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.

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.

Retinal imaging and axonal degeneration in later onset multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS typically affecting younger adults and resulting in neuro-axonal degeneration already at early stages of the disease. Less is known about the effects of a later disease onset (LOMS, onset >50years of age). Analysis of retinal layers by optical coherence tomography (OCT) is a non-invasive method to investigate retinal and neuro-axonal degeneration. We applied OCT to detect differences in retinal damage depending on a later disease manifestation. METHODS: 14 LOMS patients, 14 age- and 14 disease duration-matched normal onset (NOMS) patients with a relapsing remitting disease course and 15 healthy controls (HC) were included. OCT measurement of peripapillary retinal nerve fiber layer (RNFL), total macular volume (TMV), combined ganglion cell/inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer retinal layers (ORL) was conducted. Furthermore, analysis of clinical features and of effects of previous optic neuritis (ON) was performed RESULTS: In a GEE based analysis of age- and disease duration matched NOMS, LOMS patients show no significant differences in retinal layer thickness whereas ON significantly reduced thickness of retinal layers. All MS groups display lower retinal layer thickness as compared to HC independently of type of onset. DISCUSSION: Our LOMS findings are well in line with published OCT data of normal onset MS. As the degree of retinal layer thinning was similar in MS subgroups, retinal neurodegeneration in MS may occur independently of time of disease onset.

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.

Baseline magnetic resonance imaging of the optic nerve provides limited predictive information on short-term recovery after acute optic neuritis.

BACKGROUND: In acute optic neuritis, magnetic resonance imaging (MRI) may help to confirm the diagnosis as well as to exclude alternative diagnoses. Yet, little is known on the value of optic nerve imaging for predicting clinical symptoms or therapeutic outcome. PURPOSE: To evaluate the benefit of optic nerve MRI for predicting response to appropriate therapy and recovery of visual acuity. METHODS: Clinical data as well as visual evoked potentials (VEP) and MRI results of 104 patients, who were treated at the Department of Neurology with clinically definite optic neuritis between December 2010 and September 2012 were retrospectively reviewed including a follow up within 14 days. RESULTS: Both length of the Gd enhancing lesion (r = -0.38; p = 0.001) and the T2 lesion (r = -0.25; p = 0.03) of the optic nerve in acute optic neuritis showed a medium correlation with visual acuity after treatment. Although visual acuity pre-treatment was little but nonsignificantly lower if Gd enhancement of the optic nerve was detected via orbital MRI, improvement of visual acuity after adequate therapy was significantly better (0.40 vs. 0.24; p = 0.04). Intraorbitally located Gd enhancing lesions were associated with worse visual improvement compared to canalicular, intracranial and chiasmal lesions (0.35 vs. 0.54; p = 0.02). CONCLUSION: Orbital MRI is a broadly available, valuable tool for predicting the improvement of visual function. While the accurate individual prediction of long-term outcomes after appropriate therapy still remains difficult, lesion length of Gd enhancement and T2 lesion contribute to its prediction and a better short-term visual outcome may be associated with detection and localization of Gd enhancement along the optic nerve.

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.

Visual search as a tool for a quick and reliable assessment of cognitive functions in patients with multiple sclerosis.

BACKGROUND: Despite the high frequency of cognitive impairment in multiple sclerosis, its assessment has not gained entrance into clinical routine yet, due to lack of time-saving and suitable tests for patients with multiple sclerosis. OBJECTIVE: The aim of the study was to compare the paradigm of visual search with neuropsychological standard tests, in order to identify the test that discriminates best between patients with multiple sclerosis and healthy individuals concerning cognitive functions, without being susceptible to practice effects. METHODS: Patients with relapsing remitting multiple sclerosis (n = 38) and age-and gender-matched healthy individuals (n = 40) were tested with common neuropsychological tests and a computer-based visual search task, whereby a target stimulus has to be detected amongst distracting stimuli on a touch screen. Twenty-eight of the healthy individuals were re-tested in order to determine potential practice effects. RESULTS: Mean reaction time reflecting visual attention and movement time indicating motor execution in the visual search task discriminated best between healthy individuals and patients with multiple sclerosis, without practice effects. CONCLUSIONS: Visual search is a promising instrument for the assessment of cognitive functions and potentially cognitive changes in patients with multiple sclerosis thanks to its good discriminatory power and insusceptibility to practice effects.

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.