Progranulin levels in status epilepticus as a marker of neuronal recovery and neuroprotection.

INTRODUCTION: Recently, a mouse model showed that progranulin, a mediator in neuroinflammation and a neuronal growth factor, was elevated in the hippocampus after status epilepticus (SE). This elevated level might mirror compensating neuronal mechanisms after SE. Studies concerning neuronal recovery and neuroprotective mechanisms after SE in humans are scarce, so we tested for progranulinin the cerebrospinal fluid (CSF) after various types of SE. METHOD: We performed a retrospective analysis of progranulin levels in CSF in patients (n = 24) who underwent lumbar puncture as part of diagnostic workup after having SE and in patients after having one single tonic-clonic seizure who comprised the control group (n = 8). RESULTS: In our group with SE, progranulin levels in CSF were not significantly elevated compared to our control group. Furthermore, there was no correlation between progranulin levels and the time interval between lumbar puncture and SE. Additionally, in cases of higher CSF progranulin levels, we found no impact on the clinical outcome after SE. CONCLUSION: Although our cohort is heterogeneous and not fully sufficient, we conclude that progranulin in CSF is not elevated after SE in our cohort. Therefore, our results do not suggest a change in cerebral progranulin metabolism as a possible neuroregenerative or neuroprotective mechanism in humans after SE in acute and subacute phases. A larger cohort study is needed to further strengthen this result. This article is part of a Special Issue entitled "Status Epilepticus".

Semliki forest virus: cause of a fatal case of human encephalitis.

A fatal case of human encephalitis has been observed for which our results indicate that Semliki Forest virus (SFV) was the etiologic agent. This is surprising in view of the fact that this virus, which has been widely studied, was believed to be one of the arboviruses nonpathogenic for man. Described are the clinical course, the virological examinations performed, and the histopathological findings in the central nervous system.

Application of inhibitor titrations for the detection of oxidative phosphorylation defects in saponin-skinned muscle fibers of patients with mitochondrial diseases.

Inhibitor titrations were applied to characterize functional changes in mitochondrial energy metabolism in the skeletal muscle of patients with mitochondrial diseases. For this we titrated the maximal mitochondrial respiration rate of saponin-skinned muscle fibers isolated from the skeletal muscle biopsy with the specific inhibitors of mitochondrial oxidative phosphorylation complexes I, IV and V-rotenone, azide and oligomycin. For three patients with deletions of mitochondrial DNA and one patient with a complex I deficiency the titrations revealed at rather normal respiration activities of saponin-skinned fibers significant differences to healthy controls: (i) The inhibitor titration curves of the affected enzyme were much steeper and (ii) for almost complete inhibition of respiration a smaller amount of the inhibitor is necessary. The detailed analysis of the titration curves within the framework of metabolic control theory indicated elevated flux control coefficients of the respective complex of respiratory chain. On the other hand, for one patient with a mitochondrial DNA depletion syndrome, decreased respiration activities of skinned fibers but no redistribution of flux control was observed. We conclude, therefore, that application of inhibitor titrations and the quantitative description of the titration curve can be a valuable approach to elucidate functional defects of mitochondrial oxidative phosphorylation.

Laser-excited fluorescence studies of mitochondrial function in saponin-skinned skeletal muscle fibers of patients with chronic progressive external ophthalmoplegia.

The functional behavior of mitochondria in skeletal muscle of patients with chronic progressive external ophthalmoplegia was studied by laser-excited fluorescence measurements of NAD(P)H and flavoproteins in saponin-skinned fibers. Variations in the mitochondrial content and the presence of partially respiratory chain-inhibited mitochondria can be detected using this novel method.

Functional motor compensation in amyotrophic lateral sclerosis.

The present study investigated the fMRI correlates of functional compensation/neural reorganization of the motor system in patients with amyotrophic lateral sclerosis (ALS). The hypothesis was that ALS patients would recruit additional brain regions compared with controls in a motor task and that activity in these regions would vary as a function of task difficulty. Patients and controls executed a motor task with two sequences (a simple and a more difficult one) of consecutive button presses. Patients and controls both activated brain regions known to be involved in motor execution and control. Activity in ipsilateral motor areas as well as difficulty-related activity in the left cerebellum could only be observed in patients. The behavioral data indicated that the motor task was much more difficult for patients than for controls. At nearly equal difficulty the observed patterns of hemodynamic activity in controls were very similar to those observed in ALS. The findings suggest that functional compensation in ALS relies on existing resources and mechanisms that are not primarily developed as a consequence of the lesion.

Defective mitochondrial oxidative phosphorylation in myopathies with tubular aggregates originating from sarcoplasmic reticulum.

Abnormalities of the sarcotubular system presenting as tubular aggregates (TAs) have been described in a variety of neuromuscular disorders. Here, we report on immunohistochemical and biochemical findings in 7 patients (2 familial and 5 sporadic cases) suffering from myopathies with TAs. In muscle biopsy specimens from 5 of the 7 patients, TAs were immunopositive for the ryanodine receptor (RYR 1) of the sarcoplasmic reticulum (SR), the SR Ca2+ pump (SERCA2-ATPase), and the intraluminal SR Ca2+ binding protein calsequestrin, indicating an SR origin of these aggregates. Furthermore, these 5 cases showed decreased respiratory chain enzyme activities (NADH:CoQ oxidoreductase. complex I and cytochrome c oxidase [COX], complex IV), while the remaining 2 patients exhibited normal values. Our findings indicate a functional link between mitochondrial dysfunction and the presence of TAs originating from the sarcoplasmic reticulum.

Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman.

The circadian and pulsatile TSH secretion profiles were investigated in 5 females at the time of menstruation and 21 healthy males by sampling blood every 10 min for 24 h. Computer-assisted analysis, i.e. the Cluster and Desade programs, revealed means of 9.9 +/- 1.7 (Cluster) and 11.4 +/- 3.9 (Desade) pulses/24 h. More than 50% of the TSH pulses were detected between 2000-0400 h. Male and female subjects showed no significant difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH (200 micrograms). Repetition of the TSH secretion analysis in 4 healthy subjects after 1, 2, and 6 months (2 subjects) revealed a significantly better cross-correlation within than between individuals (P less than 0.0001). We modulate the circadian TSH secretion pattern by acute sleep withdrawal or prolonged sleep after a night of sleep withdrawal in six healthy male volunteers. Sleep withdrawal augmented the nightly TSH secretion (mean serum TSH, 2.1 +/- 1.3 mU/L; mean TSH in sleep, 1.3 +/- 0.5 mU/L; P less than 0.05), whereas sleep after sleep withdrawal almost completely suppressed the circadian variation (mean TSH, 1.1 +/- 0.7 mU/L; P less than 0.01). This modulation is due to a significant decrease in pulse amplitude, but not to an alteration in the frequency or temporal distribution of TSH pulses.

Rapid on-line estimation of responses to transcranial magnetic and peripheral nerve electrical stimulation in single human motoneurons.

Cross-correlation experiments allow to obtain information about synaptic potentials in human motoneurons. However, recording cross-correlation responses of one motoneuron to transcranial magnetic and electrical peripheral nerve stimulation requires a considerable recording time when both responses are recorded consecutively. In this paper a method is introduced yielding the same information about the responses of a single motoneuron to both types of stimuli while requiring only a fraction of the recording time necessary for a conventional cross-correlation experiment. The main features of the method introduced were: (i) use of the recharging time of the magnetic stimulator for response recording to the electrical stimulus, (ii) use of specific stimulus timing with respect to the motor unit discharges, and (iii) on-line display with statistical testing of the response functions allowing to stop stimulus application, if the responses to both types of stimuli had reached statistical significance. Application of the method is demonstrated with response recording of 70 tibialis anterior motor units from five healthy volunteers to transcranial magnetic and peroneal nerve electrical stimulation.

Effects of the amplitude threshold on the separability of neuropathic and myopathic from normal EMG using parameters of the turns/amplitude analysis.

OBJECTIVE: In this study, the relationship between the amplitude threshold used for the determination of the turns of the electromyographic (EMG) interference pattern and the parameters of the turns/amplitude analysis was examined. It was investigated whether the discrimination of myopathic and neuropathic from normal muscles could be optimized by an appropriate amplitude threshold. METHODS: The interference patterns of the tibialis anterior muscle of 15 patients with myopathies, 30 patients with neuropathies and 56 controls were recorded, using concentric needle electrodes. A computer program performed the Willison analysis, systematically varying the amplitude threshold between 10 microV and 200 microV. RESULTS: Amplitudes as well as the number of turns per second were non-linearly related to the amplitude threshold. The reduction of the amplitude threshold to 30 microV resulted in a clearly better separation of the distributions of the number of turns of neuropathic, myopathic and normal EMG, compared to the traditional threshold value of 100 microV. The distributions of amplitude values, however, were not affected. The distance between the turns parameter distributions of neuropathic patients and controls and between the distributions of myopathic patients and controls, expressed by the Kolmogoroff-Smirnov distance, had a maximum at 30 microV. CONCLUSIONS: For the turns/amplitude analysis of the tibialis anterior muscle an amplitude threshold of 30 microV should be selected.

Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis.

In skeletal muscle homogenates of 14 patients with sporadic amyotrophic lateral sclerosis, an approximately twofold lower specific activity of NADH:CoQ oxidoreductase in comparison to an age matched control group (n=28) was detected. This finding was confirmed by a detailed analysis of mitochondrial oxidative phosphorylation in skeletal muscle using saponin-permeabilized muscle fibers. (i) A significantly lowered maximal glutamate+malate and pyruvate+malate supported respiration of saponin-permeabilized fibers was detected in the patients group. (ii) Titrations with the specific inhibitor of NADH:CoQ oxidoreductase amytal revealed a higher sensitivity of respiration to this inhibitor indicating an elevated flux control coefficient of this enzyme. (iii) Applying functional imaging of mitochondria using ratios of NAD(P)H and flavoprotein autofluorescence images of saponin-permeabilized fibers we detected the presence of partially respiratory chain inhibited mitochondria on the single fiber level. A secondary defect of mitochondrial function due to the neurogenic changes in muscle seems to be unlikely since no mitochondrial abnormalities were detectable in biopsies of patients with spinal muscular atrophy. These results support the viewpoint that an impairment of mitochondria may be of pathophysiological significance in the etiology of amyotrophic lateral sclerosis.

Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis.

The mitochondrial function in skeletal muscle was investigated in skeletal muscle biopsies of 26 patients with sporadic amyotrophic lateral sclerosis (ALS) and compared with investigations of 28 age-matched control muscle samples and biopsies of 6 patients with spinal muscular atrophy (SMA) and two patients with Tay-Sachs disease. In comparison to the control, SMA and Tay-Sachs biopsies, we observed in the ALS samples a significant about two-fold lower activity of complex I of mitochondrial respiratory chain. To visualise the distribution of the mitochondrial defect in skeletal muscle fibers we applied confocal laser-scanning microscopy and video fluorescence microscopy of NAD(P)H and fluorescent flavoproteins. The redox change of mitochondrial NAD(P)H and flavoproteins on addition of mitochondrial substrates, ADP, or cyanide were determined by measurement of fluorescence intensities with dual-photon UV-excitation and single-photon blue excitation. In skeletal muscle fibers of ALS patients with abnormalities of mitochondrial DNA (multiple deletions, n=1, or lower mtDNA levels, n=14) we observed a heterogeneous distribution of the mitochondrial defects among individual fibers and even within single fibers. In some patients (n=3) a mitochondrial defect was also detectable in cultivated skin fibroblasts. These findings support the viewpoint that the observed impairment of mitochondrial function in muscle of certain ALS patients is caused by an intrinsic mitochondrial defect which may be of pathophysiological significance in the etiology of this neurodegenerative disease.

Mitochondrial complex I deficiency in a female with multiplex arthrogryposis congenita.

A 10-year-old female with arthrogryposis multiplex congenita is presented. Clinical, neurophysiologic, and histologic findings suggested a mild myopathy. The analysis of enzymatic activity in the homogenate and of mitochondrial function in saponin-permeabilized fibers from the muscle biopsy revealed an approximately twofold-decreased specific activity of the NADH:CoQ oxidoreductase (complex I of the mitochondrial respiratory chain) that was compensated for by an increased number of mitochondria. The complex I deficiency was also detected in cultivated skin fibroblasts of the patient. The observed defect of mitochondrial oxidative phosphorylation in arthrogryposis multiplex congenita may be of pathogenetic relevance.

Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells.

We report the case of a female patient, who died at the age of 66 years. Besides an insulin-dependent diabetes mellitus (IDDM) she had developed the clinical symptoms of stiff-man-syndrome (SMS) and harbored autoantibodies against glutamate-decarboxylase (GAD) in blood and liquor. GAD catalyzes the biosynthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The autopsy revealed typical alterations observed in diabetes mellitus including an incomplete fibrosis of pancreatic Langerhans islets. A decrease of GABA-ergic cells in the cerebellar cortex was observed, and a size reduction of Renshaw cells in the spinal cord. Furthermore, a dilution series of a polyclonal GABA antibody delivered a reduced immunofluorescence in the cerebellum. In skeletal muscle a neurogenic atrophy was observed. As described in literature, the clinical symptoms decayed following clonazepam administration. We suggest that this case including GAD autoantibodies, dramatic loss of GAD-expressing pancreatic cells, and loss or atrophy of GABA secretory neurons, supports the hypothesis that SMS may be an autoimmune disease directed against GABA-ergic cells. Furthermore, we suggest a neuronal hypersensitivity at the spinal cord level caused by the atrophic Renshaw cells.

Frontal-executive dysfunction in early onset cerebellar ataxia of Holmes' type.

We report the case of a 29-year-old male patient with cerebellar ataxia of Holmes' type. The combination of progressive cerebellar ataxia and hypogonadotrophic hypogonadism is a rare distinctive syndrome which was first described by Holmes in 1907. Early diagnosis is desirable because replacement of testosterone may allow normal sexual development. MRI showed severe combined superior vermian and cerebellar hemisphere atrophy. Comprehensive neuropsychological testing pointed to a more widespread cerebellar mediated functional CNS involvement in the earlier stages of this ataxic syndrome than previously described in mentally not retarded subjects.

A trend-detection algorithm for intraoperative EEG monitoring.

Intraoperative EEG-monitoring needs to discriminate random fluctuations from real systematic variations (trends). This task is made more difficult by several types of artifacts. With the goal of supporting visual EEG evaluation, a new trend-detection algorithm is presented which is based on spectral analysis and a post-processing dynamic linear model, the latter introduced by Harrison and Stevens. A gradient value provided by this model is exploited to determine the onset and relative extent of an existing trend. Artifacts are detected by several threshold measures for the original signal and its first derivative. The system was validated using a set of intraoperative EEGs recorded during carotid endarterectomy.

Primary carnitine deficiency: adult onset lipid storage myopathy with a mild clinical course.

We studied two adult patients with myalgia and muscular fatigability during prolonged physical exercise. Serum creatine kinase was increased and muscle biopsy revealed a lipid storage myopathy affecting predominantly the type I fibres. Skeletal muscle carnitine content was reduced to 15% and 21% of the normal mean values, while serum carnitine levels were either normal or decreased. Four months of oral therapy with L-carnitine (3 g per day) resolved the clinical symptoms completely in both patients, and a subsequent muscle biopsy confirmed a marked reduction of lipid storage, along with increased muscle carnitine levels. The analysis of renal carnitine excretion and the exclusion of possible secondary carnitine deficiencies in both patients are compatible with mild defects of the carnitine transporter in one patient and of carnitine biosynthesis in the other. Since myalgia and muscular fatigue are frequent but unspecified complaints of otherwise clinically unremarkable adult patients, it is important to identify myopathies associated with primary carnitine deficiency because they may be amenable to treatment.

Spinal motoneuron function in lower motor neuron disease: normal corticomotoneuronal and peripheral Ia EPSPs in patients with spinal muscular atrophy.

Responses of single tibialis anterior motor units to transcranial magnetic stimulation and to a synchronized Ia volley evoked by peripheral electrical nerve stimulation were obtained in patients with distal spinal muscular atrophy and compared to normal controls. Estimations of excitatory postsynaptic potential (EPSPs) by cross-correlations revealed no difference in rise time of EPSPs for both groups of subjects despite considerable changes in macro-EMG parameters of the motor units studied in patients with spinal muscular atrophy (SMA). The results indicate that voluntarily activated spinal motoneurons in SMA are capable of normal excitatory responses to transcranial magnetic as well as peripheral Ia stimulation.

Computer-aided EMG-analysis in patients with neurogenic lesions.

A new system for computer aided EMG-analysis was tested in 3 groups of patients with neurogenic lesions (ALS, ulnar nerve lesions, diabetic polyneuropathy). The system entails automatic segmentation and parametrization of the single MUAP as well as the automatic classification of the MUAP into motor units. Emphasis was placed on its practicability in an everyday clinical setting. All patient groups differed significantly from normal groups in most of the computed parameters of the motor units. Moreover, on the basis of the computer-aided analysis of the MUAP up to 90% of individual patients in the ALS and ulnar nerve lesion groups and up to 40% in the diabetic polyneuropathy group, who did not have any pathological spontaneous activity or paris, could be classified as pathological. It is concluded, that computer-aided EMG-analysis has become a practical tool for routine use in the clinical laboratory simplifying early diagnosis of subtle EMG-changes, and aiding the less experienced examiner.

[Surgical decompression of bilateral, compression-induced damage to the posterior interosseous nerve. A case report]. / Operative Dekompression einer bilateralen, kompressionsbedingten Schädigung des Nervus interosseus posterior. Ein Fallbericht.

Bilateral posterior interosseous nerve palsy is a rare case of radial nerve entrapment. The patient is unable to extend the fingers in the metacarpophalangeal joints. Extension of the interphalangeal joints is preserved due to the intrinsic muscles. Neither the extensor carpi radialis longus and brevis muscles are affected nor the brachioradialis muscle. However, extension of the wrist may be weak. There is no sensory loss. The neurophysiological examination underlines the clinical findings. In our case compression is caused by the arcade of Frohse and the vessels of the recurrent radial artery. A good recovery of nerve function is seen after surgical decompression.

[Electrophysiological methods for diagnosis of entrapment syndromes of peripheral nerves]. / Der Einsatz elektrophysiologischer Verfahren bei der Diagnostik peripherer Nervenkompressionssyndrome.

Summary. Apart from clinical findings, the diagnosis of compression syndromes of peripheral nerves is based on electrophysiological investigations. This includes the determination of nerve conduction velocities, distal motor latency and electromyography, which gives a qualitative indication of the condition of nerves and their related muscles. In the 1980s, new methods were developed for quantifying the diagnoses of nerve lesions and their recovery. Due to the development of new software, we can now carry out these investigations with commercial equipment. The macro-EMG and the motor-unit-estimation give information about the size and number of activated motor units of muscles. One needs a special needle which derives single-fibre- and macro-potentials for recording of the macro-EMG. The single-fibre-potential is used for triggering. The motor-unit-estimation represents a non-invasive method to determine the approximate number of motor units. Multiple point stimulation of the nerve is used to determine action potentials which are registered by surface electrodes. Afterwards, the medians of amplitudes and areas of motor unit action potential are defined and must be divided by the corresponding value of maximal compound muscle action potential for estimating motor units. In this way, the extent of nerve damage can be determined exactly. Additionally, a post-operative follow-up is possible. Furthermore, these methods give information about regeneration processes after nerve damage and their recovery after reconstruction and transplantation. From our point of view, these methods should be included in investigation routinely.