Prognostic biomarkers in primary progressive multiple sclerosis: Validating and scrutinizing multimodal evoked potentials.

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R2adj: 0.24), while EDSS and age did not. Tibial qSEP (R2adj: 0.22) and qMEP (R2adj: 0.26) were the best single modality predictors, outperformed by their combination (R2adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS.

Magnetic resonance imaging in immune-mediated myelopathies.

Immune-mediated myelopathies are a heterogeneous group of inflammatory spinal cord disorders including autoimmune disorders with known antibodies, e.g. aquaporin-4 IgG channelopathy or anti-myelin oligodendrocyte glycoprotein-associated myelitis, myelopathies in the context of multiple sclerosis and systemic autoimmune disorders with myelopathy, as well as post-infectious and paraneoplastic myelopathies. Although magnetic resonance imaging of the spinal cord is still challenging due to the small dimension of the cord cross-section and frequent movement and susceptibility artifacts, recent methodological advances have led to improved diagnostic evaluation and characterization of immune-mediated myelopathies. Topography, length and width of the lesion, gadolinium enhancement pattern, and changes in morphology over time help in narrowing the broad differential diagnosis. In this review, we give an overview of recent advances in magnetic resonance imaging of immune-mediated myelopathies and its role in the differential diagnosis and monitoring of this heterogeneous group of disorders.

[Postoperative spine]. / Postoperative Wirbelsäule.

Approximately 15-30 % of surgical procedures involving the lumbar spine are associated with complications that require further diagnostic work-up. The choice of imaging modality for postoperative complications depends on the extent, pattern and temporal evolution of the postoperative neurological signs and symptoms as well as on the preoperative clinical status, the surgical procedure itself and the underlying pathology. The interpretation of imaging findings, in particular the distinction between postoperative complications and normally expected nonspecific postoperative imaging alterations can be challenging and requires the integration of clinical neurological information and the results of laboratory tests. The combination of different imaging techniques might help in cases of equivocal imaging results.

[Pediatric intraspinal neoplasms]. / Pädiatrische intraspinale Neoplasien.

With an overall incidence of 10% of all central nervous system tumors, spinal tumors are relatively rare in children. The majority of these tumors are astrocytomas and ependymomas (70%) followed by rare non-glial tumor entities, such as gangliogliomas. They can be differentiated into intramedullary, extramedullary intradural and extramedullary extradural tumors according to their occurrence within the anatomical intraspinal compartments. The clinical presentation is generally unspecific. Longer lasting back pain or a gradually worsening scoliosis are often the first signs of the disease. Neurological deficits, such as gait disturbances and paresis often occur after a time delay. In rare cases increased intracranial pressure has been reported.Knowledge concerning potential organ manifestations, resulting complications and typical radiological presentation, especially in magnetic resonance imaging are mandatory for adequate diagnosis and treatment of affected patients.

Prediction of MS disability by multimodal evoked potentials: investigation during relapse or in the relapse-free interval?

OBJECTIVE: Little is known about optimal timing of multimodal evoked potential (EP)-investigations regarding prediction of MS disability. The aim of this study was to investigate whether timing of EP-investigations during a relapse or in the relapse-free interval influences prediction of MS disability. METHODS: Two groups of MS patients with similar age and gender distributions received visual, motor and somatosensory EPs either during a relapse (Group 1) or in the relapse-free interval (Group 2). Expanded Disability Status Score (EDSS) was obtained at baseline (T0) and year 3 (T2). Linear regression analysis was performed to examine the association between EDSS(T2) and a baseline EP compound measure (s-EP-Q(T0)) for each group. RESULTS: Median EDSS(T0) was 3.0 for Group 1 and 1.5 for Group 2. Mean disease durations were 2.0 and 2.8 years, respectively. Median EDSS(T2) was 2.0 for both groups. The s-EP-Q(T0) significantly predicted EDSS(T2) (R(2)=0.47) for patients in Group 2, but not for patients in Group 1 (R(2)=0.07). CONCLUSION: In early MS the functional remnants of relapses are a better predictor for development of medium-term disability than is the extent of impulse propagation impairment measured during relapse. SIGNIFICANCE: This suggests a role of multimodal EPs in prediction of MS disability if performed in the relapse-free interval.

Prediction of long-term disability in multiple sclerosis.

BACKGROUND: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS). OBJECTIVE: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years. METHODS: A total of 30 patients with relapsing-remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman's rank correlation. Multivariable linear regression was performed to predict EDSS(T4) as a function of z-transformed EP-latencies(T0). The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined. RESULTS: EDSS values(T4) correlated with the sum of z-transformed EP-latencies(T0) (rho = 0.68, p < 0.0001), but not with MR-parameters(T0). EDSS(T4) as predicted by the formula EDSS(T4) = 4.194 + 0.088 * z-score P100(T0) + 0.071 * z-score CMCT(UE, T0) correlated with the observed values (rho = 0.69, p < 0.0001). CONCLUSION: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions.

Faecal chymotrypsin for investigation of exocrine pancreatic function: a comparison of two newly developed tests with the titrimetric method.

Two newly developed photometric assays for the estimation of faecal chymotrypsin were studied in comparison with the established titrimetric method in 46 patients and 8 healthy volunteers, who had undergone a secretin-pancreozymin test for diagnostic purposes. The correlation between the two photometric methods and the titrimetric method was good (r = 0.90 and r = 0.91), revealing similar diagnostic sensitivity and specificity. As both photometric methods are less time-consuming and may be performed using a standard laboratory equipment, they offer a good alternative to the established titrimetric method for faecal chymotrypsin estimation.

Faecal chymotrypsin--a new photometric method using N-acetyl-L-tyrosine ethyl ester as substrate.

A photometric method for chymotrypsin is proposed, using the substrate N-acetyl-L-tyrosine ethyl ester, which is already used in the titrimetric procedure. Hydrolysis of the ester bond produces equal amounts of ethanol and acetyltyrosine, the latter being measured in the titrimetric method. The ethanol can easily be measured by the alcohol dehydrogenase method in the trichloroacetic acid supernatant. Suitable test conditions are reported.

Studies on the mechanism of the increase in serum alkaline phosphatase activity in cholestasis: significance of the hepatic bile acid concentration for the leakage of alkaline phosphatase from rat liver.

In experimental bile obstruction the serum activities of the membrane-bound liver enzymes, alkaline phosphatase, 5'-nucleotidase and gamma-glutamyltransferase are greatly increased, whereas in the liver only the alkaline phosphatase activity is elevated. After partial hepatectomy or tetrachloride poisoning the alkaline phosphatase activity in the regenerating live is increased to the same extent as in cholestasis without an accompanying elevation in serum activity. The following results support the hypothesis of a bile salt-mediated solubilization of membrane-bound enzymes in cholestatic liver: (1) 30 min after bile duct ligation the total bile acids in the liver were increased 5-fold, 2 h later as much as 10-fold. After 1 day, the bile acid concentration was still 4 times above normal. (2) Isolated plasma membranes from normal and obstructed livers were incubated in vitro with increasing amounts of tri- and dihydroxycholanic acids. At a final concentration of 1 mmol/l taurochenodeoxycholate significant amounts of membrane-bound enzymes were released into the 12,000-g supernatant. (3) In the regenerating liver, where tissue phsophatase activity was high and serum phosphatase activity unchanged, the bile salt concentration was not increased.

Evidence for an enhanced de novo synthesis of alkaline phosphatase in cholestatic rat liver using immunotitration and precursor incorporation techniques.

An antikidney phosphatase serum was produced. This showed a cross-reaction with liver phosphatase and precipitated the latter enzyme specifically in the double antibody method. An U-[14C] protein hydrolysate was injected intraperitoneally into rats, which had previously undergone bile duct ligation. Liver alkaline phosphatase was partially purified and immunoprecipitated. By determination of phosphatase labelling the extent of de novo synthesis of the phosphatase protein was evaluated. Comparing livers from control and cholestatic rats, it could be shown that 12 h after beginning of cholestasis the de novo synthesis of alkaline phosphatase was increased up to 4-fold and that is remained at a 2-fold increased level for at least 2 days.

The mechanism of the increase in the activity of liver alkaline phosphatase in experimental cholestasis: measurement of an increased enzyme concentration by immunochemical titration.

Alkaline phosphatase (EC 3.1.3.1) activity increases 5-15 fold in the livers of rats, following bile duct ligation. The mechanism of this increase has been the subject of numerous investigations. In HeLa cells the synthesis of a different phosphatase enzyme protein with higher catalytic activity has been postulated. After preparing an antiserum against rat liver phosphatase, we compared the phosphatase protein concentration in normal and cholestatic livers by immunochemical titration. Our results clearly indicate that the elevation of enzyme activity is due to an increased accumulation of enzyme protein.