Optimizing home-based long-term intensive care for neurological patients with neurorehabilitation outreach teams - protocol of a multicenter, parallel-group randomized controlled trial (OptiNIV-Study).

BACKGROUND: Even with high standards of acute care and neurological early rehabilitation (NER) a substantial number of patients with neurological conditions still need mechanical ventilation and/or airway protection by tracheal cannulas when discharged and hence home-based specialised intensive care nursing (HSICN). It may be possible to improve the home care situation with structured specialized long-term neurorehabilitation support and following up patients with neurorehabilitation teams. Consequently, more people might recover over an extended period to a degree that they were no longer dependent on HSICN. METHODS: This healthcare project and clinical trial implements a new specialised neurorehabilitation outreach service for people being discharged from NER with the need for HSICN. The multicentre, open, parallel-group RCT compares the effects of one year post-discharge specialized outpatient follow-up to usual care in people receiving HSICN. Participants will randomly be assigned to receive the new form of healthcare (intervention) or the standard healthcare (control) on a 2:1 basis. Primary outcome is the rate of weaning from mechanical ventilation and/or decannulation (primary outcome) after one year, secondary outcomes include both clinical and economic measures. 173 participants are required to corroborate a difference of 30 vs. 10% weaning success rate statistically with 80% power at a 5% significance level allowing for 15% attrition. DISCUSSION: The OptiNIV-Study will implement a new specialised neurorehabilitation outreach service and will determine its weaning success rates, other clinical outcomes, and cost-effectiveness compared to usual care for people in need for mechanical ventilation and/or tracheal cannula and hence HSICN after discharge from NER. TRIAL REGISTRATION: The trial OptiNIV has been registered in the German Clinical Trials Register (DRKS) since 18.01.2022 with the ID DRKS00027326 .

[Costs associated with multiresistant bacteria in neurorehabilitation]. / Mehrkosten durch multiresistente Erreger in der Neurorehabilitation.

BACKGROUND AND OBJECTIVES: The number of patients with multiresistant bacteria (MRB) in rehabilitation facilities is increasing. The increasing costs of hygienic isolation measures reduce resources available for core rehabilitation services. In addition to the existing lack of care, patients with MRB are at further risk of being given lower priority for admission to rehabilitation facilities. Therefore, the Hygiene Commission of the German Society for Neurorehabilitation (DGNR) attempted to quantify the overall risk for deterioration of rehabilitation care due to the financial burden of MRB. MATERIALS AND METHODS: To analyze the added costs associated with the rehabilitation of patients with MBR, the DGNR Hygiene Commission identified criteria for a cost assessment. Direct (consumables, personnel and miscellaneous costs) and indirect costs of loss of opportunity were evaluated in seven neurorehabilitation centers in different states across Germany. RESULTS: On average, hygienic isolation measures amounted to direct costs of 144 € per day (47 € consumables, 92 € personnel, 5 € for other costs such as extra transportation expenditure) and indirect costs of 274 €, totaling 418 € per patient with MRB per day. Given that approximately 10% of patients had MRB, the added costs of hygienic isolation measures equaled about one tenth of the overall budget of a rehabilitation center and can be expected to rise with the increasing numbers of patients with MRB. CONCLUSIONS: Admission of patients carrying MRB to neurorehabilitation centers triggers added costs that critically diminish the overall capacity for centers to provide their core rehabilitation services.

Diagnosis and decision making for patients with disorders of consciousness: a survey among family members.

OBJECTIVES: To examine the perceptions of family members of patients with disorders of consciousness (DOC) in regard to the patients' level of consciousness, communicative status, and prognosis as compared with the objective medical categories, and to elicit the family members' self-reported practice of treatment decision-making. DESIGN: Cross-sectional semiquantitative survey. SETTING: Five specialized neurologic rehabilitation facilities. PARTICIPANTS: Consecutive sample of primary family members (N=44) of patients with DOC as determined by the Coma Recovery Scale-Revised, surveyed 6 months after the patient's brain injury. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Perception of level of consciousness as compared with the medical diagnosis; assessment of communicative status and prognosis; and practice of treatment decision-making. RESULTS: The study included 44 family members of patients, most of whom had sustained global cerebral ischemia. Six months after brain injury, 36% were in a vegetative state (VS), 20% were in a minimally conscious state (MCS), and 39% had emerged from an MCS. In 76% of cases, the relatives assumed the same level of consciousness that diagnostic tests showed. In the other cases, consciousness was mostly underestimated. While relatives of patients in a VS, and to a lesser extent of those in an MCS, were more skeptical about the patients' chances to advance to an independent life, all had high hopes that the patients would regain the ability to communicate. Yet, 59% of family members had thought about limiting life-sustaining treatment. Most of them base treatment decisions on the patient's well-being; very few relied on previously expressed patient wishes. CONCLUSIONS: According to our sample, family members of patients with DOC largely assess the level of consciousness correctly and express high hopes to reestablish communication with the patient.

Rationale and design of the prospective German registry of outcome in patients with severe disorders of consciousness after acute brain injury.

OBJECTIVE: To describe the rationale and design of a new patient registry (Koma Outcome von Patienten der Frührehabilitation-Register [KOPF-R; Registry for Coma Outcome in Patients Undergoing Acute Rehabilitation]) that has the scope to examine determinants of long-term outcome and functioning of patients with severe disorders of consciousness (DOC). DESIGN: Prospective multicenter neurologic rehabilitation registry. SETTING: Five specialized neurologic rehabilitation facilities. PARTICIPANTS: Patients (N=42) with DOC in vegetative state or minimally conscious state (MCS) as defined by the Coma Recovery Scale-Revised (CRS-R) after brain injury. Patients are being continuously enrolled. The data presented here cover the enrollment period from August 2011 to January 2012. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CRS-R, FIM, and emergence from MCS. RESULTS: The registry was set up in 5 facilities across the state of Bavaria/Germany with a special expertise in the rehabilitation of acquired brain injury. Inclusion of patients started in August 2011. Measures include sociodemographic and clinical characteristics, course of acute therapy, electrophysiologic measures (evoked potentials, electroencephalogram), neuron-specific enolase, current medication, functioning, cognition, participation, quality of life, quantity and characteristics of rehabilitation therapy, caregiver burden, and attitudes toward end-of-life decisions. Main diagnoses were traumatic brain injury (24%), intracerebral or subarachnoid hemorrhage (31%), and anoxic-ischemic encephalopathy (45%). Mean CRS-R score ± SD at admission to rehabilitation was 5.9 ± 3.3, and mean FIM score ± SD at admission was 18 ± 0.4. CONCLUSIONS: The KOPF-R aspires to contribute prospective data on prognosis in severe DOC.

Long-term outcome after suboccipital decompressive craniectomy for malignant cerebellar infarction.

BACKGROUND AND PURPOSE: Suboccipital decompressive craniectomy (SDC) is a life-saving intervention for patients with malignant cerebellar infarction. However, long-term outcome has not been systematically analyzed. METHODS: In this monocentric retrospective study we analyzed mortality, long-term functional outcome, and quality of life of all consecutive patients that were treated by SDC for malignant cerebellar infarction in our institution between 1995 and 2006. RESULTS: A total of 57 patients were identified. All of them were treated by bilateral SDC. An external ventricular drainage was inserted in 82%, necrotic tissue was evacuated in 56% of patients. There were no fatal procedural complications. Five patients were lost for follow-up. In the remaining 52 patients, the mean follow-up interval was 4.7 years (1 to 11 years). Within the first 6 months after surgery 16 of 57 patients (28%) had died. At follow-up, 21 of 52 patients (40%) had died and 4 patients (8%) lived with major disability (mRS 4 or 5). Twenty-one patients (40%) lived functionally independent (mRS 0 to 2). The presence of additional brain stem infarction was associated with poor outcome (mRS > or =4; hazard ratio: 9.1; P=0.001). Quality of life in survivors was moderately lower than in healthy controls. CONCLUSIONS: SDC is a safe procedure in patients with malignant cerebellar infarction. Infarct- but not procedure-related early mortality is substantial. Long-term outcome in survivors is acceptable, particularly in the absence of brain stem infarction.

Virtual Reality for Neurorehabilitation: Insights From 3 European Clinics.

Virtual reality for the treatment of motor impairment is a burgeoning application of digital technology in neurorehabilitation. Virtual reality systems pose an opportunity for health care providers to augment the dose of task-oriented exercises delivered both in the clinic, and via telerehabilitation models in the home. The technology is almost exclusively applied as an adjunct to traditional approaches and is typically characterized by the use of gamified exergames which feature task-oriented physiotherapy exercises. At present, evidence for the efficacy of this technology is sparse, with some reviews suggesting it is the same or no better than conventional approaches. The purpose of this article is to provide real-world insights on the adoption of a virtual reality by 3 European clinics in 3 different service delivery models. These include an inpatient setting for Parkinson disease, a kiosk model for pediatric neurorehabilitation, and a home-based telerehabilitation model for neurologic patients. Motivations, settings, requirements for the pathology, outcomes, and challenges encountered during this process are reported with the objective of priming clinicians on what to expect when implementing virtual reality in neurorehabilitation.

Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.

BACKGROUND: Familial hemiplegic migraine is an autosomal dominant severe subtype of migraine with aura characterised by some degree of hemiparesis during the attacks. So far, mutations in two genes regulating ion translocation-CACNA1A and ATP1A2-have been identified in pedigrees with this disease. METHODS: To identify additional genes for familial hemiplegic migraine, we did a genome-wide linkage analysis of two disease pedigrees without mutations in CACNA1A and ATP1A2. Ion channel genes in the candidate interval were analysed for mutations, and the functional consequences of the recorded sequence alteration were determined. FINDINGS: We identified a novel locus for familial hemiplegic migraine on chromosome 2q24. Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A, mutations of which have been associated with epilepsy. This same mutation was present in three families with familial hemiplegic migraine. It results in a charge-altering aminoacid exchange in the so-called hinged-lid domain of the protein, which is critical for fast inactivation of the channel. Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated. INTERPRETATION: Dysfunction of the neuronal sodium channel SCN1A can cause familial hemiplegic migraine. Our findings have implications for the understanding of migraine aura. Moreover, our study reinforces the molecular links between migraine and epilepsy, two common paroxysmal disorders.

Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. MRI is sensitive in detecting preclinical involvement and changes over time. However, little is known about correlations between MRI metrics and clinical measures on a longitudinal scale. In this study, we assessed the role of quantitative MRI (T2-lesion volume and diffusion tensor imaging [DTI]-derived metrics) in monitoring and predicting disease progression. METHODS: Sixty-two CADASIL subjects were followed prospectively over a period of 26.3+/-1.2 months. Dual-echo scans, DTI scans, and clinical scales were obtained at baseline and at follow-up. T2-lesion volumes were determined quantitatively, and histograms of mean diffusivity (MD) were produced. RESULTS: At follow-up, T2-lesion volumes and MD histogram metrics had changed significantly (all P<0.01). Lesion volumes and average MD correlated with clinical scores at baseline. Changes of average MD correlated with changes of the Rankin score, the National Institutes of Health Stroke Scale score, and the structured interview for the diagnosis of Alzheimer dementia and multiinfarct dementia score (all P<0.01). On multivariate analysis, average MD and systolic blood pressure at baseline were predictors of changes of average MD during follow-up. Moreover, average MD was the main predictor of clinical progression. Sample size estimates showed that the number of individuals required to detect a treatment effect in an interventional trial may be reduced when using MD histograms as an end point. CONCLUSIONS: This study establishes correlations between changes of DTI histogram metrics and clinical measures over time. DTI histograms may be used as an adjunct outcome measure in future therapeutic trials. Moreover, DTI histogram metrics predict disease progression in CADASIL.

The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia.

OBJECTIVE: Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects. METHOD: A cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 matched comparison subjects (mean age=47.2 years, SD=14.0) was conducted. Participants underwent a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring. RESULTS: CADASIL subjects had pronounced impairments of the timed measures (Stroop II and III, Trail Making Test, symbol digit, digit cancellation). Measures of error monitoring (Stroop III, Trail Making Test, symbol digit, maze task) were also significantly affected but to a lesser extent. Prominent deficits further included verbal fluency and ideational praxis. Recall, orientation, and receptive language skills were largely preserved. Subgroup analyses indicated a similar profile in subjects with early and advanced impairment of global cognitive performance. CONCLUSIONS: The findings highlight processing speed as the most substantial area of cognitive impairment in CADASIL subjects, with less pronounced yet significant deficits in other aspects of executive performance and attention. This profile of cognitive impairment is present at an early stage and enables the construction of targeted test batteries for clinical trials. It is hypothesized that the profile of dysfunction described here represents the core of the cognitive syndrome associated with small vessel disease and subcortical ischemic vascular lesions.

Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies.

BACKGROUND: Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an important cause of stroke in young adults. Mutations are typically located within epidermal growth factor-like repeat domains in the extracellular part of the Notch3 receptor. Identification of the mutation is critical for genetic counseling and testing of relatives at risk. OBJECTIVES: To identify the spectrum of NOTCH3 mutations in CADASIL and to discuss the implications for diagnostic strategies. DESIGN: Screening for NOTCH3 mutations was performed in 125 unrelated German CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for epidermal growth factor-like repeats. Results were compared with those of previously published studies. RESULTS: We detected 54 distinct mutations (117 missense mutations and 3 in-frame deletions) in 120 (96.0%) of the 125 patients. Of the mutations, 58.3% were located in exon 4 and 85.8% in exons 2 through 6. In 5 patients (4.0%), no mutation was identified. CONCLUSIONS: Almost 90% of mutations could be detected within a few exons (exons 2-6). Thus, genetic testing should initially be focused on these exons, with some variation depending on the population in whom it is being performed. Yet, genetic testing for CADASIL is associated with a nameable proportion of false-negative results. Cases with a high index of clinical suspicion should be investigated by skin biopsy if genetic testing is negative.

Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in the NOTCH3 gene. The clinical course is highly variable. Little is known about the long-term prognosis and the causes of death in CADASIL patients. Likewise, the impact of gender and NOTCH3 genotype on disease progression remains largely unexplored. We identified 411 subjects (196 men, 215 women) with a definite diagnosis of CADASIL. Age at onset for stroke, immobilization and death as well as the causes of death and clinical status at onset of the cause of death were determined systematically. Weibull regression models were used to calculate times to event, with gender and NOTCH3 genotype as covariates. At the time of the study, 73 patients had died. The median age at onset for stroke was 50.7 years [95% confidence interval (CI) = 48.2-53.1 years] in men and 52.5 years (95% CI = 50.0-54.9 years) in women (P = n.s.). The median ages at onset for inability to walk without assistance [men 58.9 years (95% CI = 56.6-61.3 years); women 62.1 years (59.7-64.4 years)], bedriddenness [men 62.1 years (59.6-64.7 years), women 66.5 years (63.9-69.1 years); and death [men 64.6 years (61.7-67.6 years); women 70.7 years (67.6-73.9 years)] were significantly lower in men than in women (all P < or = 0.01). The median survival time of men was significantly shorter than expected from German life tables (64.6 versus 69.3 years, P = 0.01). In contrast, the median survival time of women was not significantly reduced (70.7 versus 72.2 years). The C117F mutation was associated with a lower age at death and the C174Y mutation with a lower age at onset for stroke, immobilization and death (adjusted P values <0.05). At onset of the cause of death, 78% of the subjects were completely dependent. Sixty-three per cent were confined to bed. Pneumonia was the most frequent cause of death (38%), followed by sudden unexpected death (26%) and asphyxia (12%). We conclude that male sex is a risk factor for early immobilization and death in CADASIL. Our findings suggest possible genotype-phenotype correlations with regard to disease progression. The data presented may serve as source material for counselling CADASIL patients and for designing future interventional trials.

A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease causing stroke and dementia. The aim of this study was to explore the patterns of clinical progression in CADASIL, to check for prognostic variables, and to provide sample size estimates for future therapeutic trials. METHODS: Eighty CADASIL subjects (aged 45.7+/-9.9 years [mean+SD]) were followed prospectively during a mean period of 26.3+/-1.1 months. Standardized scales on disability (Rankin), activities of daily living (Barthel index), neurological outcome (National Institutes of Health Stroke Scale [NIHSS]), and cognition (structural interview for diagnosis of Alzheimer dementia and multi-infarct dementia [SIDAM] and Mattis dementia rating scale [MDRS]) were assessed at baseline and at follow-up. RESULTS: All but 1 individual completed the protocol. At follow-up, the cohort had deteriorated with respect to all clinical scales: Rankin scores (0.3+/-0.7 [mean change+/-SD]; P=0.001), Barthel index (-5.4+/-15.9; P<0.001), NIHSS scores (1.0+/-2.6; P=0.001), SIDAM scores (-2.1+/-6.4; P=0.004), and MDRS scores (-4.3+18.5; P=0.09). The spectrum ranged from marked worsening to some degree of improvement. Seventeen patients experienced a new stroke. Overall, there were 18 strokes within 173 person-years, giving an average incidence rate of stroke of 10.4 per 100 person-years (95% CI, 5.6 to 15.2). Age at baseline was found to be a predictor of clinical progression. Sample size estimates show that the number of individuals needed to include in an interventional trial (assumed duration 2 years, assumed treatment effect 40%) is 602 when using stroke occurrence as an outcome measure. CONCLUSIONS: The clinical course of CADASIL includes periods of acute worsening, chronic progression, stabilization, and improvement. Sample size calculations emphasize the need for surrogate markers of disease progression for future interventional trials.

Prolonged cerebral transit time in CADASIL: a transcranial ultrasound study.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmophilic material in the vicinity of degenerating vascular smooth muscle cells. In this study, we measured the arteriovenous cerebral transit time (CTT) to identify changes related to the microangiopathy in CADASIL. METHODS: CTT is the time that a contrast agent needs to pass from a cerebral artery to its corresponding vein. CTT was measured in 17 CADASIL individuals (mean age, 50.2+/-12.3 years) and an equal number of age- and sex-matched control subjects (mean age, 48.9+/-13.0 years) with transcranial color-coded duplex sonography. The intensity curves were recorded in the P2 segment of the posterior cerebral artery and the vein of Galen after injection of the ultrasound contrast agent Levovist. RESULTS: CTT was significantly prolonged in individuals with CADASIL (4.4+/-1.9 seconds) compared with control subjects (1.3+/-0.5 seconds, P<0.0001). This difference was also significant when only nondisabled CADASIL individuals (Rankin score=0, n=9) were analyzed (P<0.0001). There was a nonsignificant trend for a correlation between Rankin score and CTT (r=0.39, P=0.11). CONCLUSIONS: The prolonged CTT likely reflects microvascular changes in CADASIL. Measurements of the CTT may be used clinically to disclose small-vessel disease. Studies comparing CADASIL subjects with other patient populations seem warranted to determine possible differences in CTT between different types of small-vessel disease.

Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study.

BACKGROUND AND PURPOSE: An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. METHODS: Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. RESULTS: Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects (P<0.001). The average number of MBs was 5.9+/-7.3 (range, 0 to 22) in individual CADASIL patients. MBs were associated with age (r=0.71, P=0.002) and total lesion volume (r=0.75, P=0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. CONCLUSIONS: This study shows a high frequency and multiplicity of MBs in individuals with CADASIL. Our results suggest that MBs and ischemic lesions are largely independent manifestations of the underlying angiopathy. The pattern of MBs shows a significant overlap with that reported in other types of small-vessel disease.