Can repetitive transcranial magnetic stimulation increase muscle strength in functional neurological paresis? A proof-of-principle study.

BACKGROUND AND PURPOSE: Therapeutic options are limited in functional neurological paresis disorder. Earlier intervention studies did not control for a placebo effect, hampering assessment of effectivity. A proof-of-principle investigation was conducted into the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS), using a single-blind two-period placebo-controlled cross-over design. METHODS: Eleven patients received active 15 Hz rTMS over the contralateral motor cortex (hand area), in two periods of 5 days, for 30 min once a day at 80% of resting motor threshold, with a train length of 2 s and an intertrain interval of 4 s. Eight of these eleven patients were also included in the placebo treatment condition. Primary outcome measure was change in muscle strength as measured by dynamometry after treatment. Secondary outcome measure was the subjective change in muscle strength after treatment. RESULTS: In patients who received both treatments, active rTMS induced a significantly larger median increase in objectively measured muscle strength (24%) compared to placebo rTMS (6%; P < 0.04). Subjective ratings showed no difference due to treatment, i.e. patients did not perceive these objectively measured motor improvements (P = 0.40). CONCLUSIONS: Our findings suggest that rTMS by itself can potentially improve muscle weakness in functional neurological paresis disorder. Whereas patients' muscle strength increased as measured with dynamometry, patients did not report increased functioning of the affected hand, subjectively. The results may indicate that decreased muscle strength is not the core symptom and that rTMS should be added to behavioral approaches in functional neurological paresis.

In spina bifida aperta, muscle ultrasound can quantify the "second hit of damage".

PURPOSE: In spina bifida aperta (SBA), the "second-hit hypothesis" addresses consequences by delayed neurological damage superimposed upon the congenital myelomeningocele (MMC). This secondary damage is postulated to underlie the disappearance of leg movements shortly after birth. Innovative fetal surgery might prevent this, but results are methodologically hard to prove in small and heterogeneous treatment groups. We reasoned that delayed postnatal alterations in muscle ultrasound density (MUD = muscle echogenicity) could quantitatively reflect consequences by "the second hit" of damage. In the present study, we investigated whether delayed postnatal leg-MUD alterations are associated with postnatal muscle function loss. METHODS: We cross-sectionally assessed leg-MUD in 16 postnatally operated SBA children (MMC-L5; at 0, 6, and 12 months; in n = 11/16; 11/16, and 15/16 children, respectively) and compared outcomes with 13 healthy control children. Additionally, we assessed SBA MUD caudal and cranial to the MMC and calculated MMC-L5 impact by: dMUD((MMC-L5)) = [MUD(calf muscle/S1-2)] - [MUD(quadriceps muscle/L2-4)] and associated outcomes with leg muscle function caudal to the MMC. RESULTS: At 0 month, clinically discernible dMUD was more often increased in SBA than in control newborns (p < .05), but a relationship between absolute quantitative differences and leg muscle dysfunction was still lacking. At 6-12 months, additionally increased dMUD outcomes coincided with SBA leg muscle dysfunction (p < .05). CONCLUSIONS: In post-neonatal SBA, secondarily increased dMUD (i.e., MMC impact) coincides with leg muscle dysfunction. This may implicate that muscle ultrasound could provide a quantitative tool to assess the neuromuscular impact by the second hit of damage.

Effects of a mandibular advancement device on the upper airway morphology: a cephalometric analysis.

The aims of this study were to assess changes in the upper airway morphology associated with an oral appliance in situ in patients suffering from the obstructive sleep apnoea-hypopnoea syndrome and to relate these changes to treatment response. Changes in upper airway morphology as a result of an oral appliance were assessed in 52 patients with obstructive sleep apnoea-hypopnoea syndrome by means of cephalometric analysis. Lateral cephalograms were taken at baseline and after 2-3 months of treatment. Baseline and follow-up cephalograms were traced twice and cephalometric variables were compared. The predictive value of changes in upper airway morphology for the treatment response was evaluated in univariate and multivariate regression analyses. Oral appliance therapy resulted in an increased posterior airway space at the level of the second vertebra, the uvular tip and the base of the tongue. The increase of the posterior airway space at the level of the second vertebra and the uvular tip were the best predictors for relative improvement of the apnoea-hypopnoea index. However, the predictive value for treatment response of these cephalometric upper airway changes should be interpreted with caution.

Skin capillary permeability in the diabetic foot with critical limb ischaemia: the effects of a phVEGF165 gene product.

AIMS: To measure capillary permeability, assessed by skin capillary sodium fluorescein (NaF) leakage, in patients with diabetes mellitus with critical limb ischaemia (DM-CLI) and to compare the effects of vascular endothelial growth factor (VEGF) with those of placebo. METHODS: NaF leakage was assessed in 17 patients with DM-CLI, in 24 diabetes mellitus (DM) patients without clinical signs of macrovascular disease or neuropathy (DM-C) and in 22 healthy control subjects. The 17 DM-CLI patients were randomized to receive phVEGF165 gene product (n = 11) or placebo (n = 6). Measurements were repeated after 28 days. RESULTS: DM-CLI patients had a longer dye arrival time (DAT), but NaF leakage was similar to control subjects, while capillary permeability was increased in DM-C compared with control subjects. Leakage curve rose in patients receiving VEGF and fell in those receiving placebo, 28 days after administration. The decrease in DAT in the VEGF group was not significant, whilst DAT rose in the placebo group. Perfusion pressures were similar in the two groups. CONCLUSION: No increase in capillary leakage in DM-CLI was found, probably because an increased capillary filtration coefficient is counterbalanced by a marked fall in perfusion pressures. Increased capillary leakage may be one explanation for oedema formation after VEGF treatment.

Muscle fiber conduction abnormalities in early diabetic polyneuropathy.

OBJECTIVE: Diabetic polyneuropathy (PNP) has been proposed to be a primary disorder of sensory nerves. At an early stage motor nerve conduction velocity (MNCV) and muscle strength remain preserved due to compensatory mechanisms (axonal sprouting, reinnervation). We evaluated the use of invasive muscle fiber conduction velocity (MFCV) measurements as a method to detect muscle fiber denervation atrophy, as an early sign of motor axonal loss in diabetes mellitus (DM). METHODS: Twelve selected male patients (8 type 1, 4 type 2; mean age 35.8 years, SD 10.6), without any sign of micro- or macroangiopathy, were studied by systematic clinical and neurophysiological testing including MFCV estimation. RESULTS: Hand-held dynamometry was normal in all subjects. There were no signs of recent denervation by concentric needle EMG in any of the patients. Sensory nerve conduction velocity (SNCV) was abnormal in 6 subjects, MFCV in 6 subjects (5 had also low SNCV). The ratio of fastest/slowest muscle fibers in MFCV was correlated to SNCV of sural nerve (-.59, p < .05), but not to MNCV. CONCLUSIONS: Half of the clinically asymptomatic DM subjects showed sensory involvement together with MFCV abnormalities, despite normal needle EMG and force. SIGNIFICANCE: MFCV estimation offers a sensitive method in detecting early signs of motor axonal dysfunction in DM.

Obstructive sleep apnea therapy.

In clinical practice, oral appliances are used primarily for obstructive sleep apnea patients who do not respond to continuous positive airway pressure (CPAP) therapy. We hypothesized that an oral appliance is not inferior to CPAP in treating obstructive sleep apnea effectively. We randomly assigned 103 individuals to oral-appliance or CPAP therapy. Polysomnography after 8-12 weeks indicated that treatment was effective for 39 of 51 persons using the oral appliance (76.5%) and for 43 of 52 persons using CPAP (82.7%). For the difference in effectiveness, a 95% two-sided confidence interval was calculated. Non-inferiority of oral-appliance therapy was considered to be established when the lower boundary of this interval exceeded -25%. The lower boundary of the confidence interval was -21.7%, indicating that oral-appliance therapy was not inferior to CPAP for effective treatment of obstructive sleep apnea. However, subgroup analysis revealed that oral-appliance therapy was less effective in individuals with severe disease (apnea-hypopnea index > 30). Since these people could be at particular cardiovascular risk, primary oral-appliance therapy appears to be supported only for those with non-severe apnea.

Multichannel recording of tibial-nerve somatosensory evoked potentials.

STUDY AIMS: The topography of the peaks of tibial-nerve somatosensory evoked potential (SEP) varies among healthy subjects, most likely because of differences in position and orientation of their cortical generator(s). Therefore, amplitude estimation with a standard one- or two-channel derivation is likely to be inaccurate and might partly cause the low sensitivity of SEP amplitude to pathological changes. In this study, we investigate whether 128-channel tibial-nerve SEP recordings can improve amplitude estimation and reduce the coefficient of variation. METHODS: We recorded tibial-nerve SEPs using a 128-channel EEG system in 48 healthy subjects aged 20 to 70 years (47 provided analyzable data). We compared P39, N50, and P60 amplitudes obtained with a 128-channel analysis method (based on butterfly plots and spatial topographies) with those obtained using a one-channel conventional configuration and analysis. Scalp and earlobe references were compared. RESULTS: Tibial-nerve SEP amplitudes obtained with the 128-channel method were significantly higher as compared to the one-channel conventional method. Consequently, the coefficient of variation was lower for the 128-channel method. In addition, in both methods, the N50-peak amplitude was sometimes hard to identify, because of its low amplitude. Besides, in some subjects, the N50 peak, as obtained with the conventional method, rather seemed to be a period between two positivities rather than an activation peak on itself. CONCLUSIONS: The 128-channel method can measure tibial-nerve SEP amplitude more accurately and might therefore be more sensitive to pathological changes. Our results indicate that the N50 component is less useful for clinical practice.

The Dutch neuromuscular database CRAMP (Computer Registry of All Myopathies and Polyneuropathies): development and preliminary data.

Each of the various neuromuscular diseases is rare. Consequently, solid epidemiological data are not available and it is often difficult to find sufficient patients for studies. For this reason, the Dutch neuromuscular database, CRAMP (Computer Registry of All Myopathies and Polyneuropathies), was developed in 2004 by the Dutch Neuromuscular Research Support Centre, to store information on patient characteristics and diagnoses (based on Rowland and McLeod's classification) in a uniform and easily retrievable manner. Care was taken to preserve data confidentiality. It is envisaged that CRAMP will prove particularly useful for studies in which multicentre collaboration is needed to recruit a sufficiently large number of patients. More than 10,000 patients with neuromuscular diseases (4,837 female, 5,476 male) have been registered since 2004, half of whom (n=5059) have peripheral nerve disorders.

Predictors of obstructive sleep apnea-hypopnea treatment outcome.

Oral appliance therapy is an alternative to continuous positive airway pressure (CPAP) for treating the obstructive sleep apnea-hypopnea syndrome. However, the ability to pre-select suitable candidates for either treatment is limited. The aim of this study was to assess the value of relevant variables that can predict the outcome of oral appliance and CPAP therapy. Fifty-one patients treated with oral appliance therapy and 52 patients treated with CPAP were included. Relevant clinical, polysomnographic, and cephalometric variables were determined at baseline. The predictive value of variables for treatment outcome was evaluated in univariate and multivariate analyses. The outcome of oral appliance therapy was favorable, especially in less obese patients with milder sleep apnea and with certain craniofacial characteristics (mandibular retrognathism in particular). Neither univariate nor multivariate analyses yielded variables that reliably predicted the outcome of CPAP. We conclude that the variables found in this study are valuable for pre-selecting suitable candidates for oral-appliance therapy.

Abnormal surface EMG during clinically normal wrist movement in cervical dystonia.

We investigated whether patients with cervical dystonia (CD) have abnormal muscle activation in non-dystonic body parts. Eight healthy controls and eight CD patients performed a flexion-extension movement of the right wrist. Movement execution was recorded by surface electromyography (EMG) from forearm muscles. Although patients had no complaints concerning wrist movement and had no apparent difficulty in executing the task, they demonstrated lower mean EMG amplitude (flexor: 0.32 mV and extensor: 0.61 mV) than controls (flexor: 0.67 mV; P = 0.021 and extensor: 1.18 mV; P = 0.068; borderline significant). Mean extensor muscle contraction was prolonged in patients (1860 ms) compared with controls (1334 ms; P = 0.026). Variation in mean EMG amplitude over movements tended to be higher in patients (flexor: 43% and extensor: 35%) than controls (flexor: 34%; P = 0.072 and extensor: 26%; P = 0.073). These results suggest that CD patients also have abnormal muscle activation in non-dystonic body parts at a subclinical level. This would support the concept that in dystonia, non-dystonic limbs are in a 'pre-dystonic state'.

Myoclonus subtypes in tertiary referral center. Cortical myoclonus and functional jerks are common.

OBJECTIVE: To evaluate the accuracy of clinical phenotyping of myoclonus patients and to determine differentiating clinical characteristics between cortical (CM), subcortical (SCM), spinal (SM), peripheral (PM) myoclonus, and functional jerks (FJ). METHODS: Clinical notes for all patients with myoclonus over an 8-year period (2006-2014) were reviewed retrospectively. We used the conclusion of electrophysiological testing as definite diagnosis of myoclonus or FJ. RESULTS: 85 patients were identified suffering from CM (34%), SCM (11%), SM (6%), PM (2%), and 47% FJ. The clinical diagnosis of myoclonus was confirmed by electrophysiological testing in 74% and its subtype in 78% of cases. CM was characterized by an early age of onset, facial myoclonus, and provocation by action. Differentiating features of FJ were an abrupt onset, preceding contributing events and provocation by a supine position. CONCLUSION: The majority of clinical myoclonic jerk cases were functional in our heterogeneous tertiary clinic cohort. CM was the main anatomical myoclonic subtype. Clinical diagnosis was accurate in the majority of cases, although electrophysiological testing was important to verify the clinical classification. SIGNIFICANCE: In patients with jerky movements a functional diagnosis should be considered. Determination of the myoclonic subtypes is important to initiate tailored treatment.

How typical are 'typical' tremor characteristics? Sensitivity and specificity of five tremor phenomena.

INTRODUCTION: Distinguishing between different tremor disorders can be challenging. Some tremor disorders are thought to have typical tremor characteristics: the current study aims to provide sensitivity and specificity for five 'typical' tremor phenomena. METHODS: Retrospectively, we examined 210 tremor patients referred for electrophysiological recordings between January 2008 and January 2014. The final clinical diagnosis was used as the gold standard. The first step was to determine whether patients met neurophysiological criteria for their type of tremor. Once established, we focused on 'typical' characteristics: tremor frequency decrease upon loading (enhanced physiological tremor (EPT)), amplitude increase upon loading, distractibility and entrainment (functional tremor (FT)), and intention tremor (essential tremor (ET)). The prevalence of these phenomena in the 'typical' group was compared to the whole group. RESULTS: Most patients (87%) concurred with all core clinical neurophysiological criteria for their tremor type. We found a frequency decrease upon loading to be a specific (95%), but not a sensitive (42%) test for EPT. Distractibility and entrainment both scored high on sensitivity (92%, 91%) and specificity (94%, 91%) in FT, whereas a tremor amplitude increase was specific (92%), but not sensitive (22%). Intention tremor was a specific finding in ET (85%), but not a sensitive test (45%). Combination of characteristics improved sensitivity. CONCLUSION: In this study, we retrospectively determined sensitivity and specificity for five 'typical' tremor characteristics. Characteristics proved specific, but few were sensitive. These data on tremor phenomenology will help practicing neurologists to improve distinction between different tremor disorders.

Reference values of maximum isometric muscle force obtained in 270 children aged 4-16 years by hand-held dynamometry.

Since muscle force and functional ability are not related linearly; maximum force can be reduced while functional ability is still maintained. For diagnostic and therapeutic reasons loss of muscle force should be detected as early and accurately as possible. Because of growth factors, maximum muscle force in children varies with age, which makes detection of force loss difficult. The purpose of this study was to establish reference values for muscle force in children aged 4-16 years, obtained by hand-held dynamometry in 11 muscle groups. In boys muscle force was predicted best by weight whereas in girls weight and age were best predictors. At age 14 boys become significantly stronger for nearly all tested muscle groups. These age-related reference values can be used to quantify muscle weakness in individual muscle groups in children aged 4-16 years and to evaluate the effects of therapy.

Quantitative assessment of calf circumference in Duchenne muscular dystrophy patients.

Duchenne muscular dystrophy is clinically characterised by progressive muscle weakness and a gradual increase in the size of some affected muscles, especially calf muscles. The extent of calf enlargement is usually determined by subjective visual assessment. The purpose of this study was to determine the extent of calf muscle enlargement in Duchenne muscular dystrophy (DMD) patients compared with healthy age matched boys by quantifying calf circumference. Calf circumference in the group of DMD patients is significantly increased. However, in individual patients calf enlargement can be feigned by a discrepancy between calf circumference and circumference of the upper leg and arm muscles as part of a general muscle atrophy.

Supernormal muscle fiber conduction velocity during intermittent isometric exercise in human muscle.

Muscle fiber conduction velocity (MFCV) and surface electromyographic parameters were studied in the brachial biceps muscle of healthy males during voluntary intermittent isometric contractions at 50% of maximum force. Recovery in the following 15 min was then observed. The measurements were performed during duty cycles of 33, 25, and 20%. The main finding was a supernormal MFCV during the exercise phase when the duty cycle was 25 and 20%. The level continued to increase during the recovery phase. During the exercise phase when the duty cycle was 33%, the MFCV decreased slightly (suggesting that the local anaerobic threshold had been surpassed) but increased during recovery to supernormal values. The ratio of median frequency to MFCV was constant during all experiments, indicating that the changes in median frequency reflect those in MFCV. We suggest that the supernormal MFCV was due to a combination of altered membrane properties, muscle fiber swelling, and temperature increase and hypothesize that the changes of electrical properties formed part of an adaptive mechanism of the muscle fiber membrane during exercise. In that respect, the increase of the MFCV could be a component of the well-known warm-up effect.

[Muscle weakness or rigidity due to hereditary ion channel diseases]. / Spierzwakte of -verstijving door hereditaire kanalopathieën.

Three men, aged 36, 16 and 66 years, had suffered for several years from muscular weakness; after a low serum potassium level had been established, supplementary examination revealed hypokalaemic periodic paralysis. A woman aged 25 had suffered since youth from muscular stiffness on sudden movements; she suffered from hereditary myotonia of the recessive type (Becker's disease). Both rare skeletal muscle ion channel diseases are characterized by the fact that the variable clinical expression complicates making the diagnosis. Since the causal mutations are known, genetic analysis is an essential step in confirming the diagnosis. Additional EMG procedures may be of diagnostic value, even in cases that cannot be clarified genetically.

[From gene to diseases; hypokalemic periodic paralysis]. / Van gen naar ziekte; hypokaliëmische periodieke paralyse.

Hypokalaemic periodic paralysis is an autosomal, dominantly inherited disorder, characterised by attacks of partial or total muscle weakness and serum hypokalaemia. the mutations responsible are located in the CACNA1S gene (type 1) and in the SCN4A gene (type 2), and are all missense mutations where arginine is mostly replaced by histidine or sometimes glycine. The mutation has been localised in the voltage sensor of the transmembrane segment of calcium channel (type 1) and sodium channel (type 2) respectively. How muscle weakness develops is not known. Oral or intravenous administration of potassium is helpful in treating partial or complete attacks. Acetazolamide can reduce the frequency of attacks in type-1 hypokalaemic periodic paralysis.

[Dyspnea or confusion after trauma? Consider fat embolism syndrome]. / Benauwde of verwarde patiënt na trauma? Denk aan het vetemboliesyndroom.

Three patients, 2 women aged 26 and 19 years and a 65-year-old man, underwent surgical fracture treatment after a motor vehicle accident with fractures of the lower extremity. They developed respiratory distress from fat embolism syndrome. After maximal support in the ICU 2 of them died and 1 recovered. Fat embolism syndrome is a clinical condition mostly seen after long bone fractures. The main features are respiratory distress, cerebral confusion and a petechial rash. Usually the presentation is quite benign, but severe morbidity and even mortality can occur in some cases. It is caused by a combination of a mechanical and a biochemical pathway. Therapeutic options consist of respiratory and haemodynamic support. Preventive measures are rapid fracture fixating, good analgesia, adequate fluid infusion and tissue oxygenation.

[Treatment of the obstructive sleep-apnea syndrome in adults]. / Behandeling van het obstructieve slaapapneusyndroom bij volwassenen.

When treating the obstructive sleep-apnoea syndrome (OSAS), conservative management and the correction of treatable stenoses in the upper airway should be considered first. If these measures are neither effective nor applicable, then continuous positive airway pressure (CPAP) is the preferred treatment. Surgical interventions should only be considered after failure of non-surgical treatment modalities. Pharmacological management of OSAS is usually only indicated as a form of supplementary treatment in specific patients. Oral-appliance therapy appears to be of value in the management of OSAS and, in specific groups of patients, seems likely to offer a good alternative to CPAP in the future.

[Orthopnea: not always of cardiac origin]. / Orthopneu: niet altijd cardiaal bepaald.

Respiratory insufficiency developed in a man aged 68 after cardiac surgery and in a man aged 60 with COPD and a history of cigarette smoking after an attack of 'flu', while in a woman aged 70 with non insulin-dependent diabetes mellitus it had been present for years. All three had bilateral diaphragmatic paralysis. The diagnosis is based on the triad orthopnoea, paradoxical abdominal movements during respiration in the recumbent position and a decrease of the vital capacity in the horizontal as compared with the sitting position. The patients' physical condition could be improved with the aid of (noninvasive) ventilatory support.