| 1. |
- Larsson, Jenny, 1990-
(författare)
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Population-based studies of higher-level gait disorders and hydrocephalus : focused on brain ventricular morphometry and patient outcomes following shunt surgery
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: To study gait is of great importance for the health of the aging population. Higher-level gait disorders (HLGD) are characterized by a slow, symmetrical, unsteady gait. Its cause is most often unknown. HLGD in combination with ventriculomegaly (i.e., large brain ventricles) is obligatory for the diagnosis of Idiopathic Normal pressure hydrocephalus (INPH), a syndrome that is sometimes treatable with insertion of a CSF shunt. It is therefore important to investigate the prevalence of HLGD in the population and brain morphometry in individuals with HLGD. Further, self-perceived confidence in gait and balance among patients with HLGD and INPH is unknown and important to study as slow gait velocity is associated with falls, injuries, and death. CSF shunts in INPH are associated with adverse events and little is known about epilepsy after surgery or minor and moderate adverse events such as headache and abdominal pain.Objective: In the older population investigate the prevalence of HLGD, and its association to ventriculomegaly. To investigate quality of life (QoL), depressive symptoms, and balance confidence in an HLGD population. In patients shunted for INPH, assess falls, fear of falling, balance confidence and prevalence of the possible adverse events headache, epilepsy, and abdominal pain after shunt surgery. Methods: Two population-based case-controlled cohorts were studied. In the first study, the "Ventriculomegaly and gait disturbance in the senior population in the region of Västerbotten" (VESPR) study, individuals (65-84 years) were recruited through a questionnaire (n=6467 dispatched). The final population consisted of 798 cases with gait disorders and 249 controls without gait disorders, age- and sex-matched to individuals with HLGD. All had been examined by a physician and were categorized: 1. "HLGD"; 2. "neurological gait disorder"; 3. "non-neurological gait disorder" or; 4. "no gait disorder". Participants were assessed with: the Swedish modification of the Falls-Efficacy Scale (FES(S)), the Modified Gait-Efficacy Scale (mGES), the Euro Quality of Life 5-Dimension 5-Level (EQ5D5L) instrument (EQ5D5L index and Euro Quality of life visual analogue scale (EQ VAS)) and the Geriatric depression scale 15 (GDS-15). Cases and controls had an MRI of the brain and ventricular size was measured. The second study, the "Comorbidities and vascular risk factors associated with idiopathic normal pressure hydrocephalus" (INPH-CRasH) study, consisted of 176 shunted INPH patients and 368 age- and sex-matched controls. Mean age was 74 years in INPH and 73 in controls. All had a visit to a healthcare facility. Information regarding adverse events, falls and fear of falling were gathered through a questionnaire. Additional information on diagnoses and prescribed drugs were obtained from the Swedish national patient- and drug registries. Data was compared between the groups, and before- and after surgery for INPH. Results: In the VESPR study, 87 individuals were categorized as HLGD, corresponding to a prevalence of 5.8% (95% confidence interval (CI) 4.6-7.0) in the older population. A definite cause was found in 13% (n=11) of individuals with HLGD, but ventriculomegaly was present in 63% (n=46/73, controls: 38%, n=70/184; OR 2.8 95% CI 1.6-4.9, p<0.001). HLGD had more depressive symptoms and lower quality of life (QoL), compared with individuals without gait disorder (GDS-15: 3.9±3.4 vs. 2.5±2.8, p=0.004; EQ VAS: 63±17 vs. 71±18; p<0.001; EQ5D5L index: 0.671±0.188 vs. 0.840±0.126, p<0.001). HLGD had low confidence in gait and to avoid falls compared to those without gait disorder (mGES: 60±22 vs. 74±21; p<0.001; FES(S): 93±32 vs. 111±25 p<0.001). The INPH-CRasH study revealed that patients with INPH feared falling more often (3.3±1.1) and had lower balance confidence (78±40) than controls (fear of falling: 1.6±0.9, balance confidence: 126±14; p<0.001 in both comparisons). After surgery, the proportions were reduced in INPH (p<0.001). More INPH than controls were fallers (before surgery: 67% vs. 11% OR 15.48 95% CI 9.85-24.32; after surgery: 35% vs 11% OR 4.15 95% CI 2.65-6.50, p<0.001). The proportion was reduced after surgery (p<0.001). In shunted INPH, epilepsy, antiepileptic drug (AED) treatment and headache was more common than in controls (epilepsy: 4.5% vs. 1.1% OR 4.3, 95% CI 1.3-14.6, p=0.023; AED treatment: 14.8% vs. 7.3% OR 0.5 95% CI 0.3-0.8, p=0.010; headache: 36.1% vs 11.6% OR 0.2 95% CI 0.2-0.4, p<0.001). Forty percent INPH (n=70) had abdominal pain after surgery. Conclusions: HLGD was common in the general older population and associated to ventriculomegaly. HLGD was also associated with low quality of life and depressive symptoms. Both individuals with HLGD and patients with INPH had low confidence in their balance but it was less common after surgery for INPH. However, patients shunted for INPH still had more problems with low balance confidence, falls, and fear of falling than controls. After shunt surgery for INPH, a significant portion of patients developed epilepsy, headache, and abdominal pain. The findings motivate investigations of causal relationships between HLGD and ventriculomegaly and if treatment options exist for HLGD. The observed adverse events in patients shunted for INPH should be considered in pre- and postoperative evaluations of shunt surgery, and in the development of new techniques for shunt placement. Additional interventions directed towards low balance confidence, falls and fear of falling should be considered for patients with INPH, and for individuals with HLGD.
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| 2. |
- Behzadi, Arvin, 1994-
(författare)
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Biomarkers for diagnosis and prognosis in amyotrophic lateral sclerosis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paresis, muscle atrophy, and respiratory failure. ALS can be difficult to diagnose and prognosticate early.Aim: To investigate the diagnostic and prognostic characteristics of biomarkers in cerebrospinal fluid (CSF), plasma, and skeletal muscle tissue in patients with ALS.Paper I: Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were analyzed in CSF using enzyme-linked immunosorbent assay (ELISA), and NFL in plasma was analyzed using single-molecule array (SIMOA). CSF NFL, CSF pNFH, and plasma NFL concentrations can differentiate ALS patients from ALS mimics, and were significantly negatively correlated with the disease duration in ALS patients.Paper II: Myosin heavy chain (MyHC) isoforms in extraocular muscles were investigated using immunofluorescence. Control donors had significantly higher proportion of myofibers containing MyHCIIa and significantly lower proportion of myofibers containing MyHCeom in the global layer compared to spinal-onset ALS and bulbar-onset ALS donors. Disease duration in the spinal-onset ALS donors was significantly correlated with the proportion of myofibers containing MyHCIIa in the global layer and MyHCeom in the orbital layer.Paper III: The study combined the neurofilament concentrations from Paper I, with cytokines previously analyzed in CSF and plasma using SIMOA, to investigate distinct molecular phenotypes in ALS. Patients with bulbar-onset ALS had significantly higher concentrations of CSF tumor necrosis factor α (TNF-α) compared to ALS mimics. TNF-α and NFL were significantly correlated with each other in both CSF and plasma in ALS patients. Combined analysis of NFL and IL-6 in plasma identified molecular prognostic subgroups in ALS patients.Paper IV: Creatine kinase (CK), high-sensitivity cardiac troponin T (hs-cTnT), hs-cTnI, and cystatin C (CysC) were analyzed in plasma in a fully accredited laboratory. CK and hs-cTnT concentrations were significantly elevated in limb-onset ALS compared to controls and bulbar-onset ALS. hs-cTnT concentrations were significantly elevated in truncal-onset ALS compared to controls and bulbar-onset ALS. Multivariable Cox proportional hazards models indicated elevated concentrations of CysC as a significant marker for worse prognosis in ALS.Conclusions: The papers report diagnostic and prognostic characteristics of biomarkers in CSF, plasma, and muscle tissue in ALS patients. The significant findings for biomarkers in plasma could be of value since plasma sampling does not involve a lumbar puncture.
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| 3. |
- Björnfot, Cecilia, et al.
(författare)
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Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults : a 4D flow MRI study
- 2024
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 44:8, s. 1343-1351
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Tidskriftsartikel (refereegranskat)abstract
- White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
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| 4. |
- Bobinski, Lukas, 1977-
(författare)
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On evolution of intracranial changes after severe traumatic brain injury and its impact on clinical outcome
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Severe traumatic brain injury (sTBI) is a cause of death and disability worldwide and requires treatment at specialized neuro-intensive care units (NICU) with a multimodal monitoring approach. The CT scan imaging supports the monitoring and diagnostics. The level of S100B and neuron specific enolase (NSE) reflects the severity of the injury. The therapy resistant intracranial hypertension requires decompressive craniectomy (DC). After DC, the cranium must be reconstructed to recreate the normal intracranial physiology as well as to address cosmetic issues. The evolution of the pathological intracranial changes was analyzed in accordance with the three CT classifications: Marshall, Rotterdam and Morris-Marshall. The Rotterdam scale was best in describing the dynamics of the pathological evolution. Both the Rotterdam score and Morris- Marshall classification showed strong correlation with the clinical outcome, a finding that suggests that they could be used for prognostication. We demonstrated a clear correlation between the CT classifications and concentrations of S100B and NSE. The results revealed a concomitant correlation between NSE and S100B and clinical outcome. We found that the interaction between the ICP, Rotterdam CT classification, and concentrations of biochemical biomarkers are all associated with DC. We found a high percentage of complications following cranioplasty. Our results call into question whether custom-made allograft should be considered the best material for cranioplasty. It is concluded that both the Rotterdam and Morris-Marshall classification contribute to clinical evaluation of intracranial dynamics after sTBI, and might be used in combination with biochemical biomarkers for better assessment. The decision to perform DC should include a re-assesment of ICP evolution, CT scan images and concentration of the biochemical biomarkers. Furthermore, when determining whether DC treatment should be used, surgeon should also consider the risks of the following cranioplasty.
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| 5. |
- Gasslander, Johan, et al.
(författare)
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Risk factors for developing subdural hematoma : a registry-based study in 1457 patients with shunted idiopathic normal pressure hydrocephalus
- 2021
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Ingår i: Journal of Neurosurgery. - : American Association of Neurological Surgeons. - 0022-3085 .- 1933-0693. ; 134:2, s. 668-677
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Subdural hematomas and hygromas (SDHs) are common complications in idiopathic normal pressure hydrocephalus (iNPH) patients with shunts. In this registry-based study, patients with shunted iNPH were screened nationwide to identify perioperative variables that may increase the risk of SDH.METHODS: The Swedish Hydrocephalus Quality Registry was reviewed for iNPH patients who had undergone shunt surgery in Sweden in 2004-2014. Potential risk factors for SDH were recorded preoperatively and 3 months after surgery. Drug prescriptions were identified from a national pharmacy database. Patients who developed SDHs were compared with those without SDHs.RESULTS: The study population consisted of 1457 patients, 152 (10.4%) of whom developed an SDH. Men developed an SDH more often than women (OR 2.084, 95% CI 1.421-3.058, p < 0.001). Patients on platelet aggregation inhibitors developed an SDH more often than those who were not (OR 1.733, 95% CI 1.236-2.431, p = 0.001). At surgery, shunt opening pressures had been set 5.9 mm H2O lower in the SDH group than in the no-SDH group (109.6 ± 24.1 vs 115.5 ± 25.4 mm H2O, respectively, p = 0.009). Antisiphoning devices (ASDs) were used in 892 patients but did not prevent SDH. Mean opening pressures at surgery and the follow-up were lower with shunts with an ASD, without causing more SDHs. No other differences were seen between the groups.CONCLUSIONS: iNPH patients in this study were diagnosed and operated on in routine practice; thus, the results represent everyday care. Male sex, antiplatelet medication, and a lower opening pressure at surgery were risk factors for SDH. Physical status and comorbidity were not. ASD did not prevent SDH, but a shunt with an ASD allowed a lower opening pressure without causing more SDHs.
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| 6. |
- Johnson, Ulf, 1977-
(författare)
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Pressure autoregulation of cerebral blood flow in traumatic brain injury and aneurysmal subarachnoid hemorrhage
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital.In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome.In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome.In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease.In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min).The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies
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| 7. |
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| 8. |
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| 9. |
- Lindgren, Cecilia, 1958-
(författare)
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Subarachnoid haemorrhage : clinical and epidemiological studies
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Subarachnoid haemorrhage (SAH) is a severe stroke that in 85% of all cases is caused by the rupture of a cerebral aneurysm. The median age at onset is 50-55 years and the overall mortality is approximately 45%.Sufficient cortisol levels are important for survival. After SAH hypothalamic/pituitary blood flow may be hampered this could result in inadequate secretion of cortisol. SAH is also associated with a substantial inflammatory response. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and increased ADMA levels may be involved in inflammation and endothelial dysfunction. Continuous electroencephalogram (EEG) monitoring can be used to detect non-convulsive seizures, leading to ischemic insults in sedated SAH patients. Elevated ADMA levels are risk factors for vascular diseases. Vascular disease has been linked to stress, inflammation and endothelial dysfunction. SAH possesses all those clinical features and theoretically SAH could thus induce vascular disease.Aims: 1. Assess cortisol levels after SAH, and evaluate associations between cortisol and clinical parameters. 2. Assess ADMA levels and arginine/ADMA ratios after SAH and evaluate associations between ADMA levels and arginine/ADMA ratios with severity of disease, co-morbidities, sex, age and clinical parameters. 3. Investigate occurrence of subclinical seizures in sedated SAH patients. 4. Evaluate if patients that survive a SAH ≥ one year have an increased risk of vascular causes of death compared to a normal population.Results: Continuous infusion of sedative drugs was the strongest predictor for a low (<200 nmol/L) serum cortisol. The odds ratio for a sedated patient to have a serum cortisol < 200 nmol/L was 18.0 times higher compared to an un-sedated patient (p < 0.001). Compared to admission values, 0-48 hours after SAH, CRP increased significantly already in the time-interval 49-72 hours (p<0.05), peaked in the time-interval 97-120 hours after SAH and thereafter decreased. ADMA started to increase in the time-interval 97-120 hours (p<0.05). ADMA and CRP levels were significantly higher, and arginine/ADMA ratios were significantly lower in patients with a more severe condition (p<0.05). Epileptic seizure activity, in sedated SAH patients, was recorded in 2/28 (7.1%) patients during 5/5468 (0.09%) hours of continuous EEG monitoring. Cerebrovascular disease was significantly more common as a cause of death in patients that had survived a SAH ≥ one year, compared to the population from the same area (p<0.0001).Conclusions: Continuous infusion of sedative drugs was associated with low (<200 nmol/L) cortisol levels. ADMA increased significantly after SAH, after CRP had peaked, indicating that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation. Patients with a more severe condition had significantly higher ADMA and CRP levels, and significantly lower arginine/ADMA ratio. Continuous sedation in sedated SAH patients seems to be beneficial in protecting from subclinical seizures. Cerebrovascular causes of death are more common in SAH survivors.
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| 10. |
- Malm, Jan, Professor, 1957-, et al.
(författare)
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Cerebrospinal fluid shunt dynamics in patients with idiopathic adult hydrocephalus syndrome.
- 1995
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 58:6, s. 715-723
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Tidskriftsartikel (refereegranskat)abstract
- The objective was to assess CSF dynamics of different shunt constructions in patients with adult hydrocephalus syndrome and correlate these findings to clinical outcome, neuroradiology, and the specifications of the shunts provided by the manufacturer. Thirty four patients with idiopathic adult hydrocephalus (normal pressure hydrocephalus) syndrome were included in a prospective, consecutive case series. A differential pressure valve (Cordis Hakim standard system) was used in 28 patients and a variable resistance valve (Cordis Orbis-Sigma) in six. A constant pressure infusion method was used; CSF pressure and conductance were determined before surgery. Three months after shunt placement CSF pressure, the "pressure v flow" curve, and gravity induced flow were measured. There was no difference between mean preoperative and postoperative resting CSF pressures in patients with Hakim shunts. The opening pressures of the Hakim shunts were higher than the value proposed by the manufacturer. A pronounced gravity effect induced CSF flow and decrease of the CSF pressure. In functioning variable resistance valves, CSF dynamics normalised postoperatively. There was no gravity effect and the characteristics shaped "pressure v flow" curve was sometimes seen. Six patients (three differential pressure valves, three variable resistance valves) had non-functioning shunts. Four of these patients were improved after the operation but improvement was transient in three. In all patients, there was no relation between the width of the ventricles and clinical improvement or CSF pressure. In conclusion, the differential pressure valve system does not behave according to the specifications provided by the manufacturer. A decrease in CSF pressure in patients with this shunt was solely due to the effect of gravity. Eleven percent of the differential pressure valves and 50% of the variable resistance valves were non-functioning. In the functioning variable resistance valves, the antisiphon system seems to be effective.
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