Peak Troponin I Levels Are Associated with Functional Outcome in Intracerebral Hemorrhage

Background: Troponin I is a widely used and reliable marker of myocardial damage and its levels are routinely measured in acute stroke care. So far, the influence of troponin I elevations during hospital stay on functional outcome in patients with atraumatic intracerebral hemorrhage (ICH) is unknown. Methods: Observational single-center study including conservatively treated ICH patients over a 9-year period. Patients were categorized according to peak troponin I level during hospital stay (≤0.040, 0.041–0.500, > 0.500 ng/mL) and compared regarding baseline and hematoma characteristics. Multivariable analyses were performed to investigate independent associations of troponin levels during hospital stay with functional outcome – assessed using the modified Rankin Scale (mRS; favorable 0–3/unfavorable 4–6) – and mortality after 3 and 12 months. To account for possible confounding propensity score (PS)-matching (1: 1; caliper 0.1) was performed accounting for imbalances in baseline characteristics to investigate the impact of troponin I values on outcome. Results: Troponin elevations (> 0.040 ng/mL) during hospital stay were observed in 308 out of 745 (41.3%) patients and associated with poorer status on admission (Glasgow Coma Scale/National Institute of Health Stroke Scale). Multivariable analysis revealed troponin I levels during hospital stay to be independently associated with unfavorable outcome after 12 months (risk ratio [95% CI]: 1.030 [1.009–1.051] per increment of 1.0 ng/mL; p = 0.005), but not with mortality. After PS-matching, patients with troponin I elevation (≥0.040 ng/mL) versus those without had a significant higher rate of ­unfavorable outcome after 3 and 12 months (mRS 4–6 at 3 months: < 0.04 ng/mL: 159/265 [60.0%] versus ≥0.04 ng/mL: 199/266 [74.8%]; p < 0.001; at 12 months: < 0.04 ng/mL: 141/248 [56.9%] versus ≥0.04 ng/mL: 179/251 [71.3%]; p = 0.001). Conclusions: Troponin I elevations during hospital stay occur frequently in ICH patients and are independently associated with functional outcome after 3 and 12 months but not with mortality

Genetic screening for LRRK2 mutations in MSA and PSP patients

Im Jahr 2004 sind Mutationen im Gen LRRK2 als Ursache für eine autosomal-dominant vererbte Form des Parkinsonismus identifiziert worden und gelten inzwischen als häufigste genetische Ursache sowohl familiärer als auch sporadischer Formen des idiopathischen Parkinson-Syndroms. Die Betroffenen zeichnen sich einerseits durch ein für Morbus Parkinson typisches klinisches Erscheinungsbild aus, weisen andererseits jedoch als besonderes, in dieser Form einzigartiges Merkmal die verschiedensten neuropathologischen Veränderungen auf, die bisher unterschiedlichen Gruppen neurodegenerativer Erkrankungen zugeordnet wurden. So beobachtet man neben neuronalem Zelluntergang in der Substantia nigra mit oder ohne Lewy-Körperchen sogar Tau-positive Einschlüsse in einer Ausprägung, welche die diagnostischen Kriterien einer Progressiven Supranukleären Blickparese erfüllt. In Anbetracht dieser Erkenntnisse kann eine zentrale Rolle von LRRK2 in der Entstehung neurodegenerativer Prozesse vermutet und auf diese Weise eine rationale Grundlage für die Untersuchung seines Beitrags in der Entstehung weiterer neurodegenerativer Erkrankungen, u.a. der atypischen Parkinson-Syndrome, gelegt werden. Im Rahmen dieser Arbeit wurden DNA-Proben von MSA- und PSP-Patienten auf bereits bekannte LRRK2-Mutationen gescreent. Die Untersuchung der PSP-Proben beschränkte sich, gestützt auf der Beschreibung PSP-artiger neuropathologischer Veränderungen eines R1441C-Mutationsträgers, auf Exon 31 von LRRK2. Die MSA-Proben hingegen wurden auf Mutationen in Exon 41 von LRRK2 untersucht, da bei einem Mitglied der Sagamihara-Familie mit neuropathologisch gesicherter MSA die I2020T-Mutation gefunden wurde. Des Weiteren legt die Häufigkeit der ebenfalls in Exon 41 lokalisierten G2019S-Mutation beim idiopathischen Parkinson-Syndrom deren besondere Bedeutung in der Entstehung von Synukleinopathien nahe. Bei keinem Patienten konnten im Rahmen dieser Studie LRRK2-Mutationen nachgewiesen werden. Die Ergebnisse der vorliegenden Arbeit bestätigen und erweitern diesbezüglich die derzeitige Datenlage. Zum jetzigen Zeitpunkt ist es, bis auf vereinzelte, in ihrer Bedeutung schwer einzustufende Ausnahmen somit weder gelungen, MSA- noch PSP-Fälle direkt mit Mutationen in LRRK2 in Verbindung zu bringen. Eine potentielle Rolle von LRRK2 in der Entstehung dieser beiden Erkrankungen kann dennoch nicht ausgeschlossen werden, zumal sich die bisherigen Studien meist auf wenige Abschnitte von LRRK2 beschränkt haben und aus diesem Grund Aussagen über den Rest dieses riesigen Gens nicht getroffen werden können. Man kann erwarten, dass umfassendere Untersuchungen hierbei in Zukunft weitere Klarheit schaffen werden. Außerdem gibt es viele Hinweise darauf, dass LRRK2 eine übergeordnete Position in einem Netzwerk interagierender Proteine einnimmt, in dem Störungen zu neurodegenerativen Prozessen führen können. LRRK2-Mutationen können folglich als auslösende Ereignisse in einer zu Neurodegeneration mit variablen pathologischen Veränderungen führenden Kaskade angesehen werden und somit in der Ätiologie verschiedener neurodegenerativer Erkrankungen involviert sein. Aus diesem Grund ist es möglich, dass die genauere Erforschung von LRRK2 Erkenntnisse erbringen wird, die auf verschiedene Erkrankungen übertragbar sind. Es bleibt zu hoffen, dass sich daraus in Zukunft neue diagnostische und therapeutische Möglichkeiten ergeben werden.In 2004, mutations in a gene called LRRK2 were identified as a cause of autosomal dominantly inherited parkinsonism and today are considered the most frequent genetic cause of both familial as well as sporadic forms of Parkinson’s disease. Patients harboring LRRK2 mutations on the one hand have a clinical presentation typical of idiopathic Parkinson’s disease, on the other hand, however, feature a special and unique variety of neuropathological alterations which used to be considered hallmarks of different types of neurodegenerative disorders. Besides neuronal loss in the substantia nigra with or without Lewy bodies, even Tau-positive inclusions meeting the diagnostic criteria of progressive supranuclear palsy can be seen. Given these findings, a central position of LRRK2 in the etiology of neurodegenerative processes in general can be assumed, which provides a rational basis for further research on its role in the development of other neurodegenerative disorders such as atypical parkinsonian syndromes. In this study, DNA samples of MSA and PSP patients were screened for known LRRK2 mutations. Based on the description of PSP-like neuropathological alterations in a R1441C mutation carrier, DNA samples of PSP patients were screened for mutations in exon 31 of LRRK2. As a member of the Sagamihara family with neuropathologically confirmed MSA was found to carry the I2020T mutation, DNA samples of MSA patients were analyzed for mutations in exon 41 of LRRK2. Furthermore, another mutation in this exon, G2019S, occurs frequently in idiopathic Parkinson’s disease suggesting its special importance in the etiology of synucleinopathies. No LRRK2 mutations could be found in any patient screened in this study. The results of this work confirm and expand previous knowledge. To date, with a few exceptions of uncertain relevance, no MSA or PSP case could directly be associated with mutations in LRRK2. Still, a potential role of the gene in the development of these disorders cannot be excluded completely, as studies performed so far mainly focused on a few sections of LRRK2, so that statements on the rest of this large gene cannot be made. It can be expected that more extensive studies will help calrify its role in the future. Furthermore, there is evidence that LRRK2 may have a superordinate position in a network of interacting proteins which, when disturbed, may lead to neurodegenerative processes. Thus, LRRK2 mutations can be considered upstream events in a cascade leading to neurodegeneration with variable pathological changes and in that way be involved in the etiology of diverse neurodegenerative disorders. For that reason, further exploration of LRRK2 may yield findings transferable to various diseases. It remains to be hoped that this may lead to new diagnostic and therapeutic options in the future

A Case Report of Severe Delirium after Amantadine Withdrawal

Amantadine is frequently used in addition to dopaminergic substances like dopamine agonists or L-Dopa in advanced Parkinson disease (PD). However, adverse effects like hallucinations limit its use. PD patients developing severe psychotic symptoms upon treatment with either dopaminergic substances and/or amantadine need to stop intake of any psychotropic substance. Here, we report the case of a 71-year-old PD patient without previously known cognitive impairment. He presented with drug-induced psychotic symptoms due to changes in his therapeutic regimen (increase in COMT inhibitors, newly introduced MAO B inhibitors). Also, amantadine had been part of his long-term medication for more than 2 years. The severity of his psychotic symptoms required a L-Dopa monotherapy. After changing his medication, the patient developed severe delirium that resolved rapidly after i.v. amantadine infusion, suggesting an amantadine withdrawal syndrome. Amantadine withdrawal syndrome is a rare adverse event that may present even in PD patients without cognitive impairment. This case report highlights the need for a gradual withdrawal of amantadine even if acute and severe psychotic symptoms are present. Moreover, this is the first report of a cognitively unimpaired patient developing an amantadine withdrawal syndrome

Impact of timing of continuous intravenous anesthetic drug treatment on outcome in refractory status epilepticus

Abstract Background Patients in refractory status epilepticus (RSE) may require treatment with continuous intravenous anesthetic drugs (cIVADs) for seizure control. The use of cIVADs, however, was recently associated with poor outcome in status epilepticus (SE), raising the question of whether cIVAD therapy should be delayed for attempts to halt seizures with repeated non-anesthetic antiepileptic drugs. In this study, we aimed to determine the impact of differences in therapeutic approaches on RSE outcome using timing of cIVAD therapy as a surrogate for treatment aggressiveness. Methods This was a retrospective cohort study over 14 years (n = 77) comparing patients with RSE treated with cIVADs within and after 48 h after RSE onset, and functional status at last follow-up was the primary outcome (good = return to premorbid baseline or modified Rankin Scale score of less than 3). Secondary outcomes included discharge functional status, in-hospital mortality, RSE termination, induction of burst suppression, use of thiopental, duration of RSE after initiation of cIVADs, duration of mechanical ventilation, and occurrence of super-refractory SE. Analysis was performed on the total cohort and on subgroups defined by RSE severity according to the Status Epilepticus Severity Score (STESS) and by the variables contained therein. Results Fifty-three (68.8%) patients received cIVADs within the first 48 h. Early cIVAD treatment was independently associated with good outcome (adjusted risk ratio [aRR] 3.175, 95% confidence interval [CI] 1.273–7.918; P = 0.013) as well as lower chance of both induction of burst suppression (aRR 0.661, 95% CI 0.507–0.861; P = 0.002) and use of thiopental (aRR 0.446, 95% CI 0.205–0.874; P = 0.043). RSE duration after cIVAD initiation was shorter in the early cIVAD cohort (hazard ratio 1.796, 95% CI 1.047–3.081; P = 0.033). Timing of cIVAD use did not impact the remaining secondary outcomes. Subgroup analysis revealed early cIVAD impact on the primary outcome to be driven by patients with STESS of less than 3. Conclusions Patients with RSE treated with cIVADs may benefit from early initiation of such therapy

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia

Background: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. Methods: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. Results: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). Conclusion: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact

Correction to: Gap Analysis Regarding Prognostication in Neurocritical Care: A Joint Statement from the German Neurocritical Care Society and the Neurocritical Care Society

This article was updated to correct the spelling of Karl Georg Haeusler

Presence of Concomitant Systemic Cancer is Not Associated with Worse Functional Long-Term Outcome in Patients with Intracerebral Hemorrhage

Background: Data on clinical characteristics and outcome of patients with intracerebral hemorrhage (ICH) and concomitant systemic cancer disease are very limited. Methods: Nine hundred and seventy three consecutive primary ICH patients were analyzed using our prospective institutional registry over a period of 9 years (2006-2014). We compared clinical and radiological parameters as well as outcome - scored using the modified Rankin Scale (mRS) and analyzed in a dichotomized fashion as favorable outcome (mRS = 0-3) and unfavorable outcome (mRS = 4-6) - of ICH patients with and without cancer. Relevant imbalances in baseline clinical and radiological characteristics were adjusted using propensity score (PS) matching. Results: Prevalence of systemic cancer among patients with ICH was 8.5% (83/973). ICH patients with cancer were older (77 [70-82] vs. 72 [63-80] years; p = 0.002), had more often prior renal dysfunction (19/83 [22.9%] vs.107/890 [12.0%]; p = 0.005), and smaller hemorrhage volumes (10.1 [4.8-24.3] vs. 15.3 [5.4-42.9] mL; p = 0.017). After PS-matching there were no significant differences neither in mortality nor in functional outcome both at 3 months (mortality: 33/81 [40.7%] vs. 55/158 [34.8%]; p = 0.368; mRS = 0-3: 28/81 [34.6%] vs. 52/158 [32.9%]; p = 0.797) and 12 months (mortality: 39/78 [50.0%] vs. 70/150 [46.7%]; p = 0.633; mRS = 0-3: 25/78 [32.1%] vs. 53/150 [35.3%]; p = 0.620) among patients with and without concomitant systemic cancer. ICH volume tended to be highest in patients with hematooncologic malignancy and smallest in urothelial cancer. Conclusions: Patients with ICH and concomitant systemic cancer on average are older; however, they show smaller ICH volumes compared to patients without cancer. Yet, mortality and functional outcome is not different in ICH patients with and without cancer. Thus, the clinical history or the de novo diagnosis of concomitant malignancies in ICH patients should not lead to unjustified treatment restrictions