Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients With Acute Stroke (TOPAS) Investigators.

BACKGROUND AND PURPOSE: To study the safety and efficacy of the low-molecular-weight heparin certoparin, we performed a randomized, double-blind, dose-finding multicenter trial in patients with acute ischemic stroke (Therapy of Patients With Acute Stroke [TOPAS]). METHODS: We randomized 404 patients to 4 treatment groups within 12 hours of stroke onset: 3000 U anti-factor Xa (aXa) certoparin once daily (treatment group 1); 3000 U aXa twice daily (group 2); 5000 U aXa twice daily (group 3); and 8000 U aXa twice daily (group 4). The primary efficacy variable was the proportion of patients reaching a favorable functional outcome (Barthel Index >/=90 points) at 3 months. CT was performed at trial entry, after 7 days, and on clinical deterioration. RESULTS: The proportion of patients with Barthel Index >/=90 was not different between treatment arms (61.5%, 60.8%, 63.3%, and 56.3% in the 4 groups, respectively; intent-to-treat population). European Stroke Scale scores improved in all treatment groups within the first 14 days to a similar extent. During the follow-up of 6 months, percentages of patients with recurrent stroke/transient ischemic attack were 11.0%, 5.9%, 9.7%, and 13.0% in the 4 groups, respectively. Overall mortality was only 7.4%. Two parenchymal cerebral hematomas and 1 extracranial bleeding episode occurred in treatment group 1 versus 1 and 0 in group 2, 2 and 0 in group 3, and 4 and 5 in group 4, respectively. During certoparin treatment, 1 deep vein thrombosis but no pulmonary embolism was observed. CONCLUSIONS: Dose increase of certoparin up to 8000 U aXa twice daily did not improve the functional outcome of patients with ischemic stroke. Severe bleeding tended to be more frequent in the highest dose group only.

Vitamin B 1, B 2 and B 6 deficiency in neurological disorders.

The activities of the red blood cell enzymes transketolase, glutathione reductase, and glutamic oxaloacetate transaminase were measured with and without in vitro addition of their respective coenzyme components thiamine, riboflavin, and pyridoxine in a group of patients with neurological disorders which may have been caused by malnutrition, intestinal malabsorption, hepatic failure or neoplasms arising outside the nervous system. The incidence of thiamine deficiency was 31%, of riboflavin deficiency 22% and of pyridoxine deficiency 6%. Alcoholics in particular suffered from deficiencies of vitamin B 1, and B 2. There was a correlation of vitamin B 1 and B 2 deficiency and signs of a cerebellar and/or brainstem lesion. The most frequent symptoms in this connection were gait disturbances and oculomotor signs like spontaneous and gaze nystagmus, disturbed eye tracking, diminished optokinetic nystagmus, decreased ability to suppress vestibular nystagmus by fixation. These signs hardly ever occurred in alcoholic patients who showed no deficiency of vitamin B 1, B 2 or B 6. Whenever they do appear, a vitamin B supplementation has to be performed in order to prevent the manifestation of Wernicke's encephalopathy, cerebral or cerebellar atrophy. Alcoholics showed the same incidence of polyneuropathy, whether they suffered from a deficiency of B vitamins or not. Deficiencies of vitamin B 1, B 2 or B 6 were also found in patients with intestinal malabsorption and polyneuropathy, diabetic polyneuropathy, optic atrophy, myelopathy and cerebellar ataxia of unknown etiology, neurological manifestations of neoplasms arising outside the nervous system, B 12 myeloencephalopathy and Thévenard's syndrome.

Additional biochemical criteria in the differential diagnosis of myositis.

Thirty-six biopsy specimens of human biceps and vastus lateralis muscles were examined by histometric analysis and determination of enzyme activities (phosphorylase, triosephosphate dehydrogenase, 3-hydroxacyl-CoA-dehydrogenase, lactate dehydrogenase, hexose isomerase, citrate synthetase, 6-phosphogluconate dehydrogenase). The series included 13 specimens from patients suffering from a benign form of muscular dystrophy (limb girdle and Becker type of muscular dystrophy) and 12 specimens from patients with an acute (n = 5) or chronic (n = 7) form of myositis. Muscle fibres were atrophic in myositis and hypertrophic (with an increased variation of fibre diameters) in muscular dystrophies, as has been shown previously. When myositis samples were compared with either normal or dystrophic muscles, a highly significant lowering of glycolytic enzyme activity was found in chronic myositis, while the activity of 6-phosphogluconate dehydrogenase was elevated to highly significant levels. Measurements of the latter enzyme's activity might be of additional value in differentiating chronic forms of myositis from benign muscular dystrophies.

Incidence of peripheral neuropathy and cerebellar ataxia in chronic alcoholics.

A total of 78 chronic alcoholics were examined neurologically as well as by electroneurography, myography and posturography. Clinical signs of peripheral neuropathy were detected in 45% of these patients, with electromyographic and neurographic abnormality in 67% and 55% respectively. Clinical signs of cerebellar ataxia were found in 33% of our patients, whereas posturographic measurements of increased sway were recorded in 69%. The posturographic characteristics of cerebellar anterior lobe atrophy were observed in two-thirds of the latter patients. The severity of cerebellar-ataxia did not correlate with the degree of neuropathy. This lack of correlation is interpreted as an indication of different pathogenetic mechanisms acting on peripheral nerves and cerebellum.

[Representative enzymes of energy supplying metabolism in the normal and denervated human brachial biceps, deltoid and anterior tibial muscles (author's transl)]. / Repräsentative Enzyme des energieliefernden Stoffwechsels im normalen und denervierten M. biceps brachii, M. deltoideus und M. tibialis anterior des Menschen

Representative enzyme activities of energy supplying metabolism were measured in muscle specimens of brachial biceps, deltoid or anterior tibial muscle of patients with affections of the peripheral nerves. Simultaneously performed measurements of the same enzyme activities in the contralateral normal muscles served as a control. 5 patients suffered from a lesion of the brachial plexus, 7 patients had a paralysis of the axillary nerve, and 8 patients had a peroneal paralysis. In all denervated muscles no electrophysiological signs of reinnervation were present. The activities of glycogen phosphorylase, triosephosphate dehydrogenase, lactate dehydrogenase and alpha-glycerophosphate dehydrogenase were found to be highest in the normal brachial biceps muscle. Lower activities were measured in the normal deltoid and anterior tibial muscle. The oxidative enzymes, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase as well as hexokinase, showed no significant difference from the levels of the control. It is suggested that a probable factor determining the differences of the enzyme activities of glycogenolysis, glycolysis and alpha-glycerophosphate oxidation between brachial biceps, deltoid and anterior tibial muscle, might be the pattern of impulse activity in the motor nerves of these muscles. The enzyme activities of glycogen phosphorylase, triosephosphate dehydrogenase, lactate dehydrogenase and alpha-glycerophosphate dehydrogenase, decreased rapidly during the first 2 months after denervation in the brachial biceps, deltoid and anterior tibial muscle, whereas the decrease was slight during the following months. The activities of the oxidative enzymes (3-hydroxyacyl-CoA dehydrogenase and citrate synthase) showed no significant change after denervation. The metabolic difference of glycogenolysis, glycolysis and alpha-glycerophosphate oxidation between the three muscles was no longer maintained. The possible causes of the deeply decreased enzyme activities of glycogenolysis, glycolysis and alpha-glycerophosphate oxidation, as well as the causes of the unchanged oxidative enzyme activities and of the increased hexokinase activity after denervation in the human brachial biceps, deltoid and anterior tibial muscle, are discussed.

Slowly progressive congenital myopathy with cytoplasmic bodies--report of two cases and a review of the literature.

Observations on two patients from unrelated families are reported. Both patients were 32 years old and suffered from a congenital affection of the skeletal muscles. In one (case 2) congenital paresis of the dilator muscle of pupil and cardiomyopathy were also present. In both cases muscle biopsy showed pathologic variations of muscle fiber caliber, and in case 1 atrophic fibers were grouped in some places. Inclusions consisting of dense granular and fine filamentous components were found in skeletal muscle fibers, in about a third of the fibers in case 1 and in about a tenth of the fibers in case 2. The shape and submicroscopic structure of these inclusions were consistent with so-called cytoplasmic bodies. Surrounding or apart from the inclusions, the streaming of Z disks or their disintegration were observed. In addition, pure filamentous bodies occurred in the subsarcolemmic position in both cases. Although cytoplasmic bodies are a nonspecific type of inclusion, they were the outstanding structural anomaly in both cases. A basic defect of myofilament biosynthesis is considered to be the cause of the disorder. It is presumably evoked by a neurogenic factor affecting the trophic influence of the neuron on the muscle cell. The course of the disease may (case 1) but need not (case 2) terminate in severe impairment of skeletal muscle function.

[Biochemical studies on muscles in neurogenic atrophies and central paralysis. Studies of the trophic functions of neurons]. / Biochemische Untersuchungen in der Muskulatur bei neurogenen Atrophien und zentralen Paresen. Untersuchungen zur trophischen Funktion des Neurons.

Enzyme activities of the energy supplying metabolism were investigated in muscle specimens of brachial biceps, deltoid or anterior tibial muscles of patients with traumatic nerve lesions, polyneuropathies, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, spinal muscular atrophy and hemiparesis. The key enzymes of glycogenolysis (glycogen phosphorylase), glycolysis (triosephosphate dehydrogenase, lactate dehydrogenase), alpha-glycerophosphate cycle (alpha-glycerophosphate dehydrogenase), beta-oxidation of fatty acids (beta-hydroxy-acyl-CoA-dehydrogenase), citrate acid cycle (citrate synthase, malate dehydrogenase), hexokinase reaction (hexokinase) and pentosephosphate shunt (6-phosphogluconate dehydrogenase) were measured. The present study shows that in case of disorders of the lower motor neuron--especially those with impaired axoplasmic transport--changes in the enzyme patterns of muscles occur at an early stage. The glycolytic enzyme activities are of particular significance because they are the most sensitive indicators of the onset, extent and course of neurogenic atrophy. There is a good correlation between severity of the lesion, functional state of the muscles and reduction of these enzyme activities. In case of traumatic nerve lesions re-innervation can prevent a permanent reduction of glycolytic enzymes only if it occurs during the first months after denervation. In all cases in which operative revision is considered, it is therefore not advisible to wait since the regenerative capacity of the motor neuron is not the only limiting factor but also the biochemical and morphological changes in the muscle fibre. These are permanent after long lasting denervation without re-innervation within the first months. Primary neuroaxonal degeneration of the nerve fibre which was found in the majority of our alcoholic patients obviously impairs the metabolism of the muscle to a greater extent than primary demyelination most frequently observed in diabetics with polyneuropathy. Corresponding to the chronic course of the illness over years and to the severity of the pareses, drastic reduction in the activities of glycolytic enzymes was found in patients with Charcot-Marie-Tooth disease. Simultaneously the activity of 6-phosphogluconate dehydrogenase was significantly increased as a result of the chronic neurogenic lesion of the muscle fibres. Follow-up during the treatment of diseases of the lower motor neuron can be performed because the enzyme activities can be measured even in small muscle specimens. In patients with hemiparesis slight but not significant reduction in the glycolytic enzyme activities was found by comparison with a normal control group. We assume that this reduction is due to general inactivity which is caused by the movement disorder rather than to the particular influence of the upper motor neuron.

Muscle wasting in chronic alcoholics: comparative histochemical and biochemical studies.

The comparative electrophysiologic, histochemical, and biochemical investigation of the anterior tibial muscle of 13 alcoholics indicates that neuropathy could be the cause of the chronic muscle weakness and wasting. Myopathic alterations did not predominate in the findings. It was concluded that the proximal muscle atrophy could also be attributed to neurogenic damage. Histochemical reactions in muscle specimens showed a selective type 2 atrophy and a slight increase of the mean diameter of type 1 fibres. Biochemical investigations revealed that the activities of a number of enzymes representative of energy supplying pathways--the glycogenolysis and glycolysis--as well as acid phosphatase activity in the muscle were lowered. A relationship could be assumed between the lowered glycolytic activity and the decline of the mean diameter of type 2 fibres. Oxidative enzymes were of similar activity in the alcoholics and the control group. The glycolytic enzyme activities were particularly important, being the most sensitive indicators of the onset, intensity, and course of neurogenic damage. These activities probably normalise during reinnervation of a muscle earlier than do the morphologic alterations; however, they were markedly lower in alcoholics with impaired liver function and cachexia, probably because of the catabolic metabolic conditions present in these cases.

EMG analysis of the late exteroceptive suppression period of temporal muscle activity in episodic and chronic tension-type headaches.

EMG analysis of the late exteroceptive suppression period of the temporal muscle activity is discussed as comparative methodology in the assessment of patients suffering from chronic tension-type headache and from migraineurs. After electrical perioral trigeminal nerve stimulation during maximum voluntary jaw occlusion, early (ES1) and late (ES2) exteroceptive suppression periods can be registered above the temples using surface EMG recordings. In patients suffering from chronic tension-type headache the duration of the late suppression period is shortened (p less than 0.001) compared to migraineurs or controls. However, patients suffering from episodic tension-type headache display late suppression periods of temporal muscle activity of differing lengths.

An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies.

82 patients with chronic pain resulting from mononeuropathy were treated with psychotropic drugs in an open therapeutic study. In this study we found that treatment with a combination of clomipramine (Anafranil) and small doses of neuroleptics was significantly superior to therapy with neuroleptics alone. In a subsequent double-blind study, it was attempted for the first time to determine the efficacy of clomipramine compared to that of acetylsalicylic acid in 48 patients with painful mono- and polyneuropathies. The test was carried out in a cross-over trial with two sequence groups. We evaluated assessments of pain by both patients and doctors, and were able to prove statistically that clomipramine possesses a significantly greater efficacy compared to that of acetylsalicylic acid. By taking into account recent anatomical, biochemical and pharmacological studies, it can be concluded that clomipramine probably has-in addition to the action on peripheral receptors-a direct effect upon pain modulation systems. It seems possible that clomipramine activates serotonin-containing neurons of the endorphin-mediated analgesia system that control pain transmission in the CNS.

[EMG analysis of exteroceptive suppression of temporal muscle activity in tension headache]. / EMG-Analyse der exterozeptiven Suppression der Temporalismuskelaktivität bei Kopfschmerzen vom Spannungstyp.

In modification of a method published by Schoenen et al., early (ES 1) and late (ES 2) exteroceptive suppression periods elicited by perioral electrical trigeminus-stimulation during teeth-clenching were recorded with surface electrodes over the temporalis muscles. 29 patients with chronic tension headache, 20 with migraine, 7 patients with combined tension headache and migraine and 19 controls were examined. Duration of the late suppression period for the mean of three single shocks was highly significantly reduced in chronic tension headache sufferers and patients with combined tension headache and migraine when compared with migraine cases or controls. These results are in agreement with those of Schoenen et al. EMG analysis of temporalis late exteroceptive suppression is a helpful diagnostic method in primary headache. The reduction of ES 2 in chronic tension headache sufferers might suggest a deficient activation or excessive inhibition of the motoric trigeminus nucleus by pontobulbar inhibitory neurons which receive a strong input from limbic and nociceptive structures.

[The value of clinical and chemical laboratory follow-up parameters in neuroborreliosis]. / Wertigkeit klinischer und laborchemischer Verlaufsparameter bei Neuroborreliose.

Whereas the diagnosis of acute neuroborreliosis by considering clinical and cerebrospinal fluid parameters is very reliable chronic neuroborreliosis is an excluding diagnosis. The clinical symptoms are uncharacteristic, and there is no reliable laboratory test permitting a safe diagnosis. Serological evidence of antibodies is no sign of activity of disease. Development of chronic infection after adequate treatment of acute neuroborreliosis seems to be very rare. We reinvestigated 15 patients half a year after antibiotic therapy of acute neuroborreliosis with regard to clinical and laboratory parameters. Most patients had a continuous intrathecal IgG antibody production against Borrelia burgdorferi, whereas no clinical signs of chronic neuroborreliosis existed. The antibody production against Borrelia burgdorferi must not be regarded as a sign of chronic infection.

[Virus encephalitis with symptomatic Parkinson syndrome, diabetes insipidus and panhypopituitarism]. / Virusenzephalitis mit symptomatischem Parkinsonsyndrome Diabetes insipidus und Panhypopituitarismus.

Virusencephalitis is characterised by clinical symptoms of a parenchymatous inflammation. In addition, early mental status changes often occur as a result of virusencephalitis, beside focal neurological deficiencies, epileptic seizures, cerebral compression, even coma. Other pathological manifestations of virusencephalitis are disturbances of the neurohumoral and the endocrine system, which are often recognised and treated too late. This case report describes symptoms, treatment, and complications of a 76 year old female in-patient, who was diagnosed with virusencephalitis. The number of lymphocytes in the cerebrospinal fluid was increased to 30 cells per microliter, liquor albumin was 1705 mg/l, liquor sugar was 53 mg/dl and liquor lactat was 1.9 mmol/l. IgM antibodies against herpes viruses were found in the cerebrospinal fluid and distinct contrasting foci were found near the mammillary bodies, hypothalamus, tractus opticus, hypophyseal stalk and right parahippocampal in the magnetic resonance imaging of the head, indicating a focal herpes simplex encephalitis. Within seven days, the following symptoms developed: akinetic parkinsonian syndrome, central diabetes insipidus with hypernatremia and polyuria (6 l/die), hypothyreosis, adrenal insufficiency with adynamia, sopor, hypotension and even hypophyseal coma. Panhypopituitarism was diagnosed after measuring the basal hormone levels (ACTH, TSH, FT3, FT4, Cortisol, Prolactin, LH, FSH, ADH) and conducting the pituitary stimulation test. The severeness of all symptoms was slightly improved after substitution with antidiuretic hormone at 0.4 microgram/die and administration of hydrocortisone at 50 mg/die. Administration of amantadine sulphate at 0.6 g/die and L-dopa at 187.5 mg/die for 14 days resulted in a complete regression of the parkinsonism. After administration of aciclovir at 2.25 g/die for 21 days a complete regression of the clinical symptoms could be reached in connection with a decrease of 90% in number and size of cerebral contrasting foci in the magnetic resonance imaging of the head. Three month after therapy, clinical examination and blood serum analysis revealed persistent panhypopituitarism. The present case report is the first description of a viral infection on of the central nervous system (CNS) in combination with parkinsonism, diabetes insipidus, persistent panhypopituitarism and hyperprolactinemia. Early treatment of viral infections of the brain can improve a patient's prognosis dramatically. Early determination and early treatment of a patient's neurohumoral parameters is therefore critical to prevent or reverse early mental status changes like attention disturbances, alterations of personality and behavior, apathy, and slowed cognition.

[Headache caused by polycythemia vera. Classification of a headache under the heading of metabolic disturbances]. / Kopfschmerz bei Polycythaemia vera. Klassifikation eines Kopfschmerzes bei Stoffwechselstörungen.

UNLABELLED: As polycythemia vera is a myeloproliferative syndrome, it is based on an autonomic increase in the proliferation of all hematopoetic cells--mostly of erythropoesis. An increase in blood viscosity induces disturbed microcirculation, resulting in headaches with clinical symptoms. So far, the headache in polycythemia vera has not been classified. METHODS: We would like to demonstrate a case of a female patient aged 58 years who had been complaining of persistent hemicranial right-sided headaches for the last 16 days, alternating between throbbing and stabbing pain as well as a retrobulbar feeling of pressure. Blood chemistry demonstrated pronounced changes: hemoglobin, 20,1 g/dl; hematocrit, 58%; erythrocytes, 6,8 T/l (6,800,000/microl) leucocytes, 14,400/microl; thrombocytes, 543,000/microl A punch biopsy from the pelvic rim showed cell-rich bone marrow, demonstrating a myeloproliferative syndrome suggestive of polycytemia vera. RESULTS: Following hemodilution, the headache disappeared within 3 days following normalization of blood chemistry: hemoglobin, 14.9 g/dl; hematocrit, 44%; erythrocytes, 5.2 T/l (5,200,000/microl; leucocytes, 13,100/microl. Further diagnosis of the headache by means of MRI of the head, extra and transcranial doppler sonography as well as MRI of the cervical spine did not produce findings with the exception of retrospondylophyth at C5-6. The patient was therefore managed on aspirin 300 mg daily and was given weekly isovolemic bleeding. The headaches did not recur. CONCLUSION: We diagnosed a headache caused by polycythemia vera and recommend classification of this headache under the heading of metabolic disturbances, because this classification meets the diagnostic criteria of the international headache classification.

[Recurrent cerebral ischemias due to cerebral vasculitis within the framework of incomplete POEMS syndrome with Castleman disease]. / Rezidivierende zerebrale Ischämien bei zerebraler Vaskulitis im Rahmen eines inkompletten POEMS-Syndroms mit M. Castleman.

The POEMS syndrome is a multisystem disorder characterised by polyneuropathy, organomegaly, endocrinopathy, plasma cell dyscrasia and skin changes. A coincidence with angiofollicular lymphoid hyperplasia (Castleman's disease) exists in about 60% of all cases. The POEMS syndrome may be associated with macroangiopathy and acute vascular obliterations. Most case reports refer to involvement of the coronary and lower limb arteries. There are only few reports dealing with cerebral strokes and POEMS syndrome. We report on a 32-year-old female with an incomplete form of POEMS syndrome with Castleman's disease and associated cerebral vasculitis. After sufficient treatment of the plasma cell dyscrasia, recurrent cerebral ischemias occurred. A stable state was finally reached after primary treatment of the vasculitis with cyclophosphamide.

Lactic acid permeation rate in working gastrocnemii of dogs during metabolic alkalosis and acidosis.

In isolated, blood perfused, supramaximally stimulated, isotonically working gastrocnemii of dogs lactic acid (LA) output and O2-consumption (V O2) were measured according to the Fick principle. Simultaneously concentration of muscle tissue was determined at rest and at different times during exercise. In one series of experiments metabolic alkalosis was induced by infusions of THAM of Na bicarbonate. As a result arterial pH increased to about 7.5 and standard [HCO3-1] to 31-35 mmol per 1. In another group of experiments metabolic acidosis was induced by HCl infusions. In these experiments pH decreased to 7.0-7.1 and standard [HO301] to 8-11 mmol per 1. During the first 3-4 min after the onset of exercise LA concentration of muscle tissue rose to 18-19 mumol per g wet weight in both series of experiments. During acidosis the highest average values for LA release from the muscle were about 1.1 mumoles per g per minute. During alkalosis LA permeation rate was nearly three times as high. As a consequence of increased rate of permeation, LA concentration of muscle tissue decreased more rapidly in alkalosis than in acidosis. In both series of experiments work per time and VO2 were practically equal during the first 5-6 min of exercise. Thereafter work per time and VO2 decreased more rapidly in acidosis than in alkalosis, a result which probably is due to higher LA concentration in muscle at this time in acidosis. It is concluded that LA permeation rate across muscle cell membrane is increased by high extracellular HCO3- concentration in combination with low H+ activity and vice versa.

[Unilateral caudal cranial nerve paralysis in extracranial carotid dissection]. / Einseitige kaudale Hirnnervenlähmungen bei extrakraniellen Karotisdissektionen.

Focal cerebral ischemic symptoms, Horner's syndrome and mostly ipsilateral headache are the characteristic clinical triad of extracranial carotid artery dissection. Lower cranial nerve palsies seem to be uncommon and rare. By means of two cases with identical clinical symptoms and of a literature review we make clear, that ipsilateral lower cranial nerve palsies, especially a hypoglossal nerve palsy, are not uncommon. Without focal cerebral ischemic symptoms they can be the only sign of extracranial carotid artery dissection. Computed tomography of the skull base with regard to the high cervical internal carotid artery is as an usually quickly available examination an alternative to magnetic resonance imaging.