Johannes C. Wöhrle

Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.clinicaltrials.gov Identifier: NCT01829581.

Here we test the hypothesis that there are distinct temporal patterns of synchronized neuronal activity in the pallidum that characterize untreated and treated parkinsonism and dystonia.To this end we recorded local ®eld potentials (LFPs) from the caudal and rostral contact pairs of macroelectrodes implanted into the pallidum of patients for the treatment of Parkinson's disease (12 cases recorded on and off medication, 17 macroelectrodes) and dystonia (10 cases, 19 macroelectrodes).Percentage LFP power in the 11±30 Hz band was decreased and that in the 4±10 Hz band increased across both contact pairs in treated Parkinson's disease compared with untreated Parkinson's disease.Dystonic patients had even less 11±30 Hz power and greater 4±10 Hz power compared with untreated or treated Parkinson's disease patients.The change in the 4±10 Hz band in patients with dystonia was particularly manifest in the more rostral contact pair, presumed to be within or bridging the globus pallidus externus.We conclude that untreated and treated Parkinson's disease and dystonia are characterized by different spatiotemporal patterns of activity in the human pallidum.

Object Recently, limited decompression procedures have been proposed in the treatment of lumbar stenosis. The authors undertook a prospective study to compare the safety and outcome of unilateral and bilateral laminotomy with laminectomy. Methods One hundred twenty consecutive patients with 207 levels of lumbar stenosis without herniated discs or instability were randomized to three treatment groups (bilateral laminotomy [Group 1], unilateral laminotomy [Group 2], and laminectomy [Group 3]). Perioperative parameters and complications were documented. Symptoms and scores, such as visual analog scale (VAS), Roland—Morris Scale, Short Form—36 (SF-36), and patient satisfaction were assessed preoperatively and at 3, 6, and 12 months after surgery. Adequate decompression was achieved in all patients. The overall complication rate was lowest in patients who had undergone bilateral laminotomy (Group 1). The minimum follow up of 12 months was obtained in 94% of patients. Residual pain was lowest in Group 1 (VAS score 2.3 ± 2.4 and 4 ± 1 in Group 3; p &lt; 0.05 and 3.6 ± 2.7 in Group 2; p &lt; 0.05). The Roland—Morris Scale score improved from 17 ± 4.3 before surgery to 8.1 ± 7, 8.5 ± 7.3, and 10.9 ± 7.5 (Groups 1–3, respectively; p &lt; 0.001 compared with preoperative) corresponding to a dramatic increase in walking distance. Examination of SF-36 scores demonstrated marked improvement, most pronounced in Group 1. The number of repeated operations did not differ among groups. Patient satisfaction was significantly superior in Group 1, with 3, 27, and 26% of patients unsatisfied (in Groups 1, 2, and 3, respectively; p &lt; 0.01). Conclusions Bilateral and unilateral laminotomy allowed adequate and safe decompression of lumbar stenosis, resulted in a highly significant reduction of symptoms and disability, and improved health-related quality of life. Outcome after unilateral laminotomy was comparable with that after laminectomy. In most outcome parameters, bilateral laminotomy was associated with a significant benefit and thus constitutes a promising treatment alternative.

There is still limited knowledge on the location and etiology of transient global amnesia (TGA). MR studies including diffusion-weighted imaging (DWI) have been unable to demonstrate consistently the location and underlying pathology of TGA.To investigate patients with TGA using serial DWI performed from the day of symptom onset through days 1 and 2.After reporting negative DWI results in a previous study, the authors used a modified study design to investigate patients with TGA using serial DWI performed from the day of symptom onset through days 1 and 2.Of 31 consecutive patients studied, 26 developed a small, punctate DWI lesion in the lateral aspect of the hippocampal formation (pes and fimbria hippocampi) on either side (left, n = 15; right, n = 6) or bilaterally (n = 5). Lesions were rarely noted in the hyperacute phase (n = 2), but all became visible regularly at 48 hours.The study confirms the involvement of hippocampal parenchyma in the pathophysiology of TGA. The delayed detectability of the lesions may explain the incongruence of previous MR DWI studies in TGA patients.

(23)Na MRI has the potential to noninvasively detect sodium (Na) content changes in vivo. The goal of this study was to implement (23)Na MRI in a clinical setting for neurooncological and muscular imaging. Due to the biexponential T(2) decay of the tissue Na signal with a short component, which ranges between 0.5-8 ms, the measurement of total Na content requires imaging techniques with echo times (TEs) below 0.5 ms. A 3D radial pulse sequence with a TE of 0.2 ms at a spatial resolution of 4 x 4 x 4 mm(3) was developed that allows the acquisition and presentation of Na images on the scanner. This sequence was evaluated in patients with low- and high-grade gliomas, and higher (23)Na MR signals corresponding to an increased Na content were found in the tumor regions. The contrast-to-noise ratio (CNR) between tumor and white matter increased from 0.8 +/- 0.2 to 1.3 +/- 0.3 with tumor grade. In patients with an identified muscular (23)Na channelopathy (Paramyotonia congenita (PC)), induced muscle weakness led to a signal increase of approximately 18% in the (23)Na MR images, which was attributed to intracellular Na(+) accumulation in this region.

The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).Surgical hematoma evacuation vs conservative treatment.The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH.We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03).Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Depth recordings in patients with Parkinson's disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of approximately 70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at approximately 70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep-wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle-eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at approximately 70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at approximately 70 Hz may be involved in movement and arousal.

The pathophysiology of dystonia is unclear. The authors recorded local field potentials (LFPs) from deep brain stimulation electrodes implanted in the pallidum of 13 dystonic patients. LFP power correlated with the level of dystonic EMG in the sternocleidomastoid, with maximal positive correlations at the lower contacts of pallidal electrodes. The data suggest that the neuronal synchronization indexed by LFP oscillations in the globus pallidus may be mechanistically linked to dystonic EMG activity.

Survival in amyotrophic lateral sclerosis varies considerably. About one third of the patients die within 12 months after first diagnosis. The early recognition of fast progression is essential for patients and neurologists to weigh up invasive therapeutic interventions. In a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany, we identified significant prognostic factors at time of diagnosis that allow prediction of early death within first 12 months.Incident cases, diagnosed between October 2009 and September 2012 were enrolled and followed up at regular intervals of 3 to 6 months. Univariate analysis utilized the Log-Rank Test to identify association between candidate demographic and disease variables and one-year mortality. In a second step we investigated a multiple logistic regression model for the optimal prediction of one-year mortality rate.In the cohort of 176 ALS patients (mean age 66.2 years; follow-up 100%) one-year mortality rate from diagnosis was 34.1%. Multivariate analysis revealed that age over 75 years, interval between symptom onset and diagnosis below 7 months, decline of body weight before diagnosis exceeding 2 BMI units and Functional Rating Score below 31 points were independent factors predicting early death.Probability of early death within 12 months from diagnosis is predicted by advanced age, short interval between symptom onset and first diagnosis, rapid decline of body weight before diagnosis and advanced functional impairment.ClinicalTrials.gov (NCT01955369, registered September 28, 2013).

The Mohr–Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early‐onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness–dystonia peptide (DDP1/TIMM8a) gene on the X‐chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone‐like manner to facilitate the import of nuclear‐encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient’s DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy‐generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico‐ cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.

The pattern of reoccurrence of symptoms after discontinuation of deep brain stimulation (DBS) has not been systematically studied in dystonia. Eight patients (mean age (SD) 53.8 (14.4) years) with segmental dystonia at a mean follow-up of 11.3 (4.2) months were studied after implantation of bilateral DBS electrodes in the internal globus pallidus using a standard video protocol and clinical rating scales, immediately and at 2 and 4 h after switching off DBS. Dystonic signs returned sequentially, with a rapid worsening of phasic and a slower worsening of tonic dystonic components. In all patients, phasic dystonic features appeared within a few minutes, whereas the tonic elements of dystonia reoccurred with a more variable delay. Differential clinical effects when withdrawing DBS might reflect its influence on different pathophysiological mechanisms in dystonia.

Objectives The clinical spectrum of amyotrophic lateral sclerosis (ALS) is characterized by a considerable variation. Different phenotypes have been described by previous studies. We assessed clinical variability and prognostic relevance of these phenotypes in a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany. Methods Incident ALS cases, diagnosed between October 2009 and September 2012, were prospectively enrolled and classified according to established ALS phenotype classification (bulbar, classic, flail arm, flail leg, pyramidal, respiratory). Survival probability was described using Kaplan–Meier method. Moreover, the influence of an additional frontotemporal dementia (FTD) was analysed. Results Phenotypes of all 200 patients were determined. Bulbar and classic phenotypes accounted for 75% of all cases. Deterioration of functional impairment during disease progression was lowest in flail leg and pyramidal variants, and most pronounced in bulbar and classic phenotypes. A poor survival prognosis was observed for bulbar, classic or respiratory phenotypes. Patients with an additional FTD showed an even worse outcome. Conclusions Results suggest that ALS is a heterogeneous disease, as ALS phenotypes differ in disease progression and survival time. Patients classified as suffering from bulbar, classic and respiratory ALS, as well as those with an additional FTD, show a marked reduction of survival time.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Purpose: To prospectively examine whether sodium 23 (23Na) magnetic resonance (MR) imaging can be used to visualize acute intracellular Na+ accumulation and the effects of specific therapy in patients with paramyotonia congenita (PC). Materials and Methods: Ethics committee approval and informed consent were obtained. Sixteen patients (four women, 12 men; mean age, 46.7 years ± 16.7 [standard deviation]) with confirmed PC and 10 healthy volunteers (three women, seven men; mean age, 26.6 years ± 3) were examined by using a 1.5-T MR system with a 16.8-MHz surface coil. 23Na MR imaging was performed before and after local cooling of the nondominant lower leg and exercising, with experimentally induced weakness scored by a neurologist. The 23Na MR examination was repeated in 13 patients and all volunteers after 3 days and, additionally, in seven patients after 4 days of oral administration of mexiletine, which blocks Na+ channels. The 23Na MR protocol comprised two-dimensional (2D) fast low-angle shot (FLASH), 2D radial, and free induction decay (FID) sequences. The FID data were fitted to a biexponential decay curve to evaluate the slow and fast components of the T2 relaxation time. Fast and slow components were assigned to intra- and extracellular Na+ concentrations, respectively. Radial and FLASH MR images were evaluated by means of a region-of-interest analysis by using 0.3% saline solution for reference. T1- and T2-weighted MR imaging were also performed. Data were analyzed by using a parametric t test. Results: After exercising, all patients developed considerable weakness exclusively in the cooled lower leg; no weakness was observed in volunteers. In patients, all 23Na MR images showed a significant increase in 23Na signal intensity in the cooled lower leg (P < .001) in comparison with nonsignificant findings in volunteers. After treatment with mexiletine, cooling and exercise induced almost no muscle weakness and no changes in 23Na MR signal intensity in patients. Conclusion: 23Na MR imaging enables visualization of muscular Na+ accumulation associated with muscle weakness in patients with PC, and effects of specific therapy can be detected. © RSNA, 2006

Objective To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. Methods Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. Results IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume &lt;4.4 mL: 0.18 (0.04–0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS &lt;4: 0.29 (0.11–0.78); p=0.014) were significantly associated with fewer IHC. Conclusions Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

HomeStrokeAhead of PrintOrolingual Angioedema in Stroke Without r-tPA Treatment: Evidence for Insular and Opercular Contribution No AccessArticle CommentaryRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessOrolingual Angioedema in Stroke Without r-tPA Treatment: Evidence for Insular and Opercular Contribution Ralph Werner and Johannes C. Wöhrle Ralph WernerRalph Werner Correspondence to: Ralph Werner, MD, Department of Neurology and Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Kardinal-Krementz-Str. 1-5, 56073 Koblenz, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2216-3954 Department of Neurology and Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Germany. and Johannes C. WöhrleJohannes C. Wöhrle Department of Neurology and Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Germany. Originally published12 Apr 2024https://doi.org/10.1161/STROKEAHA.124.046401Stroke. 2024;0"Orolingual Angioedema in Stroke Without r-tPA Treatment: Evidence for Insular and Opercular Contribution." Stroke, , pp. FootnotesFor Sources of Funding and Disclosures, see page XXX.Correspondence to: Ralph Werner, MD, Department of Neurology and Stroke Unit, Katholisches Klinikum Koblenz-Montabaur, Kardinal-Krementz-Str. 1-5, 56073 Koblenz, Germany. Email r.werner@bbtgruppe.de eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2024 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.124.046401PMID: 38606554 Originally publishedApril 12, 2024 Keywordsangioedemainsular cortexrisk factorsstrokevasodilationPDF download Advertisement SubjectsCerebrovascular Disease/Stroke

A 68 year old woman with sporadic Creutzfeldt-Jakob disease is described, who neither showed characteristic EEG abnormalities nor a positive test of the neuronal protein 14-3-3 or neuron specific enolase (NSE) in CSF, despite a clinical presentation with ataxia of cerebellar type, rapidly progressive dementia, myoclonus, and marked hyperintense signal abnormalities in the deep cortical layers and the basal ganglia on T2 and diffusion weighted MRI. Moreover she showed atypical clinical features with a syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and a peripheral sensorimotor polyneuropathy. Whether these disturbances are independent of Creutzfeldt-Jakob disease or a feature of it is discussed. It has recently been shown that in Creutzfeldt-Jakob disease different clinical and pathological phenotypes correlate with the polymorphism at codon 129 of the prion protein gene (PRNP) and the type of the protease resistant fragment that accumulates in the brain. According to the new classification at least six sporadic variants of Creutzfeldt-Jakob disease exist. The molecular genetic analysis showed heterozygosity of PRNP at codon 129 for methionine and valine and the presence of PrP(CJD) type 2 in the brain of this patient. As a new feature of changes on MRI, striking cortical changes of hyperintense signals are described in diffusion weighted as well as T2 weighted MRI that directly correlate with the histomorphological spongy degeneration of the brain in this region. In cases of rapidly progressive dementia, Creutzfeldt-Jakob disease always needs to be considered even if unusual features are present and current diagnostic criteria are not in favour of this disease.

Chronic axonal polyneuropathy is a well-known clinical sequela of excessive alcohol consumption; however, acute axonal polyneuropathy related to alcohol abuse is less well recognized.To describe alcohol-related acute axonal polyneuropathy in 5 chronic alcoholics who developed ascending flaccid tetraparesis and areflexia within 14 days.Case series with clinical, laboratory, electrophysiological, and, in 1 patient, biopsy data.All 5 patients consumed a daily average of 250 g of alcohol, and 4 had lost a substantial amount of weight recently. Additional clinical features included painful paresthesia, myalgia, and glove and stocking-type sensory loss. Repeated cerebrospinal fluid examinations failed to show the marked increase of protein concentration with normal cell count typical of Guillain-Barré syndrome, although the protein level was mildly elevated in 1 patient. Blood laboratory findings were consistent with longstanding alcohol abuse. Compound muscle and sensory nerve action potentials were absent or reduced, while conduction velocities were normal or mildly reduced. Three to 4 weeks after onset, needle electromyography displayed moderate to severe fibrillations and positive sharp waves in addition to normal motor unit potentials, indicating an acute axonal polyneuropathy; this was confirmed by sural nerve biopsy in 1 patient.Excluding other factors, we assume that in these patients the combination of alcohol abuse and malnutrition caused severe acute axonal polyneuropathy. Its distinction from Guillain-Barré syndrome is important because treatment requires balanced diet, vitamin supplementation, and abstinence from alcohol, while immunotherapy may not be indicated.

The possibility to survive with amyotrophic lateral sclerosis (ALS) varies considerably and survival extends from a few months to several years. A number of demographic and clinical factors predicting survival have been described; however, existing data are conflicting. We intended to predict patient survival in a population-based prospective cohort of ALS patients from variables known up to the time of diagnosis.Incident ALS patients diagnosed within three consecutive years were enrolled and regularly followed up. Candidate demographic and disease variables were analysed for survival probability using the Kaplan-Meier method. The Cox proportional hazard regression model was used to assess the influence of selected predictor variables on survival prognosis.In the cohort of 193 patients (mean age 65.8, standard deviation 10.2 years), worse prognosis was independently predicted by older age, male gender, bulbar onset, probable or definite ALS according to El Escorial criteria, shorter interval between symptom onset and diagnosis, lower Functional Rating Scale, diagnosis of frontotemporal dementia, and living without a partner.Taking into account these predictor variables, an approximate survival prognosis of individual ALS patients at diagnosis seems feasible.

There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. During the period 2010–2011, consecutive incident patients with amyotrophic lateral sclerosis according to the revised El Escorial criteria were included and followed up using multiple overlapping sources of case ascertainment. One hundred and forty-six patients were enrolled. The annual crude incidence for amyotrophic lateral sclerosis in Rhineland-Palatinate was 1.8/100,000 person-years (95% CI 1.6–2.2). Male to female ratio was 1.1:1. Incidence increased with age reaching a peak in the 70–74 years age group and declined thereafter. Late-onset ALS (≥ 75 years) was found in 14.4% of patients. About 32% of patients presented with bulbar onset. In conclusion, incidence rate of amyotrophic lateral sclerosis in Rhineland-Palatinate is within the range of other prospective population based registers in Europe and North America. Gender ratio is nearly balanced.

Abstract Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor and other cardinal symptoms in Parkinson's disease (PD), the precise mechanisms of action of DBS are still unclear. We analyzed the time course of resting tremor amplitude and frequency during discontinuation and subsequent reinitiation of STN‐DBS in nine PD patients, using a computerized three‐dimensional motion analysis combined with surface electromyography. Following discontinuation of STN‐DBS, resting tremor amplitude rapidly increased, reaching maximum amplitude after 2 min (mean ± 95%CI: 34.3 ± 13.8 mm; P &lt; 0.01), subsequently stabilizing at a medium level. Reinitiation of stimulation after 30 min resulted in rapid, nearly complete suppression of tremor activity within 1 min (1.4 ± 1.3 mm; P &lt; 0.01) and, furthermore, increased tremor frequency within a few seconds in seven of nine patients. These findings support the hypothesis that STN‐DBS acts by direct interference with the neurotransmission of basal ganglia networks involved in tremor. © 2009 Movement Disorder Society

A 67-year-old man with risperidone-responsive segmental dystonia underwent bilateral deep brain stimulation (DBS) of the globus pallidus internus. Prospectively, the authors assessed the Burke–Fahn–Marsden Dystonia Rating Scale in medication (M) and stimulation (S) "on"/"off" states. With DBS at 9 months, the score improved by 86% to 8.5 in M-"on"/S-"on" and 12.5 in M-"off"/S-"on." Studies of the effects of DBS and concomitant medication may be warranted in selected patients treated by DBS for dystonia.

Abstract OBJECTIVE: We report on the effect of multifocal deep brain stimulation for the treatment of posttraumatic peripherally-induced dystonia. CLINICAL PRESENTATION: A 34-year-old woman presented with an 8-year history of painful tonic dystonia starting in her left leg after injury of the third metatarsal bone. She did not benefit from right-sided pallidal stimulation by an electrode misplaced in the globus pallidus externus in another hospital. INTERVENTION: Quadripolar deep brain stimulation electrodes were placed in the globus pallidus internus and the ventrolateral thalamus by computed tomographic-guided stereotactic surgery and microelectrode recording contralateral to the side of dystonia. The Burke-Fahn-Marsden motor score of 34 did not improve with chronic pallidal or thalamic stimulation. CONCLUSION: Although deep brain stimulation is received with great enthusiasm, it is important to identify its limitations in certain subtypes of dystonia.

It is well known that brain injury or central traumatic lesions may result in the subsequent appearance of movement disorders such as dystonia or tremor. The concept that peripheral lesions to neural structures may be involved in the pathogenesis of movement disorders has been discussed controversely but has gained more widespread acceptance only recently. Here, we report on 6 patients who developed movement disorders after spinal disc surgery. The movement disorders became manifest with a delay of 1 day to 12 months after surgery. Of the six patients, 4 underwent cervical disc surgery, and 2 patients were operated on for lumbar disc herniation; 2 patients presented with paroxysmal kinesigenic segmental dystonia, 1 patient with focal dystonia, 2 with unilateral tremor, and 1 with bilateral tremor. The appearance of the movement disorder was associated with persistent dermatomal or segmental pain. In all patients, the anatomic distribution of the movement disorder was related to the nerve root or spinal segment of the corresponding disc level and the manifestation was in close temporal relation to the surgery. We conclude that spinal disc surgery may be another, thus far neglected, cause for movement disorders. The postoperative pain syndrome in all patients should be considered as an important factor of pathogenesis. Overall, movement disorders associated with disc surgery appear to be rare, yet they may cause significant discomfort to the affected individual.

✓ Propriospinal myoclonus is a rare form of spinal myoclonus. In most cases the cause has remained unclear. Secondary propriospinal myoclonus has been described secondary to various disorders including trauma, tumor, and infection. Thus far, propriospinal myoclonus caused by cervical disc herniation has not been reported. In the present report, the authors describe the case of a 53-year-old man who presented with radicular symptoms of the right C-6 nerve root and myoclonic twitches predominantly affecting the abdominal muscles but spreading to adjacent muscles. The spread was triggered and enforced by certain movements. Magnetic resonance imaging studies revealed a C-6 nerve root compression at the C5–6 level on the right side but no cervical myelopathy. Electromyography studies confirmed the diagnosis of propriospinal myoclonus. After discectomy and cage-augmented fusion via an anterior approach, the myoclonic movement disorder gradually subsided. To the authors' knowledge, this is the first report on successful treatment of propriospinal myoclonus by spinal disc surgery.

Multifocal deep brain stimulation (DBS) is a new technique that has been introduced recently. A 39-year-old man with dystonia-parkinsonism underwent the simultaneous implantation of subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS electrodes. While bilateral STN DBS controlled the parkinsonian symptoms well and allowed for a reduction in levodopa, the improvement of dystonia was only temporary. Additional GPi DBS also alleviated dystonic symptoms. Formal assessment at the 1-year follow-up showed that both the parkinsonian symptoms and the dystonia were markedly improved via continuous bilateral combined STN and GPi stimulation. Sustained benefit was achieved at 3 years postoperatively.

In acute stroke, a magnetic resonance (MR) perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) mismatch (PWI>DWI mismatch) may indicate tissue at risk for infarction and poor prognosis. However, different to early enthusiasm about this surrogate marker, its validity has shown several drawbacks in individual patients. Rather than relying on imaging, we evaluated motor evoked potentials (MEP) as a measure of cerebral function in the acute stroke setting.Thirteen patients with acute hemiparetic stroke underwent time to peak PWI and DWI within 6 h after onset as well as recordings of early MEP of first dorsal interosseous muscles. Outcome was assessed by the Unified Neurological Stroke Scale and Barthel Index at day 42.Of 8 patients with PWI>DWI mismatch, 4 patients with normal MEP had a good clinical outcome and 4 patients with absent or pathological MEP had an unfavourable outcome (p < 0.05, Fisher's exact test). In all patients without PWI>DWI mismatch, MEP findings predicted clinical outcome. Normal MEP at day 0--but not PWI/DWI findings--significantly correlated with a good clinical outcome.Early MEP recordings in acute stroke patients provide valid prognostic information; they may become more useful for specific treatment decisions than presently available MRI surrogate parameters.

Muscle & NerveVolume 18, Issue 8 p. 904-906 Short Report Motor evoked potentials to magnetic stimulation in chronic and acute inflammatory demyelinating polyneuropathy Dr. Johannes C. Wöhrle MD, Corresponding Author Dr. Johannes C. Wöhrle MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanyDepartment of Neurology, University of Heidelberg, Klinikum Mannheim, 68135 Mannheim, FRGSearch for more papers by this authorThomas Kammer MD, Thomas Kammer MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this authorWolfgang Steinke MD, Wolfgang Steinke MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this authorMichael Hennerici MD, Michael Hennerici MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this author Dr. Johannes C. Wöhrle MD, Corresponding Author Dr. Johannes C. Wöhrle MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanyDepartment of Neurology, University of Heidelberg, Klinikum Mannheim, 68135 Mannheim, FRGSearch for more papers by this authorThomas Kammer MD, Thomas Kammer MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this authorWolfgang Steinke MD, Wolfgang Steinke MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this authorMichael Hennerici MD, Michael Hennerici MD Department of Neurology, University of Heidelberg, Klinikum Mannheim, Mannheim, GermanySearch for more papers by this author First published: August 1995 https://doi.org/10.1002/mus.880180816Citations: 13AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume18, Issue8August 1995Pages 904-906 RelatedInformation

Abstract We tested the characteristics and the differential pattern of upper extremity motor compromise, comparing hand tapping in patients with subcortical vascular encephalopathy (SVE; n = 18), idiopathic Parkinson's disease (PD; n = 18), and in healthy controls (n = 18). Both patient groups showed significant compromise in hand tapping compared with that in controls, with higher coefficients of variability (CV) regarding tapping amplitude and angular velocity, determined using a computerized movement analysis system. A differential tapping pattern in both patient groups could be demonstrated in that patients with PD showed lower tapping amplitudes than patients with SVE. Both patient groups displayed abnormalities in tapping rhythmicity compared with that in the control group. © 2005 Movement Disorder Society

Mutations in the X-linked deafness-dystonia peptide 1 (DDP1) gene cause Mohr-Tranebjaerg syndrome (MTS), a rare form of deafness associated with dystonia. In the patient presented here, improvement of dystonic symptoms upon treatment with alcohol and GABAergic substances is demonstrated for the first time.

Abstract Peptide-HLA (pHLA) targeting therapeutics like TCR-based adoptive cell therapy or bispecific T cell engaging receptor molecules hold great promise for the treatment of cancer. Comprehensive pre-clinical screening of therapeutic candidates is important to ensure patient safety but is challenging because of the size of the potential off-target space. By combining stabilized peptide-receptive HLA molecules with microarray printing and screening, we have developed an ultra-high-throughput screening platform named ValidaTe that enables large scale evaluation of pHLA-binder interactions. We demonstrate its potential by measuring and analyzing over 30.000 binding curves for a high-affinity T cell Engaging Receptor (TCER) towards a large pHLA library. Compared to a dataset obtained by conventional bio-layer interferometry (BLI) measurements, we illustrate that a massively increased throughput is obtained by our microarray screening without compromises in data quality, paving the way for use in pre-clinical safety screening of pHLA-targeting drugs.

This case report describes monocular blurred vision and photopsia with headache.

Contrasting the more benign causes known for meralgia paraesthetica we report a case due to a malignant tumour of the psoas muscle. We discuss the use of sensory nerve conduction study and somatosensory evoked potentials of the lateral femoral cutaneous nerve as well as needle EMG and diagnostic nerve block to detect the site of the lesion along its course. This appears of major importance, as causes located above the inguinal ligament can bear a more serious prognosis than the ones below.

We describe a case of acute multifocal motor neuropathy with normal sensory conduction studies in the nerve segments of severe motor conduction block. Antiganglioside antibodies were not detected in serum and the patient recovered spontaneously. The clinical picture and course of time of the illness allowed the diagnosis of a Guillain-Barré syndrome (GBS). The electrophysiological findings closely matched the typical findings of chronic multifocal motor neuropathy with persistent conduction block. From these similarities, we conclude that acute and chronic forms of acquired demyelinating motor neuropathies have to be accepted as variants of acute GBS and chronic inflammatory demyelinating polyneuropathy (CIDP), respectively. We suggest that the conduction block cannot always be attributed to antiganglioside antibodies, as chronic cases without antiganglioside antibodies have also been reported and further elevation of antibody titres has been seen after spontaneous recovery.

Objective: To report the treatment of ischemic stroke in a pregnant woman with intravenous recombinant tissue plasminogen activator (IV rtPA). Background Although cerebrovascular complications of pregnancy are well recognized, the data on IV rtPA in acute ischemic stroke of pregnant women is exceedingly scarce. Design/Methods: Single case study. Results: A 35-year old woman in her 27 th week of pregnancy presented one hour after the onset of global aphasia and mild right-sided brachiofacial hemiparesis (NIHSS 7). Cerebrovascular risk factors included hypercholesterolemia, a history of smoking and migraine, and a persistent foramen ovale. Immediate cerebral magnetic resonance (MR) imaging of a stroke protocol showed a faint diffusion weighted MR hyperintensity in the anterior territory of the left middle cerebral artery with normal appearance in FLAIR. Color-coded duplex sonography directly visualized a high-grade stenosis of a branch of the left MCA and documented a greater than 30% reduction of flow velocity in M1 as compared to the right MCA. MR angiography supported this diagnosis of left M2/M3 stenosis. After informed consent from the husband, the patient received IV rtPA at a dose of 0.9 mg/kg body weight over 1 hour, starting 1,75 h after onset of symptoms. The patient fully recovered within 1 hour after the end of IV rtPA administration. Anticoagulation was started after 24 h with subcutaneous low molecular weight heparin for the rest of the pregnancy. At term, the delivery of a healthy baby (2700g, 47 cm, Apgar Index 9-10-10) occured. Conclusions: The use of rtPA in pregnant women is neither particularly tested nor recommended, however, it is known not to cause fetotoxicity or teratogenicity and does not cross the placenta. IV rtPA may be considered in severe ischemic stroke in pregnant women, especially when alternative therapies are lacking. Disclosure: Dr. Wohrle has nothing to disclose. Dr. Tveici has nothing to disclose. Dr. Werner has nothing to disclose.

Muscle & NerveVolume 21, Issue 10 p. 1354-1355 Letter to the Editor Collision technique in Martin–Gruber anastomosis Georgios Amoiridis MD, Corresponding Author Georgios Amoiridis MD [email protected] Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanyNeurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorLudger Schöls MD, Ludger Schöls MD Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorHorst Przuntek MD, Horst Przuntek MD Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorJohannes Wöhrle MD, Johannes Wöhrle MD Klinikum Mannheim, Fakultät für klinische Medizin der Universität Heidelberg, Heidelberg, GermanySearch for more papers by this author Georgios Amoiridis MD, Corresponding Author Georgios Amoiridis MD [email protected] Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanyNeurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorLudger Schöls MD, Ludger Schöls MD Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorHorst Przuntek MD, Horst Przuntek MD Neurologische Klinik der Ruhr-Universität, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, GermanySearch for more papers by this authorJohannes Wöhrle MD, Johannes Wöhrle MD Klinikum Mannheim, Fakultät für klinische Medizin der Universität Heidelberg, Heidelberg, GermanySearch for more papers by this author First published: 07 December 1998 https://doi.org/10.1002/(SICI)1097-4598(199810)21:10<1354::AID-MUS22>3.0.CO;2-0Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Amoiridis G: Motorische Neurographie: Simultane Ableitung des Muskelantwortpotentials mittels Nadelund Oberflächenelektrode. Ein Vergleich beider Methoden. Medizinische dissertation, Bochum, Bundesrepublik Deutschland, 1987. 2 Amoiridis G, Haan JJ: Motorische Neurographie: Simultanableitung mittels Oberflächenund Nadelelektroden. Vergleichende Untersuchung von proximaler und distaler Latenz sowie motorischer Nervenleitgeschwindigkeit. Z EEG-EMG 1990; 21: 51– 55. 3 Amoiridis G: Median-ulnar nerve communications and anomalous innervation of the intrinsic hand muscles: an electrophysiological study. Muscle Nerve 1992; 15: 576– 579. 4 Amoiridis G: Fact and fallacy in electrophysiological studies of anomalous innervation patterns of the intrinsic hand muscles. Muscle Nerve 1994; 17: 245– 246. 5 Amoiridis G: Motorische Innervationsanomalien im Bereich der Hand und des Fusses: Untersuchungsmethoden, Häufigkeit, klinische und elektrophysiologische Relevanz. Habilitationsschrift, Bochum, 1997. 6 Hopf HC, Hense W: Anomalien der motorischen Innervation an der Hand. Z EEG-EMG 1974; 5: 220– 224. 7 Kimura J: Collision technique. Neurology 1976; 26: 680– 682. 8 Kimura J, Murphy MJ, Varda DJ: Electrophysiological study of anomalous innervation of intrinsic hand muscles. Arch Neurol (Chicago) 1976; 33: 842– 844. 9 Sander HW, Quinto C, Chokroverty S: Median-ulnar anastomosis to thenar, hypothenar, and first dorsal interosseous muscles: collision technique confirmation. Muscle Nerve 1997; 20: 1460– 1462. Citing Literature Volume21, Issue10October 1998Pages 1354-1355 ReferencesRelatedInformation

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A 73-year-old man developed progressive respiratory failure within 24 hours, requiring emergency admission for mechanical ventilation. The cause of the dyspnoea and tachypnoea could not be ascertained by routine medical and neurological examination. Neuromuscular disease or a cerebral lesion was considered in the differential diagnosis, together with a cardiovascular cause.Neither laboratory tests nor additional investigations (chest radiogram, echocardiography) gave a diagnosis. Magnetic resonance imaging and computed tomography excluded a focal cerebral or spinal lesion or a space-occupying lesion in the region of the phrenic nerve. An electrophysiological tests (EPT) failed to establish a neuromuscular disease. However, when signs of upper motor neurone irritation appeared, more detailed EPTs, also of the muscles of breathing, provided the diagnosis of amyotrophic lateral sclerosis (ALS).Symptomatic treatment with pyridostigmine made it possible gradually to wean the patients off the ventilator so that he could be sent home on intermittent mechanical ventilation.In case of acute respiratory failure without cardiopulmonary cause motoneurone disease with initial involvement of respiratory musculature should be considered, even in the absence of clinical signs, and special electrophysiological tests may be necessary to recognize the underlying disease.

Hans von Bülow (1830-1894) was a conductor and pianist of worldwide reputation and founder of many stylistic interpretations of classic and romantic symphonies. The close friendship with Richard Wagner, but not the enthusiastic admiration of his dramatic musical opus, ended abruptly when Hans von Bülow became aware of the betrayal of his wife Cosima and Richard Wagner. Hans von Bülow reported symptoms and signs of neurological disease in many letters that were kept and edited by his second wife Marie. For decades he suffered from chronic neuralgiforme headaches, which were caused by a tumor of the cervical radicular nerves. At the age of 45 years, he suddenly developed a motorsensory deficit in the right arm and hand and a contralateral facial deficit, suggestive of brainstem infarction. He recovered and celebrated even greater successes as a musician, although phases of major depression also interfered with his professional life. In the last, phase of his life, he experienced the consequences of generalized atherosclerosis and cerebral microangiopathy. It was a second cerebrovascular accident of the brainstem that caused his death, only 10 months after his last concert performance. Although his death occurred in Egypt, an autopsy was performed by Professor Ludwig Edinger and the results will be presented.

We report the case of a 40 year-old man with a severe lesion of the anterior rami of the left spinal nerves L5 and S1 who showed hypertrophy of the leg and atrophy of the intrinsic foot and gluteal muscles. In the biopsy of the hypertrophied gastrocnemius muscle, perivascular inflammatory infiltrates were observed, apart from atrophied and hypertrophied muscle fibres. Electromyography revealed no pathologic spontaneous activity but chronic neurogenic changes. The precise site of the lesion was predicted by electrophysiologic investigations. The lesion was caused by two perineural cysts in the region of the upper sacral plexus, as demonstrated by MRI and CT of the small pelvis and confirmed at operation. Three years earlier, when almost only L5 muscles were affected, an intervertebral disc prolapse L5/S1 had been suspected on myelography and CT but could not have been confirmed at operation.

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While idiopathic TN is associated with some delay in P19 response of the cortical trigeminal somatosensory evoked potential (T-SEP) in up to 50 % of patients, the blink reflex (BR) evoked by stimulation of the supraorbital nerve is usually not involved. We present a case of symptomatic TN in which the combination of electrophysiological findings was remarkable. A 74 year-old man had a 3 month history of dull and diffuse pain of the left maxilla. Ten days before admission, he developed short-lasting attacks of severe sudden, sharp and stabbing pain in the left maxilla radiating to the temporal, frontal and mandibular regions of the left face. There were 1 to 4 attacks per day, no triggers could be identified. Neurological examination revealed hypaesthesia in the left face (V1-3) and mild asymmetry of the facial innervation due to peripheral paresis on the left. Other cranial nerve functions were normal, as was the rest of the neurological examination. T-SEP of the left trigeminal nerve (simultaneous stimulation of upper and lower lip) revealed a delayed P19 response of 24.1 ms versus a normal response on the right of 20.1 ms. Blink reflex studies of the trigeminal and facial nerves were typical of an afferent lesion of the left trigeminal nerve with delays of ipsilateral R1 and ipsi- and contralateral R2 while these potentials were normal on the right (Fig. 1). Electrical stimulation of the facial nerve at the foramen stylomastoideum and magnetic stimulation of the canalicular part of the facial nerve gave normal results, bilaterally. Finally, MRI of the head demonstrated a T1-contrast enhancing mass lesion in the region of the left cavum Meckeli, which reached to the cavernous sinus and the internal carotid artery, presumably of mesenchymal origin (meningeoma? Fig. 2). Symptomatic pain control was achieved by administration of carbamazepine and pregabaline, and the patient awaited neurosurgical biopsy. Our case demonstrates that TN is more likely to be of symptomatic than idiopathic or vascular compressive origin if not only T-SEP but also BR are abnormal, indicating a demyelinating lesion. MRI with thorough examination of the anatomical course of the TN is necessary to guide therapeutic decisions including neurosurgical intervention and biopsy.

Introduction: Contactin-associated protein like-2 (CASPR2)- autoantibodies are associated with distinctive syndromes 1 , such as agrypnia excitata, psychosis, neuromytonia and limbic encephalitis. All of them are highly responsive to immunotherapy. The target of these directly pathogenetic autoantibodies are surface-exposed domains of CASPR2 2 . Due to the fact of multiple variations of clinical presentations, it may be challenging to distinguish particular an autoimmune encephalitis associated with anti-neuronal autoantibodies, from primary psychiatric disorders such as psychosis. First medical treatment should be immediate immunotherapy, such as steroids, intravenous antibodies or plasma exchange given fast diagnosis of encephalitis is made. In our case the EEG showed focal slow waves with the clinical presentation of an acute psychosis which leaded to an admission to the neurology ward and further investigations. Patient and methods: A 75-years-old man was hospitalized on a psychiatric ward for psychotic symptoms characterized by psychomotor agitation, thought disorganization, persecutory delusions and auditory hallucinations with commanding voices and global insomnia. Cerebral Imaging with cMRI and cCT scan showed no acute abnormalities. EEG showed focal intermittent slow delta-theta wave activity (4-6 Hz) on the left temporal lobe, reactive to visual stimuli and provided focal cerebral dysfunction and pathology. CSF did not reveal any evidence of infection, but CASPR2- autoantibodies (1:10.000) were indentified and the diagnosis of limbic encephalitis with CASPR2-antibodies was made. Treatment with high dose dexamethasone and intravenous immunoglobulin (IVIG) was made and the clinical conditions improved. Conclusion: Fast and first medical treatment of autoimmune encephalitis should be initiated in early stages. To avoid an unnecessary delay in diagnosis and treatment, EEG, cMRI and expanded CSF examination should be performed as soon as possible to prevent severe disability in patients with limbic encephalitis with CASPR2-antibodies. References: 1 Irani SR, Alexander S, Waters P et al (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133:2734–2748. 2 Lancaster E, Martinez-Hernandez E, Dalmau J (2011) Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77:179–189.

Zusammenfassung Verkürzte Liegezeiten, wachsender administrativer Aufwand, eine zunehmende Komplexität in Diagnostik und Therapie und der wirtschaftliche Druck gehen mit einer Zunahme der Arbeitsdichte für Ärzte in neurologischen Kliniken einher. Eine zu hohe Arbeitsdichte kann die Behandlungsqualität beeinträchtigen und die Ausbildung von Assistenzärzten gefährden. In der Pflege, in psychiatrischen Kliniken und im Bereich der neurologischen Rehabilitation gibt es aktuell Ansätze, Mindestpersonalstandards einzuführen. Vor diesem Hintergrund plädieren die Autoren für: – die Einführung von Personaluntergrenzen für Ärzte in neurologischen Kliniken, aber auch für andere Berufsgruppen und andere medizinische Fächer – die Entwicklung eines Personalbemessungsinstruments, mit dessen Hilfe für jede Klinik ein angemessener Personalschlüssel festgelegt werden kann – eine Verbindlichkeit der Personalstandards einschließlich einer kompletten Gegenfinanzierung – realistische Übergangsfristen angesichts des aktuellen Ärztemangels

Zusammenfassung Hintergrund Demografischer Wandel, Urbanisierung sowie eine zunehmende Spezialisierung der Akutversorgung von Schlaganfallpatienten erfordern eine Anpassung von Versorgungsstrukturen mit dem Ziel, auch Patienten in ländlichen Regionen leitliniengerecht behandeln zu können. Methodik Im Frühjahr 2016 wurde ein landesweites telemedizinisches Schlaganfallnetzwerk unter Einbeziehung aller 6 überregionalen Stroke Units im Land Rheinland-Pfalz etabliert. Die Zuständigkeit für den Konsildienst wechselt täglich zwischen den Kliniken und steht rund um die Uhr zur Verfügung. Alle Kriterien des OPS 8.98b werden erfüllt. Am Netzwerk teilnehmen können alle regionalen Stroke Units und Kliniken, die prädefinierte Kriterien erfüllen und nicht in regionaler Konkurrenz mit etablierten Stroke Units stehen. Ergebnisse Zu Projektbeginn am 01.04. 2016 nahmen 6 Kliniken teil, die alle eine regionale Stroke Unit unter internistischer Leitung besitzen. Innerhalb des ersten Jahres erfolgten 1568 telemedizinische Konsile. Die Diagnosen waren ischämische Infarkte (n = 802 Patienten; 51,2 %), intrazerebrale Blutungen (n = 46; 2,9%), transitorisch ischämische Attacken (TIA; n = 319; 20,4 %) und nicht vaskuläre Ursachen (sog. Stroke Mimics; n = 400; 25,5 %). Die Latenz zwischen Klinikaufnahme und Konsilbeginn betrug im Median 21 Minuten (Interquartilrange (IQR) 22 Minuten), die mediane Konsildauer lag bei 24 Minuten (IQR 22 Minuten). Bei den Patienten mit ischämischen Schlaganfällen betrug die Lyserate 12,5 % (n = 100). Eine mechanische Thrombektomie wurde nach Weiterverlegung in eines der Zentren bei 4,6 % (n = 37) der Patienten durchgeführt. Schlussfolgerung Die telemedizinische Netzwerkbildung ist geeignet, die landesweite Versorgung von Schlaganfallpatienten sicherzustellen. Weitere Analysen, insbesondere zum Outcome, werden benötigt.

Die Behandlung des fortgeschrittenen Pleuramesothelioms ist nach wie vor eine therapeutische Herausforderung und leider sind die Überlebenszeiten nach Erstdiagnose selten länger als 12 Monate. Ziel der therapeutischen Maßnahmen ist das Erzielen von Krankheitskontrolle. Remissionen (partiell oder komplett) sind äußerst selten zu beobachten. Studien mit PDL-1 Inhibitoren sind im Gange. Bisherige Ergebnisse sind eher ernüchternd.

Warum dieser Fall? Die vorliegende Kasuistik demonstriert, dass Neuromyelitis optica-Spektrum-Erkrankungen (NMOSD) im Liquor die Befundkonstellation einer bakteriellen Infektion und im zerebralen MRT das Vorliegen einer Progressiven multifokalen Leukenzephalopathie (PML) imitieren können, was insbesondere bei Antikörpernegativität zu erheblichen differenzialdiagnostischen Schwierigkeiten führen kann.

Objective: To assess demographic and hemodynamic characteristics of TGA patients in order to identify risk factors of the syndrome. Background: The etiology of transient global amnesia is still a matter of debate. Previous studies refuted a cerebrovascular pathology as they neither found a higher burden of vascular risk factors nor revealed an increased incidence of strokes after TGA. Design/Methods: We reviewed the clinical records and the magnetic resonance imaging time of flight angiographies of 169 TGA patients and compared the findings to an age and sex matched control group of neurological patients. Results: In TGA, 103 patients (60.9%) were female, 66 male (39.1%), the sex ratio was 1.56:1. The average age was 66.8 years; women were about 5 years older than men (68.8 vs. 63.7 years, p Conclusions: Our large single centre study identified female sex and a status of private health insurance (vs. public health care) as potential demographic risk factors. Differences in the diameters of the intracranial vessels may argue for a pathophysiologic contribution of hemodynamic factors. Disclosure: Dr. Werner has nothing to disclose. Dr. Ekstrom has nothing to disclose. Dr. Wohrle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boehringer Ingelheim Pharma GmbH & Co. KG, and Daiichi Sankyo Deutschland.

Die Parkinsonkrankheit (Morbus Parkinson, primäres oder idiopathisches Parkinsonsyndrom, im Englischen Parkinson’s disease, PD) ist eine der häufigsten altersabhängigen neurodegenerativen Erkrankungen. Sie wird durch einen progredienten Verlust pigmentierter, dopaminerger Neurone pathologisch-anatomisch charakterisiert. Im Jahre 1817 beschrieb der englische Arzt James Parkinson (1755–1824) in seinem „Essay on the Shaking Palsy“ die grundlegenden klinischen Charakteristika der Parkinsonkrankheit (Ruhe-) Tremor, Rigor, Akinese und gestörte posturale Kontrolle, die eine unveränderte Wertigkeit für die klinische Diagnose besitzen: „Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forwards and to pass from a walking to a running pace; the senses and intellects being uninjured.“ Parkinson nahm verschiedene Ursachen für die Erkrankung seiner Patienten an und wies so auf ihre Heterogenität hin. Heute unterscheiden wir neben der Parkinsonkrankheit verschiedene Parkinsonsyndrome (Parkinsonismus), die zum einen sekundär bei bekannter Ursache (z.B. nach Intoxikation mit 1 -Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) oder medikamenteninduziert durch Neuroleptika), und zum anderen als Teil einer sporadischen oder hereditären neurodegenerativen Erkrankung mit mehr oder weniger im Vordergrund stehender rigidakinetischer Symptomatik auftreten.

Hintergrund: Die motorischen Symptome einer Dystonie führen bei vielen Patienten im Verlauf zu körperlicher Behinderung und sozialen Beeinträchtigungen, was oft in einer Verschlechterung der Lebensqualität resultiert. Da eine medikamentöse Therapie zumeist ineffektiv ist, hat sich die tiefe Hirnstimulation (DBS) als eine Behandlungsalternative bei generalisierten und segmentalen Dystonien etabliert. Der Effekt der DBS auf die gesundheitsbezogene Lebensqualität ist bei der segmentalen Dystonien bislang nur in Einzelfallberichten untersucht worden. Wir evaluierten in einer Serie von 10 Patienten mit segmentaler Dystonie prospektiv den Effekt der DBS auf die Lebensqualität.

Introduction: It is known that the duration of the silent period (SP) following transcranial magnetic stimulation (TMS) can be used as a measure of intracortical inhibition. Thus, the SP is used in the clinical routine and in many studies, e.g., in order to evaluate the prognosis of motor recovery after stroke or for examining the cortical excitability in epilepsy patients. In most studies using TMS, recordings of the SP are performed by asking the subjects to contract their muscles (e.g., the first dorsal interosseous muscle, FDI) with maximal or sub-maximal strength. However, a possible modulation of the SP depending on the grade of voluntary muscle contraction strength has not been sufficiently examined. If present, such a modulation could influence the assessment of the results of TMS examinations. The purpose of our study was to investigate the duration of the SP in the contralateral FDI with different levels of contraction strength. Methods: 6 young healthy subjects (i.e., 12 hemispheres) participated in this study. We used a focal stimulating coil, which was placed over the hand area of the primary motor cortex. After the motor hot spot of the contralateral FDI was identified, the motor threshold (MT) and the maximal voluntary contraction strength (MVC) were determined. TMS was performed with 25%, 50%, 75% and 100% of the MVC, using 120% and 150% of the MT. Contraction strength was controlled and made visible to both the subject and the investigator using a hydraulic pinch dynamometer which allowed comfortable pressure application by the finger tips. Results: Using stimuli with an intensity of 120% of the MT, no changes in the duration of the SP became apparent when the subjects contracted their muscles at the different strength levels. The mean SP values for all subjects (in ms,±standard deviation) were 110.8 (±36) for 25% MVC, 112.3 (±35) for 50% MVC, 105.6 (±28) for 75% MVC and 109.4 (±32) for 100% MVC. With stimulation using 150% of the MT, the duration of the SP tended to be longer when the force applied from the subjects was higher, but it did not reach significant levels (137.5±39 ms for 25% MVC, 147.3±36 ms for 50% MVC, 146.6±28 ms for 75% MVC and 153.1±42 ms for 100% MVC). Conclusions: The contraction strength does not influence the duration of the SP significantly. This may be explained by modulations of the intracortical inhibition taking place in relation with the changing innervation level of the target muscle.

ZusammenfassungDie transkranielle Magnetstimulation (TMS) stellt eine Routinemethode zur Untersuchung des zentralmotorischen Systems dar. Sie ergänzt die Diagnostik evozierter Potenziale um sog. motorisch evozierte Potenziale (MEP), die evozierte Muskelsummenpozentiale der Zielmuskeln nach Stimulation des motorischen Kortex sind. Hemmende Effekte bei Stimulation geeigneter Kortexareale mit fokalen Spulen erlauben ein topografisches Mapping von Funktionen an der Schädeloberfläche, womit sich beispielsweise eine kortikale Plastizität in Läsions- oder Lernmodellen demonstrieren lässt. Mit Doppelreiztechnik können Funktionen der interhemisphärischen Transmission oder pharmakologische Effekte überprüft werden. Die repetitive hochfrequente TMS bietet positive therapeutische Effekte bei akinetischen Bewegungsstörungen (z. B. idiopathisches Parkinson-Syndrom) und schweren depressiven Episoden.

ZusammenfassungDie apparativen Bewegungsanalysen haben mit der enormen Entwicklung der Computertechnik hinsichtlich Schnelligkeit der Datenakquisition und -analyse sowie großen Speicherkapazitäten vielfältige neue Möglichkeiten erhalten. Sie sind ein wichtiges Instrument bei der Erforschung neurologischer Erkrankungen, einige gelangen auch in der klinischen Routine zum Einsatz.

ZusammenfassungEvozierte Potenziale sind Potenziale der Hirnaktivität, welche auf einen spezifischen Reiz hin entstehen und aus der allgemeinen EEG-Aktivität herausgemittelt werden können. Als einfache Reize kommen sensible Stimuli (SEP), visuelle Muster (VEP) oder Töne (AEP) in Frage, andererseits kann bei einer weiteren Begriffsfassung auch ein komplexer Reiz bei einer Diskriminationsaufgabe (ereigniskorreliertes Potenzial P300, „oddball experiment“) zu einem Potenzial führen, welches aus den späten Potenzialkomponenten der jeweiligen Modalität erkannt werden kann. Die sog. motorisch evozierten Potenziale (MEP), welche eigentlich evozierte motorische Potenziale heißen müssten, unterscheiden sich hiervon grundlegend, da sie nach Stimulation des zentralmotorischen Systems in der Peripherie vom Muskel abgeleitet werden. Sie werden daher in einem gesonderten Kapitel behandelt.

ZusammenfassungDie Elektroneurografie ist die Untersuchung der Fortleitung der Nervenimpulse in peripheren motorischen und sensiblen Nerven. Zur aussagekräftigen Beurteilung des peripheren Nervensystems und der Muskeln muss sie in Kombination mit der Elektromyografie angewandt werden, da sowohl myogene als auch neurogene Störungen eine Veränderung der motorischen Neurografie bewirken.

ZusammenfassungDas autonome Nervensystem reguliert sämtliche vegetative Körperfunktionen, wie die Herz-Kreislauf-Parameter Pulsrate und Blutdruck, die Aktivität exokriner Drüsen, Blasen- und Mastdarmfunktion. Neurophysiologische Methoden ergänzen die klinische Funktionsdiagnostik um apparative Messanordnungen.

ZusammenfassungUnter Elektromyografie (EMG) versteht man die Aufzeichnung der elektrischen Aktivität der Muskulatur. Sie gibt Auskunft über die Integrität der Muskelfasern und die Zahl und Größe der motorischen Einheiten, sodass mit dieser Untersuchung neurogene von primär muskulären Schädigungen und akute von chronischen Veränderungen abgegrenzt werden können.

ZusammenfassungDie neurophysiologische Diagnostik umfasst eine Reihe von Untersuchungsmethoden, die über die unterschiedlichen Funktionen des zentralen und peripheren Nervensystems eine Aussage erlauben. Die Elektroenzephalografie (EEG) stellt die am weitesten verfügbare und am längsten praktizierte elektrophysiologische Messmethode in der Neurologie dar, sie zeichnet die elektrische Aktivität des Gehirns an der Schädeloberfläche auf.

This historical review addresses major neurological disorders associated with deficiencies of water-soluble B vitamins: beriberi, Wernicke–Korsakoff syndrome, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord.Beriberi: Beriberi was known for millennia in Asia, but was not described by a European until the 17th century when Brontius in the Dutch East Indies reported the progressive sensorimotor polyneuropathy. The prevalence of beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century. In the 1880s, Takaki demonstrated the benefits of dietary modification in sailors, and later instituted dietary reforms in the Japanese Navy, which largely eradicated beriberi from the Japanese Navy by 1887. In 1889 Eijkman in Java serendipitously identified dietary factors as a major contributor to “chicken polyneuritis,” which he took to be an animal model for beriberi; the polyneuritis could be cured or prevented by feeding the chickens either unpolished rice or rice polishings. By 1901, Grijns, while continuing studies of beriberi in Java, suggested a dietary deficiency explanation for beriberi after systematically eliminating deficiencies of known dietary components and excluding a toxic effect.Wernicke–Korsakoff syndrome: In the late 1870s, Wernicke identified a clinicopathological condition with ophthalmoparesis, nystagmus, ataxia, and encephalopathy, associated with punctate hemorrhages symmetrically arranged in the grey matter around the third and fourth ventricles and the aqueduct of Sylvius. In the late 1880s, Korsakoff described a spectrum of cognitive disorders, including a confabulatory amnestic state following an agitated delirium, occurring in conjunction with peripheral polyneuropathy. Beginning around 1900, investigators recognized the close relationship between Korsakoff's psychosis, delirium tremens, and Wernicke's encephalopathy, but not until several decades later were Wernicke's encephalopathy, Korsakoff's psychosis, and beriberi all linked to the deficiency of a specific dietary factor, i.e. thiamin.Thiamin: Thiamin was crystallized from rice polishings by Jansen and Donath in 1926, and synthesized by Williams and Cline in 1936. In the late 1930s and early 1940s, characteristic pathological changes of Wernicke–Korsakoff syndrome were produced in animal models, the biochemical roles of thiamin in intermediary carbohydrate metabolism were elaborated by Peters and others, and the therapeutic benefits of thiamin for Wernicke–Korsakoff syndrome and beriberi were demonstrated. By the 1950s synthetic forms of the vitamin were produced cheaply, allowing both therapeutic administration and prevention with food enrichment.Pellagra and niacin: Pellagra was unknown prior to the introduction of maize into Europe from the New World. In the 18th century, Casàl and Frapolli described the clinical features of pellagra in Europe, and linked it with poverty and subsistence on nutritionally marginal corn-based diets. In the United States, pellagra became epidemic among poor Southerners in the early 20th century, in part because of economically-driven reliance on monotonous, nutritionally inadequate diets, combined with new manufacturing methods that removed vitamins from processed grain. From 1914–1929, Goldberger completed well-designed epidemiologic investigations, tested theories with human experiments, and utilized an animal model (“black tongue” in dogs) – all strongly supporting a dietary deficiency explanation for pellagra over prevailing toxic and infectious theories. Initial prevention and treatment approaches proved inadequate because of complex social issues linked to poverty, even after Goldberger and colleagues established that dried brewer's yeast could cure or prevent pellagra less expensively than dietary modification. During the depression, the collapse of cotton as an economically viable crop facilitated crop diversification, which contributed to an abrupt decline in pellagra mortality in the early 1930s. In 1937 Elvehjem isolated the P-P (pellagra preventive) factor, identified it as nicotinic acid (niacin), and demonstrated that nicotinic acid and nicotinic acid amide cure black tongue in dogs. Although clinical trials soon confirmed dramatic therapeutic effects in individual people, therapeutic administration of niacin had relatively little impact on population-level morbidity and mortality. Vitamin fortification of foodstuffs during World War II ultimately eradicated endemic pellagra in the United States. In the 1940s and 1950s, with expanded biochemical knowledge, pellagra was reformulated as a deficiency disease due to inadequate niacin and its amino acid precursor tryptophan.Neural tube defects and folate: Folate deficiency was initially recognized clinically as a macrocytic anemia in the 1920s, and only clearly separated from pernicious anemia by the mid-20th century. When folic acid was isolated and synthesized in the 1940s, it was shown to correct the macrocytic anemia associated with pernicious anemia, while the neurological manifestations progressed. In the 1950s and 1960s, the biochemical role of folates in transferring single carbon units was elucidated. Beginning in the 1960s, folate deficiency was increasingly recognized as the major cause of preventable neural tube defects. In the early 1990s well-designed randomized trials established that folate supplementation could prevent neural tube defects. Trial data, collectively indicating that periconceptual folate administration reduces both the occurrence and recurrence risks of neural tube defects by at least 70%, helped establish governmental recommendations concerning folic acid intake and health policy concerning vitamin fortification of foodstuffs. When dietary modification and supplementation strategies proved inadequate, folic acid food fortification was legally mandated in the US in the late 1990s, which significantly improved population folate status and produced an abrupt decline (20%–27%) in the prevalence of neural tube defects at birth. Recent studies have established genetic predispositions for neural tube defects, including both infant and maternal gene polymorphisms for enzymes involved in folate-dependent homocysteine metabolism, which help explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g. folate intake) can all impact on the risk of neural tube defects.Subacute combined degeneration and B12 deficiency: Pernicious anemia was recognized clinically in the mid-19th century by Addison, but the most important neurological manifestation – subacute combined degeneration of the spinal cord – was not recognized clinically and linked with pernicious anemia until the end of the 19th century, particularly by Lichtheim, Putnam, and Dana. At the beginning of the 20th century, pernicious anemia and the associated subacute combined degeneration of the spinal cord were considered, by many investigators, to result from infectious or toxic causes. During the first quarter of the 20th century, various therapies were employed, but, with the possible exception of transfusion, were largely ineffective. In the 1920s, Minot and Murphy showed that large quantities of ingested liver could be used to effectively treat pernicious anemia, and specifically could improve or prevent progression of neurological manifestations, and could extend life expectancy beyond 2 years. Beginning in the late 1920s, Castle demonstrated that a substance elaborated by the gastric mucosa (“intrinsic factor”) was essential for the absorption of a dietary factor (“extrinsic factor,” later shown to be vitamin B12) needed to prevent pernicious anemia. Over two decades, from the late 1920s until the late 1940s, increasingly potent liver extracts were manufactured that could be given either intramuscularly or intravenously. In 1947, vitamin B12 was isolated by Folkers and colleagues, and nearly simultaneously by Smith. Shortly thereafter the therapeutic efficacy of vitamin B12 on subacute combined degeneration was demonstrated by West and Reisner and others. By 1955, Hodgkin determined the molecular structure of cyanocobalamin using computer-assisted x-ray crystallography, allowing complete chemical synthesis of vitamin B12 in 1960 by an international consortium. Beginning in the late 1950s, the absorption and biochemistry of vitamin B12 were elaborated, and several lines of evidence converged to upport an autoimmune basis for pernicious anemia.