Cognitive functions over the course of 1 year in multiple sclerosis patients treated with disease modifying therapies

Objectives: Disease-modifying therapies (DMTs) are applied to delay or prevent disease progression in multiple sclerosis (MS). While this has mostly been proven for physical symptoms, available studies regarding long-term effects of DMTs on cognitive functions are rare and sometimes inconsistent due to methodological shortcomings. Particularly in the case of fingolimod, comprehensive data on cognitive functions are not yet available. Therefore, we set out to reliably assess cognitive functions in patients with relapsing-remitting MS (RRMS) treated with DMTs over 1 year. Methods: Cognitive functions were assessed with eight tests at three timepoints: baseline, 6-month follow up and 12-month follow up. First, we investigated whether the stability of cognitive functions (i.e. not falling below the 5% cut-off in more than one test) over 1 year in RRMS patients (n = 41) corresponds to the stability in healthy individuals (n = 40) of a previous study. Second, we compared the percentage of declined and improved patients in the different tests. Third, we compared patients treated with fingolimod (n = 22) with patients treated with natalizumab (n = 11) with regard to cognitive stability. Fourth, based on the patient data, the Reliable Change Index was applied to compute cut-offs for reliable cognitive change. Results: Approximately 75% of RRMS patients treated with DMTs remained stable over the course of 1 year. The Paced Auditory Serial Addition Test (PASAT) and the Spatial Recall Test (SPART), produced improvements in 12.5% and 30.6%, respectively, probably due to practice effects. Patients treated with fingolimod did not differ from patients treated with natalizumab with regard to cognitive stability. Conclusions: Cognitive functions remain relatively stable under DMT treatment over 1 year, irrespective of the type of medication. Furthermore, the tests PASAT and SPART should be interpreted cautiously in studies examining performance changes over time. The provided RCI norms may help clinicians to determine whether a difference in two measurements observed in a RRMS patient is reliable

Immunological and clinical consequences of splenectomy in a multiple sclerosis patient treated with natalizumab

Objective Here we report a case of a splenectomized white woman with natalizumab-associated progressive multifocal leukoencephalopathy (PML), occurring as early as after 11 infusions and provide blood fluorescence-activated cell sorting (FACS) analyses before and after natalizumab treatment. Design This is a report of a single case with immunological studies. Methods Methods comprised neurologic examination, magnetic resonance imaging, and cerebrospinal fluid (CSF) studies as well as immune cell FACS analyses from blood. Results Diagnosis of PML was established after positive John Cunningham virus (JCV) DNA was detected in the CSF. An immune reconstitution inflammatory syndrome was treated with repeated cycles of steroid pulses and intravenous immunoglobulins. Reduced numbers of memory B cells, which might play an important role in antiviral immune response, were detected in the blood. Moreover the percentage of CD19+ B cells was elevated in our post-splenectomy patient as compared to a control cohort of multiple sclerosis (MS) patients under natalizumab therapy. Conclusion Splenectomy may increase the risk for the development of natalizumab-associated PML via effects on the B cell compartment. It may be regarded as a risk factor in MS patients independent from the duration of disease

Patient preferences for disease-modifying drugs in multiple sclerosis therapy: a choice-based conjoint analysis

Objectives: With an increasing number of disease-modifying treatments (DMTs) for multiple sclerosis (MS), patient preferences will gain importance in the decision-making process. We assessed patients’ implicit preferences for oral versus parenteral DMTs and identified factors influencing patients’ treatment preference. Methods: Patients with relapsing–remitting MS (n = 156) completed a questionnaire assessing treatment preferences, whereby they had to decide between pairs of hypothetical treatment scenarios. Based on this questionnaire a choice-based conjoint analysis was conducted. Results: Treatment frequency and route of administration showed a stronger influence on patient preference compared with frequency of mild side effects. The latter attribute was more important for treatment-naïve patients compared with DMT-experienced patients. The higher the Extended Disability Status Scale score, the more likely pills, and the less likely fewer side effects were preferred. Pills were preferred over injections by 93% of patients, when treatment frequency and frequency of side effects were held constant. However, preference switched to injections when pills had to be taken three times daily and injections only once per week. Injections were also preferred when pills were associated with frequent side effects. Conclusions: Our results suggest that route of administration and treatment frequency play an important role in the patients’ preference for a given DMT

The P2 Receptor Antagonist PPADS Supports Recovery from Experimental Stroke In Vivo

BACKGROUND: After ischemia of the CNS, extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations due to cell damage and subsequent increase of membrane permeability. ATP may cause cellular degeneration and death, mediated by P2X and P2Y receptors. METHODOLOGY/PRINCIPAL FINDINGS: The effects of inhibition of P2 receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on electrophysiological, functional and morphological alterations in an ischemia model with permanent middle cerebral artery occlusion (MCAO) were investigated up to day 28. Spontaneously hypertensive rats received PPADS or vehicle intracerebroventricularly 15 minutes prior MCAO for up to 7 days. The functional recovery monitored by qEEG was improved by PPADS indicated by an accelerated recovery of ischemia-induced qEEG changes in the delta and alpha frequency bands along with a faster and sustained recovery of motor impairments. Whereas the functional improvements by PPADS were persistent at day 28, the infarct volume measured by magnetic resonance imaging and the amount of TUNEL-positive cells were significantly reduced by PPADS only until day 7. Further, by immunohistochemistry and confocal laser scanning microscopy, we identified both neurons and astrocytes as TUNEL-positive after MCAO. CONCLUSION: The persistent beneficial effect of PPADS on the functional parameters without differences in the late (day 28) infarct size and apoptosis suggests that the early inhibition of P2 receptors might be favourable for the maintenance or early reconstruction of neuronal connectivity in the periinfarct area after ischemic incidents

Ultrasound in Dual Nerve Impairment after Proximal Radial Nerve Lesion

Introduction Sonography in classical nerve entrapment syndromes is an established and validated method. In contrast, few publications highlight lesions of the radial nerve, particularly of the posterior interosseus nerve (PIN). Method Five patients with a radial nerve lesion were investigated by electromyography, nerve conduction velocity and ultrasound. Further normative values of 26 healthy subjects were evaluated. Results Four patients presented a clinical and electrophysiological proximal axonal radial nerve lesion and one patient showed a typical posterior interosseous nerve syndrome (PINS). The patient with PINS presented an enlargement of the PIN anterior to the supinator muscle. However four patients with proximal lesions showed an unexpected significant enlargement of the PIN within the supinator muscle. Conclusion High-resolution sonography is a feasible method to demonstrate the radial nerve including its distal branches. At least in axonal radial nerve lesions, sonography might reveal abnormalities far distant from a primary proximal lesion site clearly distinct from the appearance in classical PINS

Normative values.

<p>Cross sectional area (CSA) and antero-posterior diameter (APD) of the radial nerve and the posterior interosseus nerve (PIN) of 26 healthy volunteers (= 52 nerves) presented as mean ± standard deviation.</p><p>Normative values.</p

Antero-posterior diameter (APD) of posterior interosseous nerve (PIN).

<p>Antero-posterior diameter (APD) of PIN in four patients shows a significant swelling of the PIN in comparison to controls. ** <i>p</i><0.001</p

Patient data.

<p>Detailed clinical, electrodiagnostic and sonographic findings of all patients. (AD—active denervation, APD—anterior-posterior diameter, BR—brachioradialis muscle, ECR—extensor carpi radialis muscle, ECU—extensor carpi ulnaris muscle, EDC—extensor digitorum communis muscle, MRC—medical researche council, SNAP—sensory nerve action potential, SCV—sensory conduction velocity, T—triceps brachii muscle, WFE—wrist/finger extension, + mild, ++ moderate, +++ severe)</p><p>Patient data.</p

Sonographic studies of a patient with a proximal radial nerve lesion.

<p>(A, B) Transversal study of the posterior interosseous nerve (PIN; arrow) within the supinator muscle (asterisk) on the healthy side (A) in comparison to the affected side (B) with a significant swelling of the PIN within the muscle. (C) Longitudinal study of the PIN with a swelling before entering the Arcade of Frohse (thin arrows) and within the supinator muscle (asterisk). (D) Longitudinal study of the radial nerve in the distal upper arm with impression of the nerve (arrow) by a screw (thin arrow). p—proximal, d—distal</p

Sonographic studies of the patient with a posterior interosseous nerve (PIN) syndrome.

<p>(A, B) Longitudinal study of healthy PIN (A) and the affected side (B) with significant swelling (thick arrow) before entering the supinator muscle (asterisk). (C) Transversal study with a significant swelling of the PIN (arrow) anterior to the supinator muscle. p—proximal, d—distal</p