In vivo 1H magnetic resonance spectroscopy of rat brain after valproate administration.

Previous studies have shown that valproate is detectable in vitro by 1H magnetic resonance spectroscopy (MRS) at 1.5 T, whereas in patients on valproate monotherapy, no significant dose-dependent valproate signal could be seen. To investigate whether an increased signal-to-noise ratio as provided by higher valproate doses and increased magnetic field strength would enable detection of valproate in vivo, six Wistar rats were examined using volume-selective 1H MRS at 2.34 T. The spectra were analyzed by fitting a linear superposition of the basis spectra of valproate, brain metabolites, and simulated lipid signals. The analysis revealed no significant signal contributions after valproate administration of up to 330 mg/kg body weight. To analyze how underlying mechanisms, such as potential drug interactions with macromolecules, may affect the valproate signal, additional in vitro spectra of valproate were measured before and after adding albumin. The spectra exhibited a strong decrease of the valproate signal with increasing albumin concentration. The results support the hypothesis that in vivo valproate is bound to a high degree to macromolecules and will therefore not be detectable by 1H MRS.

Is the blood-CSF barrier altered in disease?

OBJECTIVE: To illustrate the influence of cerebrospinal fluid (CSF) flow on lumbar CSF protein concentration and to test for an altered blood-CSF barrier permeability as additional influence. PATIENTS AND METHODS: Consecutively hospitalized patients with normotensive hydrocephalus (n = 21) underwent lumbar puncture with CSF being sampled in sequential portions. CSF/blood quotients of albumin (QAlb) and of immunoglobulin G (QIgG) were compared intra-individually and with calculated values from a reference patient sample. RESULTS AND CONCLUSIONS: QAlb and QIgG of intra-individual sequential portions correlated highly with each other (median r = 0.95), suggesting lumbar CSF flow as the main thecal determinant of lumbar QAlb and QIgG variation. In addition, QIgG, relative to QAlb, was significantly lower in study patients compared with a reference patient sample (P = 0.002), implying an alteration of the blood-CSF barrier permeability as a minor determinant of QAlb and QIgG variation in study patients.

Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy.

We performed volume-selective 1H MR spectroscopy (1H-MRS) on 12 patients on valproate monotherapy to detect valproate in vivo in the brain. We also acquired reference valproate spectra in vitro in subphysiological 15 g/l albumin solution in saline, in which valproate showed two resonance peaks at 0.7 and 1.2 ppm and a minimum detection threshold of 240 mg/l. In vivo 1H-MRS spectra in brain showed peaks between 0.6 and 1.6 ppm. Simultaneous serum valproate concentrations did not correlate with these integrated MRS peaks. On follow-up, changes in these signals also did not correlate with increasing serum valproate levels. The inconsistency of in vivo 1H-MRS signals at varying serum levels and the high detection levels in vitro suggest that valproate signals are missed in vivo because valproate is metabolised or strongly bound, presumably to brain macromolecules.

Neuroleptic malignant syndrome in a patient with succinic semialdehyde dehydrogenase deficiency.

A patient suffering from a rare enzyme deficiency developed a malignant neuroleptic syndrome after having been treated with one single dose of haloperidol. We investigated the patient's serum for all frequent polymorphisms in cytochrome P450 2D6, assuming him to be a poor neuroleptic metabolizer. We will also discuss other potential mechanisms inducing this disturbance and its differential diagnoses.

Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants.

Administration of anticonvulsant drugs is clinically monitored by checking seizure frequency and by determining the serum concentration of the drug. In a few reports, drug concentrations in brain parenchyma have been determined using ex vivo techniques. Little is known about the in vivo concentration in the brain parenchyma. Our goals were to characterise the NMR spectra of the anticonvulsants at therapeutic concentrations, to determine the minimum detectable concentrations, and to quantify the drugs noninvasively. Volume-selective 1H-MR spectroscopy (MRS) was performed under standard clinical conditions using a single-voxel STEAM (stimulated-echo acquisition mode) sequence at 1.5 T. Spectra of the anticonvulsants carbamazepine, phenobarbital, phenytoin and valproate were acquired in vitro in hydrous solutions at increasing dilution. Phenytoin, phenobarbital and valproate were detectable below maximum therapeutic serum concentrations. Within therapeutic ranges, there was good agreement between concentrations determined by 1H-MRS and those by standard fluorescence polarisation immunoassay. Due to the absence of signals of brain metabolites, the aromatic protons of phenobarbital, phenytoin and carbamazepine, with resonance lines around 7.4 ppm, allow the drugs to be detected. Valproate, with two resonances around 1.2 ppm, should be differentiable from potential brain metabolites using nonlinear analysis of the brain spectrum. Volume-selective 1H-MRS is therefore expected to be able to monitor anticonvulsant therapy in vivo.

Interrater agreement for high grade carotid artery stenosis measurement and treatment decision.

OBJECTIVES: Randomized trials in North America (NASCET, ACAS) and Europe (ECST) have shown a beneficial effect of endarterectomy for patients with high grade carotid artery stenosis. The results of the NASCET and the ECST further suggest that the effect of endarterectomy differed by degree of stenosis, supporting the importance of stenosis measurement as a factor in the decision process regarding surgery. We investigated the interrater agreement for carotid artery stenosis measurements and treatment decision in a post hoc study on patients undergoing carotid surgery. METHODS: In a one-year series, 45 consecutive patients underwent preoperative conventional cerebral angiography followed by endarterectomy. Using a magnifying eyepiece and applying the two different measurement criteria of the randomized trials, angiograms were re-evaluated post hoc by three masked raters. Intra-class correlation coefficients (ICCs) with one-sided 95% confidence intervals (CIs) were calculated for the estimation of interrater agreement for degree of stenosis. Conger s kappa (k) statistics were used for the estimation of interrater agreement for a dichotomized stenosis evaluation, i.e. therapeutic decision on surgery (cut-off point for symptomatic stenosis: 70%, cut-off point for asymptomatic stenosis: 60%). RESULTS: ICCs were.74 (CI.63) for NASCET/ACAS criteria and.72 (CI. 59) for ECST criteria. k values were.55 (CI.42) for NASCET/ACAS criteria and.57 (CI.44) for ECST criteria. Disagreement for a therapeutic decision was seen in 6 of 23 symptomatic patients by NASCET criteria, in 2 of 23 symptomatic patients by ECST and in 4 of 22 asymptomatic patients by ACAS criteria. CONCLUSIONS: Overall, the interrater agreement for stenosis measurements was good. Agreement for therapeutic decisions on carotid surgery, however, was less strong. These findings suggest that accurate stenosis measurement may not suffice for reliable treatment decisions in patients with high grade carotid artery stenosis.

Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis.

Currently there is no treatment available to improve a stable deficit in multiple sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg) can enhance central nervous remyelination, and the first open trials were promising. We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with multiple sclerosis with a stable clinical deficit. The primary outcome parameter was the change in central motor conduction time as an indirect measure of central myelination. Secondary outcome parameters were neurological examinations including the expanded disability status scale (EDSS), neurological rating scale (NRS), and manual muscle testing (MMT). Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks. There was no difference in the central motor conduction times measured before and 6 weeks after each treatment. Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo. In conclusion, our data do not support a role for IVIg in the remyelination of stable multiple sclerosis lesions as measured by central conduction time. The importance of the small clinical benefit is currently not clear.

Mydriatic pupil as the presenting sign of common carotid artery dissection.

BACKGROUND: Ipsilateral mydriasis is known to accompany signs of cerebral ischemia in unilaterally compromised carotid blood flow. Mydriasis as the presenting sign of common carotid artery (CCA) dissection has not been reported thus far. CASE DESCRIPTION: We report the case of a patient who presented with a mydriatic pupil after intraoperative injury of the ipsilateral CCA. Mydriasis preceded complete third-nerve palsy and symptoms of cerebral ischemia for 12 hours. Cerebral angiography revealed occlusion of the CCA with slow collateral flow to the internal carotid artery and fetal origin of the posterior cerebral artery, suggesting a hemodynamic mechanism causing ischemia of the oculomotor nerve. Signs of cerebral ischemia and third-nerve palsy resolved completely after reconstructive surgery of the occluded vessel. CONCLUSIONS: A mydriatic pupil may be the unusual first sign of compromised carotid blood flow and impending cerebral ischemia.

Identification of a renin threshold and its relationship to salt intake in a patient with pure autonomic failure.

Animal studies have demonstrated a threshold below which renin release increases proportionally to a decrease in renal perfusion pressure. Demonstration of a similar mechanism in humans, however, has proved difficult, as any attempt to lower blood pressure below the putative renin threshold results in renin release mediated by reflex activation of the sympathetic nervous system. In this study, we report on our observations in a 71-year-old woman who presented with a 20-year history of faintness and syncope and was diagnosed as having pure autonomic failure. Graded head-up tilting resulted in a stepwise reduction in mean arterial blood pressure to a minimum of 54 mm Hg, with no signs of increased sympathetic activity. A fall in blood pressure below 80 mm Hg resulted in a distinct rise in plasma renin activity, and a similar threshold pressure was observed under both a 50- and a 100-mmol/d sodium chloride diet. Below the threshold, response to changes in perfusion pressure was proportionally greater under the 50-mmol/d diet than under a 100- or 200-mmol/d diet. These observations demonstrate that a pressure threshold for renin release at 10 to 15 mm Hg below ambient blood pressure, as described previously in animal studies, is also present in humans. The significance of this pressure-dependent mechanism of renin release for the long-term regulation of blood pressure and water and mineral balance in humans remains to be determined.

Dermatome variations in patients with transitional vertebrae.

OBJECTIVES: To test whether the position of lumbosacral dermatomes varies in the presence of transitional vertebrae. MATERIAL AND METHODS: Fifty consecutive male patients were tested for thoracolumbar and lumbosacral transitional vertebrae by radiography and for the position of the dermatome gap between the lumbar dermatomes L1, L2, L3, and the sacral dermatomes S2 and S3. The dermatome gap was documented with the use of the cremasteric reflex, the receptive field of which ends sharply at the gap which allows its delineation. RESULTS: Thirty two of 50 patients had a normal thoracolumbosacral spinal configuration, 10 patients had transitional vertebrae. The patients with a cranial displacement of the thoracolumbar or lumbosacral vertebral transition showed a dermatome gap which lay significantly more ventrally than in the patients with a normal spinal configuration. CONCLUSION: The finding supports the notion of a variant position of lumbosacral dermatomes in the presence of transitional vertebrae in males.

Adhesion of leucocytes to microscope slides as influenced by electrostatic interaction.

The adhesion of leucocytes to standard microscope slides is low, which severely limits the cell recovery in cytological preparations on such slides. We coated the slides with various polycations with the aim of achieving an electrostatic surface charge which would increase the cell adhesion but would still avoid cell disruption. The adhesion of leucocytes from a K562 myeloid cell suspension and from cerebrospinal fluid was measured on standard slides made of glass and of oxidized polystyrene, and on slides coated with several chemically different cationic polymers. The electrostatic surface charge and the surface tension of these matrices were determined. We found the cell adhesion to be significantly higher on the matrices with a more attractive zeta potential and not to be measurably influenced by the surface tension of the matrices. The results help to improve the cytological preparation technique, especially for suspensions with a low cell content.

The value of magnetic resonance imaging in carpal tunnel syndrome.

We examined 62 patients (72 hands) with carpal tunnel syndrome (CTS) by magnetic resonance imaging (MRI) of the carpal tunnel and latency measurements of the median nerve. In 32 of 72 hands a probable causative lesion of the CTS was identified by MRI, for example tenosynovitis, a cyst-like structure, or an aberrant muscle. The MRI findings were confirmed by surgery in 16 of 24 hands, slightly corrected in 5, and not substantiated in 3. In 65 of 72 hands, MRI disclosed pathology of the median nerve, most prominently an enlargement of the nerve at the level of the os pisiforme, a finding not seen during surgery. Oedema of the nerve was found in 14 of 72 hands. The distal latencies were prolonged in 62 of 72 hands. The sensory latencies correlated significantly with the MRI-determined cross-sectional area of the nerve at the level of the distal radius. The lack of other correlations suggests that partly independent features of the nerve lesion are demonstrated in each method or that the sensitivity and specificity of both methods are limited. Further experience with MRI in CTS is desirable. At present, the practical use of MRI in CTS should be restricted to special diagnostic problems such as carpal tunnel syndromes which do not respond adequately to conservative or surgical treatment.

HTLV-1-associated myelopathy in China. A disease acquired overseas?

This case report documents the first patient from mainland China with an HTLV-1-associated myelopathy. The available epidemiological data suggest a low rate of HTLV1 infection in China, although the surveys are comparatively small. Possible transmission routes and the risk of encountering the disease outside endemic areas are discussed.

An improved sedimentation technique for the cytologic preparation of cerebrospinal fluid cells.

The conventional CSF cell preparation methods suffer from a poor cell recovery rate (mean rates of 10-50% with the sedimentation techniques, which makes it unlikely, that the cell sampling on the slide is representative) or from suboptimal cell visualization (filter techniques). An improved sedimentation technique is described with a mean recovery rate of 80% and excellent cell visualization.

Cerebrospinal fluid cell preparation methods. An evaluation.

Although the cells from cerebrospinal fluid are widely used for diagnostic purposes, the cell yield on the microscopic slide is only rarely considered and mostly unsatisfactory. A reevaluation of several preparatory methods showed a very low yield with the Sayk-type chamber, a modest yield with the cytocentrifuge and the best yield with a simple, self-adhering chamber on slides coated with a polycation.

Endocrine function in multiple sclerosis.

In 31 patients with multiple sclerosis (MS) the endocrine functions of the hypothalamus, the pituitary and several peripheral endocrine glands were assessed with a combined pituitary test; 3/31 patients had an endocrine disease: one primary hypothyroidism, one primary amenorrhea and one primary male hypogonadism. We found no patient with endocrine disease of the hypothalamus, the pituitary or the adrenals. However, the poststimulatory secretion of cortisol, growth hormone or thyroid-stimulating hormone was impaired in 7/31 patients, suggesting a possible preclinical endocrine insufficiency in these patients.

Multiple sclerosis and other immunologic diseases.

A characteristic feature of immunologic diseases is their association with each other. For multiple sclerosis (MS), several retrospective studies reported increased as well as expected coincidence rates with other immunologic diseases. We conducted a prospective case-control study of MS patients and healthy volunteers and found 13/101 MS patients and 2/97 controls with such diseases (P = 0.009, chi-square test), as well as 47/88 MS patients versus 31/95 controls with a variety of circulating autoantibodies (P = 0.004, chi-square test). These results speak for an increased coincidence of MS with other immunologic diseases and support the idea that MS is also an immunologic disease.

[The effect of blood glucose on the course of cerebral ischemia]. / Der Einfluss des Blutzuckers auf den Verlauf zerebraler Ischämien.

Experimental und clinical data suggest a negative influence of diabetes mellitus and hyperglycemia on the outcome of cerebral ischemia. In a retrospective analysis of 135 consecutive patients with cerebral ischemia we found more severe clinical defects in diabetics and patients with initial hyperglycemia but without previously known diabetes mellitus than in patients with initial normoglycemia. This was especially true for blood glucose above 10 mmol/l. Before drawing therapeutic conclusions, further prospective studies are necessary.

[Patients with transient ischemic attacks. Their cardiac status and its prognostic significance]. / Patienten mit transitorischer ischämischer Attacke. Ihr kardialer Status und seine prognostische Bedeutung.

In 51 consecutive patients with acute transitory cerebral ischaemia cross-sectional echocardiograms, 24-hour electrocardiograms (ECG) and exercise ECGs were recorded. The subsequent observation period averaged 13 (3-30) months. The echocardiogram was abnormal in 27 of 46 patients (58%). A holosystolic mitral-valve prolapse was found in eight: cerebral ischaemia recurred in five. There was no correlation between arrhythmias in the 24-hour ECG and renewed cerebral ischaemia. In addition to the 14 patients who--according to history and resting ECG--had already had a myocardial infarction, the exercise ECG revealed probably coronary heart disease in a further 11, i.e. half of the patients had coronary heart disease. Renewed attacks of cerebral ischaemia occurred in 13 patients during the follow-up period; four patients died, all of them also having had coronary heart disease. Because of the high prevalence of coronary heart disease (often previously undiagnosed) in the whole group, routine exercise ECGs are recommended for patients with transitory ischaemic attacks, protracted ischaemic neurological deficit or "minimal stroke", while 24-hour ECG monitoring does not seem essential. Randomized trials are needed to determine whether patients with cerebral ischaemia and echocardiographic evidence of mitral-valve prolapse should be treated prophylactically.

Primidone and essential tremor.

To clarify whether primidone itself, and not only its metabolite phenobarbitone, suppresses essential tremor, the effect of a high single dose of primidone was tested. Of 11 patients, 8 showed a reduction of their tremor by 54%-69% for up to 28 h. The serum concentration of primidone was as expected, whereas those of the metabolites phenyl-ethyl-malonamide and phenobarbitone were very low. The tremor suppression can thus be considered to be an effect of primidone. Three of the 11 patients did not show a reduction of tremor.