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".

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.

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.

[Myosonographic and electromyographic (EMC) evaluation of donor-site morbidity after microsurgical TRAM flap]. / Evaluation der Hebemorbidität nach Entnahme eines mikrovaskulären TRAM-Lappens durch Elektromyographie und Myosonographie.

Due to improved microsurgical techniques the role of autologous breast reconstruction is expanding. One reason is the decreased donor-site morbidity compared to other techniques. Perforator based flaps (DIEP flaps) seemingly decrease the damage of the abdominal wall due to flap harvesting. However, complication rate in perforator flaps is still considered to be higher than in TRAM flaps. Additionally, operating time is increased due to the meticulous microsurgical dissection of perforators. To evaluate whether donor-site morbidity is caused by harvesting a part of the rectus muscle (as TRAM flaps), 15 patients after unilateral muscle sparing TRAM flap underwent EMG and myosonographic examination of the rectus muscle. EMG is the only technique to assess the muscle functionally, as the electrical activity of the muscle is recorded, and motor unit recruitment can be shown. EMG examination clearly revealed that harvesting of a muscle sparing TRAM flap did not impair the rectus muscle compared to the intact contralateral muscle. However, motor units were enlarged. Myosonography (in contrast to MRI) detected particular damage of isolated muscle fibres indicating nerve-related muscle changes. Taking all findings together, harvesting of a part of the rectus muscle shows a distinct damage to the muscle. The muscle however still acts functionally. This indicates that problems after harvesting a TRAM flap (bulging, hernias etc.) are not due to the partial removal of muscle, but due to the general dissection of the abdominal wall, as seen in other abdominal operations.

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.

Effect of creatine supplementation on metabolite levels in ALS motor cortices.

Mitochondrial pathology is an early observation in motor neurons and skeletal muscle of patients with amyotrophic lateral sclerosis (ALS). To clarify the relevance of this finding, we determined the effects of a 1-month oral administration of creatine on (1)H NMR-visible metabolites in the motor cortices of 15 controls and 15 patients with sporadic ALS, most of whom had mitochondrial pathology in skeletal muscle. In the motor cortex of the ALS group the N-acetylaspartate (NAA)/creatine (Cr(t)) metabolite ratio was lower than in our control group, indicating NAA loss. Upon creatine supplementation we observed in the controls a decline in the NAA/Cr(t), NAA/choline (Cho), glutamate + glutamine (Glx)/Cr(t), and Glx/Cho metabolite ratios. In contrast, in the ALS patient group the NAA/Cr(t) and the NAA/Cho metabolite ratios remained unchanged, while the Glx/Cr(t) and Glx/Cho metabolite ratios decreased. These data are compatible with the interpretation that creatine supplementation causes an increase in the diminished NAA levels in ALS motor cortex as well as an increase of choline levels in both ALS and control motor cortices. Because NAA is synthesized by mitochondria in an energy-dependent manner and the NAA/Cho metabolite ratios in the ALS motor cortices were found to be correlated to the degree of mitochondrial pathology in ALS skeletal muscle, our results can be explained by a deficiency of enzymes of mitochondrial respiratory chain in the ALS motor cortex which might affect motor neuron survival.

[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.

Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a neurodegenerative disease affecting the anterior horn cells of the spinal cord and cortical motor neurons. Previous findings have suggested a specific impairment of mitochondrial function in skeletal muscle of at least a limited number of patients. Applying flavoprotein/NAD(P)H autofluorescence imaging of mitochondrial function in saponin-permeabilized muscle fibres, we detected a heterogeneous distribution of the respiratory chain defect among individual fibres in muscle biopsies of patients (11 out of 17) with sporadic amyotrophic lateral sclerosis (SALS). These findings correlate with the presence of cytochrome c oxidase (COX)-negative muscle fibres detected histologically. We established the molecular basis for the decreased activities of NADH:CoQ oxidoreductase and COX in SALS muscle. In the skeletal muscle of the investigated patients, diminished levels (13 out of 17) or multiple deletions (one out of 17) of mitochondrial DNA (mtDNA) were observed. These alterations of mtDNA seem to be related to decreased levels of membrane-associated mitochondrial Mn-superoxide dismutase. Our results support the viewpoint that an oxygen radical-induced impairment of mtDNA is of pathophysiological significance in the aetiology of at least a subgroup of patients with SALS.

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.

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.

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.

Characterisation of paired-pulse transcranial magnetic stimulation conditions yielding intracortical inhibition or I-wave facilitation using a threshold-hunting paradigm.

Short-interval, paired-pulse transcranial magnetic stimulation (TMS) is usually used to demonstrate intracortical inhibition. It was shown recently that with short-interval, paired-pulse TMS a facilitation - called intracortical I-wave facilitation - can also be demonstrated. It was the aim of this study to investigate which stimulus conditions lead to intracortical inhibition and what conditions yield an intracortical I-wave facilitation in a hand muscle of normal subjects. Paired-pulse TMS responses with an interstimulus interval of 1.2 ms were obtained from the abductor digiti minimi muscle of four normal subjects. A threshold-hunting paradigm with hunting through first or second stimulus variation was used to obtain a curve of threshold-pair strengths. All subjects showed two branches of stimulus interaction on this diagram. If the first stimulus of a threshold pair was below approximately 65% of resting motor threshold it modified the response primarily due to the second stimulus through intracortical inhibition. However, if the first stimulus of a threshold pair exceeded approximately 65% of resting motor threshold it became responsible for the spinal action-potential initiation. The subsequent second stimulus served as a "booster" for the ongoing intracortical I-wave activity, making it impossible to observe the intracortical inhibition evoked by the first stimulus.

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.

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.

Mitochondrial tRNA(Cys) mutation A5823G in a patient with motor neuron disease and temporal lobe epilepsy.

We discovered a new homoplasmic mutation in the mitochondrial cysteine tRNA of a 60-year-old Caucasian male suffering from asymmetrical pure lower motor neuron disease (MND) and temporal lobe epilepsy (TLE). Furthermore, titrations with Amytal, an inhibitor of NADH:CoQ oxidoreductase, revealed mild mitochondrial dysfunction in skeletal muscle tissue, which was described in patients with MND in an earlier report. The mutation was undetectable in 155 Caucasian controls of both sexes, in 40 MND patients and in 13 individuals suffering from TLE. It was, however, detected in a heteroplasmic state in the patient's mother, who did not suffer from a neurological disorder. Since this rare mutation affected a nonconserved base position and was not observed in MND or TLE materials, its relation to disease remains unclear.

Common peroneal nerve palsy caused by a ganglion. Case report.

A common peroneal nerve palsy caused by a ganglion cyst is a rare entity. A 48-year old man was referred with a six year history of intermittent pain that had resulted in a complete palsy of the common peroneal nerve. A magnetic resonance (MR) scan showed compression of the nerve by a ganglion, which was excised and the nerve was released. Three months later the lost muscle function had returned completely.

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.

Plasticity and function--the fate of a free, neurovascular muscle graft ten years post-reconstruction.

A 16-year-old female sustained a subtotal amputation of the left thigh. Debridement resulted in a bone and soft-tissue defect of 20 cm in length. The whole quadriceps muscle was lost, and the knee joint was open. The femur was stabilized by transfer of corticocancellous bone grafts. A latissimus dorsi muscle was harvested and transferred to reconstruct the lost quadriceps muscle. The thoracodorsal nerve was coaptated to the motor branch of the femoral nerve. The years after trauma, the muscle provides excellent motor function. EMG evaluation reveals no sign of denervation; macro-electromyography reveals only a moderate enlargement of motor units. There is recruitment of all motor units. Maximum voluntary torque of the transplanted muscle has decreased, compared to the contralateral rectus femoris. Histologic evaluation demonstrates a normal skeletal muscle with typical fiber distribution. These results indicate complete adaptability of the muscle at an atypical site, with a high degree of functional and structural plasticity of the skeletal muscle. The decreased voluntary torque of the transferred latissimus dorsi depends on the lower, total-fiber, cross-sectional area--the result of a parallel fiber structure.

[Use of automatic, computer-assisted EEG analysis in clinical practice]. / Der Einsatz einer automatischen, rechnergstützten EEG-Analyse in der klinischen Praxis.

Digital EEG-recorders are being increasingly accepted for clinical routine application, thereby offering the possibility for an automated computerised EEG evaluation. This paper presents the results of a corresponding computer programme developed in our group. Based on 313 clinical routine-EEG we compared the computer reports to the visual EEG-interpretations and obtained the following result: Background activity is reliably detected with a rate comparable to a human interpreter. Similar results were observed with focussed pathological activity. Intermittent activity (Parenrhythmia, dysrhythmia) however lacks a sufficiently high score of correct evaluation and requires further development. Epileptiform potentials, especially spikes, are detected with high sensitivity, however, at the cost of low specificity, and are therefore still in need of further improvement.