Psychogenic Movement Disorders: Gait Is a Give-Away!

The aim of this article is to point out that an incongruity of gait disorder (either in relation to the presenting movement disorder or incongruity with any type of organic gait disorder) is a useful clue in diagnosing psychogenic movement disorders. To illustrate this, we present a case series of patients with various types of psychogenic movement disorders (rest tremor, myoclonus, dystonia, and chorea). Incongruity of the walking pattern with the presenting movement disorder was a revealing diagnostic clue in all cases. "Incongruity" is currently a main plank in the diagnosis of psychogenic conditions. Our series emphasizes that incongruity of the gait pattern may be the most important sign in a patient where it is otherwise difficult to establish whether the movement disorder is congruous or incongruous with an organic disorder.

Outcome measurement in multiple sclerosis: detection of clinically relevant improvement.

Because the development of new treatments in multiple sclerosis as well as the awareness of the importance of patient-oriented measures have become more important in the last two decades, new outcome measures have been developed with the aim of being more responsive to change and more clinically relevant to patients. The ability to detect improvement is sparsely studied. In the present study we evaluate the responsiveness of the Expanded Disability Status Scale and two quantitative tests (the timed 25-foot walk test and the nine-hole peg test) separately and in combination, to detect improvement after intravenous methylprednisolone. The Expanded Disability Status Scale, the timed 25-foot walk test and the nine-hole peg test were assessed in 112 multiple sclerosis patients before and 6 weeks after intravenous methylprednisolone. In addition patients were asked to rate their change as an anchor to evaluate the performance of the tests. Combining the timed 25-foot walk test and the nine-hole peg test turned out to be the optimal combination of measures to predict patient perceived improvement (positive predictive value of 67% and a negative predictive value of 59%, likelihood ratio of positive test 2.31 (95% confidence interval 1.08-4.95)). In the higher Expanded Disability Status Scale range (4.5 and higher), for all measures a significant change was more often perceived as clinically relevant than in the lower disability range. The Expanded Disability Status Scale seems not to be the preferred outcome of choice to detect patient perceived improvement in multiple sclerosis, especially in the lower Expanded Disability Status Scale range. Combining the timed walk test and the nine-hole peg test can improve the sensitivity to detect clinically relevant changes without conceding with respect to specificity.

Suppressive effect of glucocorticoids on TNF-alpha production is associated with their clinical effect in multiple sclerosis.

A reduced sensitivity to glucocorticoids can affect the clinical effect of treatment with high-dose intravenous methylprednisolone in multiple sclerosis. We prospectively studied 27 multiple sclerosis patients who were treated with intravenous methylprednisolone. Before and after treatment in vitro stimulated TNF-alpha production in blood cells and the effect of in vitro administered glucocorticoids were determined as a measure of glucocorticoid sensitivity. The suppression of TNF-alpha production after intravenous methylprednisolone, and the in vitro suppressive effect of glucocorticoids prior to treatment was related to subsequent clinical improvement after intravenous methylprednisolone. The results suggest the existence of a partial glucocorticoid resistance, in a subgroup of multiple sclerosis patients, which may have implications for treatment efficacy.

A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis.

CONTEXT: In patients with multiple sclerosis (MS), glucocorticoids (GCs) might not be sufficiently able to restrain the immune system, possibly due to decreased GC sensitivity. This may be, at least partially, genetically determined. Previously, we reported a more aggressive disease course in patients with the glucocorticoid receptor (GR) gene ER22/23EK polymorphism, which has been shown to decrease GC sensitivity. OBJECTIVE: In 646 MS patients and 317 healthy controls, we investigated whether haplotypes, including the ER22/23EK polymorphism or the GR 9beta polymorphism, which is also associated with a relative GC resistance, were associated with a more aggressive disease course. PATIENTS AND METHODS: Polymorphisms in the GR gene (9beta, ER22/23EK, TthIIII, BclI, and N363S), which have previously been associated with altered GC sensitivity were determined and haplostructure was characterized. We evaluated whether the haplotypes were associated with disease susceptibility and several other disease characteristics. The association with disease progression was analyzed using Cox regression with time to Expanded Disability Status Score 6 as outcome. RESULTS: None of the haplotypes was associated with disease susceptibility, age at onset, or onset type. Haplotype 6 (TthIIII, ER2223EK, and 9beta-G) was associated with a more rapid disease progression (hazard ratio 2.3; 95% confidence interval 1.5-3.7; P < 0.001). This seems to result from the presence of ER22/23EK, and not from the 9beta and TthIIII polymorphisms. CONCLUSIONS: MS patients carrying the haplotype 6 (TthIIII, ER22/23EK, and 9beta) have a more aggressive disease course. This is probably due to the presence of the polymorphism ER22/23EK, which causes a decreased GC sensitivity.

Proteolytic shedding of the macrophage scavenger receptor CD163 in multiple sclerosis.

The scavenger receptor CD163 is selectively expressed on tissue macrophages and human monocytes. CD163 has been implicated to play a role in the clearance of hemoglobin and in the regulation of cytokine production by macrophages. Membrane CD163 can be cleaved by matrix metalloproteinases (MMP) resulting in soluble CD163 (sCD163). In the present report the shedding of CD163 was investigated in multiple sclerosis (MS). An upregulation of plasma sCD163 and a down regulation of membrane CD163 in MS patients compared to healthy controls was observed. The levels of plasma sCD163 correlated with plasma MMP-9 levels in controls, but not in MS patients. Moreover, evidence was obtained for CD163-cleaving MMP activity in plasma of MS patients. Finally, the increased proteolytic shedding of CD163 correlated to reduced plasma levels of circulating inflammatory cytokines. Collectively, our results provide evidence for proteolytic shedding of CD163 in MS and suggest a possible link to cytokine production.

Sensitivity to glucocorticoids is decreased in relapsing remitting multiple sclerosis.

Endogenous glucocorticoids (GC), which are under control of the hypothalamic-pituitary-adrenal axis, play an important role in controlling chronic inflammatory demyelinating diseases, like multiple sclerosis (MS). Increased hypothalamic-pituitary-adrenal axis activity has been found in MS patients and appeared to be negatively associated with acute inflammation. Exogenous GC are frequently used to treat relapses in MS, but the response to this treatment differs among patients, suggesting differences in sensitivity to GC. Previous, relatively small studies investigating GC sensitivity have yielded conflicting results. In the present study, we have investigated GC sensitivity in peripheral blood cells of MS patients (n = 117) and healthy controls (n = 45). GC sensitivity was measured by the in vitro suppressive effect of GC on lipopolysaccharide-stimulated TNF-alpha production. Blood cells of MS patients, especially relapsing remitting MS patients, were less sensitive to GC compared with blood cells of healthy controls. This turned out to be unrelated to previous treatment with exogenous GC expressed as frequency of courses of iv steroids or interval since last course. The use of interferon beta was found to be associated with a lower GC sensitivity. However, after correction for the use of interferon beta, relapsing remitting MS patients remained less sensitive to GC.