Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis.

OBJECTIVE: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. METHODS: sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. RESULTS: sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. CONCLUSION: sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Use of NEedle Versus suRFACE Recording Electrodes for Detection of Intraoperative Motor Warnings: A Non-Inferiority Trial. The NERFACE Study Part II.

In the NERFACE study part I, the characteristics of muscle transcranial electrical stimulation motor evoked potentials (mTc-MEPs) recorded from the tibialis anterior (TA) muscles with surface and subcutaneous needle electrodes were compared. The aim of this study (NERFACE part II) was to investigate whether the use of surface electrodes was non-inferior to the use of subcutaneous needle electrodes in detecting mTc-MEP warnings during spinal cord monitoring. mTc-MEPs were simultaneously recorded from TA muscles with surface and subcutaneous needle electrodes. Monitoring outcomes (no warning, reversible warning, irreversible warning, complete loss of mTc-MEP amplitude) and neurological outcomes (no, transient, or permanent new motor deficits) were collected. The non-inferiority margin was 5%. In total, 210 (86.8%) out of 242 consecutive patients were included. There was a perfect agreement between both recording electrode types for the detection of mTc-MEP warnings. For both electrode types, the proportion of patients with a warning was 0.12 (25/210) (difference, 0.0% (one-sided 95% CI, 0.014)), indicating non-inferiority of the surface electrode. Moreover, reversible warnings for both electrode types were never followed by permanent new motor deficits, whereas among the 10 patients with irreversible warnings or complete loss of amplitude, more than half developed transient or permanent new motor deficits. In conclusion, the use of surface electrodes was non-inferior to the use of subcutaneous needle electrodes for the detection of mTc-MEP warnings recorded over the TA muscles.

Comparing Motor-Evoked Potential Characteristics of NEedle versus suRFACE Recording Electrodes during Spinal Cord Monitoring-The NERFACE Study Part I.

Muscle-recorded transcranial electrical stimulation motor-evoked potentials (mTc-MEPs) are used to assess the spinal cord integrity. They are commonly recorded with subcutaneous needle or surface electrodes, but the different characteristics of mTc-MEP signals recorded with the two types of electrodes have not been formally compared yet. In this study, mTc-MEPs were simultaneously recorded from the tibialis anterior (TA) muscles using surface and subcutaneous needle electrodes in 242 consecutive patients. Elicitability, motor thresholds, amplitude, area under the curve (AUC), signal-to-noise ratio (SNR), and the variability between mTc-MEP amplitudes were compared. Whereas amplitude and AUC were significantly higher in subcutaneous needle recordings (p < 0.01), motor thresholds and elicitability were similar for surface and subcutaneous needle recordings. Moreover, the SNRs were >2 in more than 99.5% of the surface and subcutaneous needle recordings, and the variability between consecutive amplitudes was not significantly different between the two recording electrode types (p = 0.34). Surface electrodes appear to be a good alternative to needle electrodes for spinal cord monitoring. They are non-invasive, can record signals at similar threshold intensities, have adequately high SNRs, and record signals with equivalent variability. Whether surface electrodes are non-inferior to subcutaneous needle electrodes in detecting motor warnings is investigated in part II of the NERFACE study.

The Intraoperative Microlesion Effect Positively Correlates With the Short-Term Clinical Effect of Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: During the surgical procedure of deep brain stimulation (DBS), insertion of an electrode in the subthalamic nucleus (STN) frequently causes a temporary improvement of motor symptoms, known as the microlesion effect (MLE). The objective of this study was to determine the correlation between the intraoperative MLE and the clinical effect of DBS. MATERIALS AND METHODS: Thirty Parkinson's disease (PD) patients with Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) part III (MDS-UPDRS III) scores during bilateral STN-DBS implantation were included in this retrospective study. MDS-UPDRS III subscores (resting tremor, rigidity, and bradykinesia) of the contralateral upper extremity were used. During surgery, these subscores were assessed directly before and after insertion of the electrode. Also, these subscores were determined in the outpatient clinic after 11 weeks on average (on-stimulation). All assessments were performed in an off-medication state (at least 12 hours of medication washout). RESULTS: Postinsertion MDS-UPDRS motor scores decreased significantly compared to preinsertion scores (p < 0.001 for both hemispheres). The MLE showed a positive correlation with the clinical effect of DBS in both hemispheres (rho = 0.68 for the primarily treated hemisphere, p < 0.001, and rho = 0.59 for the secondarily treated hemisphere, p < 0.01). CONCLUSION: The MLE has a clinically relevant correlation with the effect of DBS in PD patients. These results suggest that the MLE can be relied upon as evidence of a clinically effective DBS electrode placement.

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients.

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism.

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis.

OBJECTIVE: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. METHODS: sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNP+ and AL/PNP-, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNP+), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age- and sex-matched to both AL/PNP- (HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. RESULTS: sNfL levels were increased both in 10 AL/PNP+ patients (p < .001) and in 10 AL/PNP- patients (p < .005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNP+ patients than in AL/PNP- patients (p < .005). sNfL levels were also increased in 15 ATTRv/PNP+ patients, compared to both 15 HC/TTRv (p < .0001) and 15 TTRv carriers (p < .0001). ATTRv/PNP+ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p = .05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. CONCLUSION: sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis.

Eye movement disorders and neurological symptoms in late-onset inborn errors of metabolism.

Inborn errors of metabolism in adults are still largely unexplored. Despite the fact that adult-onset phenotypes have been known for many years, little attention is given to these disorders in neurological practice. The adult-onset presentation differs from childhood-onset phenotypes, often leading to considerable diagnostic delay. The identification of these patients at the earliest stage of disease is important, given that early treatment may prevent or lessen further brain damage. Neurological and psychiatric symptoms occur more frequently in adult forms. Abnormalities of eye movements are also common and can be the presenting sign. Eye movement disorders can be classified as central or peripheral. Central forms are frequently observed in lysosomal storage disorders, whereas peripheral forms are a key feature of mitochondrial disease. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders are often not reported by the patient, and abnormalities can be easily overlooked in a general examination. In adults with unexplained psychiatric and neurological symptoms, a special focus on examination of eye movements can serve as a relatively simple clinical tool to detect a metabolic disorder. Eye movements can be easily quantified and analyzed with video-oculography, making them a valuable biomarker for following the natural course of disease or the response to therapies. Here, we review, for the first time, eye movement disorders that can occur in inborn errors of metabolism, with a focus on late-onset forms. We provide a step-by-step overview that will help clinicians to examine and interpret eye movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The interrelation between clinical presentation and neurophysiology of posthypoxic myoclonus.

OBJECTIVE: Posthypoxic myoclonus (PHM) in the first few days after resuscitation can be divided clinically into generalized and focal (uni- and multifocal) subtypes. The former is associated with a subcortical origin and poor prognosis in patients with postanoxic encephalopathy (PAE), and the latter with a cortical origin and better prognosis. However, use of PHM as prognosticator in PAE is hampered by the modest objectivity in its clinical assessment. Therefore, we aimed to obtain the anatomical origin of PHM with use of neurophysiological investigations, and relate these to its clinical presentation. METHODS: This study included 20 patients (56 ± 18 y/o, 68% M, 2 survived, 1 excluded) with EEG-EMG-video recording. Three neurologists classified PHM into generalized or focal PHM. Anatomical origin (cortical/subcortical) was assessed with basic and advanced neurophysiology (Jerk-Locked Back Averaging, coherence analysis). RESULTS: Clinically assessed origin of PHM did not match the result obtained with neurophysiology: cortical PHM was more likely present in generalized than in focal PHM. In addition, some cases demonstrated co-occurrence of cortical and subcortical myoclonus. Patients that recovered from PAE had cortical myoclonus (1 generalized, 1 focal). INTERPRETATION: Hypoxic damage to variable cortical and subcortical areas in the brain may lead to mixed and varying clinical manifestations of myoclonus that differ of those patients with myoclonus generally encountered in the outpatient clinic. The current clinical classification of PHM is not adequately refined to play a pivotal role in guiding treatment decisions to withdraw care. Our neurophysiological characterization of PHM provides specific parameters to be used in designing future comprehensive studies addressing the potential role of PHM as prognosticator in PAE.

Age-related botulinum toxin effects on muscle fiber conduction velocity in non-injected muscles.

OBJECTIVE: We studied systemic effects of botulinum toxin (BTX) treatment on muscle fiber conduction velocity (MFCV) and possible effects of age. METHODS: MFCV was determined by an invasive EMG method in the biceps brachii muscle. Seventeen BTX treated patients and 58 controls were investigated. BTX injections were applied in the neck region or forearm, depending on the indication for treatment. RESULTS: We found an increased ratio between fastest and slowest muscle fiber conduction velocity in BTX treated patients. This suggests systemic BTX effects on MFCV distant from the site of injection, probably fiber atrophy secondary to end-plate dysfunction. Furthermore, we found an increased MFCV in part of the patients, suggesting hypertrophy of some of the muscle fibers. No relation was found between the MFCV disturbances and treatment duration or the cumulative dose of BTX. CONCLUSIONS: We found a strong positive correlation between the age and the BTX-induced changes of MFCV in patients, suggesting a BTX related, diminished repair capacity of end-plates or muscle fibers with age. SIGNIFICANCE: Our findings suggest a reduced repair capacity of end-plates or muscle fibers in elderly patients. MFCV is a sensitive method to show changes related to damage and compensation of the neuromuscular system. Our finding suggests a decreasing efficiency of repair mechanisms in aging.

A new surface electromyography analysis method to determine spread of muscle fiber conduction velocities.

Muscle fiber conduction velocity (MFCV) estimation from surface signals is widely used to study muscle function, e.g., in neuromuscular disease and in fatigue studies. However, most analysis methods do not yield information about the velocity distribution of the various motor unit action potentials. We have developed a new method-the interpeak latency method (IPL)-to calculate both the mean MFCV and the spread of conduction velocities in vivo, from bipolar surface electromyogram (sEMG) during isometric contractions. sEMG was analyzed in the biceps brachii muscle in 15 young male volunteers. The motor unit action potential peaks are automatically detected with a computer program. Associated peaks are used to calculate a mean MFCV and the SD. The SD is taken as a measure of the MFCV spread. The main finding is that the IPL method can derive a measure of MFCV spread at different contraction levels. In conclusion, the IPL method provides accurate values for the MFCV and additionally gives information about the scatter of conduction velocities.