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The still continuing accelerated development of neurology in Germany is described in this article by a contemporary witness who was active in this field from 1965 to 2005. The personal experiences of the author are obviously only reflected over these 40 years so that the glorious antecedents in the period up to 1933, the era in which our predecessors were the world leaders in neurology, is not sufficiently covered. This dominance was lost by the anti-Semitism during the era of National Socialism and the sequelae of World War II. As a result of the war, German neurologists became effectively isolated and their participation in international congresses was forbidden so that a gradual reestablishment of alignment only became possible after 1960. In this brief description no attempt at completeness has been made and only subjectivity and brevity have been considered. An attempt is made to retrospectively convey what essentially happened. An exact dating of advances over the period was sometimes difficult. The readership will have the opportunity to share the surprise of the author on how meagre the neurological knowledge and diagnostic methods were 50 years ago, how rapidly the subsequent development happened, how rapidly things became obvious which 20 years ago nobody was aware of and despite the progress how pleased we were to find ourselves at the most recent state of error and probably still find ourselves nowadays. In particular, how powerless and untested the therapeutic efforts were at that time. The progress can only be measured by a comparison between then, 50 years ago and the present. A projection of the future based on these experiences is not attempted but it seems to be certain that many conceptions, diagnostic advances and therapy options are still undiscovered and that further exciting times can be expected.

All living creatures are subject to aging, but our understanding of what governs aging is limited. In the course of a lifetime, with the constant renewal of the organic substance of living creatures errors arise, e.g. in the formation, disposal, and reproduction of DNA, proteins and lipids or in the constant substitution of aging cells in the organs. These errors are recognized and generally counterbalanced by appropriate repair mechanisms. This process is obviously determined partly by environmental influences (e.g. UV radiation, oxidizing influences, thermal shock) and genetic factors (such as the significance of so-called survival genes and gene mutations). In this paper the authors both explain and test the hypothesis that the aging of organs and organisms is the consequence of and not the reason for a progressive weakening of the repair mechanisms throughout life.

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.

Neurons of the central nervous system in general do not multiply after birth. Therefore, no replacement or biological renewal of individual cells affected by aging or death is possible. Morphological changes occurring in the aging brain are found substantially more pronounced in neurodegenerative diseases. Systemic degenerations of selective brain areas in these disorders, e.g. in Alzheimer's, Parkinson's, Huntington's disease or in amyotrophic lateral sclerosis, may be considered as models of accelerated aging and may allow to study the genetic and environmental influences of selective aging and cell death in modules of the central nervous system. Although neurodegenerative diseases are disparate disorders on the basis of their symptomatology and the anatomic distribution of pathologic lesions, they actually share key attributes with respect to biochemical and cellular determinants of selective vulnerability. Most strikingly, many show a conversion of disease specific and only recently identified proteins into unsoluble aggregates which form intra- or extracellular deposits. These protein aggregates may, over time, affect neuronal function, eventually leading to neurodegeneration and neurodegenerative pathology. The pathological process is counterbalanced by protective mechanisms that may loose their efficacy during normal aging. This could explain the late onset of even the inherited neurodegenerative disorders. Since the expression of disease-specific proteins is often not restricted to the affected brain areas (as exemplified by the expression of polyglutamine containing proteins in trinucleotide repeat disorders in non-affected brain areas and even outside the brain), the anatomical specificity of the degenerative process may be determined by associated binding proteins. Therapeutic strategies include the reinforcement of physiological defense mechanisms and intervention at early phases of the pathological biochemistry of disease specific proteins.

The hereditary ataxias are a heterogeneous group of inherited neurodegenerative disorders characterised by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. With respect to the pathogenic mechanisms, the hereditary ataxias may be tentatively divided into three groups: (1) The recessive ataxias are induced by the functional impairment of a protein that is essential for the survival of specific neurons while the autosomal dominant ataxias are either caused by (2) mutations of genes coding for ion channels thus resulting in a channelopathy or by (3) a novel deleterious function of a extended polyglutamine sequence within the proteins encoded by the respective genes.

Primary central nervous system lymphomas (PCNSLs) are increasing in frequency both in immunocompetent and immunodeficient individuals. The majority of PCNSLs are high grade B cell lymphomas. In AIDS patients most tumors contain EBV genome. PCNSLs usually present as intracerebral, often deep-seated lesions half of which are multilocular. Less frequent are diffuse periventricular, exclusively leptomeningeal, ocular or spinal spread. On imaging PCNSLs show as contrast-enhancing lesions with relatively little perifocal edema. CSF protein is usually elevated. Malignant cells are present in 20-30% of cases. Demonstration of a monoclonal B cell population by immunocytology or FACS analysis may also be diagnostic. Once PCNSL is suspected extensive systemic evaluation is not useful. Instead, (stereotactic) biopsy of brain lesion(s) should be performed. Prior to biopsy, corticosteroids should be withheld as they may obscure diagnosis. Symptomatic edema or increased intracranial pressure should therefore initially be treated with osmotherapeutics. All immunodeficient patients should receive empiric anti-toxoplasmosis therapy for about 14 days prior to biopsy. AIDS patients with PCNSL survive 3 to 5 months (median) after whole brain irradiation and usually do not benefit from chemotherapy. Immunocompetent patients have a median survival of 12 to 18 months after whole brain irradiation alone, but a median survival of 33 to 43 months after combined radiochemotherapy using cytostatic drugs which penetrate the blood-brain barrier. Based on these encouraging results current concepts aim to intensify chemotherapy and to reduce or delay radiotherapy in the treatment of immunocompetent patients.

Extensive research in the field of multiple sclerosis (MS) has lead to a preliminary pathogenetic concept without solving the etiopathogenesis. According to animal experiments and human in vitro studies MS is a T cell-mediated autoimmune disease. Experimental therapeutical strategies are aiming at the inhibition of T cell activation, transmigration through the blood brain barrier and local inflammation and demyelination. Several substances are already being tested in clinical studies with magnetic resonance imaging as a tool to quantify inflammatory lesions and to shorten the study course. This review will give a summary about actual experimental therapies resulting from the current pathogenetic concept.

Many side effects of steroid treatment have been reported. Even experienced neurologists may not know all important side effects to the nervous system. Autonomic nervous system dysfunction, psychosis and myopathy are more frequently encountered than dependency, reversible dementia, brain atrophy and benign intracranial hypertension. This review describes symptomatology, pathogenesis and treatment of these steroid-induced side effects.

So far, it has not been possible to treat many neurological conditions causally. However, in the past few years underlying genetic defects have been characterized for a substantial number of neurodegenerative disorders. Experimental methods have been developed that allow for efficient gene transfer into defined regions of the mammalian CNS. Such techniques can be applied to deliver genes into target cells of a recipient organism or to transfer genetically modified cells into defined regions of the CNS. Candidate genes for gene therapy are those encoding for neurotrophins and neurotransmitters for symptomatic therapy and, in the case of neurodegenerative disorders with localized gene defects, the wild-type allele as a causal treatment approach. In this review article, we describe some of the most widely used strategies for gene transfer to the CNS. We also report on the results obtained with animal models for human disease, and discuss both the chances and problems of gene therapy approaches in clinical medicine.

The degenerative ataxias comprise a wide spectrum of neurodegenerative diseases with varying clinical characteristics and heterogeneous neuropathology. Traditionally, classification of these diseases has been based on neuropathological criteria. Recently, however, clinical and genetic classifications have gained wide acceptance. These classifications distinguish between hereditary and non-hereditary ataxias. According to their mode of inheritance, the hereditary ataxias are further subdivided into autosomal-recessive and autosomal-dominant ataxias. The non-hereditary ataxias are divided into symptomatic ataxias with an identified cause and idiopathic ataxia with unknown cause. Diagnostic criteria based on history, clinical presentation and a number of laboratory tests have been defined for each category. More extensive ancillary tests are necessary to identify or exclude symptomatic causes of ataxia. Recent molecular genetic research has led to the identification of a number of gene loci and mutations responsible for certain types of hereditary ataxia.

Several types of lesions of the mature central nervous system (CNS), such as craniocerebral trauma or spinal cord trauma, may initiate secondary cascades, which may cause damage to primarily uninjured neurons. The exact mechanisms which cause neuronal cell death are still unknown. It has been suggested that retrogradely transported target-derived neurotrophic factors which are necessary for neuronal survival might be lacking after certain types of lesions. On the other hand, neurons might be damaged by calcium-overload resulting from excessive release of excitatory amino acids (EAAs) after trauma. The present review summarizes current concepts of post-traumatic neuronal cell damage with a focus on the putative neuroprotective role of calcium channel blockers and their interaction with glutamate mediated cytotoxicity, neurotrophic factors and free radicals.

Metastatic leptomeningeal disease occurs in 5-30% of patients with breast or lung cancer, malignant melanoma, non-Hodgkin's lymphoma, leukemia and primary malignant brain tumors. Intrathecal chemotherapy with methotrexate, cytarabine, or thiotepa combined with irradiation of the site of major involvement increases overall median survival from 1-2 months to 2-7 months. Clinical outcome is limited by progression of systemic or CNS disease and by the neurotoxic side effects of therapy, i.e. leukoencephalopathy. New immunotherapeutic strategies of intrathecal treatment may be effective and less toxic, but are not yet sufficiently defined and available. This review covers the current diagnostic and therapeutic features of metastatic leptomeningeal disease. Pragmatic therapeutic recommendations, based on available clinical knowledge are given with special consideration of the side effects of therapy.

A stystematic neurological and electroencephalographical follow-up study in 344 head injured adults gave the following results: 1. 52% of all the hospitalized (mostly primarily amnesic) patients had a cerebral contusion. A contusion was assumed in cases with focal neurological signs (13%), amnesias of more than 8 hours (16%) and/or EEG-abnormalities lasting for more than 24 hours (49%). 2. Traumatic EEG-abnormalities were general slowing (43%) and foci (32%). In 40% of the cases with general slowing the slowing (greater than or equal to 1.5/sec) was within the alpha-frequency band and could only retrospectively be assed. 3. The EEG was invariably abnormal in cases with an amnesia exceeding 8 hours. If the amnesia exceeded 1 hour abnormalities were found in 73%. 4. Among the patients with contusion 6.5% had no amnesia, 48% less than 30 minutes and only 30% an amnesia for more than 8 hours. In 75% of the patients with concussion amnesia lasted less than one hour. 5. Skull fractures were mostly combined with contusion (74%). 6. Impaired drive, reduced ability to concentrate, memory deficits, headache and dizziness were significantly more frequent 6 months after contusion than after concussion. 7. 21% of the patients with traumatic dizziness (44%) had a labyrinthine contusion. 8. Among the contusions diagnosed with the aid of EEG recordings 58% would have been missed after exclusive neurological examination and 82% after application of the classical criteria used by surgeons and general practitioners.

The present retrospective study compared the incidence of TIA, stroke, and death in patients with asymptomatic carotid stenosis (greater than 50%) during a follow-up period of 24 to 30 months. 65 patients were operated and 193 treated medically. The incidence of death was comparable in both groups. Death in most patients was due to cardiac disease or cancer. The annual incidence of TIA and stroke was not different between the two populations. Despite the low incidence of perioperative complications (%) surgery of asymptomatic carotid stenosis cannot be recommended at the present time.

The development of the visual contribution to postural stabilization has been tested using a large visual display rotating around the stationary subject's line of sight. This, in the adult, causes a marked optokinetic postural reaction with a shift of the body center of gravity toward the direction of pattern motion. Scalings of the reactions in children between 6 months and 16 years revealed three phases of development: (1) 6--12-month-old-babies show none or very little optokinetic disturbance of their newly acquired ability to sit. With the development of upright stance and gait, optokinetic influences become increasingly important. (2) Children between the age of 2--5 show a marked dependence of postural stability on vision. In them, the disturbing optokinetic stimulus leads to a marked ipsilateral postural deviation or irresistible fall. (3) From 5 to 15 years of age, visual effects on postural balance slowly decrease to their final strength in adulthood--moderate head and body tilt--in response to the rotating stimulus. It is concluded that the optokinetic loop participates rather late in the multisensory process of postural stabilization. The calibration of the three main loops, visual, vestibular, and proprioceptive, seems to be sequential and mutually interactive. Optimal functioning requires the continuous evaluation of the reafferent sensory consequences of self-generated body movements. Optokinetic destabilization of stance requires the maturity of opto-vestibulo-spinal pathways. Its clinical applicability as a maturity test, however, sofar seems limited.

Neurophysiological methods which allow to identify objectively lesions of the efferent cortico-spinal pathways in humans are with the exception of transcutaneous electrical stimulation of the motor cortex nor available. Long latency EMG responses from leg muscles are mediated by a "transcortical loop" and offer the possibility to detect in combination with sensory evoked potentials lesions both of the afferent proprioceptive and the efferent motor pathways. Subjects stood on a platform which was rotated toe-up (50 degrees/s, 4 degrees) around the axis of the ankle joint. This lead to two EMG responses of short- and medium latency in the stretched triceps surae muscle, and an EMG response of long latency (LL) from the antagonistic anterior tibial muscle. We investigated 135 patients with a spinal or cerebral lesion, detected by neuroradiological methods. We found a significant delay of LL in patients with spinal lesions and in patients with cerebral lesions on the affected side. A significant delay of LL could also be observed in patients with pure motor symptoms and normal latency of the cerebral potential (P 40) alone in the group of patients with spinal lesions revealed in about 45% a pathological result. The rate of pathological findings was about 65% when both methods (SEP and LL) were combined. The results indicate that the recording of LL is helpful to detect lesions of the efferent central pathways. In a follow-up study we investigated patients who underwent successful surgical treatment. We found a close correlation between the decrease in latencies of LL and the improvement of clinical signs.

Spontaneous eye movements and responses to visual and vestibular stimuli were recorded in 30 patients with pontine angle tumors (26 neurinomas, 2 meningeomas, 1 chosteatoma, 1 angioma). Pre- and postoperative recordings in most cases showed a bilateral dimunition of horizontal optokinetic nystagmus (OKN) that prevailed towards the side contralateral to the tumor. This is explained by a homolateral floccular lesion and cannot be the consequence of spontaneous nystagmus or asymmetrical gaze nystagmus. The predominance of a homolateral OKN-diminution often described in the literature was found in advanced cases or post-operatively as a sign of pontine reticular formation damage. The neighbourhood of the flocculus to the VIIIth nerve and animal experiments with floccular lesions causing a contralateral OKN diminution support out explanation. Additional arguments for damage of cerebellar oculomotor functions are the predominance of cogwheeled smooth pursuit and the occasional observation of hypermetric saccades, both toward the side of the tumor. Patients with very large tumors finally develop a complete disruption of OKN toward the homolateral side together with concomitant gaze paralysis.

A new rating scheme (score) is presented for ocular symptomatology in myasthenia gravis. The score (0-10) combines separate ratings upper eyelid weakness (ptosis) and paralysis of the outer ocular muscles (double vision). It is relatively insensitive to subjective influences and to the rater's experience. It yields replicable values which are especially important for longitudinal studies, for testing new therapeutic strategies and for their statistical validation.

The results of a systematic neurological and electro-encephalographical follow-up study in 344 head injured adults and 116 children were compared. The results show that posttraumatic EEG abnormalities lasting more than 24 hours, are equally frequent in children (53%) and in adults (49%). Mostly short lasting neurological signs of focal tissue damage are however significantly more frequent in children (30% vs. 13% and EEG-abnormalities (foci and general slowing) are on the average more pronounced. The recovery of EEG abnormalities follows the same pattern as in adults, occurs however faster among children. In both groups the normalization of general slowing precedes that of focal abnormalities only in 25% of the cases. Amnesias on the average last shorter in infants. Their duration seems of lesser significance for the judgement of the severity of the trauma in children than in adults. 6 months after the trauma children complain less frequently about headache, dizziness, or impaired memory and diminished ability to concentrate; emotional lability and impairement of drive, however, are more frequent than in adults. The results indicate an equal diagnostic and prognostic importance of systematic EEG studies (within 2 days, after 1 week and 6 month after the trauma) in both groups.

Doppler sonography of the extracranial arteries was done in 556 unselected patients (greater than 40 years) in a prophylactic study. 226 high risk patients with arterial occlusive leg disease (AOD) served as control group. Doppler sonography revealed stenoses or occlusions of the carotid, vertebral and (or) subclavian arteries in 9.17% of normal persons and in 38.05% of AOD patients. Medical treatment is available only for stenoses (not occlusions) of the carotid arteries. Thus the frequency of asymptomatic internal carotid stenoses--only stenoses of more than 50% lumen diminution can be detected--of 2.33% in the group of normal probands and of 17.2% in the patient group is the reference value and justification for use of Doppler sonography for prophylactic assessment. The atraumatic and safe method with a success rate of 2.33% is suitable particularly in increased risk factors (age, males, smoking, hypertension, diabetes). As a prophylactic investigation in patients with arterial occlusive disease Doppler sonography is mandatory before prospective operations.

Tetrabenazine (50-150 mg/day) was a moderate to excellent efficacy in each of six patients with severe spontaneous oral dyskinesia. Slight akinesia, rigidity, and transient disorientation were occasional side effects that could easily be controlled and were tolerated by the patient in view of the lasting amelioration of this debilitating symptom. When tetrabenazine was administered for blepharospasm, only two of six cases showed partial improvement with more severe side effects.

The correlation between the severity of symptoms in myasthenia gravis (score) and the level of acetylcholine receptor-antibodies (ACHR-Ab) was studied in 24 patients treated with immunosuppressive therapy. This correlation was significant in every case regardless of whether or not thymectomy was performed in addition. It was demonstrated by means of a long-term follow up study, that a change in ACHR-Ab preceeds the corresponding change in score by 2-4 months in 80% of our patients. Measurements of ACHR-Ab ease the management of the therapy with immunosuppressants and make it safer. This is particularly true prior to and after termination of the treatment. A change in ACHR-Ab level by more than 20% indicates a change in score.

Fifty-two patients, most of whom had had daily headaches for years, were examined and treated. Among them there were 40 who originally had migraine, the others had vasomotor or post-contusional headaches. Average duration of the migraine was 21 years, of chronic headache 7.6 years. All patients had been taking analgesics of a mixed type regularly and for a long time, on average 35.6 tablets or suppositories weekly. All patients had taken more than three different drugs. After an observation period of 3-6 months for grading the headaches and registering the amount of drug intake, all patients were admitted to hospital when all analgesics were at once discontinued. Changing degrees of withdrawal symptoms were the rule: increased headaches, nausea, vomiting, tachycardia, sweating, sleep disorders, and in some also hallucinations and cerebral episodes. At the end of the hospital stay chronic headache had completely disappeared or markedly improved in 77% of patients. Even after an average of 16 months of subsequent observation, chronic headache continued to be significantly improved in 70% of patients. There was a significant reduction in frequency and intensity of attacks in the patients with originally typical migraine. Regular intake of analgesics of the mixed type induces chronic headaches. These are most commonly caused by ergotamine tartrate and aminophenol derivatives, while psychological and physical dependence on anti-migraine drugs is initiated and maintained by additional barbiturates, caffeine and codeine.

Posturography is a very useful clinical instrument to quantify, analyze, and document postural sway and to differentiate patterns of instability that are typical for the different types of lesions encountered within the cerebellum and to differentiate cerebellar ataxia from spinal ataxia. An objective method of measurement like this is most valuable for follow-up studies and the surveillance of therapeutic efficacy. The method of recording short, medium, and long latency reflexes in leg muscles after a sudden tilt of a movable platform toe-up is not only totally atraumatic and fast, but more importantly it gives significant hints towards the possible site of a central lesion in the sensory-motor system.

Correlation studies on patients with myasthenia gravis are reported in which clinical assessment of fatigue and neurophysiological findings are compared to blood levels of pyridostigmine. Measurements using a high-pressure liquid chromatography method (HPLC), give reproducible results. The levels of pyridostigmine in the serum or plasma of healthy controls and of patients show no essential differences. Components of coffee, tea, chocolate and cigarettes can markedly disturb the chromatography by adding additional peaks, so that interpretation becomes difficult or impossible. Blood levels can be measured approximately one hour after oral intake of 60 mg pyridostigmine. Concentrations rise for two to four hours and then decline exponentially. The half-life of pyridostigmine was between 156 and 210 minutes. Despite identical oral dosages, the concentration differed intraindividually and interindividually among patients. While the blood level does not reach its maximum value for 1-1 1/2 to 3 hours, the maximum clinical and neurophysiological effect of pyridostigmine appears 30-60 minutes after ingestion. Variable distribution of cholinesterase inhibitors over the different compartments (blood, synaptic region) is assumed to cause this temporal lag. If the total amount of pyridostigmine is divided into 4-5 doses, the concentration profiles over the course of a day are relatively stable. There is no significant correlation between the variations in blood level throughout one day, and changes in myasthenic symptomatology. Effects of pyridostigmine can be measured at levels as low as 5 ng/ml; at levels above 40 ng/ml further improvement can be detected only rarely. Blood levels were lower if corticosteroids were administered simultaneously; azathioprine had no influence on blood levels. Blood levels assays allow better differentiation of cholinergic and myasthenic crises and the identification of disturbed absorption and interactions with other medications.