Posttraumatic stress disorder is characterized by functional dysregulation of dermal fibroblasts.

Incidence of mental health disorders are rising in modernity, with psychological stress linked to a propensity for developing various chronic diseases due to a relative inability of the body to counter the allostatic load on cellular level. Despite these high rates of comorbidities associated with posttraumatic stress disorder (PTSD), there is still a lack of understanding in terms of the peripheral effects of PTSD on tissue level. Therefore, the purpose of this study was to profile basal dermal fibroblast functional status in PTSD using a wide range of markers involved in the cell-to-cell communication facilitated by fibroblasts. Primary dermal fibroblasts derived from patients diagnosed with PTSD (n = 11) and matched trauma exposed controls (i.e. who did not develop PTSD, n = 10) were cultured using standard techniques. The patients and controls were matched based on age, sex, body-mass index (BMI) and lifestyle. The growth rate, population doubling time, cell surface marker expression (CD31, FNDC5) (flow cytometry), secretome (TIMP-2, MMP-9) (ELISAs), intracellular signalling capacity (Fluo-4 Ca2+ flux) and gene expression (IL-6, IL-10, PTX-3, iNOS, Arg1) were compared between groups. The data illustrated significant PTSD-associated fibroblast conditioning resulting in a blunted signalling capacity. This observation highlights the importance of including tissue-specific investigations in future studies focused on elucidating the association between PTSD and subsequent risk for somatic disease.

High species homology potentiates quantitative inflammation profiling in zebrafish using immunofluorescence.

Due to substantial homology between the human and zebrafish genome and a high level of conservation of the innate immune system across species, zebrafish larvae have become an invaluable research tool for studying inflammation and modelling inflammatory disease. However, further microscopy techniques need to be developed for better profiling of inflammation and in particular, integrated cytokine responses to different stimuli - approaches are currently largely limited to assessment of changes in cytokine gene transcription and in vivo visualisation using transgenics, which is limited in terms of the number of cytokines that may be assessed at once. In this study, after confirming substantial homology of human vs zebrafish cytokine amino acid sequences, immunofluorescence staining using antibodies directed at human cytokines was performed. Inflammatory cytokine signalling responses to experimental tailfin transection was assessed over 24 h (1 hpi (hours post injury), 2 hpi, 4 hpi, 24 hpi) in zebrafish larvae, with experimental end point at 120 h post fertilization (hpf). When immunofluorescence results were compared to responses observed in rodent and human literature, it is clear that the cytokines follow a similar response, albeit with a condensed total time course. Notably, tumor necrosis factor-α and monocyte chemoattractant protein-1 increased and remained elevated over the 24-h period. In contrast, interleukin-1ß and interleukin-6 peaked at 4 hpi and 2 hpi respectively but had both returned to baseline levels by 24 hpi. Macrophage migration inhibitory factor was lowest at 1 hpi, potentially encouraging macrophage movement into the site of injury, followed by a sharp increase. This protocol provides valuable insight into inflammation over a time course and more so, provides an affordable and accessible method to comprehensively assess inflammation in zebrafish disease models.

[Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation]. / Perampanel in der Behandlung eines Patienten mit Glioblastoma multiforme ohne IHD-1-Mutation und ohne MGMT-Promotor-Methylierung.

Malignant gliomas like glioblastoma multiforme (GBM) release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. We report the case of a patient with GBM treated with the AMPA receptor blocker Perampanel (PER) in combination therapy for partial seizures. Histological work-up of a biopsy showed the tissue of a GBM without mutation of the isocitrate dehydrogenase 1 (IDH1) and without promotor methylation of the O6-methylguanine-DNA methyltransferase (MGMT). In a group of patients with IDH 1 wild type and non-methylated MGMT a median survival of 199 days after surgery (i. e. 6.5 months) was described. Our patient lived about one year longer. PER rendered our patient seizure-free for at least the last seven months of his life. It was well tolerated and did not increase the toxicity of temozolomide. When choosing an antiepileptic drug (AED) for the treatment of seizures in patients with malignant brain tumors, the efficacy, the tolerability and perhaps possible effects on tumor progression of the AED should be taken into account.

Effects of intrathecal triamincinolone-acetonide treatment in MS patients with therapy-resistant spasticity.

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease affecting young people and is a major cause of disability. In the course of time, disability progresses and symptoms like spasticity may occur. Spasticity is a major cost factor in MS patients. Various agents are approved for the treatment of spasticity, but each of those agents may have several side effects. Intrathecally administered steroids (triamcinolone-acetonide (TCA)) may be efficient in treating spasticity in patients with lesions in the spinal cord and no response to first-line therapeutics. The aim of this study is to show effects of TCA treatment on clinical parameters in patients with MS. METHODS: This multicentre open label study included 54 patients with MS. The clinical outcome parameters were spasticity, disability, maximum walking distance, bladder function and quality of life. All patients received physiotherapy in addition to TCA treatment to obtain optimal effects on clinical parameters. RESULTS: Spasticity, maximum walking distance as well as disability improved significantly (P ⩽ 0.001) during TCA applications. Bladder function improved in every seventh patient. CONCLUSION: We observed the effects of intrathecally administered TCA on different clinical parameters including bladder function. TCA administration is a safe method to treat different symptoms in MS patients. Longitudinal trials with repeated TCA cycles are needed to show long-term effects. Besides TCA treatment, physiotherapy contributes to the improvement of clinical parameters.

Effects of repeated intrathecal triamcinolone-acetonide application on cerebrospinal fluid biomarkers of axonal damage and glial activity in multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. METHODS: In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH)(SMI35), tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing-remitting and secondary progressive MS). RESULTS: NfH(SMI35) levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle (p = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 (p = 0.03) and at day 8 (p ≤ 0.001). S-100B protein levels decreased significantly (p ≤ 0.05) during treatment with TCA. CONCLUSION: NfH(SMI35) levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfH(SMI35) and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.

Sonographic detection of basal ganglia abnormalities in spasmodic dysphonia.

BACKGROUND AND PURPOSE: Abnormalities of the lenticular nucleus (LN) on transcranial sonography (TCS) are a characteristic finding in idiopathic segmental and generalized dystonia. Our intention was to study whether TCS detects basal ganglia abnormalities also in spasmodic dysphonia, an extremely focal form of dystonia. METHODS: Transcranial sonography of basal ganglia, substantia nigra and ventricles was performed in 14 patients with spasmodic dysphonia (10 women, four men; disease duration 16.5 ± 6.1 years) and 14 age- and sex-matched healthy controls in an investigator-blinded setting. RESULTS: Lenticular nucleus hyperechogenicity was found in 12 spasmodic dysphonia patients but only in one healthy individual (Fisher's exact test, P < 0.001) whilst other TCS findings did not differ. The area of LN hyperechogenic lesions quantified on digitized image analysis correlated with spasmodic dysphonia severity (Spearman test, r = 0.82, P < 0.001). CONCLUSION: Our findings link the underlying pathology of spasmodic dysphonia to that of more widespread forms of dystonia.

CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently defined inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and in particular the pons. The condition features a combination of clinical symptoms essentially referable to brainstem pathology and a characteristic magnetic resonance imaging (MRI) appearance with punctate and curvilinear gadolinium enhancement 'peppering' the pons. The radiological distribution is focused in the pons and adjacent rhombencephalic structures such as the cerebellar peduncles, cerebellum, medulla and the midbrain. While the lesion burden with a perivascular pattern is typically most dense in these pontine and peripontine regions, enhancing lesions may additionally extend into the spinal cord and supratentorial structures such as the thalamus, basal ganglia, capsula interna, corpus callosum and the cerebral white matter. Another core feature is clinical and radiological responsiveness to glucocorticosteroid (GCS)-based immunosuppression. As withdrawal of GCS treatment results commonly in disease exacerbation, long-term immunosuppressive therapy appears to be mandatory for sustained improvement. Diagnosis of CLIPPERS is challenging, and requires careful exclusion of alternative diagnoses. A specific serum or cerebrospinal fluid (CSF) biomarker for the disorder is currently not known. Pathogenesis of CLIPPERS remains poorly understood, and the nosological position of CLIPPERS has still to be established. Whether CLIPPERS represents an independent, actual new disorder or a syndrome that includes aetiologically heterogeneous diseases and/or their prestages remains a debated and not finally clarified issue. Clinicians and radiologists should be aware of this condition and its differential diagnoses, given that CLIPPERS constitutes a treatable condition and that patients may benefit from an early introduction of GCS ensued by long-term immunosuppression. Based on previous reports in literature - currently encompassing more than 50 reported cases of CLIPPERS - this review addresses clinical features, diagnostic criteria, differential diagnoses and therapeutic management of this peculiar disorder.

An open-label cohort study of the improvement of quality of life and pain in de novo cervical dystonia patients after injections with 500 U botulinum toxin A (Dysport).

OBJECTIVES: It remains to be determined whether the benefits of botulinum toxin type A (BoNT-A) on cervical dystonia (CD) motor symptoms extend to improvements in patient's quality of life (QoL). This analysis of a large, multicentre study was conducted with the aim of investigating changes in QoL and functioning among de novo patients receiving 500 U BoNT-A (abobotulinumtoxinA; Dysport) for the treatment of the two most frequent forms of CD, predominantly torticollis and laterocollis. DESIGN: A prospective, open-label study of Dysport (500 U; Ipsen Biopharm Ltd) administered according to a defined intramuscular injection algorithm. SETTING: German and Austrian outpatient clinics. PARTICIPANTS: 516 male and female patients (aged ≥18 years) with de novo CD. The majority of patients had torticollis (78.1%). 35 patients had concomitant depression (MedDRA-defined). MAIN OUTCOME MEASURES: Change from baseline to weeks 4 and 12 in Craniocervical Dystonia Questionnaire (CDQ-24) total and subscale scores, patient diary items ('day-to-day capacities and activities', 'pain' and 'duration of pain') and global assessment of pain. RESULTS: Significant improvements were observed in CDQ-24 total and subscale scores at week 4 and were sustained up to week 12 (p<0.001). Changes in CDQ-24 scores did not significantly differ between the torticollis and laterocollis groups or between patients with or without depression. There were also significant reductions in patient diary item scores for activities of daily living, pain and pain duration at weeks 4 and 12 (p<0.001). Pain relief (less or no pain) was reported by 66% and 74.1% of patients at weeks 4 and 12, respectively. Changes in pain parameters demonstrated a positive relationship with change in Tsui score. CONCLUSIONS: After standardised open-label treatment with Dysport 500 U, improvements in QoL and pain intensity up to 12 weeks in patients with CD were observed.

[Experience with levetiracetam in the treatment of status epilepticus]. / Erfahrungen mit Levetiracetam in der Behandlung des Status epilepticus.

Non-convulsive status epilepticus and epilepsia partialis continua are common epileptic conditions for which straightforward recommendations based on controlled randomised trials for treatment of therapy refractory courses are lacking. Therefore in these conditions sometimes antiepileptic drugs that are not approved by governmental authorities for the treatment of status epilepticus (SE) are used. Here we review all case reports and case series concerning the treatment of SE with levetiracetam (LEV), that had been listed in pub-med up to December 12th 2011. Additionally we analysed abstracts and papers in peer reviewed journals, that were listed in the references of the primarily reviewed papers. Furthermore we looked for LEV treatments in papers on the use of lacosamide (LCM) in SE. LEV was given in dosages ranging from 500 mg to 9000 mg per day. Side effects were especially sedation and irritability. Estimated on the basis of the case series the overall success-rate of LEV in terminating status epilepticus may be set in a range between 53.7% and 58.1%. Therefore LEV may be a useful alternative for the treatment of SE when the approved drugs are contraindicated or when these drugs have been taken without success.

Interhemispheric inhibition in different phenotypes of progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome and an important differential diagnosis of parkinson's disease (PD). The clinical diagnosis of PSP relies on characteristic symptoms. There is evidence of clinical subgroups within the entity of PSP interfering with making the firm diagnosis. It was the aim of the study to clarify the differences between phenotypical subtypes of PSP and PD focusing on transcallosal inhibition (TI). A systematic chart review of 67 patients supposed to have probable PSP was done in a standardized diagnostic work-up. As only complete data sets were included into further analysis, 26 PSP patients (mean age 68.6 ± 7.1 years) could be evaluated and subdivided into Richardson's syndrome (RS) (n = 15) or PSP of parkinsonian type (PSP-P) (n = 11). Fifteen PD patients served as controls. TI was evaluated by investigation of the ipsilateral silent period (iSP) with transcranial magnetic stimulation (TMS). Cognition was assessed by the Addenbrooke's cognitive examination (ACE-R). TMS revealed a significantly more severe affection of TI in RS patients as compared to PSP-P and PD patients who showed similar neurophysiological findings. 47 % of RS patient displayed an iSP loss, whereas PSP-P and PD did not. There was a significant correlation between iSP latency and ACE-R (Spearman's coefficient -0.369, P = 0.010). In conclusion, RS patients-contrary to PSP-P and PD patients-had pathological TI at least in one hemisphere indicating more severe involvement of transcallosally projecting output neurons in RS.

Insular stroke is associated with acute sympathetic hyperactivation and immunodepression.

BACKGROUND AND PURPOSE: Post-stroke immunodepression has been related to brain lesion size but not a specific lesion location. Here, we studied the influence of lesion location within middle cerebral artery (MCA) territory on parameters related to activation of sympathetic adrenomedullar pathway, immunodepression, and associated infection. METHODS: We analyzed clinical, brain imaging, and laboratory data of 384 patients (174 women; mean age 70.8 ± 12.9 years) consecutively admitted to the stroke unit no later than 24 h after onset of acute ischaemic stroke involving the MCA territory. RESULTS: Patients with lesion affecting >33% of MCA territory had increased serum metanephrine and normetanephrine levels, elevated neutrophil counts but decreased eosinophil, helper T lymphocyte, and cytotoxic T lymphocyte counts compared to patients with lesion in <33% of MCA territory. Patients with large infarctions had increased frequency of infections within 14 days after stroke, especially chest infections (P < 0.001). Considering only patients with non-lacunar infarction in <33% of MCA territory, those with insular lesion had significantly higher normetanephrine levels, higher neutrophil but lower eosinophil and helper T lymphocyte counts than those with non-insular lesion, despite similar lesion diameters. This coincided with an increased frequency of chest infections (P < 0.01) in patients with insular lesion. Whilst patients with right insular lesion showed decreased heart rate variability, lesion laterality had no impact on laboratory findings or infection frequency. CONCLUSION: These findings suggest a specific role of insular lesion in the pathogenesis of stroke-induced sympathetic hyperactivation and immunodepression. Neuroimaging studies applying lesion volume calculation techniques are warranted to confirm these findings.

Recurrent aphasic status epilepticus after prolonged generalized tonic-clonic seizures versus a special feature of Todd's paralysis.

Postictal aphasia may be a feature of Todd's paralysis or the presentation of aphasic nonconvulsive status epilepticus (NCSE). We describe a 74-year-old woman with three episodes of aphasic status epilepticus after prolonged generalized tonic-clonic seizures. In the first episode, the NCSE was not definitively diagnosed, but an increase in the epileptic medication led to resolution of the epileptic activity within 2 weeks. During the second episode, NCSE was terminated within 7 days under intensified antiepileptic treatment. In the third episode, phenytoin treatment led to intoxication and resulted in further treatment on an intensive care unit. The patient required several months to recover from this episode. NCSE in the elderly is difficult to recognize, especially when it presents as a prolonged postictal deficit like aphasia. Once diagnosed it has to be treated carefully, because in the elderly, aggressive treatment strategies may be associated with a high risk of adverse events.

Malignant brain oedema after radiosurgery of a medium-sized vestibular schwannoma.

CASE REPORT: We present a patient with an unusual malignant brain oedema occurring after gamma knife radiosurgery of a medium-sized vestibular schwannoma. CLINICAL PRESENTATION: A 62-year-old female with a large vestibular schwannoma underwent partial microsurgical resection; 6 months later she underwent a second intervention with gamma knife radiosurgery for a medium-sized tumour remnant. With a latency period of 6 months after radiosurgery, she presented with progressive neurological deterioration. Serial magnetic resonance imaging revealed progression of the tumour and of the perifocal oedema which finally extended up to the ipsilateral internal capsule. The patient became comatose. INTERVENTION: The tumour was nearly completely removed via a standard retrosigmoid craniotomy. Histopathological examination demonstrated increased mitotic activity compared to the initial histology. The patient became conscious 10 days after surgery and recovered slowly. Surprisingly, the brain oedema resolved rapidly. The CT scan obtained 11 days after surgery showed almost complete disappearance of the oedema. CONCLUSION: Although rare, radiosurgery of medium-sized vestibular schwannomas causing brainstem compression may lead to life-threatening tumour progression and malignant brain oedema. Therefore, microsurgical gross total resection should be the preferred treatment option in vestibular schwannomas causing significant brainstem compression.

Xeomin in the treatment of cervical dystonia.

BACKGROUND AND PURPOSE: Botulinum toxin type A (BoNT/A) is a highly effective and well-tolerated treatment for focal dystonias. The BoNT/A in Botox and Dysport is part of a high-molecular-weight complex that contains hemagglutinins and other non-toxic proteins, whilst Xeomin is a highly purified BoNT/A free of such complexing proteins. In the largest controlled study of BoNT/A published to date (Neurology 2005; 64: 1949), it was demonstrated that Xeomin is non-inferior to Botox and has 1:1 efficacy in the treatment of cervical dystonia. A possible limitation of continued BoNT/A treatment is antibody development. Based on its physiochemical properties and toxicological evidence, Xeomin is expected to have a reduced incidence of non-responders after long-term treatment compared with other marketed BoNT/A products. METHODS AND RESULTS: In our ongoing open-label study, 100 patients suffering from cervical dystonia are continuously treated with Xeomin; 50 patients were treated de novo, the remaining patients had been previously treated with Botox, Dysport or NeuroBloc/Myobloc. All patients showed negative results in antibody testing at the beginning of Xeomin treatment. During continuous treatment with Xeomin up to 2 years, patients continued to respond well to Xeomin treatment. CONCLUSION: The treatment was well tolerated and no patient has developed neutralizing antibodies as measured using the sensitive mouse hemidiaphragma assay within these first 2 years.

Transcranial brain sonography findings predict disease progression in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), an early neurodegenerative affection of subcortical gray matter has been suggested. Transcranial sonography (TCS) shows hyperechogenic lesions of substantia nigra (SN) and basal ganglia, thought to reflect iron accumulation, in a number of primary neurodegenerative diseases. The present study deals with the question of whether TCS can also display deep gray matter lesions in patients with MS and whether sonographic findings relate to severity and progression of MS. METHODS: We prospectively studied 75 patients with different courses of MS and 55 age-matched healthy subjects clinically and with TCS. Twenty-three patients additionally had 1.5-T MRI at the time of TCS. Disease progression was assessed clinically 2 years after TCS. RESULTS: Abnormal hyperechogenicity of SN, lenticular nucleus (LN), caudate nucleus, and thalamus was found in 41%, 54%, 40%, and 8% of the patients with MS, with similar frequency in patients with relapsing-remitting and primary or secondary progressive MS if corrected for disease duration, but only in 13%, 13%, 5% (each, p < 0.001), and none (p = 0.028) of the control subjects. Hyperechogenicity of SN and LN correlated with more pronounced MRI T2 hypointensity, thought to reflect iron deposition. Larger bilateral SN echogenic area was related to higher rate of disease progression, whereas small SN echogenic area (SN hypoechogenicity) predicted a disease course without further progression within 2 years. CONCLUSIONS: Neurodegenerative disease-like deep gray matter lesions can be frequently detected by transcranial sonography (TCS) in patients with multiple sclerosis (MS). Findings suggest that TCS shows changes of brain iron metabolism which correlate with future progress of MS.

[Deep brain stimulation for essential tremor. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei essenziellem Tremor. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

In Germany, deep brain stimulation (DBS) of the thalamic ventralis intermedius nucleus (VIM) is licensed for treatment of essential tremor in cases unresponsive to pharmacotherapy. Especially a bothersome hand tremor interfering with activities of daily living will improve, whereas head, tongue or vocal tremor shows less response. DBS was proven to be superior to lesional thalamotomy with better functional outcome and less adverse effects. The consensus statement presented here reflects the current recommendations of the German Deep Brain Stimulation Study Group for inclusion and exclusion criteria as well as for peri-, intra- and postoperative neurological management.

[Deep brain stimulation for dystonia. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Dystonie. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

Medical treatment of dystonia, particularly generalised forms of the disorder, is often not satisfactory or causes intolerable side effects. In focal dystonia, a reasonable treatment option with botulinum toxin exists but some patients either do not respond well or develop neutralising antibodies with secondary therapy failure. Deep brain stimulation (DBS) of the globus pallidus internus has been shown to be effective in both generalised and focal dystonia. This paper gives recommendations regarding the use of DBS in different forms of dystonia based on the currently available scientific data as well as the longstanding personal experience of the authors. The inclusion criteria for DBS candidates as well as the peri- and postoperative patient management are addressed. These recommendations were developed in a consensus procedure in the German Deep Brain Stimulation Association.

[Deep brain stimulation for tremor in multiple sclerosis : consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Multiple-Sklerose-Tremor : Empfehlungen der Arbeitsgemeinschaft Tiefe Hirnstimulation.

Deep brain stimulation (DBS) in the nucleus ventralis intermedius thalami (VIM) is a common procedure to treat disabling tremor in multiple sclerosis which is refractory to pharmacological treatment. The sparse studies on DBS in multiple sclerosis tremor remain controversial regarding the clinical effect on postural and action tremor of hands, trunk and head. Furthermore, it remains unclear whether DBS in multiple sclerosis tremor is superior to thalamotomy and whether patients show an overall improvement in quality of life and activities of daily living. Therefore, the consensus recommendations of the German Deep Brain Stimulation Study Group rely primarily on expert opinion and include (1) extensive preoperative characterisation of tremor, ataxia with accompanying disabilities, status of the multiple sclerosis, co-morbidities and burden of disease, (2) careful intraoperative testing of effects and side effects and (3) intensive postoperative testing and programming as well as regular re-evaluation of the therapeutic effect.