Skin and not dorsal root stimulation reduces hypertonus in thoracic motor complete spinal cord injury: a single case report.

On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons.NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.

The effect of suboccipital muscle dysfunction on the biomechanics of the upper cervical spine: a study based on finite element analysis.

OBJECTIVE: Muscle dysfunction caused by repetitive work or strain in the neck region can interfere muscle responses. Muscle dysfunction can be an important factor in causing cervical spondylosis. However, there has been no research on how the biomechanical properties of the upper cervical spine change when the suboccipital muscle group experiences dysfunction. The objective of this study was to investigate the biomechanical evidence for cervical spondylosis by utilizing the finite element (FE) approach, thus and to provide guidance for clinicians performing acupoint therapy. METHODS: By varying the elastic modulus of the suboccipital muscle, the four FE models of C0-C3 motion segments were reconstructed under the conditions of normal muscle function and muscle dysfunction. For the two normal condition FE models, the elastic modulus for suboccipital muscles on both sides of the C0-C3 motion segments was equal and within the normal range In one muscle dysfunction FE model, the elastic modulus on both sides was equal and greater than 37 kPa, which represented muscle hypertonia; in the other, the elastic modulus of the left and right suboccipital muscles was different, indicating muscle imbalance. The biomechanical behavior of the lateral atlantoaxial joint (LAAJ), atlanto-odontoid joint (ADJ), and intervertebral disc (IVD) was analyzed by simulations, which were carried out under the six loadings of flexion, extension, left and right lateral bending, left and right axial rotation. RESULTS: Under flexion, the maximum stress in LAAJ with muscle imbalance was higher than that with normal muscle and hypertonia, while the maximum stress in IVD in the hypertonic model was higher than that in the normal and imbalance models. The maximum stress in ADJ was the largest under extension among all loadings for all models. Muscle imbalance and hypertonia did not cause overstress and stress distribution abnormalities in ADJ. CONCLUSION: Muscle dysfunction increases the stress in LAAJ and in IVD, but it does not affect ADJ.

Cluster analysis of impairment measures to inform an evidence-based classification structure in RaceRunning, a new World Para Athletics event for athletes with hypertonia, ataxia or athetosis.

RaceRunning enables athletes with limited or no walking ability to propel themselves independently using a three-wheeled frame that has a saddle, handle bars and a chest plate. For RaceRunning to be included as a para athletics event, an evidence-based classification system is required. This study assessed the impact of trunk control and lower limb impairment measures on RaceRunning performance and evaluated whether cluster analysis of these impairment measures produces a valid classification structure for RaceRunning. The Trunk Control Measurement Scale (TCMS), Selective Control Assessment of the Lower Extremity (SCALE), the Australian Spasticity Assessment Scale (ASAS), and knee extension were recorded for 26 RaceRunning athletes. Thirteen male and 13 female athletes aged 24 (SD = 7) years participated. All impairment measures were significantly correlated with performance (rho = 0.55-0.74). Using ASAS, SCALE, TCMS and knee extension as cluster variables in a two-step cluster analysis resulted in two clusters of athletes. Race speed and the impairment measures were significantly different between the clusters (p < 0.001). The findings of this study provide evidence for the utility of the selected impairment measures in an evidence-based classification system for RaceRunning athletes.

Improving the objectivity of the current World Para Swimming motor coordination test for swimmers with hypertonia, ataxia and athetosis using measures of movement smoothness, rhythm and accuracy.

The current protocol for classifying Para swimmers with hypertonia, ataxia and athetosis involves a physical assessment where the individual's ability to coordinate their limbs is scored by subjective clinical judgment. The lack of objective measurement renders the current test unsuitable for evidence-based classification. This study evaluated a revised version of the Para swimming assessment for motor coordination, incorporating practical, objective measures of movement smoothness, rhythm error and accuracy. Nineteen Para athletes with hypertonia and 19 non-disabled participants performed 30 s trials of bilateral alternating shoulder flexion-extension at 30 bpm and 120 bpm. Accelerometry was used to quantify movement smoothness; rhythm error and accuracy were obtained from video. Para athletes presented significantly less smooth movement and higher rhythm error than the non-disabled participants (p < 0.05). Random forest algorithm successfully classified 89% of participants with hypertonia during out-of-bag predictions. The most important predictors in classifying participants were movement smoothness at both movement speeds, and rhythm error at 120 bpm. Our results suggest objective measures of movement smoothness and rhythm error included in the current motor coordination test protocols can be used to infer impairment in Para swimmers with hypertonia. Further research is merited to establish the relationship of these measures with swimming performance.

Impaired neuromuscular transmission of the tibialis anterior in a rodent model of hypertonia.

Early-onset hypertonia is characteristic of developmental neuromotor disorders, including cerebral palsy (CP). The spa transgenic mouse displays early-onset spasticity, abnormal gait, and motor impairments that are remarkably similar to symptoms of human CP. Previously, we showed that spa mice have fewer motor neurons innervating the tibialis anterior (TA). An expanded innervation ratio may result in increased susceptibility to neuromuscular transmission failure (NMTF). We assessed NMTF in an ex vivo TA muscle nerve preparation from spa and wild-type (WT) mice by comparing forces elicited by nerve versus muscle stimulation. TA muscle innervation ratio was assessed by counting the number of muscle fibers and dividing by the number of TA motor neurons. Muscle fiber cross-sectional areas were also assessed in the TA muscle. We observed that NMTF was immediately present in spa mice, increased with repetitive stimulation, and associated with increased innervation ratio. These changes were concomitant with reduced TA muscle fiber cross-sectional area in spa mice compared with WT. Early-onset hypertonia is associated with increased innervation ratio and impaired neuromuscular transmission. These disturbances may exacerbate the underlying gait abnormalities present in individuals with hypertonia.NEW & NOTEWORTHY Nerve-muscle interaction is poorly understood in the context of early-onset spasticity and hypertonia. In an animal model of early-onset spasticity, spa mice, we found a marked impairment of tibialis anterior neuromuscular transmission. This impairment is associated with an increased innervation ratio (mean number of muscle fibers innervated by a single motor neuron). These disturbances may underlie weakness and gait disturbances observed in individual with developmental hypertonia and spasticity.

Phrenic motor neuron loss in an animal model of early onset hypertonia.

Phrenic motor neuron (PhMN) development in early onset hypertonia is poorly understood. Respiratory disorders are one of the leading causes of morbidity and mortality in individuals with early onset hypertonia, such as cerebral palsy (CP), but they are largely overshadowed by a focus on physical function in this condition. Furthermore, while the brain is the focus of CP research, motor neurons, via the motor unit and neurotransmitter signaling, are the targets in clinical interventions for hypertonia. Furthermore, critical periods of spinal cord and motor unit development also coincide with the timing that the supposed brain injury occurs in CP. Using an animal model of early-onset spasticity (spa mouse [B6.Cg-Glrbspa/J] with a glycine receptor mutation), we hypothesized that removal of effective glycinergic neurotransmitter inputs to PhMNs during development will result in fewer PhMNs and reduced PhMN somal size at maturity. Adult spa (Glrb-/-), and wild-type (Glrb+/+) mice underwent unilateral retrograde labeling of PhMNs via phrenic nerve dip in tetramethylrhodamine. After three days, mice were euthanized, perfused with 4% paraformaldehyde, and the spinal cord excised and processed for confocal imaging. Spa mice had ~30% fewer PhMNs (P = 0.005), disproportionately affecting larger PhMNs. Additionally, a ~22% reduction in PhMN somal surface area (P = 0.019), an 18% increase in primary dendrites (P < 0.0001), and 24% decrease in dendritic surface area (P = 0.014) were observed. Thus, there are fewer larger PhMNs in spa mice. Fewer and smaller PhMNs may contribute to impaired diaphragm neuromotor control and contribute to respiratory morbidity and mortality in conditions of early onset hypertonia.NEW & NOTEWORTHY Phrenic motor neuron (PhMN) development in early-onset hypertonia is poorly understood. Yet, respiratory disorders are a common cause of morbidity and mortality. In spa mice, an animal model of early-onset hypertonia, we found ~30% fewer PhMNs, compared with controls. This PhMN loss disproportionately affected larger PhMNs. Thus, the number and heterogeneity of the PhMN pool are decreased in spa mice, likely contributing to the hypertonia, impaired neuromotor control, and respiratory disorders.

Heart rate variability alterations in infants with spontaneous hypertonia.

BACKGROUND: Hypertonia is characterized by increased resting muscle tone. Previous studies have shown that adult patients with hypertonia displayed autonomic imbalance. However, cardiac sympatho-vagal control in infants with hypertonia have not been explored. The main aim was to estimate cardiac autonomic control in infants with hypertonia using heart rate variability (HRV). METHODS: Thirty infants (0-2 years old) were studied. Heart rate (HR) and R-R interval time series were obtained in 15 Control and 15 Hypertonia infants. HRV was analyzed in time and frequency domains. Additionally, non-linear analysis and entropy measurements were performed. RESULTS: Infants with hypertonia showed cardiac autonomic imbalance as evidenced by alterations in HRV, characterized by an increased power spectral density of low frequency (LF) over high frequency (HF) components of HRV. Indeed, a ∼7% increase in LF, and ∼30% reduction in HF, were found in infants with hypertonia vs. control infants. In addition, time domain and non-linear HRV analysis (Root-mean-square of successive normal sinus R-R interval difference, entropy, and R-R interval variability) were all significantly decreased in hypertonia vs. control subjects. CONCLUSIONS: Our results showed that hypertonia infants displayed HRV disturbances, which suggest an alteration in overall autonomic cardiac modulation in infants with hypertonia compared with healthy condition.

The Impact of Paratonia on Fine and Gross Motor Function in Older Adults With Mild and Moderate Dementia.

BACKGROUND: Dementia is associated with impairment in gait, balance, and fine motor function. Paratonia, a form of hypertonia, is often present in severe dementia. However, little is known about muscle tone in early dementia, and the eventual relation between muscle tone abnormalities and changes in fine and gross motor function. METHODS: Three groups of participants were included in the study: healthy controls (n=60), participants with mild dementia (MiD) (n=31), and participants with moderate dementia (n=31). Measurements of fine motricity (Purdue pegboard test), balance and gait (Dynaport Hybrid), the presence of paratonia (PAI), and muscle tone measurements (MyotonPRO) were performed. RESULTS: Paratonia was present in 42% of participants with MiD and in 58% of participants with moderate dementia. Participants with paratonia had lower Purdue Pegboard scores (P<0.001), lower balance coordination in semitandem stance (P<0.001), lower walking speed at a fast pace (P=0.001), and lower step regularity at normal (P=0.025) and fast (P<0.001) pace. CONCLUSIONS: Paratonia is already present in participants with MiD and is associated with a decline in both fine and gross motor performance. Early detection of paratonia might be helpful to detect persons at higher risk of motor deterioration and falls.

Pelvic floor hypertonicity in women with pelvic floor disorders: A case control and risk prediction study.

AIM: Myofascial pelvic pain is a chronic and debilitating condition, sometimes associated with pelvic floor disorders (PFD) such as urinary incontinence, defecatory dysfunction or pelvic organ prolapse. Our aim was to identify risk factors in women with PFD and hypertonic pelvic floor, compared to controls without hypertonicity. METHODS: Case control study (2009-2017) of patients with PFD and a diagnosis of hypertonic pelvic floor. Cases were matched with patients who presented with the same PFD but without pelvic floor hypertonicity. Postoperative patients with hypertonic pelvic floor were matched with patients who underwent surgery for the same PFD but did not develop pain. Risk factors were compared between groups. RESULTS: Ninety-five cases were matched; 71% had urogynecologic surgery as a possible trigger for myofascial pain. Most were post-menopausal. Overall, case patients were younger than controls (mean 54 vs 59, P = 0.002). Multivariate logistic regression identified risk factors of younger age (OR 1.45, 95%CI 1.04-2.07), history of depression (OR 3, 95%CI 1.03-9.09), musculoskeletal spine injury (OR 4.32, 95%CI 1.01-21.26) and transobturator midurethral sling (OR 8.36, 95%CI 2.68-31.32). Retropubic midurethral sling was protective against pelvic floor hypertonicity (OR 0.37, 95%CI 0.15-0.86). A clinical prediction model including depression, endometriosis, irritable bowel, spine injury and type of midurethral sling was developed to estimate the probability for myofascial pain after urogynecologic surgery. CONCLUSIONS: Specific risk factors predispose women with PFD to chronic pelvic floor hypertonicity. Knowledge of these can help with patient counselling and choice of midurethral sling prior to PFD surgery.

Lumbar muscles biomechanical characteristics in young people with chronic spinal pain.

BACKGROUND: The prevalence of low back pain is rising among the young adult population. Altered lumbar muscle tone was suggested to be associated with underlying pathologies and symptoms. To date, there is minimum information available on the repeatability of lumbar spine muscle mechanical properties in the young adults who experienced low back pain. This study aimed to assess the reproducibility of mechanical properties of lumbar spinal muscle in young adults with spinal pain by myotonometer and explored the difference in reproducibility when different number of indentations was used. METHODS: Participants who aged between 18 to 25 and reported chronic LBP were recruited. Lumbar muscle tone (Hz) and stiffness (N/m) were assessed by myotonometer on one occasion by two assessors. Parameters were recorded by triple scans and 5-scans mode. Intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Bland and Altman analysis were used to assess agreement between two measurements. The relationship between muscle mechanical properties and pain score and disability level were assessed by Spearman's rank correlation coefficient. RESULTS: The results of ICCs indicated excellent repeatability in triple scans and 5-scans mode for each lumbar level bilaterally (ICC > 0.75). SEM and SRD were smaller in triple scans than 5-scans mode for most levels. Bland and Altman analysis revealed no systematic bias. Spearman's rank correlation analysis indicated significant high correlations between muscle tone and disability level (r = 0.80, p < 0.05), and between muscle stiffness and disability level (r = 0.81, p < 0.05). CONCLUSIONS: This study found that lumbar spinal muscle tone and stiffness were repeatable parameters when measured by myotonometer. The reproducibility of muscle mechanical parameters did not appear to differ between the two scanning modes with different number of indentations. Muscle tone and stiffness measured by myotonometer may therefore be reliable as outcome measures to assess intervention induced changes. The lack of significant association between intensity of pain and mechanical properties of paraspinal muscles may suggest that muscle properties measured at rest might not be related to pain level at rest but more related to pain elicited during movement.

Hypertonicity-induced cation channels in HepG2 cells: architecture and role in proliferation vs. apoptosis.

KEY POINTS: Na+ conducting hypertonicity-induced cation channels (HICCs) are key players in the volume restoration of osmotically shrunken cells and, under isotonic conditions, considered as mediators of proliferation - thereby opposing apoptosis. In an siRNA screen of ion channels and transporters in HepG2 cells, with the regulatory volume increase (RVI) as read-out, δENaC, TRPM2 and TRPM5 were identified as HICCs. Subsequently, all permutations of these channels were tested in RVI and patch-clamp recordings and, at first sight, HICCs were found to operate in an independent mode. However, there was synergy in the siRNA perturbations of HICC currents. Accordingly, proximity ligation assays showed that δENaC was located in proximity to TRPM2 and TRPM5 suggesting a physical interaction. Furthermore, δENaC, TRPM2 and TRPM5 were identified as mediators of HepG2 proliferation - their silencing enhanced apoptosis. Our study defines the architecture of HICCs in human hepatocytes as well as their molecular functions. ABSTRACT: Hypertonicity-induced cation channels (HICCs) are a substantial element in the regulatory volume increase (RVI) of osmotically shrunken cells. Under isotonic conditions, they are key effectors in the volume gain preceding proliferation; HICC repression, in turn, significantly increases apoptosis rates. Despite these fundamental roles of HICCs in cell physiology, very little is known concerning the actual molecular architecture of these channels. Here, an siRNA screening of putative ion channels and transporters was performed, in HepG2 cells, with the velocity of RVI as the read-out; in this first run, δENaC, TRPM2 and TRPM5 could be identified as HICCs. In the second run, all permutations of these channels were tested in RVI and patch-clamp recordings, with special emphasis on the non-additivity and additivity of siRNAs - which would indicate molecular interactions or independent ways of channel functioning. At first sight, the HICCs in HepG2 cells appeared to operate rather independently. However, a proximity ligation assay revealed that δENaC was located in proximity to both TRPM2 and TRPM5. Furthermore, a clear synergy of HICC current knock-downs (KDs) was observed. δENaC, TRPM2 and TRPM5 were defined as mediators of HepG2 cell proliferation and their silencing increased the rates of apoptosis. This study provides a molecular characterization of the HICCs in human hepatocytes and of their role in RVI, cell proliferation and apoptosis.

Psychometric Properties of the MyotonPRO in Dementia Patients with Paratonia.

BACKGROUND: Paratonia is a distinctive form of hypertonia, causing loss of functional mobility in early stages of dementia to severe high muscle tone and pain in the late stages. For assessing and evaluating therapeutic interventions, objective instruments are required. OBJECTIVE: Determine the psychometric properties of the MyotonPRO, a portable device that objectively measures muscle properties, in dementia patients with paratonia. METHODS: Muscle properties were assessed with the MyotonPRO by 2 assessors within one session and repeated by the main researcher after 30 min and again after 6 months. Receiver operating characteristic curves were constructed for all MyotonPRO outcomes to discriminate between participants with (n = 70) and without paratonia (n = 82). In the participants with paratonia, correlation coefficients were established between the MyotonPRO outcomes and the Modified Ashworth Scale for paratonia (MAS-P) and muscle palpation. In participants with paratonia, reliability (intraclass correlation coefficient) and agreement values (standard error of measurement and minimal detectable change) were established. Longitudinal outcome from participants with paratonia throughout the study (n = 48) was used to establish the sensitivity for change (correlation coefficient) and responsiveness (minimal clinical important difference). RESULTS: Included were 152 participants with dementia (mean [standard deviation] age of 83.5 [98.2]). The area under the curve ranged from 0.60 to 0.67 indicating the MyotonPRO is able to differentiate between participants with and without paratonia. The MyotonPRO explained 10-18% of the MAS-P score and 8-14% of the palpation score. Interclass correlation coefficients for interrater reliability ranged from 0.57 to 0.75 and from 0.54 to 0.71 for intrarater. The best agreement values were found for tone, elasticity, and stiffness. The change between baseline and 6 months in the MyotonPRO outcomes explained 8-13% of the change in the MAS-P scores. The minimal clinically important difference values were all smaller than the measurement error. CONCLUSION: The MyotonPRO is potentially applicable for cross-sectional studies between groups of paratonia patients and appears less suitable to measure intraindividual changes in paratonia. Because of the inherent variability in movement resistance in paratonia, the outcomes from the MyotonPRO should be interpreted with care; therefore, future research should focus on additional guidelines to increase the clinical interpretation and improving reproducibility.

What Is the Longitudinal Profile of Impairments and Can We Predict Difficulty Caring for the Profoundly Affected Arm in the First Year Poststroke?

OBJECTIVES: To establish the longitudinal profile of impairments of body functions and activity limitations of the arm, and to evaluate potential predictors of difficulty caring for the profoundly affected arm poststroke. DESIGN: Prospective cohort study. SETTING: Stroke services. PARTICIPANTS: People unlikely to regain functional use of the arm (N=155) were recruited at 2 to 4 weeks poststroke, and followed up at 3, 6, and 12 months. Potential predictors at baseline were hypertonicity, pain, motor control, mood, sensation/perception, age, and stroke severity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Difficulty caring for the arm (Leeds Arm Spasticity Impact Scale), pain, hypertonicity, range of movement, arm function, and skin integrity. Multivariable linear regression identified the best fitting model for predicting Leeds Arm Spasticity Impact Scale score at 12 months. RESULTS: There were 110 participants (71%) reviewed at 1 year. There was a large variation in the profile of arm functions and activity limitations. Inability or severe difficulty caring for the arm affected 29% of participants. Hypertonicity developed in 77%, with severe hypertonicity present in 25%. Pain was reported by 65%, 94% developed shoulder contracture, and 6% had macerated skin. Difficulty caring for the arm increased with age, greater level of hypertonicity, and stroke classification; collectively, these factors accounted for 33% of the variance in Leeds Arm Spasticity Impact Scale scores. CONCLUSIONS: At 1 year poststroke, there was a high incidence of impairments of body functions and activity limitations in people with a profoundly affected arm. Individual profiles were very variable and although some predisposing factors have been identified, it remains difficult to predict who is at greatest risk.

Development and validation of a bowel-routine-based self-report questionnaire for sacral sparing after spinal cord injury.

STUDY DESIGN: An observational study. OBJECTIVE: To develop a self-administered tool for assessment of sacral sparing after spinal cord injury (SCI) and to test its validity in individuals with SCI. SETTING: Peking University Third Hospital, Beijing, China. METHODS: A 5-item SCI sacral sparing self-report questionnaire was developed based on several events that most patients might experience during bowel routine. 102 participants who sustained SCI within 12 months were asked to complete the questionnaire followed by an anorectal examination. Agreements of answers to the questionnaire and the physical examination were analyzed. Sensitivity, specificity and Youden's index of each item was calculated. RESULTS: The first four questions regarding the S4-5 sensation including deep anal pressure showed high agreement with the results of the physical examination (κ: 0.79-0.93). Sensitivity, specificity and Youden's index were also high (all above 80%). For the fifth question related to the voluntary anal contraction, the agreement was almost perfect with good sensitivity and specificity among patients without increased anal sphincter tone (AST). In patients with increased AST, the agreement was fair. CONCLUSION: The validity of this questionnaire for the assessment of sacral sparing in up to 12 months post injury is good except for the motor function when there was increased AST. In some situations it could be considered as an alternative tool for digital rectal examination, especially when repeated examinations are not feasible. It is suggested that change of sacral sparing may be detected by the questionnaire.

GLRB is the third major gene of effect in hyperekplexia.

Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and ß-subunits (GLRB) in a 2α(1):3ß configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.

Modulation of Muscle Tone and Sympathovagal Balance in Cervical Dystonia Using Percutaneous Stimulation of the Auricular Vagus Nerve.

Primary cervical dystonia is characterized by abnormal, involuntary, and sustained contractions of cervical muscles. Current ways of treatment focus on alleviating symptomatic muscle activity. Besides pharmacological treatment, in severe cases patients may receive neuromodulative intervention such as deep brain stimulation. However, these (highly invasive) methods have some major drawbacks. For the first time, percutaneous auricular vagus nerve stimulation (pVNS) was applied in a single case of primary cervical dystonia. Auricular vagus nerve stimulation was already shown to modulate the (autonomous) sympathovagal balance of the body and proved to be an effective treatment in acute and chronic pain, epilepsy, as well as major depression. pVNS effects on cervical dystonia may be hypothesized to rely upon: (i) the alteration of sensory input to the brain, which affects structures involved in the genesis of motoric and nonmotoric dystonic symptoms; and (ii) the alteration of the sympathovagal balance with a sustained impact on involuntary movement control, pain, quality of sleep, and general well-being. The presented data provide experimental evidence that pVNS may be a new alternative and minimally invasive treatment in primary cervical dystonia. One female patient (age 50 years) suffering from therapy refractory cervical dystonia was treated with pVNS over 20 months. Significant improvement in muscle pain, dystonic symptoms, and autonomic regulation as well as a subjective improvement in motility, sleep, and mood were achieved. A subjective improvement in pain recorded by visual analog scale ratings (0-10) was observed from 5.42 to 3.92 (medians). Muscle tone of the mainly affected left and right trapezius muscle in supine position was favorably reduced by about 96%. Significant reduction of muscle tone was also achieved in sitting and standing positions of the patient. Habituation to stimulation leading to reduced stimulation efficiency was observed and counteracted by varying stimulation patterns. Experimental evidence is provided for significantly varied sympathovagal modulation in response to pVNS during sleep, assessed via heart rate variability (HRV). Time domain measures like the root mean square of successive normal to normal heart beat intervals, representing parasympathetic (vagal) activity, increased from 37.8 to 67.6 ms (medians). Spectral domain measures of HRV also show a shift to a more pronounced parasympathetic activity.

Can We State Stable Bladder? How Many Repetitions Should We Do for an Appropriate Demonstration of Involuntary Detrusor Contraction?

AIMS: Involuntary Detrusor Contraction (IDC) may alter therapeutic plans; therefore, urodynamic demonstration (UD) is pivotal. We explore if same session repetitions enhance its demonstration and minimize false-negative results. METHODS: Two hundred fifty two women (mean age 47 ± 5.7) had 4 full repetitions of UD with the last round filled with 4°C fluid (Ice-water test). IDC was diagnosed if with at least 3 cm H2O after artifacts were ruled out. RESULTS: 44.4% of the cases showed IDC in the first round of the exam but it could be demonstrated in 88.5% of the women if 4 rounds are taken into account. Only 2 cases showed IDC exclusively in the first round. Nine cases (3.5%) showed IDC in the first round and only on Ice-test, while all other IDC-detected cases revealed it in scattered patterns along the repetitions. Likewise, IDC detection on the second, third and fourth rounds varied widely and unpredictably, many failing to show a consistent pattern of presentation after its detection. IDC wave amplitude did not show any correlation to the detection. CONCLUSIONS: Urodynamic repetition is a necessary procedure where IDC is important to demonstrate, as its false-negative rate is high and its unpredictable pattern of detection may be improved by repetition.

[The volume of residual urine correlates with bladder outlet obstruction and detrusor contractility in patients with benign prostatic hyperplasia].

OBJECTIVE: To identify the correlation of the volume of residual urine (VRU) with the severity of bladder outlet obstruction (BOO) and detrusor contractility in patients with benign prostatic hyperplasia (BPH). METHODS: A total of 152 patients with clinically diagnosed BPH underwent ultrasonography for measurement of the prostate volume and RVU, free uroflowmetry, and urodynamic examination for the severity of BOO and detrusor contractility. Using the software SPSS20. 0, we analyzed the correlation between the ultrasonographic results and urodynamic parameters and compared the two sample means by the t-test. RESULTS: The prostate volume was correlated positively with BOO severity (r = 0.432, P < 0.01) and detrusor contractility (r = 0.343 , P < 0.01) while Qmax negatively with BOO severity (r = 0.327, P < 0.01) but not significantly with detrusor contractility (r = 0.123, P > 0.05). VRU showed a significantly negative correlation with detrusor contractility when > 150 ml (r = -0.490, P < 0.01), even more significantly when > 300 ml (r = -0.717, P < 0.01), but exhibited no significant correlation with it when ≤ 150 ml (r = 0.041, P > 0.05). CONCLUSION: VRU can somehow predict the detrusor function. For patients with VRU > 150 ml, especially for those with VRU > 300 ml, the detrusor function should be evaluated and urodynamic examination is recommended for exact assessment of BOO severity and detrusor contractility.