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Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

The multiple chemical sensitivity syndrome (MCS) is a new cluster of environmental symptoms which have been described and commented on for more than 15 years now in the USA. In the meantime it has also been observed in European countries. The main features of this syndrome are: multiple symptoms in multiple organ systems, precipitated by a variety of chemical substances with relapses and exacerbation under certain conditions when exposed to very low levels which do not affect the population at large. There are no lab markers or specific investigative findings. In our view, MCS is not a separate clinical syndrome but a collective term. A very small part of the patients in question may actually exhibit a somatic or psychosomatic response to low levels of a variety of chemicals in the environment. For another part, even if the MCS symptoms are induced by chemical substances in the environment, the basic hypersensitivity is a psychological stress reaction. In the third and largest group, the patients have been misdiagnosed, i.e. a somatic or psychiatric disease has been overlooked. There is a fourth group of patients in whom there is no evidence of any exposure at all but instead a belief system installed by certain physicians, the media and other groups in society. This paper tries to describe the neurological and neurotoxic aspects of MCS problems and to illustrate it with examples of an alleged outbreak of chronic neurotoxic disease caused by pyrethroids in Germany. Research strategy should establish clearly determined diagnostic criteria, agreement on the use of specific questionnaires as well as clinical and technical diagnostic procedures, prospective clinical studies of MCS patients and comparative groups as well as experimental approaches.

Since the ban of PCBs at the end of the 1970s, extensive measures have been undertaken in Germany to dispose of PCB contaminated transformers. We report on three patients with considerable skin exposure to PCBs, in particular to Clophen A 30, while repairing or dismounting transformers. The periods of exposure range from 4 and 5 to 20 years. All patients presented with distal-symmetrical sensorimotor polyneuropathy as well as encephalopathy. In one of the cases, the neuropathy and encephalopathy progressed for a period of over 8 years after termination of exposure. In the two other cases the neurological deficits persisted over an observed period of 2-3 years. The reported clinical results may suggest that the long half-life of Clophen and its accumulation in fatty tissue can lead to persistence of PNS and CNS impairment long after the period of exposure.

In 1993, 64 cases of chronic pyrethroid intoxication were reported to the Federal Health Office in Germany. Shortly afterwards the media spoke of thousands of cases of pyrethroid intoxication in homes. 23 of the persons reported were examined in a neurological department on an inpatient basis using clinical neurological, neuroradiological and laboratory investigations, including the examination of pyrethroid values in blood and urine. The pyrethroid exposure involved carpets, moth killers, pesticide sprays and wood preservatives. Nine of the cases presented with severe somatic or psychiatric disorders with completely different clinical diagnoses, such as pituitary tumor, radiogenic lumbosacral plexus paralysis, Guillain- Barré syndrome, spinal muscular atrophy, with no plausible relationship to exposure. Eight cases presented with multiple chemical sensitivity syndrome (MCS) and normal somatic findings. In six of the cases, a causal link between acute complaints and pyrethroid exposure could be established or not ruled out. There was, however, not a single case in which evidence for irreversible PNS or CNS lesions could be found.

The multiple chemical sensitivity syndrome (MCS) is a novel constellation of symptoms in environmental medicine that has been extensively described and commented on in the USA. The main features of this syndrome are: multiple symptoms in different organ systems triggered by a variety of chemical substances, with relapses and exacerbations under certain precipitating circumstances at very low levels which do not cause any reactions in the population at large. There are no lab markers or specific investigative findings. This paper describes the historical development of the term MCS, its diagnostic criteria and pathophysiological aspects using 10 patient histories from our hospital.

Although their manufacture and use have been restricted or banned in Europe and the United States since the 1970s, polychlorinated biphenyls (PCBs) are still an ubiquitous environmental contaminant whose low-term effects are as yet not completely clear. Clinical case studies of patients with occupational exposure report cognitive impairment and peripheral neuropathy. In our defined nerve cell culture models in which we use pure neurons, pure glia and mixed cultures prepared from dorsal root ganglia of chick embryos we observed a neurotoxic effect after the application of a PCB compound (Clophen). It was only at higher concentrations that an additional gliatoxic effect could be observed.

Of the metabolites of hexane, 2,5-hexanedione (2,5 HD) has the strongest neurotoxic effect. There is a wealth of experimental studies in animals showing an axonotoxic mechanism consisting of an accumulation of 10 nm neurofilaments. Only few studies deal with a possible action of 2,5-HD on Schwann cells, glia cells or both. Pure neurons, pure glia and mixed cultures prepared from dorsal root ganglia (DRG) of chick embryos were studied in this model. DRG were chosen because they constitute a linkage between the peripheral and central nervous system and provide the additional advantage of containing only few defined glial and neuronal cell types. Additionally, pure neuronal cultures of sympathetic ganglia and mixed cultures of spinal cord and brain were prepared. In cultures of the different parts of the nervous system investigated, we observed at a concentration of 0.25% 2,5-HD massive toxic alterations of glial cells, whereas neurons and neurites were virtually unaffected.

A 31-year-old woman developed an acute, potentially fatal rhabdomyolysis of undetermined origin. Muscle biopsy revealed selective lysis involving exclusively type 2a fibers. Myoadenylate-deaminase (MAD) deficiency was proven by a negative histochemical reaction as well as by an enzymatic biochemical determination. The significantly greater energetic dependence of type 2a fibres on MAD explains their selective damage. The patient's mother also suffers from a similar muscle disease of still unclarified origin.

Adult rats were exposed to the solvents n-hexane and methylethylketone (MEK) in different concentrations. Lung tissue was examined systematically after various periods by electron microscopy. The direct toxic effect to pneumocytes could be demonstrated as definite regressive alterations, such as fatty degeneration and changements of lamellar bodies of type II pneumocytes as well as increased detachment of cells. Besides these findings, after chronic inhalation of solvents conspicuous aggregation of lamellar discharge material of type II pneumocytes can be seen, and probably, as a result of an irritated fat metabolism, large lysosome-like bodies with densely packed lipid material appear in type I pneumocytes. The most distinguished changements could be demonstrated after exposure to a mixture of n-hexane and MEK, while they were less obvious after n-hexane alone. The observation suggests a profound enzymatic irritation of metabolism.

The effects of the solvents n-hexane, butanone (methyl-ethyl-ketone, MEK) and a mixture of both in the intrapulmonary nerve system of rats were studied by light and electron microscopy. The alteration in the fine structures of the tissue consisted in a disseminated swelling of axons due to a striking multiplication of neurofilaments. Nonspecific axonal alterations could be demonstrated as well. The latter consisted in clusters of phospholipid material within the axoplasm of nerve fibers and the cytoplasm of Schwann cells plus an accumulation of glycogen granules in the axoplasm. Additionally, single degenerative changes of Schwann cells were observed. An enzyme-associated metabolic damage with a concomitant impairment of axonal flow is discussed as a possible underlying pathomechanism

25 cases of clinically severe toxic polyneuropathy were observed among young people in Berlin who were addicted to sniffing methylethylketone-containing solvents. The peripheral motor defects took 2 1/2 to 3 years to regress. In severe cases there were additional spastic signs. This form of neurotoxic effect can be reproduced in animals. It is due to a disorder of axonal transport which destroys peripheral and central axons.

In West Berlin in the autumn of 1975 through the following 5 months we observed 18 juvenile patients who had a toxic polyneuropathy and had sniffed a glue thinner. The neurological picture consisted of a symmetrical, progressive, ascending, mainly motor, polyneuropathy with pronounced muscle atrophy and characteristic vegetative alterations. The height of the disease was reached after 1 1/2-2 1/2 months and was characterized by tetraplegia in 7 patients. After 8 months all patients still had a motor deficit. Nerve biopsy showed paranodal axon swelling, dense masses of neurofilaments and secondary myelin retraction. The neurological and morphological data correspond to the "glue sniffer's neuropathy" and the n-hexane and MBK polyneuropathy after industrial exposure, as described in 10 cases to date. However, there was no MBK in the glue thinner. The polyneuropathies occurred in close time relation with the denaturation of the thinner with MEK (2-butanone). It is concluded from the data n-hexane and MBK have a common toxic mechanism with primary axonal changes and that there is an additional synergistic effect of MEK.

Predisposing factors and concomitant diseases were examined in cluster headache patients. A positive or negative correlation to a particular disease, e.g. gastrointestinal ulcerative disease, could not be showen. Factors indicating a genetic predisposition could also not be found. In the Freiburg Personality Inventory cluster and migraine patients had an essentially normal profile; however, both groups evidenced a tendency towards psychosomatic reactions.

An outbreak of neuropathies among Berlin solvent sniffers was closely related to the denaturation by methyl-ethyl-ketone (MEK) of the mixture used. The solvent was composed of n-hexane, toluene and ethyl-acetate. Nervous system responses to chronic repeated exposure to 10,000 ppm pure n-hexane, 10,000 ppm MEK/n-hexane (ratio 1:9) and 6000 ppm pure MEK were investigated in rats. Motor neuropathy of the dying back type with giant swelling of axons in the peripheral and central nervous system developed in animals exposed to MEK/n-hexane and n-hexane. Severe potentiation of n-hexane neurotoxicity and shortened onset of morphological and clinical signs were demonstrated in animals exposed to MEK/n-hexane. MEK alone did not produce neuropathy under these conditions. The findings suggest that commercial solvent mixtures containing MEK/n-hexane should be avoided.

Treatment with the histamine H2 receptor antagonist, cimetidine, alone and/or in combination with the histamine H1 receptor antagonist, chlorpyramine, in 13 patients showed that cimetidine alone was ineffective. 7 of 9 patients taking the combination of H1 and H2 receptor antagonists responded well to the treatment; in 1 patient, medication was ineffective and in 1 patient, success was doubtful. In 3 patients with chronic cluster headache, the effect faded after 4 weeks. The results are discussed.

Four men aged 16 to 19 years who had sniffed contact glue ("Pattex") thinner almost daily for 3 to 7 years developed a pronounced polyneuropathy. They had to be admitted nearly at the same time. A uniform neurological syndrome similar to Landry's paralysis with progressive ascending symmetrical pareses had developed. Motor deficiencies and atrophies affected the lower extremities more frequently and more severely. Only minimal sensory disturbances were found. The disease shows remarkable similarity to the "glue-sniffing neuropathy" described in the US and Japan which is attributed to n-hexane.

25 cases of clinically severe toxic polyneuropathy were observed among young people in Berlin who were addicted to sniffing methylethylketone-containing solvents. The peripheral motor defects took 2 1/2 to 3 years to regress. In severe cases there were additional spastic signs. This form of neurotoxic effect can be reproduced in animals. It is due to a disorder of axonal transport which destroys peripheral and central axons.

The effects of long-term continuous and intermittent inhalation exposure to selected concentrations of n-hexane and mixtures of n-hexane and methyl-ethyl-ketone (MEK) on the nervous system of rats were investigated. Animals exposed continuously (24 h/d, 7 d/week) to 500 ppm n-hexane displayed complete hindlimb paralysis after 9 weeks. Histological examination showed hexacarbon-specific axonal lesions in peripheral nerves, particularly tibial branches to calf muscles, and in the gracile tract at cervical levels of the spinal cord. Similar clinical and pathological signs of neuropathy appeared one week earlier in animals treated with a mixture of 500 ppm n-hexane/MEK (4:1 or 3:2) and 5 weeks earlier with 700 n-hexane/MEK mixture (5:2) or 700 ppm of n-hexane alone. Rats exposed to the latter concentrations intermittently, 8 hours daily for 40 weeks, did not develop clinical or morphological signs of a hexacarbon neuropathy.

Predisposing factors and concomitant diseases were examined in cluster headache patients. A positive or negative correlation to a particular disease, e.g. gastrointestinal ulcerative disease, could not be showen. Factors indicating a genetic predisposition could also not be found. In the Freiburg Personality Inventory cluster and migraine patients had an essentially normal profile; however, both groups evidenced a tendency towards psychosomatic reactions.

n-Hexan, Methyl-n-Butyl-Keton (MBK) und 2,5-Hexandion (2,5 HD) werden im englischen Sprachraum wegen ihrer Konfiguration mit 6 C-Atomen als Hexacarbone bezeichnet. Die Hexacarbone finden als organische Losungsmittel eine weite Verbreitung in Industrie, Werkstatt und Haushalt. n-Hexan beispielsweise ist mit 20 bis 30% in Industriebenzin enthalten, ferner haufiger Bestandteil von organischen Losemittelgemischen in Farben, Lacken, Verdunnern und Klebstoffen.

Hexacarbon-containing solvents can induce specific functional and morphological disorders in the peripheral and central nervous system. The neurological manifestations consist in polyneuropathy syndromes and neuromyelopathies. Such clinical pictures have been observed both after exposure at industrial work and after abuse of hexacarbon-containing solvents as narcotics. An outbreak of neuropathies among solvent-sniffers after denaturation of the hexacarbon-containing solvent with methyl-ethyl-ketone led to the assumption that the neurotoxic properties of n-hexane can be considerably potentiated with methyl-ethyl-ketone. Experimental studies on laboratory rats have shown that solvent mixtures with n-hexane and methyl-ethyl-ketone bring about an earlier onset of clinical-neurological deficits and hexacarbon-specific morphological changes than exposure to n-hexane alone. First results of a combined exposure to lead and n-hexane solvents also indicate an intensified effect of the combined neurotoxins.

SYNOPSIS HLA typing was performed in 42 cluster headache patients. In the total group, no significant deviation in HLA antigen frequencies could be found. This result was also true for the subgroup of the episodic type (37 patients). However, all 5 patients with the chronic form of cluster headache carried the HLA-A1 antigen. The results are discussed.

Im Mai und Juni 1981 trat epidemieartig in Spanien in Madrid und in nordwestlichen Regionen von Madrid ein neuartiges Krankheitsbild auf, das spater als toxisches Speiseolsyndrom (toxic oil syndrome) bezeichnet wurde. Die Krankheit breitete sich explosionsartig aus und wurde zunachst fur eine Infektion gehalten. Die Angaben zur Gesamtzahl der Erkrankten schwanken zwischen 19.828 und 20.178 (7). Gegen die Infektionstheorie sprach die fehlende Ausbreitung der Krankheit innerhalb von Krankenhausern oder Schulen, die auffallende Haufung in Familien unter Aussparung von Kindern unter sechs Monaten, die Ausbreitung in Arbeiterwohnvierteln ohne Ubergreifen auf benachbarte Mittelschichtswohngebiete.

Es wird uber eine Ende 1975 in Berlin beobachtete Reihe schwerer toxischer Polyneuropathien (PN) berichtet. Betroffen waren ausschliesch Schnuffler, die zur Rauscherzeugung einen bestimmten Klebstoffverdunner inhalierten. Die PN stellten sich ein, nachdem ein zuvor jahrelang ge- oder besser misbrauchter n-Hexan-haltiger Klebstoffverdunner vom Hersteller mit Butanon vergallt worden war [1].

Treatment with the histamine H2 receptor antagonist, cimetidine, alone and/or in combination with the histamine H1 receptor antagonist, chlorpyramine, in 13 patients showed that cimetidine alone was ineffective. 7 of 9 patients taking the combination of H1 and H2 receptor antagonists responded well to the treatment; in 1 patient, medication was ineffective and in 1 patient, success was doubtful. In 3 patients with chronic cluster headache, the effect faded after 4 weeks. The results are discussed.

The pathomechanism of the Spanish mass oil poisoning, which affected more than 20,000 people in the spring of 1981 and has so far caused more than 500 deaths, has not yet been clarified. Subsequent to a toxic-allergic initial phase of the disease with fever as well as lung and skin manifestations, 10 to 20% of the patients, after passing through an interval of reduced symptoms, entered a second disease phase characterized by marked vasculitis and fibrosis in diverse organ systems. The most frequent manifestation type involved in this connection was a severe neuromyopathy with pronounced joint contractures and skin alterations. A survey of the disease course is presented on the basis of our own examinations at the Centro Especial Ramon y Cajal as well as morphological studies on nerve-muscle and brain tissue, chemical analysis studies with oil samples from affected families and the literature available so far.

A severe potentiating effects of methyl-ethyl-ketone (MEK) on the peripheral and central neurotoxicity of n-hexane could be demonstrated in a chronic inhalation study in rats.