Serial neurophysiological studies of intramuscular botulinum-A toxin in humans

To characterize the time course of intramuscular botulinum toxin–induced paresis, we serially performed electrophysiological measurements and recorded the sonographic size of an extensor digitorum brevis (EDB) muscle in 10 human subjects before and after injecting the EDB with 10 units of botulinum-A toxin. All EDB CMAPs decreased within 48 h, with peak decline at day 21 (8.3 ± 3.1 mV to 3.0 ± 0.9 mV). Decline of mean rectified voltage during maximal voluntary contraction of the EDB paralleled the change in CMAP amplitude. Average decrements to 2-Hz repetitive stimulation never exceeded 6% (day 42) and exercise failed to facilitate Significantly CMAP amplitude. Atrophy peaked at day 42. The F-wave to M-wave ratio increased at day 2; silent periods did not change. Our findings confirm a primary peripheral action of the toxin, but a superimposed, transient central effect of the drug cannot be excluded. Intramuscular injections into EDB provide a useful model for studying chemodenervation effects. © 1994 John Wiley & Sons, Inc.     

Botulinum toxin type-A treatment in spastic paraparesis: a neurophysiological study

OBJECTIVE: The aim of this study was to verify the action of Botulinum toxin type-A (BoNT-A) by means of neurophysiological techniques, in patients presenting lower limb spasticity and requiring BoNT-A injections in the calf muscles, due to the poor response to medical antispastic treatment. SUBJECTS AND METHOD: Patients presenting paraparesis were enrolled. They underwent clinical evaluation for spasticity according to the Ashworth scale and neurophysiological recordings including: motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the leg area; compound motor action potential (cMAP) to tibial nerve stimulation, F-wave, and H-reflex before the treatment and 24 h, 2 weeks and 1 month after the injection of BoNT-A. In all patients, gastrocnemius was treated and in some cases soleus or tibialis posterior muscles were also injected. RESULTS: In all patients, BoNT-A injections induced a clear clinical improvement as showed by the reduced spasticity values of the Ashworth scale. A significant increment of MEP latency and central conduction time (CCT) duration were observed 2 weeks after the treatment only in the injected muscles. CONCLUSIONS: Prolonged MEP latencies and CCT after BoNT-A injections is probably due to a central alteration in responsiveness of spinal motor neurons to descending impulses from the corticospinal tracts. Such changes represent objective parameters heralding clinical efficacy of treatment.     

A neurophysiological evaluation of a cognitive cycle in humans

The present review describes and analyzes several recent papers in which the processes of preparation, evaluation and changing a cue's predictive value on a trial-by-trial basis conform a cycle that permits behavior to be constantly updated. This approach is an extension of Joaquin Fuster's proposal of a “perception-action” cycle in which executive networks are constantly updated as a function of the trials’ outcome. The presented results can also be considered in relation to the computational Bayesian brain framework proposed by Friston (2009). The present approach is based on human electrophysiological studies of Posner's central cue paradigm, which provides the possibility to dissociate the following processing steps: (i) preparation for certain stimuli, (ii) evaluation of the validity or invalidity of the preparatory state, and (iii) the feedback cycling of the information extracted from one trial to the next. This trial-by-trial learning would be a potential basis for organism adaptation.     

Longitudinal study of clinical and neurophysiological features in essential tremor

Background and purpose

Essential tremor (ET) is a common and heterogeneous disorder characterized by postural/kinetic tremor of the upper limbs and other body segments and by non-motor symptoms, including cognitive and psychiatric abnormalities. Only a limited number of longitudinal studies have comprehensively and simultaneously investigated motor and non-motor symptom progression in ET. Possible soft signs that configure the ET-plus diagnosis are also under-investigated in follow-up studies. We aimed to longitudinally investigate the progression of ET manifestations by means of clinical and neurophysiological evaluation.

Methods

Thirty-seven ET patients underwent evaluation at baseline (T0) and at follow-up (T1; mean interval ± SD = 39.89 ± 9.83 months). The assessment included the clinical and kinematic evaluation of tremor and voluntary movement execution, as well as the investigation of cognitive and psychiatric disorders.

Results

A higher percentage of patients showed tremor in multiple body segments and rest tremor at T1 as compared to T0 (all p-values < 0.01). At T1, the kinematic analysis revealed reduced finger-tapping movement amplitude and velocity as compared to T0 (both p-values < 0.001). The prevalence of cognitive and psychiatric disorders did not change between T0 and T1. Female sex, absence of family history, and rest tremor at baseline were identified as predictive factors of worse disease progression.

Conclusions

ET progression is characterized by the spread of tremor in multiple body segments and by the emergence of soft signs. We also identified possible predictors of disease worsening. The results contribute to a better understanding of ET classification and pathophysiology.     

Neurophysiological changes after intramuscular injection of botulinum toxin

Botulinum toxin (BT) acts peripherally by inhibiting acetylcholine release from the presynaptic neuromuscular terminals and by weakening muscle contraction. Therefore, its clinical benefit is primarily due to its peripheral action. As a result, local injection of BT has become a successful and safe tool in the treatment of several neurological and non-neurological disorders. Studies in animals have also shown that the toxin can be retrogradely transported and even transcytosed to neurons in the central nervous system (CNS). Further human studies have suggested that BT could alter the functional organisation of the CNS indirectly through peripheral mechanisms. BT can interfere with and modify spinal, brainstem and cortical circuits, including cortical excitability and plasticity/organisation by altering spindle afferent inflow directed to spinal motoneurons or to the various cortical areas. It is well demonstrated that the distant CNS effects of BT treatment parallel the peripheral effect, although there is limited evidence as to the cause of this. Therefore, further studies focussed on central changes after BT treatment is needed for a better understanding of these non-peripheral effects of BT.     

Acute neurophysiological effects of the hypnotic zolpidem in healthy volunteers

INTRODUCTION: The imidazopyridine zolpidem is a hypnotic drug with relative selectivity for the benzodiazepine (BZP) type 1 receptor subtypes displaying a different biochemical structure to that of BZPs. Little is known of its electrophysiological effects. PURPOSE: The aim of the present study was to investigate the acute neurophysiological effects of clinical oral doses of zolpidem. METHODS: This was a double blind, independent group design study. Thirty-six young, healthy volunteers were randomly allocated to one of three groups--zolpidem (5 mg and 10 mg) and placebo. In addition to ERPs, behavioural measures were used to examine sedative effects of the drug. RESULTS: ERPs were affected in a similar way to that described after sedative/hypnotic drug ingestion: increased N2 and P3 latencies and decreased N2 and P3 amplitudes. However, contrary to what is expected of a hypnotic drug, there was no change with N1 while P2 amplitude increased after the highest dose. CONCLUSIONS: Because zolpidem showed different effects in different components, it seems to first enhance or preserve initial orienting (no change in N1), after an increase of P2 and then drastically diminish resource allocation (affecting N2 and P3 latencies and amplitudes). The study with ERPs, therefore, allows a more direct "moment to moment" investigation of finer mechanisms of changes in cerebral processes underlying the acute ingestion of the drug in question. The effects on N2 and P3 amplitudes and latencies were similar to those of other sedative/hypnotic drugs. However, zolpidem led to an unexpected increase in P2 amplitude; this effect may be related to its selective receptor binding profile and warrants further research.     

Trait aggressiveness modulates neurophysiological correlates of laboratory-induced reactive aggression in humans

Reactive aggression following provocation is a frequent form of human social behavior. The neural basis of reactive aggression, especially its control, remains poorly understood, however. We conducted an event-related potential (ERP) study using a competitive reaction time task that elicits aggression through provocation. Participants were selected from a larger sample because of extreme scores in trait aggressiveness, yielding high and low trait aggressive groups. As each trial in the task is separated into a decision phase, during which the punishment level for the opponent is set, and an outcome phase, during which the punishment is applied or received, we were able to disentangle provocation-related and evaluation-related modulations of the ERPs during the aggressive interaction. Specifically, we observed an enhanced frontal negativity during the decision phase under high provocation that was positively correlated with the participants' ability to refrain from retaliation. This held true for high trait aggressive participants only, pointing to a higher need for inhibitory and control processes in these people when provoked. During the outcome phase, we detected a mediofrontal negativity in loss compared to win trials, resembling previous ERP findings to negative feedback stimuli, which have been linked to the evaluation of an outcome's valence. This mediofrontal negativity was differentially pronounced in aggressive and nonaggressive participants: Nonaggressive participants showed only a slightly smaller mediofrontal negativity in win than in loss trials, suggesting that for them punishing the opponent had a similar negative valence as being punished.     

Botulinum toxin type-A and plaster cast treatment in children with upper brachial plexus palsy

Summary

BACKGROUND AND PURPOSE: Electrical stimulation, physical therapy and occupational therapy remain the main treatment for children with upper brachial plexus palsy (UBPP), when surgery has been excluded. A pilot study was undertaken to investigate whether botulinum toxin type A (BoNT-A) and plaster casting, as adjunct to the physical therapy, decreased muscle contracture and improved the position and function of the impaired arm. METHOD: Twenty-two children (mean age 5.6 +/- 3.4 years) with mild UBPP who previously underwent serial cast treatment, unsuccessfully, were enrolled. Neurological impairment and functional status were quantified using Medical Research Council (MRC) and Mallet scales and the Nine-Hole Peg Test (NHPT). Elbow extension was measured using a goniometer. Biceps brachii, brachialis, pronator teres and pectoralis major muscles were injected with 22 units kg(-1) BoNT-A (Dysport, Ipsen). After injection, the treated arm was fixed with a plaster cast and progressively lengthened over 14 days. The cast was maintained for 30 days. Assessments of elbow extension, MRC, Mallet Scale and NHPT were made at baseline, 3, 6 and 12 months. RESULTS: After BoNT-A injection, children had significant improvement of active elbow extension (15.5 degrees +/- 17.1 at 12 months after injection, compared with 42.0 degrees +/- 10.4 at baseline; p < 0.001). NPHT scores improved significantly over the 12 months (51.1 +/- 21.8 seconds compared with 56.7 +/- 19.3 seconds at baseline, p < 0.01). MRC and Mallet scale scores of the paretic muscles were unchanged. CONCLUSION: The children showed a reduction in muscular contracture and improvements of the arm position and elbow extension. The data support the use of BoNT-A and plaster casting as an adjunct to physical therapy, in the treatment of children with mild UBPP.     

A multimodal neurophysiological assessment in terminal renal failure

A prospective multimodal neurophysiological study was conducted on 36 patients with end-stage renal failure, 16 of whom subsequently underwent renal transplantation (TR). Nerve conduction study and somatosensory evoked potentials revealed that peripheral conduction deficit, often sub-clinical, was the commonest abnormality, and TR resulted in substantial improvement. Visual evoked potentials demonstrated subclinical impairment, which did not improve after TR. The brainstem auditory evoked potentials were essentially normal and unaffected by TR.     

Effects of ultrasound-guided botulinum toxin type-A injections with a specific approach in spastic cerebral palsy

The aim of this study was to detect effects of ultrasound-guided botulinum toxin type-A (US-guided BoNT-A) injections prepared according to lower extremity innervation zones on spasticity and motor function in 3–16 years children with diplegic and hemiplegic spastic cerebral palsy. This study included 25 patients between 3 and 16 years of age who admitted to our clinic in 2017, were being followed in our clinic with a diagnosis of cerebral palsy, had BoNT-A injections due to lower extremity spasticity. The US-guided BoNT-A injections were administered into the spastic muscles using a specific approach according to innervation zones of muscle. Modified Ashworth Scale (MAS) and Gross Motor Functional Classification System (GMFCS) were assessed at the baseline, and 4 and 12 weeks after the BoNT-A injections. Minimum and maximum ages of the patients were 45 and 192 months, and gender distribution was 8 females and 17 males. Significant decreases in the MAS scores of the knee and ankle tones were measured 4 and 12 weeks after the BoNT-A injection when compared to the baseline scores (p?<?0.025). Hip muscle tonus only decreased 12 weeks after the injection (p?<?0.025). In parallel with a reduction in spasticity GMFCS improved from 3 to 2 in the 4th and 12th weeks. US-guided BoNT-A injections with Euro-musculus approach is a practical and effective method to perform injections into proper points of proper muscles in children with spastic cerebral palsy.     

Systemic toxicity of botulinum toxin by intramuscular injection in the monkey

Botulinum toxin (Oculinum) was injected intramuscularly into eight monkeys. The LD50 dose is estimated to be approximately 39 U/kg body weight. The lowest dose that caused systemic toxicity, 33 U/kg, was close to the fatal dose range, 38-42 U/kg.     

The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A -- initial experiences.

The increasing use of botulinum toxin type-A, especially for focal dystonia and spasticity has highlighted the issue of secondary non-responsiveness. Within the last few years botulinum toxin type-B (Myobloc/Neurobloc) has become commercially available as an alternative to type-A. This paper discusses our initial experience of botulinum toxin type-B in a total of 63 individuals who attended our botulinum clinic. Thirty-six patients had cervical dystonia and a secondary non-response to type-A toxin. Thirteen of these patients (36%) had a reasonable clinical response to Neurobloc and continue to have injections. The other 23 patients either had no response, or a poor response, or had unacceptable side effects and ceased treatment. A small number of people with blepharospasm, hemifacial spasm and foot dystonia also had a disappointing response to injection. Twenty patients with spasticity were also type-A resistant. Seven of these show some continuing response to type-B, without unacceptable side effects. These findings demonstrate that botulinum toxin type-B has a place in the management of patients who have become non-responsive to type-A, but overall the responses to type-B toxin were disappointing.     

Clinical neurophysiological assessment of children with sacral anomalies

Clinical neurophysiological investigations were carried out in 8 children with various forms of sacral dysplasia. No EMG activity was found in leg muscles in two children with complete sacral agenesis, even though pelvic floor activity was preserved in one of these. The external anal sphincter and puborectalis were examined in all cases, and it was easy to demonstrate neuropathic changes in individual motor unit potentials by attenuation of their low frequency components. There was only a loose association between any pelvic floor neuropathy and the level of the bony defect in the sacrum, confirming recent reports. Trans-cutaneous stimulation of the spinal nerve roots in the lumbar canal was carried out in four children. Unilateral slowed conduction in L5 roots corresponded with the clinical signs in one patient, and absent innervation of leg muscles was confirmed in the two children with complete agenesis. Normal L1-L4 conduction times were found in a child with no clinical signs. Early assessment of children with sacral anomalies is important in order to prevent secondary complications. Clinical neurophysiological investigations are useful in delineating the different patterns of neurological involvement, especially in the pelvic floor, and the results complement those obtained with imaging techniques.     

Botulinum toxin type-A in the management of spastic equinovarus deformity after stroke: Comparison of 2 injection techniques

Objective:

To retrospectively compare 2 injection techniques in the management of spastic equinovarus deformity after stroke.

Methods:

Patients with stroke were seen at King Hussein Medical Center, Amman, Jordan between January and December 2009. The study design involved an open label retrospective analysis of medical records of 2 groups of comparable age and onset of first stroke. Botulinum toxin was injected into the calf muscles at 2 sites in group I (12 patients) and 4 sites in group II (14 patients). Functional gain was evaluated by the time to walk 10 meters at month one, 3, and 6 compared with baseline.

Results:

There was significant improvement in walking time in each study group. However, there was no significant difference between the 2 groups as measured by the 10-meter walking time.

Conclusion:

Fewer injection sites would minimize patient discomfort and possibly the production of antibodies, yielding similar therapeutic effects.Stroke is the second leading cause of death and disability globally, according to the World Health Organization.1 More than one third of stroke survivors never regain adequate limb function.2 A contributing impediment to regaining function is spasticity. Defined as a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, spasticity results from hyper-excitability of the stretch reflex, one component of upper motor neuron syndrome.3 This may affect limb position and activities of daily living.4 Spasticity contributes to disability in post-stroke patients with a frequency of 41.6%.5 Botulinum toxin is a neurotoxin that acts on the neuromuscular junction at the presynaptic site. It inhibits the release of acetylcholine, thus leading to muscle weakness and reduced muscle tone.6 The use of botulinum toxin type-A (BTX-A)7,8 in the management of spastic equinovarus deformity after stroke has been shown to be effective in reducing muscle tone, reducing pain, improving gait, and facilitating other rehabilitation programs.9,10 Side effects of botulinum toxin include local skin reaction and the spread of weakness to the adjacent non-injected muscles. Contraindications to botulinum toxin include pregnancy, lactation, neuromuscular junction disorders, and concurrent use of aminoglycosides.11 However, so far there has been no agreement on the number of injection sites for the best delivery of the toxin to produce the maximum therapeutic effects.12,13 The objective of the current study was to compare the clinical efficacy of injecting BTX-A (Dysport^®) into 2 sites (the lateral and medial heads of gastrocnemius) with a 4-site technique (gastrocnemius and soleus) in the management of post-stroke lower limb spasticity.     

Botulinum toxin treatment of muscle cramps: A clinical and neurophysiological study

Botulinum toxin is now widely used in the treatment of severla hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign crampfasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection signifcantly lowered our patients' clinical cramp severity scores (mean ± SD: before, 3.80 ± 0.44; after, 1.40 ± 0.54), left muscle strength unchanged and significanlty increased their cramp threshold frequencies (before, 4.22 ± 2.26 Hz; after, 10.0 ± 3.74 Hz). The clinical beefit induced by botulinum toxin lasted about 3 months. Boutlinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 ± 0.19 fasciculations/sec; after, 0.45 ± 0.11 fasciculations/sec). These findings show that local intramuscular injection of botulinum toxin provide effective, safe, and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.     

Central effect of botulinum toxin type A in humans

This study investigated the changes in the cortical excitability with a paired-pulse transcranial magnetic stimulation (TMS) model after a botulinum toxin type A (BTA) injection in normal humans. Ten healthy subjects were enrolled in the study, which involved applying paired TMS to the motor cortex and recording the motor evoked potentials (MEP) before and after the BTA injection. BTA (2.5 mouse units) was injected into the right extensor digitorum brevis muscle. The amplitudes of MEP during rest and the cortical silent period (CSP) for the period of the tonic muscle contraction were measured at an interstimulus interval (ISI) of 3 ms and 20 ms. One month and three months after BTA injection, the level of intracortical inhibition increased significantly at an ISI of 3 ms and the intracortical facilitation decreased at an ISI of 20 ms. The duration of CSP shortened significantly at an ISI of 3 ms 1 month after BTA injection, which was also shortened significantly at an ISI of 20 ms. These findings were maintained until 3 months after the injection. It was concluded that cortical excitability could be modified by BTA injection in normal humans.