Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is presented by a large heterogeneity of clinical phenotypes. Around 50% of patients suffer from typical CIDP and show better therapy response than atypical variants. The goal of our study was to search for cellular immunological differences in typical versus atypical CIDP in comparison to controls. METHODS: We evaluated 26 (9 typical, 17 atypical) patients with mainly active-unstable CIDP using clinical and immunological examinations (enzyme-linked immunospot assay ELISPOT, fluorescence-activated cell sorting FACS) in comparison to 28 healthy, age-matched controls (HC). Typical or atypical CIDP measurements were compared with HC using Kruskal-Wallis test. RESULTS: Atypical CIDP patients showed increased frequencies of T cell subsets, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM) as well as a tendency of higher T cell responses against the peripheral myelin antigens of PMP-22, P2, P0 and MBP peptides compared to typical CIDP. Searching for novel auto-antigens, we found that T cell responses against P0 180-199 as well as MBP 82-100 were significantly elevated in atypical CIDP patients vs. HC. CONCLUSIONS: Our results indicate differences in underlying T cell responses between atypical and typical CIDP characterized by a higher peripheral myelin antigen-specific T cell responses as well as a specific altered CD4+ memory compartment in atypical CIDP. Larger multi-center studies study are warranted in order to characterize T cell auto-reactivity in atypical CIDP subgroups in order to establish immunological markers as a diagnostic tool.

MRI-imaging and clinical findings of eleven children with tick-borne encephalitis and review of the literature.

OBJECTIVES: The incidence of tick-borne encephalitis (TBE) is increasing in many countries. Magnetic resonance imaging (MRI) in the course of TBE is not regularly performed in children. The aim of our study was evaluating MRI-findings of children and adolescents with TBE. PATIENTS AND METHODS: Retrospective evaluation of the charts and MRIs of patients who had been treated for TBE in the four participating hospitals in the last twenty years. RESULTS: 11 patients (5 male; age at TBE 3 weeks-15 9/12 years; mean 104.9 months) were included. MRI (within the first week after admission) revealed symmetric or asymmetric T2-hyperintensities in both thalami in 7/11 patients with additional bilateral lesions in putamen and/or caudate nucleus in 3 patients, and additional cortical lesions in 2 patients. Our youngest patient presented with T2-hyperintensities affecting the whole left cerebral hemisphere including white and grey matter and both cerebellar hemispheres. One patient had a minimal reversible T2-hyperintensity in the splenium of the corpus callosum (RHSCC). 3/11 patients had a normal MRI. 4/11 patients showed complete neurological recovery (2/4 with a normal MRI, RHSCC patient). 6/11 children survived with significant sequelae: hemiparesis (n = 4); cognitive deficits (n = 4); pharmacoresistant epilepsy (n = 2). One patient died of a malignant brain edema. DISCUSSION: A spectrum of MRI findings can be found in children with TBE, often showing involvement of the subcortical deep grey matter structures. In children presenting with a meningoencephalitis and bilateral thalamic involvement TBE should be included in the differential diagnosis.

First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome).

INTRODUCTION: We evaluated the long-term efficacy and tolerability of the orphan drug rufinamide (RUF) in children with pharmacoresistant myoclonic-astatic epilepsy (MAE, Doose syndrome). METHODS: This was a retrospective European multicenter study on eight patients who had started an intention-to-treat trial of RUF between July 2007 and June 2010. Clinical information was collected via questionnaire. Responder rate was defined as reduction of seizure frequency ≥50% in comparison to four weeks before starting RUF. Maximum follow-up was eighteen months. RESULTS: Responder rates were 7/8 patients after 3 months, 6/8 patients after 6 months and 5/8 patients after 12 months. RUF seemed particularly effective in the prevention of myoclonic-astatic seizures (comparable with drop attacks in Lennox-Gastaut-Syndrome, for which RUF is particularly effective). Some loss of efficacy was noticed in the long-term observation. Side-effects occurred in two patients. Seizure aggravation was not observed. CONCLUSION: RUF seems to be a promising therapeutic option in children with MAE. Further studies are warranted to confirm these first observations.

Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome.

In this retrospective European multicenter study we evaluated the efficacy and tolerability of rufinamide in patients with Dravet syndrome and refractory seizures. Twenty patients were included; in 16 patients a SCN1A mutation was detected. The responder rate after 6 months was 20%, and after 34 months, 5%. The retention rate was 45% after 6 months and 5% after 34 months. Rufinamide treatment was stopped because of aggravation of seizures (30%), no effect (45%), and side effects (10%). The efficacy and long-term retention rate were low in our patients with Dravet syndrome and refractory seizures, far lower than in patients with Lennox-Gastaut syndrome; one-third of our patients experienced seizure aggravation. Therefore, rufinamide does not seem to be a suitable option for long-term treatment in patients with Dravet syndrome.

Refractory focal epilepsy in a patient with methylmalonic aciduria: case report on positive and long-lasting effect of rufinamide.

We report on a 5-year-old boy with methylmalonic aciduria, an autosomal recessive inborn error of metabolism leading to accumulation of methylmalonic-CoA and thereby causing intoxication with leading symptoms of hyperammonaemia and metabolic acidosis. Hyperammonemia itself causes brain oedema. In our patient, this led to a vast metabolic stroke of the left hemisphere and subsequent pharmacoresistant epilepsy. Guided by his main seizures--drop attacks--the orphan drug rufinamide (RUF) was introduced as "off-label use" and led to freedom of drop attacks and tonic-clonic seizures over a period of 14 months as well as normalisation of the electroencephalogramm. Only once during an episode of fever and diarrhoea with reduced level of RUF did some provoked seizures with focal complex semiology for the time period of infection occur. In the 16 months follow-up, the patient also improved in his development, showing a more stable gait with the hemiparesis and understanding more complex sentences.

Determinants of survival in patients with brain metastases from cutaneous melanoma.

BACKGROUND: This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma. METHODS: In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study. Kaplan-Meier analyses were performed to estimate and to compare overall survival. Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups. RESULTS: In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans. In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)). The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3-5.7). Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase (P<0.001), administered therapy (neurosurgery or SRS vs other, P=0.002), number of brain metastases (single vs multiple, P=0.032) and presence of bone metastasis (false vs true, P=0.044). Three prognostic groups with significantly different overall survival were identified. Candidates for local treatment (group I) had the longer median survival (9 months). Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase. CONCLUSION: Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma. Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.

Functional relevance of ipsilateral motor activation in congenital hemiparesis as tested by fMRI-navigated TMS.

Many, but not all patients with congenital hemiparesis (i.e., hemiparesis due to a pre-, peri- or neonatally acquired brain lesion) control their paretic hands via ipsilateral cortico-spinal projections from the contra-lesional hemisphere (CON-H). Patients who still control their paretic hands via preserved crossed cortico-spinal projections from the damaged hemisphere nevertheless show increased fMRI activation during paretic hand movements in the CON-H. We used fMRI-navigated rTMS induced functional lesions over the primary motor cortex (M1) hand area, the dorsal premotor cortex (dPMC) and the superior parietal lobe (SPL) of the CON-H in four of these patients to investigate whether this increased ipsilateral activation during finger movements of the paretic hand contributes to movement performance. Functional lesions of the dPMC and M1 but not SPL of the CON-H induced decreased temporal preciseness of finger sequences. The present results argue for a possible role of dPMC and M1 of the CON-H on complex motor behavior even in those patients with congenital hemiparesis who control their paretic hands via crossed cortico-spinal projections from the damaged hemisphere.

Do patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to constraint-induced movement therapy?

This study investigates whether the type of corticospinal reorganization (identified by transcranial magnetic stimulation) influences the efficacy of constraint-induced movement therapy (CIMT). Nine patients (five males, four females; mean age 16y [SD 6y 5mo], range 11-30y) controlling their paretic hand via ipsilateral corticospinal projections from the contralesional hemisphere and seven patients (three males, four females; mean age 17y [SD 7y], range 10-30y) with preserved crossed corticospinal projections from the affected hemisphere to the paretic hand underwent 12 consecutive days of CIMT. A Wolf motor function test applied before and after CIMT revealed a significant improvement in the quality of upper extremity movements in both groups. Only in patients with preserved crossed projections, however, was this amelioration accompanied by a significant gain in speed, whereas patients with ipsilateral projections tended to show speed reduction. These data, although preliminary, suggest that patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to CIMT.

Reorganization of the cerebro-cerebellar network of language production in patients with congenital left-hemispheric brain lesions.

Patients with congenital lesions of the left cerebral hemisphere may reorganize language functions into the right hemisphere. In these patients, language production is represented homotopically to the left-hemispheric language areas. We studied cerebellar activation in five patients with congenital lesions of the left cerebral hemisphere to assess if the language network is reorganized completely in these patients, i.e. including also cerebellar language functions. As compared to a group of controls matched for age, sex, and verbal IQ, the patients recruited an area not in the right but in the left cerebellar hemisphere. The extent of laterality of the cerebellar activation correlated significantly with the laterality of the frontal activation. We suggest that the developing brain reacts to early focal lesions in the left hemisphere with a mirror-image organization of the entire cerebro-cerebellar network engaged in speech production.

(Re-)organization of basal ganglia in congenital hemiparesis with ipsilateral cortico-spinal projections.

In congenital hemiparesis after pre- or perinatally acquired unilateral brain lesions, many patients control their paretic hand via ipsilateral cortico-spinal projections from the contralesional hemisphere. In order to clarify the pattern of basal ganglia activation in case of such a shift of the primary motor cortical representation (M1) of the paretic hand to the contralesional hemisphere, fMRI was performed in eight patients with congenital hemiparesis due to unilateral periventricular white matter lesions and ipsilateral corticospinal projections to the paretic hand (as determined by focal transcranial magnetic stimulation). FMRI during active movements of the paretic hand yielded basal ganglia activation in the ipsilateral (=contralesional) hemisphere, but not in the contralateral (lesioned) hemisphere. Thus, (re-)organization in congenital hemiparesis with ipsilateral cortico-spinal projections includes, in addition to the ipsilateral primary motor cortex (M1), also the ipsilateral basal ganglia - in contrast to the primary somatosensory cortex (S1), which is typically preserved in the affected hemisphere.

Cortical neuromodulation by constraint-induced movement therapy in congenital hemiparesis: an FMRI study.

OBJECTIVE: The aim of this study was to assess neuromodulative effects of CIMT in congenital hemiparesis. PATIENTS AND METHODS: Ten patients (age range: 10-30 years) with congenital hemiparesis due to unilateral cortico-subcortical infarctions in the middle cerebral artery territory, and with preserved cortico-spinal projections from the affected hemisphere to the paretic hand, were included. After a twelve-day period of constraint-induced movement therapy (CIMT), all showed a significant improvement of paretic hand function. Immediately before and after therapy, functional MRI during active and passive hand movements was performed to monitor cortical activation. RESULTS: Four patients showed consistent increases in cortical activation during movements of the paretic hand in the primary sensorimotor cortex of the affected hemisphere. Of the remaining six patients, three showed similar changes, but these results were potentially contaminated by an improved task performance after therapy. No significant alteration in activation was observed in two patients, and one showed movement artifacts. CONCLUSIONS: Even a short period of CIMT can induce changes of cortical activation in congenital hemiparesis. In our sample, increases in fMRI activation were consistently observed in the primary sensorimotor cortex of the affected hemisphere. Thus, the potential for neuromodulation is preserved in the affected hemisphere after early brain lesions.

Interference of multimode photon echoes generated in spatially separated solid-state atomic ensembles.

High-visibility interference of photon echoes generated in spatially separated solid-state atomic ensembles is demonstrated. The solid-state ensembles were LiNbO(3) waveguides doped with erbium ions absorbing at 1.53 microm. Bright coherent states of light in several temporal modes (up to 3) are stored and retrieved from the optical memories using two-pulse photon echoes. The stored and retrieved optical pulses, when combined at a beam splitter, show almost perfect interference, which demonstrates both phase preserving storage and indistinguishability of photon echoes from separate optical memories. By measuring interference fringes for different storage times, we also show explicitly that the visibility is not limited by atomic decoherence. These results are relevant for novel quantum-repeater architectures with photon-echo based multimode quantum memories.

Cerebro-muscular and cerebro-cerebral coherence in patients with pre- and perinatally acquired unilateral brain lesions.

The cerebral networks involved in motor control were analyzed in four young hemi-paretic patients (21-25 years) with pre- and perinatally acquired brain lesions (3 with left periventricular brain lesions, 1 with left schizencephaly) by means of MEG source coherence analysis. Previous TMS and fMRI studies on the same patients had investigated their residual ability to move the paretic hand by means of a reorganized primary motor cortex (M1) representation in the contralesional hemisphere. The purpose of this study is to identify the effects of such a cerebral reorganization and the related dynamic aspects which allow the patients to move the paretic arm. Patients underwent a pinch grip task (1-N isometric contraction) using their paretic and non-paretic hands in alternation. MEG signals were recorded using a whole-head 151-channel magnetoencephalograph. EMG was simultaneously recorded as a reference for coherence calculations. 3D coherence mapping was performed in the beta frequency range (14-30 Hz). This approach confirmed the relocation of motor functions from the lesioned (left) to the contralesional (right) hemisphere. In case of left, non-paretic pinch grip, coherent activity originated from contralateral (right) M1 exclusively. In the case of right (paretic) grip, coherent activity in ipsilateral M1 as well as significant coherence of ipsilateral cerebellum with both muscle activity and M1 itself was detected in 3 out of 4 subjects. As expected, the patient with no cerebellar involvement during paretic hand contraction showed the worst motor performance in the grip task. Coupling direction analysis demonstrated that throughout pinch grip the coupling direction goes from M1 to cerebellum. The present study verified the assumption that the intact hemisphere takes over motor control from the paretic (ipsilateral) hand in the presence of early unilateral brain lesion. Moreover, the role of cerebellum in motor deficit compensation and its close interaction with ipsilateral primary motor cortex was studied in detail.

Fidelity of an optical memory based on stimulated photon echoes.

We investigated the preservation of information encoded into the relative phase and amplitudes of optical pulses during storage and retrieval in an optical memory based on stimulated photon echo. By interfering photon echoes produced in a single-mode Ti:Er:LiNbO(3) waveguide, we found that decoherence in the medium translates only as loss and not as degradation of information. We measured a visibility for interfering echoes close to 100%. These results may have important implications for future long-distance quantum communication protocols.

The Rta/Orf50 transactivator proteins of the gamma-herpesviridae.

The replication and transcription activator protein, Rta, is encoded by Orf50 in Kaposi's sarcoma-associated herpesvirus (KSHV) and other known gammaherpesviruses including Epstein-Barr virus (EBV), rhesus rhadinovirus (RRV), herpesvirus saimiri (HVS), and murine herpesvirus 68 (MHV-68). Each Rta/Orf50 homologue of each gammaherpesvirus plays a pivotal role in the initiation of viral lytic gene expression and lytic reactivation from latency. Here we discuss the Rta/Orf50 of KSHV in comparison to the Rta/Orf50s of other gammaherpesviruses in an effort to identify structural motifs, mechanisms of action, and modulating host factors.

Developing somatosensory projections bypass periventricular brain lesions.

The authors studied four hemiparetic patients with large unilateral periventricular brain lesions acquired during the early third trimester of pregnancy. fMRI and magnetoencephalography demonstrated that the primary somatosensory representation of their paretic hands was nevertheless located in the contralateral rolandic cortex. Thus, outgrowing thalamocortical somatosensory projections had apparently bypassed the lesion to reach their original cortical destination. Such somatosensory projections curving around the lesion were effectively visualized by magnetic resonance diffusion tractography.

Pyramidal tract damage correlates with motor dysfunction in bilateral periventricular leukomalacia (PVL).

In children with periventricular leukomalacia (PVL), motor dysfunction is thought to be related to involvement of pyramidal tract fibres in the periventricular white matter. The purpose of the present study was to test this hypothesis. Thirteen former preterm adolescents with PVL, ten of whom were suffering from bilateral spastic cerebral palsy, were studied by MRI. The severity of pyramidal tract damage was assessed on semicoronal MRI reconstructions along anatomical landmarks of somatotopy in the precentral gyrus and the internal capsule; for comparison, the overall volume of cerebral white matter (determined by automated volumetry) served as a global measure of lesion severity. The motor dysfunction of each of the four extremities correlated much more strongly with the severity of pyramidal tract damage assessed on the respective MRI reconstruction (range of correlation coefficients, 0.647 to 0.922) than with the total volume of white matter (range of correlation coefficients, - 0.458 to - 0.212; Spearman). These findings corroborate the notion that an involvement of pyramidal tract fibres in the periventricular white matter is indeed a relevant factor for motor dysfunction in children with PVL.