Bone metabolic activity in hyperostosis cranialis interna measured with 18F-fluoride PET

F-18-Fluoride PET/CT is a relatively undervalued diagnostic test to measure bone metabolism in bone diseases. Hyperostosis cranialis interna (HCI) is a (hereditary) bone disease characterised by endosteal hyperostosis and osteosclerosis of the skull and the skull base. Bone overgrowth causes entrapment and dysfunction of several cranial nerves. The aim of this study is to compare standardised uptake values (SUVs) at different sites in order to quantify bone metabolism in the affected anatomical regions in HCI patients. Nine affected family members, seven non-affected family members and nine non-HCI non-family members underwent F-18-fluoride PET/CT scans. SUVs were systematically measured in the different regions of interest: frontal bone, sphenoid bone, petrous bone and clivus. Moreover, the average F-18-fluoride uptake in the entire skull was measured by assessing the uptake in axial slides. Visual assessment of the PET scans of affected individuals was performed to discover the process of disturbed bone metabolism in HCI. F-18-Fluoride uptake is statistically significantly higher in the sphenoid bone and clivus regions of affected family members. Visual assessment of the scans of HCI patients is relevant in detecting disease severity and the pattern of disturbed bone metabolism throughout life. F-18-Fluoride PET/CT is useful in quantifying the metabolic activity in HCI and provides information about the process of disturbed bone metabolism in this specific disorder. Limitations are a narrow window between normal and pathological activity and the influence of age. This study emphasises that F-18-fluoride PET/CT may also be a promising diagnostic tool for other metabolic bone disorders, even those with an indolent course

Rapid quantification of underivatized amino acids in plasma by hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass-spectrometry

Background: Amino acidopathies are a class of inborn errors of metabolism (IEM) that can be diagnosed by analysis of amino acids (AA) in plasma. Current strategies for AA analysis include cation exchange HPLC with post-column ninhydrin derivatization, GC-MS, and LC-MS/MS-related methods. Major drawbacks of the current methods are time-consuming procedures, derivative problems, problems with retention, and MS-sensitivity. The use of hydrophilic interaction liquid chromatography (HILIC) columns is an ideal separation mode for hydrophilic compounds like AA. Here we report a HILIC-method for analysis of 36 underivatized AA in plasma to detect defects in AA metabolism that overcomes the major drawbacks of other methods. Methods: A rapid, sensitive, and specific method was developed for the analysis of AA in plasma without derivatization using HILIC coupled with tandem mass-spectrometry (Xevo TQ, Waters). Results: Excellent separation of 36 AA (24 quantitative/12 qualitative) in plasma was achieved on an Acquity BEH Amide column (2.1×100 mm, 1.7 μm) in a single MS run of 18 min. Plasma of patients with a known IEM in AA metabolism was analyzed and all patients were correctly identified. Conclusion: The reported method analyzes 36 AA in plasma within 18 min and provides baseline separation of isomeric AA such as leucine and isoleucine. No separation was obtained for isoleucine and allo-isoleucine. The method is applicable to study defects in AA metabolism in plasma

Energy cost optimized dorsal leaf ankle-foot-orthoses reduce impact forces on the contralateral leg in people with unilateral plantar flexor weakness

Background: In individuals with unilateral plantar flexor weakness, the second peak of the vertical ground reaction force (GRF) is decreased. This leads to a higher ground reaction force, e.g. impact, of the contralateral leg, potentially explaining quadriceps muscle and/or knee joint pain. Energy cost optimized dorsal leaf ankle-foot-orthoses (AFOs) may increase the push-off ground reaction force, which in turn could lead to lower impact forces on the contralateral leg. Research questions: 1) Are impact forces increased in the contralateral leg of people with unilateral plantar flexor weakness compared to healthy subjects? 2) Do energy cost optimized AFOs reduce impact forces and improve leg impact symmetry compared to walking without AFO in people with unilateral plantar flexor weakness? Methods: Nine subjects with unilateral plantar flexor weakness were provided a dorsal leaf AFO with a stiffness primarily optimized for energy cost. Using 3D gait analyses peak vertical GRF during loading response with and without AFO, and the symmetry between the legs in peak GRF were calculated. Peak GRF and symmetry were compared with reference data of 23 healthy subjects. Results: The contralateral leg showed a significant higher peak vertical GRF (12.0 ± 0.9 vs 11.2 ± 0.6 N/kg, p = 0.005) compared to healthy reference data. When walking with AFO, the peak vertical GRF of the contralateral leg significantly reduced (from 12.0 ± 0.9 to 11.4 ± 0.7 N/kg, p = 0.017) and symmetry improved compared to no AFO (from 0.93 ± 0.06 to 1.01 ± 0.05, p < 0.001). Conclusion: In subjects with unilateral plantar flexor weakness, impact force on the contralateral leg was increased when compared to healthy subjects and dorsal leaf AFOs optimized for energy cost substantially reduced this force and improved impact symmetry when compared to walking without AFO. This indicates that dorsal leaf AFOs may reduce pain resulting from increased impact forces during gait in the contralateral leg in people with unilateral plantar flexor weakness

Validation of forward simulations to predict the effects of bilateral plantarflexor weakness on gait

Background: Bilateral plantarflexor muscle weakness is a common impairment in many neuromuscular diseases. However, the way in which severity of plantarflexor weakness affects gait in terms of walking energy cost and speed is not fully understood. Predictive simulations are an attractive alternative to human experiments as simulations allow systematic alterations in muscle weakness. However, simulations of pathological gait have not yet been validated against experimental data, limiting their applicability.  Research question: Our first aim was to validate a predictive simulation framework for walking with bilateral plantarflexor weakness by comparing predicted gait against experimental gait data of patients with bilateral plantarflexor weakness. Secondly, we aimed to evaluate how incremental levels of bilateral plantarflexor weakness affect gait.  Methods: We used a planar musculoskeletal model with 9 degrees of freedom and 9 Hill-type muscle-tendon units per leg. A state-dependent reflex-based controller optimized for a function combining energy cost, muscle activation squared and head acceleration was used to simulate gait. For validation, strength of the plantarflexors was reduced by 80 % and simulated gait compared with experimental data of 16 subjects with bilateral plantarflexor weakness. Subsequently, strength of the plantarflexors was reduced stepwise to evaluate its effect on gait kinematics and kinetics, walking energy cost and speed.  Results: Simulations with 80 % weakness matched well with experimental hip and ankle kinematics and kinetics (R > 0.64), but less for knee kinetics (R 0.82) with plantarflexor strength.  Significance: Our simulation framework predicted most gait changes due to bilateral plantarflexor weakness, and indicates that pathological gait features emerge especially when bilateral plantarflexor weakness exceeds 60 %. Our framework may support future research into the effect of pathologies or assistive devices on gait

Validation of forward simulations to predict the effects of bilateral plantarflexor weakness on gait

Background: Bilateral plantarflexor muscle weakness is a common impairment in many neuromuscular diseases. However, the way in which severity of plantarflexor weakness affects gait in terms of walking energy cost and speed is not fully understood. Predictive simulations are an attractive alternative to human experiments as simulations allow systematic alterations in muscle weakness. However, simulations of pathological gait have not yet been validated against experimental data, limiting their applicability. Research question: Our first aim was to validate a predictive simulation framework for walking with bilateral plantarflexor weakness by comparing predicted gait against experimental gait data of patients with bilateral plantarflexor weakness. Secondly, we aimed to evaluate how incremental levels of bilateral plantarflexor weakness affect gait. Methods: We used a planar musculoskeletal model with 9 degrees of freedom and 9 Hill-type muscle-tendon units per leg. A state-dependent reflex-based controller optimized for a function combining energy cost, muscle activation squared and head acceleration was used to simulate gait. For validation, strength of the plantarflexors was reduced by 80 % and simulated gait compared with experimental data of 16 subjects with bilateral plantarflexor weakness. Subsequently, strength of the plantarflexors was reduced stepwise to evaluate its effect on gait kinematics and kinetics, walking energy cost and speed. Results: Simulations with 80 % weakness matched well with experimental hip and ankle kinematics and kinetics (R > 0.64), but less for knee kinetics (R 0.82) with plantarflexor strength. Significance: Our simulation framework predicted most gait changes due to bilateral plantarflexor weakness, and indicates that pathological gait features emerge especially when bilateral plantarflexor weakness exceeds 60 %. Our framework may support future research into the effect of pathologies or assistive devices on gait

Validation of forward simulations to predict the effects of bilateral plantarflexor weakness on gait

Background: Bilateral plantarflexor muscle weakness is a common impairment in many neuromuscular diseases. However, the way in which severity of plantarflexor weakness affects gait in terms of walking energy cost and speed is not fully understood. Predictive simulations are an attractive alternative to human experiments as simulations allow systematic alterations in muscle weakness. However, simulations of pathological gait have not yet been validated against experimental data, limiting their applicability. Research question: Our first aim was to validate a predictive simulation framework for walking with bilateral plantarflexor weakness by comparing predicted gait against experimental gait data of patients with bilateral plantarflexor weakness. Secondly, we aimed to evaluate how incremental levels of bilateral plantarflexor weakness affect gait. Methods: We used a planar musculoskeletal model with 9 degrees of freedom and 9 Hill-type muscle-tendon units per leg. A state-dependent reflex-based controller optimized for a function combining energy cost, muscle activation squared and head acceleration was used to simulate gait. For validation, strength of the plantarflexors was reduced by 80 % and simulated gait compared with experimental data of 16 subjects with bilateral plantarflexor weakness. Subsequently, strength of the plantarflexors was reduced stepwise to evaluate its effect on gait kinematics and kinetics, walking energy cost and speed. Results: Simulations with 80 % weakness matched well with experimental hip and ankle kinematics and kinetics (R > 0.64), but less for knee kinetics (R 0.82) with plantarflexor strength. Significance: Our simulation framework predicted most gait changes due to bilateral plantarflexor weakness, and indicates that pathological gait features emerge especially when bilateral plantarflexor weakness exceeds 60 %. Our framework may support future research into the effect of pathologies or assistive devices on gait