgA. There was a male predominance, a mean age of onset at the end of the sixth decade and sensory signs were more pronounced than motor deficits. On entry into the study and during the 5 years of follow-up, we quantified the neuropathy in a standard way: totals of motor and sensory scores; vibration perception threshold; tapping tests; quantified Romberg test; electrophysiological parameters. A significant difference in the natural history between the polyneuropathy associated with IgM-MGUS and IgG/IgA-MGUS was found for the motor and sensory sum scores, the vibration perception threshold and the tapping tests. The polyneuropathy in IgM-MGUS is more progressive, with significantly more weakness and sensory signs, indicating that the neuropathies associated with IgM-MGUS and IgG/A-MGUS may be two different entities. A rapid progression of the neuropathy was found in five patients. We found no predictive factors for this severe progression of the neuropathy of these five patients. Of these five, three (two IgM, one IgG) developed a non-Hodgkin lymphoma.

Seventy five patients with chronic idiopathic axonal polyneuropathy (CIAP) were studied for five years. The standardised and quantified neurological examination shows that progression of CIAP is slow, and handicap, if present, is not severe. During the follow up period a definite cause of the neuropathy was found in only four patients (two hereditary motor and sensory neuropathy type 2, one sensory chronic inflammatory demyelinating polyneuropathy, one alcoholic neuropathy). At the end of the follow up CIAP was not related to malignancy or gammopathy. Routine repetition of laboratory tests was not informative and these tests should be performed on clinical grounds only.

Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the insight into the effects of cisplatin on the peripheral nervous system a combined electrophysiological and histomorphological investigation was performed on 2 groups of 6 rats, treated with cisplatin for 7.5 weeks, and a control group (n = 6). Concomitant administration of ORG 2766, an ACTH(4-9) analog, was previously shown to prevent cisplatin neurotoxicity in this model and more recently in patients as well. One group of rats was therefore co-treated with this peptide during the complete treatment period. A marked decrease in SCNV was observed in cisplatin/saline treated rats, but not in cisplatin/ORG 2766 treated rats. Though no statistically significant difference was seen in the total number of myelinated fibers in the sural nerves of cisplatin treated rats, a decrease in the proportion of thick myelinated fibers was present in the cisplatin/saline treated rats. This shift in fiber distribution was absent in ORG 2766 co-treated animals. Mean internodal distances and g-ratios were not affected, and signs of axonal degeneration, or de- or remyelination were not observed.

Changes in calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) at the motor endplates of botulinum toxin-paralysed rat muscles were investigated using immunohistochemistry. One day following toxin injection, a dramatic increase in CGRP-LI was detected at the motor endplates and within preterminal axons of the soleus and gastrocnemius muscles. The upregulation of CGRP-LI persisted throughout the period during which muscle fibres were paralysed and new neuromuscular junctions were being formed by the growing sprouts. Decline of CGRP-LI at the motor endplates coincided with clinical recovery. Both up- and down-regulation of CGRP-LI took place earlier in the soleus than in the gastrocnemius muscle. Up-regulation of CGRP-LI was also detected in a subpopulation of motor axons in the sciatic nerves and in the spinal motor neurons innervating the paralysed muscles. These results indicate that levels of CGRP are regulated, at least partly, by changes in the target innervation. They also suggest an important role for CGRP in the regenerative processes following muscle paralysis.

Objective: To study the clinical features and natural course of idiopathic polyneuropathy., Design: Prognostic and descriptive cohort study., Setting: University Hospital, Utrecht, the Netherlands., Method: 75 patients (46 men, 29 women) with a mean age of 56.5 years at onset of symptoms were clinically investigated during two years., Results: The features of chronic idiopathic polyneuropathy were heterogeneous. Clinically, 44 patients had a sensorimotor, 29 patients a sensory and 2 patients a motor polyneuropathy. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. The overall clinical course was slowly progressive. None of the patients became severely disabled. After one year of follow up one patient proved to have a hereditary neuropathy. In the other 74 patients no cause for the polyneuropathy was found even after 2 years of follow-up., Conclusion: Chronic idiopathic polyneuropathy is a heterogeneous entity, leading to only slight disability. The neuropathy is due to axonal degeneration.

In order to determine the fate of the superfluous neuromuscular junctions (NMJs) formed during the course of botulinum toxin (BoTx)-induced paralysis, we have quantified the change in the total length of the nerve muscle contact area(s) following BoTx injection into rat calf muscles. The results indicate that: (1) at least some of the superfluous NMJs are eliminated following muscle recovery; (2) synapse elimination is a slow process, as 4 months after recovery it was not yet complete; (3) muscles with different content of type I and II fibers follow a different time course during synapse formation and elimination. We further investigated the possibility that the neural cell adhesion molecule (NCAM) would be the element whose loss from the NMJ might play a role in synapse elimination. Using immunofluorescence and immunoelectron microscopy we show that NCAM is exclusively localized between nerve terminals and Schwann cells and not between nerve terminals and muscle. This localization was maintained throughout paralysis and following recovery, suggesting that NCAM does not play a role in synapse elimination.

Peripheral nerve lesion results in changes in protein expression by neurons and denervated Schwann cells. In the present study we have addressed the question whether similar changes take place following functional denervation. Using immunohistochemistry and immunoelectron microscopy we examined changes in growth-associated protein (GAP-43) and low-affinity nerve growth factor receptor (p75NGFR) in rat gastrocnemius muscle following botulinum toxin-induced paralysis. GAP-43 and p75NGFR were selected because they are not expressed by mature intact motor neurons or Schwann cells, but are expressed following nerve lesion in both motor neurons and denervated Schwann cells. In control muscle, GAP-43 and p75NGFR immunoreactivity was seen only in nerve fibres near blood vessels. Two weeks after toxin injection, GAP-43 immunoreactivity could be seen at the motor endplates and in axons. Intensity of staining increased with longer survival and reached a peak between 4 and 8 weeks post-injection. Ultrastructurally, GAP-43 immunoreactivity was confined to nerve terminals and axons, whereas Schwann cells remained negative. Immunostaining for p75NGFR also increased following toxin injection and was detected in some terminal Schwann cells and in perineurial cells of small nerve fascicles near the paralyzed target cells, but not in axons. These results show that changes in expression of GAP-43 in motor neurons following functional denervation closely resemble the changes following anatomical interruption of nerve-muscle contact. GAP-43 was not expressed in Schwann cells, indicating that its upregulation in these cells is induced by loss of axonal contact or nerve degeneration products. There is no support for a role of p75NGFR in incorporation of neurotrophins in axons. The restriction of p75NGFR expression to terminal Schwann cells and perineurial cells in close proximity to the paralyzed target suggests a role for a target-derived signal or, alternatively, macrophages in eliciting this expression.

The affected members of the family described in this article exhibit congenital nonprogressive atrophy and weakness of lower limb muscles in association with contractures. Clinical and laboratory findings support a dominant lower motor neuron disorder. DNA analysis excluded linkage of the disease with SMA markers on the long arm of chromosome 5. The condition must be differentiated from congenital and infantile SMA, from "arthrogryposis multiplex congenita, distal type," and from non hereditary types of congenital arthrogryposis.

In the present study we examined the effect of recombinant human ciliary neurotrophic factor (rH-CNTF) on muscle fibre reinnervation. After facial nerve crush, rats were treated systemically with either rH-CNTF (1 mg/kg per 48 h) or saline and were killed on days 10-13 after nerve crush when muscle fibre reinnervation becomes apparent. Blind counting of the number of reinnervated motor endplates and the length of the synaptophysin-positive staining was used to assess the effect of CNTF treatment on muscle fibre reinnervation in the whisker muscle. On day 10, both treatment groups showed a limited number of reinnervated motor endplates. Both the saline- and CNTF-treated rats showed a significant increase in the percentage of reinnervated motor endplates and in the length of the synaptophysin-positive staining with time. On days 10 and 11, there was no difference in muscle fibre reinnervation between the treated groups. On days 12 and 13, the CNTF-treated rats showed an increased muscle fibre reinnervation which was significant compared to the saline-treated rats. These results suggest that after facial nerve crush in young rats, CNTF enhances muscle fibre reinnervation, most probably by stimulating the intramuscular branching. There is no support for an effect of CNTF on nerve sprouting in the proximal axonal part or on axonal elongation; the CNTF effect on intramuscular branching might be mediated by the muscle fibres.

Insulin-like growth factors (IGF-I and IGF-II) and fibroblast growth factors [acidic FGF (aFGF) and basic FGF (bFGF)] are trophic for motor neurones in vitro and (in laboratory animals) in vivo. An immunohistochemical investigation was performed on the distribution of these factors in the neuromuscular system of control patients and patients with amyotrophic lateral sclerosis (ALS). Comparisons were made with rat tissue. IGF-I immunoreactivity (IGF-I-IR) was seen in motor neurone cell bodies and axons, astroglia and Schwann cells, and in muscle fibres. IGF-II-IR was weak in all these cells. aFGF-IR was present in motor neurone cell bodies and axons, oligodendroglia and muscle fibres, but was not demonstrable in Schwann cells. bFGF-IR was present in motor neurone cell bodies and axons, and in astroglia, but was not seen in Schwann cells or muscle fibres. The distribution of the IGFs and FGFs in material from motor neurone disease (MND) and controls was similar. A role for any of these factors in the etiology of MND is, therefore, unlikely. IGF-I-IR and aFGF-IR were stronger in type II than in type I muscle fibres and were increased in denervated fibres. Species differences were found for IGF-I and bFGF. The function of these factors is apparently not entirely similar in humans and rats.

The indistinctness of the HMSN type III concept of Dyck (1975) prompted us to evaluate the diagnostic criteria. Based on a literature review and the observations in five of our own cases, restricted criteria are formulated. We conclude that at present the diagnosis of AR HMSN type III can be applied reasonably to the condition of "congenital hypomyelination", which shows a congenital or early childhood onset, extremely slow motor nerve conduction velocities of less than 6-7 m s-1 in upper limbs, and in nerve biopsy only fibres with no or hardly any myelin and "onion bulbs" of basal lamina. Amyelination might be the most severe or earliest expression of congenital hypomyelination. The existence of an inherited type III with mainly classical onion bulbs is uncertain, as only sporadic cases have been described.

We have used immunohistochemistry and electron microscopy to investigate the distribution of basic fibroblast growth factor (bFGF) in the peripheral motor system of the adult rat. In the lumbar segments of the spinal cord, bFGF immunoreactivity (bFGF-I) was seen in motor neurons and glial cells but not in axons. The neuronal immunostaining was seen as two or three intensely fluorescent spots in the nuclei with weak and more diffuse staining of the perinuclear cytoplasm. In the sciatic nerve, bFGF-I was seen in Schwann cells with strong intensity at the nodes of Ranvier. Axonal immunostaining could not be detected. At the electron microscopic level, the intense nodal immunostaining of Schwann cells was confirmed and was found to be localized to the Schwann cell membrane at the nodal gap. The intensity of staining decreased with distance from the node. In the soleus and gastrocnemius muscles, bFGF-I was seen at the motor endplates in sites corresponding to the motor nerve terminals in addition to faint staining within the muscle fibers. Electron microscopy showed that bFGF-I was localized within the nerve terminals. Histochemical localization of bFGF in the peripheral motor system is compatible with the functions ascribed for this protein in this system.

Following peripheral nerve crush, microglial cells proliferate and migrate to motoneuron cell bodies of the injured nerves. Newly formed glial processes displace nerve terminals from the cell bodies. This process is known as synaptic stripping. In animal models of peripheral nerve diseases, the ACTH(4-9) analogue, ORG2766, was shown to facilitate axonal regeneration and to protect against experimental neuropathy. In the present study we examined the effect of ORG2766 on the microglial reaction. After facial nerve crush, rats were treated with either ORG2766 (75 micrograms/kg/48 h) or saline and were killed on day 2-6 after operation. Blind counting of the number of perineuronal glial cells in the facial nucleus was used to assess the effect of ORG2766 treatment on the microglial reaction. In the saline-treated animals the number of perineuronal glial cells per motoneuron cell body on the crushed side increased significantly. This number increased up to day 5 after operation and decreased significantly from day 5 to 6. After an initial increase in the peptide-treated animals, however, the number of perineuronal glial cells remained constant from day 3 onwards. Hence, on post-operation days 4 and 5, this number was significantly less than that seen in saline-treated animals. Microglial cells proliferate, presumably through signalling by injured motoneurons. It is suggested that the decrease in the number of perineuronal glial cells in the ORG2766-treated animals is the result of a peptide-induced reduction in the release of mediating signals/cytokines or, alternatively, increased protection of motoneurons by stress proteins. Further research should address the mechanism of action of ORG2766 in animal models of motoneuron disease.

The clinical and electrophysiological features were prospectively studied of 75 patients (46 men and 29 women) with chronic polyneuropathy presenting in middle or old age in whom a diagnosis could not be made even after extensive evaluation and a follow up of six months. The mean age at the onset of symptoms was 56.5 years. The clinical features of chronic idiopathic polyneuropathy are heterogeneous. On clinical grounds 44 patients had a sensorimotor, 29 patients a sensory, and two patients a motor polyneuropathy. The overall clinical course in chronic idiopathic polyneuropathy was slowly progressive. None of the patients became severely disabled. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. Antibodies against myelin associated glycoprotein, gangliosides, and sulphatides were assessed in 70 patients and found to be negative.

Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.

Twenty four patients with motor neuron disease (MND) participated in a double-blind, placebo-controlled trial with the ACTH 4-9 analog, Org 2766. Patients were examined three times during an 8 week treatment period, using a summated score for several manually and functionally tested muscles (sum score), myometry, jitter, fibre density (FD), macro motor unit potential (MUP), and supramaximal evoked muscle action potentials. No differences were found between Org 2766 and placebo treated patients. In an open 1 yr follow-up study, 5 out of 13 patients treated with Org 2766 died; the others showed continued progression of weakness. The methods used for assessment of muscle function were compared. The highest interest reliability was obtained in the sum score and myometry. Mean differences that might be detectable were relatively small for the sum score and myometry, and large for FD and MUP. We concluded that clinical function testing and myometry are superior to electromyographic measurements for assessment of changes in MND patients.

The aim of this study was to establish the time scale of developmental changes in innervation of skeletal muscle fibers in man. Specimens of thigh and intercostal muscle from 19 embryos and 18 infants were examined with histological methods which enabled the discrimination between fetal (gamma) and adult (epsilon) types of acetylcholine receptors (AChRs). At 8 weeks of development, AChRs were distributed diffusely in the myotube membranes. Following onset of innervation in approximately the ninth week the length of the AChR positive area diminished and reached its shortest size at the sixteenth developmental week. At the sixteenth and eighteenth week some nerve terminals opposed the muscle membrane outside the AChR positive area. Decrease in the number of nerve terminals, strongly suggesting elimination of polyneuronal innervation, started in the sixteenth week and was completed in the twenty-fifth week. This fetal (gamma) type of AChR could no longer be demonstrated after the thirty-first week. The length of the end-plates as determined by the presence of AChRs increased again in the last week before birth and reached a plateau size by the end of the first year after birth. It is concluded that in man the transition from poly- to mononeuronal innervation takes place between the sixteenth and twenty-fifth weeks of development. The evidence available suggests that the retraction of nerve terminals is preceded by loss of AChRs from the muscle membrane facing the terminals. There is no relationship between retraction of nerve terminals and the switch from fetal to adult type of AChR. The size of the presynaptic apparatus changes little after the first year of life.

Patients with a clinical diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were randomised in a double-blind, placebo-controlled multicentre trial to investigate whether high-dose intravenous immunoglobulin treatment (IVIg) for 5 consecutive days has a beneficial effect. Fifteen patients were randomised to IVIg and 13 to placebo. In the IVIg treatment group 4 patients improved and 3 patients in the placebo group. The degree of improvement of the patients in the IVIg treatment group was no different from the patients in the placebo group. Electrophysiological studies did not show significant differences between the groups. Since a previously performed cross-over trial showed that a selected group of CIDP patients responded better to IVIg than to placebo, it is concluded that we need better criteria to select CIDP patients for treatment with IVIg.