[Standardized bicycle ergometry test in mitochondrial myopathies. Indications, interferences and clinical parameters]. / Standardisierter Fahrradergometertest bei mitochondrialen Myopathien. Indikation, Störfaktoren und klinisch aussagekräftige Parameter.

Exercise tests are widely used as simple, non-invasive screening methods in the differential diagnosis of metabolic myopathies. Exercise protocols have not been standardized with regard to duration of the test, workload, or monitored metabolic parameters. Potentially interfering parameters such as gender or maximal isometric force of the individuals have not been investigated. Here we describe a standardized bicycle ergometry protocol with a stepwise increasing workload between 30 and 100 watts. The venous lactate/pyruvate (L/P) ratio proved to be the one clinically most useful parameter in the functional diagnosis of mitochondrial myopathies with pathological exercise values in all nine examined patients. Additionally, the effects of coenzyme Q therapy in these patients were most clearly mirrored by changes in the L/P ratio. Nonspecifically elevated venous lactate concentrations above 5 mmol/l are rarely found in healthy female volunteers with low maximal isometric force of the M. quadriceps femoris. Other parameters such as serum free fatty acids, ketone bodies, intermediate products of the Krebs cycle or spirometric investigations add only little additional information. The exercise test described may be useful as an additional investigation in the differential diagnosis of metabolic myopathies.

Stages and syndromes of neuroborreliosis.

To ascertain the varieties of neuroborreliosis, 330 patients were identified at the Departments of Neurology in Würzburg and Giessen from 1979 to 1994. Patients who fullfilled at least one of three strict case definitions based on clinical and laboratory criteria were included in the study. Ninety-one per cent of the patients had second-stage neuroborreliosis (duration of symptoms < or = 6 months). The most common syndrome was a painful spinal meningoradiculitis, alone (37%) or in combination with a cranial radiculitis (29%). Meningoradiculitis cranialis (9%), isolated meningitis (4%) and erythema chronica migrans-associated mono/polyneuritis (3%) were further stage II features. Central nervous system involvement occurred either as an acute meningomyelitis or meningomyeloradiculitis (5%) and meningoencephalitis or meningenocephaloradiculitis (4%). Less than 9% of the patients ran a chronic course (stage III) with a disease duration between 6 months and 9 years, either as acrodermatitis chronica atrophicans associated mono- or polyneuritis (2%) or a chronic progressive encephalomyelitis (6%). Cerebrovascular neuroborreliosis (1%) occurred in both stages; however, the primary nature of the course was a chronic one. Involvement of other organs except the skin was rare (joints 3%, heart 1%) but elevated hepatic enzymes were frequent. Our study demonstrates that neuroborreliosis has to be considered in the differential diagnosis of a wide variety of neurological conditions. Cerebrospinal fluid analysis and the search for specific intrathecal antibody production are important diagnostic procedures.

Relationship between the Borrelia burgdorferi specific immune response and different stages and syndromes in neuroborreliosis.

One hundred untreated neuroborreliosis patients were investigated by IgG/IgM immunoblot to find out if different stages and syndromes are characterized by different patterns of their Borrelia burgdorferi specific immune responses in CSF and serum. Stage III (n = 10) was characterized by a broad, highly specific intrathecal immune response (the mean number of IgM bands in CSF was 3.1 and of IgG bands 6.3). All patients recognized one or more of the following proteins (p35, p21, p18) or the 5 kd glycolipid. In contrast, the immune response in stage II (n = 90) was less restricted (28%) and heterogeneous (mean number of IgM bands 1.4 and of IgG bands 3.4). It was mainly directed against the highly crossreactive p41 antigen (91%). The different clinical features of stage II were comparable regarding the intrathecal immune response. However anti-glycolipid and anti-p35, -p21, -p18 IgG antibodies were detected in a small subset of patients, mainly corresponding to more severe courses of the disease. Our data are compatible with a direct agent-related pathomechanism in neuroborreliosis. Antibodies against certain proteins and the glycolipid of B. burgdorferi seem to have a prognostic value as to the development of more severe disease or transition to stage III.

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis.

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging.

Adhesion molecules are important in T-cell trafficking to sites of inflammation. We determined levels of circulating vascular cell adhesion molecule-1 (VCAM-1), L-selectin, and E-selectin in the serum of 147 patients with definite multiple sclerosis of the remitting-relapsing or secondary progressive type. Soluble VCAM-1 and L-selectin concentrations were increased compared to levels in a large group of control subjects. Levels were highest in patients with gadolinium-enhancing lesions on magnetic resonance imaging (VCAM-1: 1,011 +/- 276 vs 626 +/- 87 ng/ml; L-selectin: 1,130 +/- 272 vs 793 +/- 207 ng/ml [mean +/- standard deviation]; p < 0.0001 vs patients without enhancing lesions). Serum levels of soluble tumor necrosis factor receptor (60 kd) were also raised (2.64 +/- 1.23 vs 2.17 +/- 0.69 ng/ml in subjects with other neurological diseases and 2.1 +/- 0.77 ng/ml in healthy control subjects; p < 0.05). Soluble VCAM-1 and L-selectin levels were correlated to concentrations of soluble tumor necrosis factor receptor. In 13 patients with viral encephalitis, similar observations were made. Raised levels of soluble VCAM-1 and L-selectin probably reflect cytokine-induced endothelial cell and T-lymphocyte/monocyte activation occurring in the process of T-cell migration into the central nervous system. Tumor necrosis factor-alpha may be critically involved.

[Risk of endocrine activation in interventions of paragangliomas in the head-neck area]. / Zum Risiko endokriner Aktivierung bei Eingriffen an Paragangliomen im Kopf-Hals-Bereich.

The intracytoplasmatic glycolytic enzyme neuron-specific enolase (NSE) can be found in cells of endocrine tissue and their derived tumours. The enzyme is not secreted but released if cells are destroyed, i.e. continuously in malignant tumours. The serum level of neuron-specific enolase (NSE) has been used as a marker for small cell carcinomas of the lung, glioblastomas and malignant phaeochromocytomas. In this investigation blood samples were taken prior to and following surgical manipulation of the tumour in 21 patients with paragangliomas of the head and neck region and 6 controls. 22 serum samples were obtained before angiography and two hours after angiography, 41 before surgery, during surgery and after surgery. The serum level of NSE was measured by NSE-RIA test (Diagnostics, Uppsala). In all tumour specimens NSE could be demonstrated by the immunohistological PAP method (Abb. 1). Only two patients had preoperatively elevated serum-NSE levels. An arterial venous shunt had been detected by angiography in one of these patients. No significant effect on NSE serum level could be produced in the majority of patients by an angiography with embolisation or surgical manipulation of the tumour (Fig. 1, 2). A reduction in serum NSE level was observed postoperatively in both cases mentioned before. None of the 6 controls showed any significant change in serum NSE level (Fig. 3). It can be concluded from this study that embolisation does not lead to direct or indirect cell destruction through ischaemia. Manipulation of the tumour does not destroy a significant number of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Meningoradiculitis and encephalomyelitis due to Borrelia burgdorferi: a follow-up study of 72 patients over 27 years.

In 1987, follow-up studies were conducted on 72 patients who had had meningoradiculitis and encephalomyelitis (8 patients) due to Borrelia burgdorferi 5-27 years previously. These patients had not been treated with antibiotics, either during the acute disease or during the interval prior to follow-up studies. The patients had exhibited the typical symptoms of Bannwarth's syndrome during the acute phase. At the follow-up studies, 33 patients showed no, and 23 only mild, clinical residual symptoms including normal CSF findings and low-positive serum IgG borrelia antibody titres (IFT; ELISA). Three patients without sequelae exhibited persistent intrathecal secretion of oligoclonal B. burgdorferi-specific CSF IgG antibodies (Immunoblot; positive borrelia CSF IgG antibody titres). Thirteen patients exhibited mild-to-medium sequelae with persistent intrathecal formation of oligoclonal B. burgdorferi-specific CSF IgG antibodies, up to 21 years after the acute illness. This persistence can be interpreted as an "immunological scar syndrome". Our follow-up studies appear to indicate that neurological manifestations of B. burgdorferi infections are generally (with few exceptions) of a benign nature. Most patients can be classified as having been cured without antibiotic therapy. No late manifestations of chronic progressive CNS borreliosis comparable to that of neurosyphilis have been seen following acute untreated neuroborreliosis.

[Seizure prevention using carbamazepine following severe brain injuries]. / Anfallsprophylaxe mit Carbamazepin nach schweren Schädelhirnverletzungen.

In this article the efficacy of carbamazepine for seizure prophylaxis in severe head injuries is tested. In addition, conditions with high risk of seizures requiring prophylactic regimen, were defined. One hundred and thirty-nine patients above 15 years of age with severe head injuries were included in the study. They were randomly divided into two groups--carbamazepine versus placebo. Prophylaxis was started immediately after the accident and was continued for one and a half to two years. Carbamazepine dosage was adjusted individually to provide serum levels within therapeutic range. In case of a seizure all the necessary clinical management was initiated. Patients on carbamazepine showed a lower probability of post-traumatic seizures than those on placebo (p less than 0.05). This difference was statistically significant with regard to early seizures within the first week and with regard to the follow-up time in total, but not regarding late seizures per se. Brain lesions with a high risk of post-traumatic seizures were situated in the parietal and temporal areas and included acute subdural haematomas in all locations, temporal lobe contusions, parietal epidural haematomas accompanied by other lesions and the deep stages of coma. Brain stem contusions were accompanied by a rather low probability of seizures. The above mentioned types and locations of brain lesions with the exception of brain stem contusions justify antiepileptic prophylaxis. The regimen consists of oral carbamazepine 100 mg three times daily by gastric tube during the first two days increasing to about 200 mg three times daily on the third day corresponding to the serum level. If oral medication is not possible within the initial twelve hours, phenytoin in a dose of 750 mg Phenhydan-Infusion Konzentrate is given on the first day, followed by an intravenous dose of 250-500 mg on the second day or until oral carbamazepine administration is tolerated. Treatment should be continued for one year.

[T3, T4, TSH and circulating antithyroglobulin antibodies in myasthenia gravis]. / T3, T4, TSH und zirkulierende Schilddrüsenantikörper bei Myasthenia gravis.

Myasthenia gravis (MG) is a rare neuromuscular disease which is known to be associated with hyperthyroidism at high frequency (3-10%). These investigations, however, are basing on studies of the basal metabolic rate, protein bound iodine (PBI) and the thyroidal radioiodine uptake. In our study (104 MG patients, 104 control subjects) we wanted to evaluate thyroid function on the basis of T3, T4, TBG and TSH radioimmunoassays and in addition we looked for the presence of circulating antithyroglobulin antibodies (Tab) and antimicrosomal antibodies (Mab). The following thyroidal states were disclosed: Thyrotoxicosis (5.8%), hypothyroidism (1.9%), preclinical hypothyroidism (3.8%) and euthyroidism (88.5%). Twenty-eight myasthenic patients were Mab-positive and twelve in addition Tab-positive. Comparing the twenty euthyroid antibody-positive MG-patients with euthyroid antibody-negatives no statistically significant differences were found in thyroid function parameters. It is discussed that part of the thyroid antibody-positive patients may have a symptomless autoimmune thyroiditis which is finally resulting in hypothyroidism via a preclinical hypothyroid status.

Thyroid function and circulating antithyroid antibodies in myasthenia gravis.

Evaluation of thyroid function in 104 patients with myasthenia gravis by T3, T4, TBG, and TSH radioimmunoassays and the TRH-stimulation test in 47 patients disclosed thyrotoxicosis in 5.7%, preclinical hyperthyroidism probably due to autonomously functioning thyroid tissue in about 10% of patients stimulated with TRH, hypothyroidism in 1.9%, and preclinical hypothyroidism in 3.4%. Eighty-four percent were euthyroid. Antithyroid antibody activity was detected by hemagglutination tests. Twelve patients had antithyroglobulin antibodies (Tab), and 28 had antimicrosomal antibodies (Mab). Among the euthyroid myasthenic patients, 7 were Tab-positive and 20 were Mab-positive. Euthyroid antibody-positive patients had a significantly higher TSH response in the TRH stimulation test and may be at high risk for hypothyroidism.

[Myoglobin radioimmunoassay: experience of the diagnosis of skeletal muscle disorders (author's transl)]. / Myoglobin-Radioimmunoassay: Erfahrungen bei der Diagnostik von Skeletmuskelerkrankungen.

Serum myoglobin was measured by a sensitive radioimmunoassay in healthy controls and in patients with skeletal muscle disorders such as polymyositis and Duchenne type muscular dystrophy. The serum myoglobin levels were closely related to the serum creatine kinase (CK) activity, thus indicating that myoglobin is a useful adjunct in the assessment of muscle cell damage.

Demonstration of oligoclonal immunoglobulin G in Guillain-Barré syndrome and lymphocytic meningoradiculitis by isoelectric focusing.

Isoelectric focusing (IEF) of serum and CSF revealed oligoclonal IgG in 13 out of 16 patients with the Guillain-Barré syndrome (GBS), in 10 of them in serum only and in 3 in serum and CSF. Seventeen out of 19 patients with lymphocytic meningoradiculitis (LMR) showed oligoclonal IgG, 12 of them in CSF only. These findings, together with additional results, mean that in GBS oligoclonal IgG is synthesized mainly outside the CNS and in LMR within the CNS. Follow-up studies revealed changes in the oligoclonal IgG during the course of GBS and LMR. After treatment by plasma exchange the disappearance of oligoclonal IgG bands was followed by an improvement of GBS symptoms. The oligoclonal IgG bands returned in correlation with worsening of the disease. We were not able to elucidate the antibody character of oligoclonal IgG in GBS or LMR. No antibodies against the myelin basic protein (fragment 89-169) were detectable in the sera and CSF in any of the patients tested.

A simplified radioimmunological method for the determination of human beta-endorphin in cerebrospinal fluid.

Human beta-endorphin-like immunoreactive substances (beta h-EI) in human cerebrospinal fluid (CSF) were determined radioimmunologically. The cross reactivity of the antibodies to human beta-endorphin (beta h-E) amounted to 40% for human beta-lipotropin (beta h-LPH) whilst it was less than 1% for leu- and metenkephalin, alpha- and gamma-endorphin, fraction I and II [5], substance P and alpha-MSH. Prior to radioimmunological determination, an adsorbtion of beta h-EI from CSF with silicic acid was carried out and followed by a desorbtion, using a mixture of aceton/hydrochloric acid. This method was chosen because of the ratio of beta h-LPH to beta h-E in the desorbate can be shifted in favour of beta h-E owing to the variation in recoveries r (r beta h-LPH = 33%, r beta h-E = 64%). On the one hand, this enables a more specific determination of beta h-E and, on the other hand, and separation of any peptidase than may be present [9]. An adsorbtion/desorbtion of 2 ml CSF surfaces to prove the presence of 20-150 pg/ml (65-48 fmol/ml) of beta h-EI. The CSF of 28 patients with various neurological diseases was examined and 24 of them had concentrations of 20-70 pg/ml beta h-EI. The remaining four which had concentrations less than 20 pg/ml, came from meningitis patients undergoing corticoid therapy. A purchasable RIA kid was tested for its determination of beta h-E and was found to be unsuitable.

Serum myoglobin in primary and secondary skeletal muscle disorders.

Serum myoglobin was measured by a sensitive radioimmunoassay in healthy controls and patients with primary and secondary skeletal muscle disorders. The results indicate that serum myoglobin is a useful parameter in the assessment of muscle damage.

Thyroid function in multiple sclerosis.

Thyroid function was studied in 112 MS patients and 175 controls on the basis of T3, T4, T.B.G. and T.S.H. radioimmunoassays. In 33 MS patients with T.R.H. stimulation test was employed additionally. The MS patients had significantly increased T4 levels whereas T3 and T.S.H. were found to be significantly lower. No differences were found in the T.R.H.- stimulated T.S.H. response. The changes in thyroid function parameters were similar in different courses of MS and did not correlate with the degree of clinical disability. The results suggest that in MS the T4/T3 conversion might be reduced as seen in acute or chronic diseases. X

Effect of furosemide (lasix) on acute severe experimental cerebral edema.

The effect of furosemide (Lasix) therapy on a standardized experimental cerebral edema, induced in rats by applying a cooling stamp to the right side of the skull over the right coronal suture by means of a stereotactic instrument, was examined. The hemispherically separated water and electrolyte contents of the brain were analyzed after 24 h. Following furosemide therapy, the behavior of these edema parameters was compared statistically with dexamethasone, glycerol and albumin. An increase of the water and sodium content, and a decrease of potassium was observed 24 h after the trauma, especially in the right hemisphere. Furosemide did not improve either the water content or the electrolyte balance. By contrast, the administration of dexamethasone, glycerol and albumin was followed by a significant improvement of the edema. In experiments with cats, the course of the edema and the effect of furosemide on the cold brain injury of the right hemisphere were observed by measuring the intracranial pressure (ICP) values, and by continuous monitoring of the EEG. The ventricular CSF pressure and epidural pressures were also recorded. The electrical brain activity was continuously compared with the course of the ICP by means of computer analysis. In addition, the blood osmolality and diuresis were monitored. The ICP increased rapidly after the trauma, establishing considerable pressure gradients, and the EEG power intensities decreased markedly on the right side. Histologically, there was an extended edema of the white matter of both hemispheres. The ICP was not lowered by single injections or high dose infusions of furosemide, and the EEG power intensities also did not improve. Infusions of large volumes of furosemide even resulted in an increase of ICP, but infusion of 40% sorbitol effected a rapid decrease of ICP and EEG recovery over the left hemisphere. Sorbitol infusion also caused a marked rise in the blood osmolality, whereas furosemide had no such effect. The results raise considerable doubts as to the propriety of the exclusive use of furosemide for cases of acute cerebral edema with raised ICP. The diuretic effect is insufficient to establish an osmotic gradient, and its general dehydrating effect does not acutely influence the ICP. The absence of effect on the experimental tissue edema would not appear to commend furosemide as basic therapy for cases of traumatic cerebral edema.