Frequency and risk factors of antibody-induced secondary failure of botulinum neurotoxin therapy.

OBJECTIVE: To investigate the risk factors of neutralizing antibody (NAB)-induced complete secondary treatment failure (cSTF) during long-term botulinum neurotoxin (BoNT) treatment in various neurologic indications. METHODS: This monocenter retrospective cohort study analyzed the data of 471 patients started on BoNT therapy between 1995 and 2015. Blood samples of 173 patients were investigated for NABs using the mouse hemidiaphragm test (93 with suspected therapy failure, 80 prospective study participants). The frequency of NAB-cSTF was assessed for various indications: hemifacial spasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. A priori defined potential risk factors for NAB-cSTF were evaluated, and a stepwise binary logistic regression analysis was performed to identify independent risk factors. RESULTS: Treatment duration was 9.8 ± 6.2 years (range, 0.5-30 years; adherence, 70.6%) and number of treatment cycles 31.2 ± 22.5 (3-112). Twenty-eight of 471 patients (5.9%) had NAB-cSTF at earliest after 3 and at latest after 103 treatment cycles. None of the 49 patients treated exclusively with incobotulinumtoxinA over 8.4 ± 4.2 (1-14) years developed NAB-cSTF. Independent risk factors for NAB-cSTF were high BoNT dose per treatment, switching between onabotulinumtoxinA and other BoNT formulations (except for switching to incobotulinumtoxinA), and treatment of neck muscles. CONCLUSIONS: We present a follow-up study with the longest duration to date on the incidence of NAB-cSTF in patients treated with various BoNT formulations, including incobotulinumtoxinA. Whereas the overall risk of NAB-cSTF is low across indications and BoNT formulations, our findings underpin the recommendations to use the lowest possible dose particularly in cervical dystonia, and to avoid unnecessary switching between different formulations.

Long-Term Effects of Repeated Cycles of Intrathecal Triamcinolone Acetonide on Spasticity in MS Patients.

MAIN PROBLEM: Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters. METHODS: A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25-foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle. RESULTS: Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long-lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months. CONCLUSION: Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re-administration of TCA and that an interval of 3 months between the treatments might be too long.

Frequency and profile of Parkinson's disease prodromi in patients with malignant melanoma.

OBJECTIVE: The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma. METHODS: 100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2±14.9 years) and another 35 served as control participants (19 women; 54.6±20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants. RESULTS: Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck. CONCLUSIONS: History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research.

No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study.

BACKGROUND/AIMS: A substantial proportion of amyotrophic lateral sclerosis (ALS) patients develop cognitive impairments. Longitudinal investigations of cognition in ALS have shown mixed results. While some authors report that cognitive performance remains stable as the disease progresses, others have found evidence for deterioration in various domains. Our objective was to investigate cognitive performance in ALS longitudinally, using the example of executive functions. METHODS: 93 ALS patients and 73 age-, sex- and education-matched healthy controls underwent up to four neuropsychological evaluations, separated by 3- to 6-month intervals. We examined whether performance declined longitudinally on seven tests assessing various sub-components of executive functioning. Furthermore, we assigned an executive-performance-based 'cognitive status' to each participant for every evaluation, examining whether cognitive deterioration (if present) was modulated by their baseline cognitive status and whether cognitive status changed over time. RESULTS: Regardless of their cognitive status at baseline, ALS patients showed no significant decline in the sub-components of executive functioning. CONCLUSION: Our findings imply that the executive deficits which develop in some ALS patients emerge before motor symptoms and remain stable after an initial decline. The discrepancy between this trajectory and the progressive decline in motor functions may result from a differential vulnerability of motor and non-motor prefrontal neurons to the pathomechanism of ALS.

Magnetic resonance-transcranial ultrasound fusion imaging: A novel tool for brain electrode location.

BACKGROUND: A combination of preoperative magnetic resonance imaging (MRI) with real-time transcranial ultrasound, known as fusion imaging, may improve postoperative control of deep brain stimulation (DBS) electrode location. Fusion imaging, however, employs a weak magnetic field for tracking the position of the ultrasound transducer and the patient's head. Here we assessed its feasibility, safety, and clinical relevance in patients with DBS. METHODS: Eighteen imaging sessions were conducted in 15 patients (7 women; aged 52.4 ± 14.4 y) with DBS of subthalamic nucleus (n = 6), globus pallidus interna (n = 5), ventro-intermediate (n = 3), or anterior (n = 1) thalamic nucleus and clinically suspected lead displacement. Minimum distance between DBS generator and magnetic field transmitter was kept at 65 cm. The pre-implantation MRI dataset was loaded into the ultrasound system for the fusion imaging examination. The DBS lead position was rated using validated criteria. Generator DBS parameters and neurological state of patients were monitored. RESULTS: Magnetic resonance-ultrasound fusion imaging and volume navigation were feasible in all cases and provided with real-time imaging capabilities of DBS lead and its location within the superimposed magnetic resonance images. Of 35 assessed lead locations, 30 were rated optimal, three suboptimal, and two displaced. In two cases, electrodes were re-implanted after confirming their inappropriate location on computed tomography (CT) scan. No influence of fusion imaging on clinical state of patients, or on DBS implantable pulse generator function, was found. CONCLUSIONS: Magnetic resonance-ultrasound real-time fusion imaging of DBS electrodes is safe with distinct precautions and improves assessment of electrode location. It may lower the need for repeated CT or MRI scans in DBS patients.

Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients.

OBJECTIVES: Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease. PARTICIPANTS: Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18-69 years). OUTCOME MEASURES: Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. RESULTS: A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd+) MRI lesions (p = 0.001) and EDSS ≤ 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd+ MRI lesions was significantly altered (p = 0.004). CONCLUSION: Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd+ MRI lesions before treatment were the best predictor of the response to TPE in our cohort.

Cognitive outcome of pallidal deep brain stimulation for primary cervical dystonia: One year follow up results of a prospective multicenter trial.

BACKGROUND: Pallidal deep brain stimulation (DBS) is effective in alleviating motor symptoms of medication refractory cervical dystonia, but little is known about effects on cognitive functions. METHODS: As part of the first randomized, sham-controlled multicenter trial on DBS in medication-refractory primary cervical dystonia (ClinicalTrials.gov, number NCT00148889), a subgroup of 13 patients aged 39 to 69 underwent prospective neuropsychological long-term follow-up assessments. Various cognitive domains (memory, executive functions, attention, visual perception, mental arithmetic and verbal intelligence) were examined before and after 12 months of continuous DBS. RESULTS: Only the number of produced words in a verbal fluency task which included alternating categories decreased after stimulation (p = 0.020). All other cognitive domains remained unchanged. CONCLUSIONS: These findings indicate that long-term pallidal DBS for the treatment of primary cervical dystonia seems to be safe regarding global cognitive functioning.

Comparison of the effectiveness of four antiepileptic drugs in the treatment of status epilepticus according to four different efficacy criteria.

The preliminary data presented here shall give an impression on how different criteria for the identification of an antiepileptic drug (AED) with a possible or certain treatment effect can have an influence on the results of retrospective case series. We present a data subset from a large retrospective study which, when completed, will cover all treatment episodes of status epilepticus (SE) at the neurological department of the Universitätsmedizin Rostock from January 2010 to June 2013. We compare and contrast the results of four different efficacy criteria for the effectiveness of phenytoin (PHT), valproate (VPA), levetiracetam (LEV), and lacosamide (LCM): criterion 1 = the last AED administered before SE termination; criterion 2 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination and without changes in the comedication; criterion 3 = the last drug introduced into the antiepileptic therapy or increased in dose within 24h before SE termination without changes in the comedication; and criterion 4 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination, even allowing changes in the comedication. Thirty-seven treatment episodes in 32 patients (13 male and 19 female, mean age at first episode: 68 years, SD: 17) could be analyzed. In 31 episodes, at least one AED was given intravenously. Efficacy rates in the whole case series according to all four criteria were not significantly different between the four AEDs, but there was a considerable difference in the efficacy rates of each AED when evaluating them with the different efficacy criteria. Our data show that statistically significant results concerning the efficacy of different AEDs in different subtypes of SE may depend on the outcome criteria. Therefore, efficacy criteria for the effectiveness of AEDs in the treatment of SE should be standardized. This article is part of a Special Issue entitled Status Epilepticus.

Dysexecutive functioning in ALS patients and its clinical implications.

Pronounced cognitive and behavioural impairments in amyotrophic lateral sclerosis (ALS) concern executive functions and executive behaviour. The valid measurement is challenging as motor disabilities may mask everyday functioning. The aim of this study was to determine a detailed characteristic pattern of executive impairment in ALS in order to effectively interpret their clinical impact. We investigated 98 ALS patients without or with frontotemporal dementia (FTD), and 70 healthy controls using a comprehensive neuropsychological test battery focusing on executive functions and executive behaviour. We analysed the impairment of executive functions and their clinical significance for patients' daily routines. Results demonstrated that around 70% of cognitively impaired ALS patients without FTD showed disturbances in executive functioning. Behavioural abnormalities primarily manifested in symptoms of apathy. Patients without FTD were most impaired in the executive domain regarding initiation and shifting; this contrasted their almost preserved processes relating to updating, inhibition, and complex problem solving. ALS-FTD patients showed deficits in all analysed processes. Our study suggests that executive dysfunctioning in cognitively impaired ALS patients without FTD does not preferentially affect the more complex regulatory processes. These findings indicate potential mechanisms for ALS patients to compensate for executive dysfunction in daily routine.

Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders.

BACKGROUND: IncobotulinumtoxinA (Xeomin(®)) is a purified botulinum neurotoxin type A formulation, free from complexing proteins, with proven efficacy and good tolerability for the treatment of neurological conditions such as blepharospasm, cervical dystonia (CD), and post-stroke spasticity of the upper limb. This article provides a comprehensive overview of incobotulinumtoxinA based on randomized controlled trials and prospective clinical studies. SUMMARY: IncobotulinumtoxinA provides clinical efficacy in treating blepharospasm, CD, and upper-limb post-stroke spasticity based on randomized, double-blind, placebo-controlled trials with open-label extension periods (total study duration up to 89 weeks). Adverse events were generally mild or moderate. The most frequent adverse events, probably related to the injections, included eyelid ptosis and dry eye in the treatment of blepharospasm, dysphagia, neck pain, and muscular weakness in patients with CD, and injection site pain and muscular weakness when used for treating spasticity. In blepharospasm and CD, incobotulinumtoxinA was investigated in clinical trials permitting flexible intertreatment intervals based on the individual patient's clinical need; the safety profile of intervals shorter than 12 weeks was comparable to intervals of 12 weeks and longer. There were no cases of newly formed neutralizing antibodies during the Phase III and IV incobotulinumtoxinA trials. Phase III head-to-head trials of incobotulinumtoxinA versus onabotulinumtoxinA for the treatment of blepharospasm and CD have demonstrated therapeutic equivalence of both formulations. Additional Phase III trials of incobotulinumtoxinA in conditions such as lower-limb spasticity, spasticity in children with cerebral palsy, and sialorrhea in various neurological disorders are ongoing. CONCLUSION: IncobotulinumtoxinA is an effective, well-tolerated botulinum neurotoxin type A formulation. Data from randomized clinical trials and further observational studies are expected to help physicians to optimize treatment by tailoring the choice of formulation, dose, and treatment intervals to the patient's clinical needs.

Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.

We provide some evidence concerning the efficacy of perampanel (PER) in refractory status epilepticus (SE). We retroactively identified patients with SE treated in our department by searching for the term "status epilepticus" in the electronic archive of medical records. We present and analyze in this paper the subset of data of the patients treated with PER. We analyzed ten episodes of SE in nine patients. At the first administration, PER was given in a dosage of 6mg to most of our patients (7 of 10). On average, PER was administered as the 6th antiepileptic drug (AED) (range: 2-10). Depending on the criterion for efficacy, PER appears effective for the termination of SE in 2 to 6 (of 10) episodes. Unfortunately, safety data for the administration of PER with loading doses needed for the treatment of SE are lacking. Because of this, PER should be used very carefully in refractory SE and only after first-line treatment options have failed.

Prediction of Parkinson's disease subsequent to severe depression: a ten-year follow-up study.

Major depressive disorder (MDD) has been associated with an increased risk of subsequent Parkinson's disease (PD) in case-control and cohort studies. However, depression alone is unlikely to be a useful marker of prodromal PD due to its low specificity. In this longitudinal observational study, we assessed whether the presence of other potential markers of prodromal PD predicts the subsequent development of PD in MDD patients. Of 57 patients with severe MDD but no diagnosis of PD who underwent a structured interview, olfactory and motor investigation and transcranial sonography at baseline, 46 (36 women; mean age 54.9 ± 11.7 years) could be followed for up to 11 (median, 10) years. Three patients (2 women; age 64, 65 and 70 years) developed definite PD after 1, 7, and 9 years, respectively. The combined finding of mild asymmetric motor slowing, idiopathic hyposmia, and substantia nigra hyperechogenicity predicted subsequent PD in all patients who could be followed for longer than 1 year. Out of the whole study cohort, only the subjects with subsequent PD presented with the triad of asymmetric motor slowing, idiopathic hyposmia, and substantia nigra hyperechogenicity in combination with at least two out of four reportable risk factors (family history of PD, current non-smoker, non-coffee drinker, constipation) at baseline investigation. Post-hoc analysis revealed that additional rating of eye and eye-lid motor abnormalities might further improve the prediction of PD in larger cohorts. Findings of this pilot-study suggest that MDD patients at risk of subsequent PD can be identified using an inexpensive non-invasive diagnostic battery.

Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy.

Effect of methylprednisolone on mammalian neuronal networks in vitro.

Glucocorticosteroids (GCS) are widely used for the treatment of neurological diseases, e.g. multiple sclerosis. High levels of GCS are toxic to the central nervous system and can produce adverse effects. The effect of methylprednisolone (MP) on mammalian neuronal networks was studied in vitro. We demonstrate a dose-dependent excitatory effect of MP on cultured neuronal networks, followed by a shut-down of electrical activity using the microelectrode array technique.

Microstructural white matter changes underlying cognitive and behavioural impairment in ALS--an in vivo study using DTI.

BACKGROUND: A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients. METHODS: We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures. RESULTS: Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts. CONCLUSION: In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial.

BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 µs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.