Clinical trial NCT05198921: The Effectiveness of Repetitive Transcranial Magnetic Stimulation for Spastic Diplegia Cerebral Palsy
Official title: The Effectiveness of Repetitive Transcranial Magnetic Stimulation for the Treatment of Spastic Diplegia Cerebral Palsy Based on the Gross Motor Function in School-aged Children: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Cerebral Palsy, Spastic
Lead sponsor: Universitat de Lleida
Sponsor class: OTHER
First posted: 2022-01-20
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: randomized crossover double-blind trial. It is a pre-post study with follow-up at 1 month
Primary purpose: TREATMENT

Brief summary: Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain.

Nowadays, CP is not fully curable, and physiotherapy should be used in conjunction with other interventions such as oral drugs, botulinum toxin type A, continuous pump-administered intrathecal baclofen, orthopaedic surgery and selective dorsal rhizotomy. However, several systematic reviews conclude that there is low evidence that these invasive therapies are more effective than placebo.

Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulatory technique through magnetic impulses. The effect of rTMS depends on the frequency of the emitted electromagnetic field; low frequencies (≤1 Hz) lead to an inhibition of neuronal electrical activity at the stimulation site, while high frequencies (≥3 Hz) cause neuronal depolarization.

The objective of the project is to evaluate the effectiveness of a repetitive Transcranial Magnetic Stimulation (rTMS) protocol, as an adjunct treatment to neurorehabilitation to improve gross motor function and quality of life in school-age children with spastic diplegia-type infantile cerebral palsy.

Detailed description: Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain.

The reported worldwide prevalence rates of CP are approximately between 2 and 3 per 1000 live births. In Spain, it is estimated that between 2 and 2.5 per thousand born has cerebral palsy, that is, 1 per in 500 live births. In other words, in Spain there are 120,000 people with cerebral palsy.

The Spastic Diplegia form is the most common form with around 65-70 % of the CP children. It is characterized by gross motor difficulties, marked in the lower limb and partially affection noticeable in the upper limb.

Spasticity is defined as "disordered sensori-motor control, resulting from an upper motoneuron lesion, presenting as intermittent or sustained involuntary activation of muscles". Spasticity is a velocity-dependent motor disorder, characterized by an increased stretch reflex, resulting in immoderate muscle activation that causes a muscle hypertonia. The pathophysiology of spasticity is characterized, in general, by a deregulation of the motor pathways (mainly the corticospinal, reticulospinal, and the vestibulospinal tracts) running from the cerebral cortex, and brain stem to the spinal cord. In children who suffer from an early brain abnormality, spasticity is affected by the reorganization of supraspinal input and impaired motor maturation, causing a loss in descending inhibitory inputs and an increase of the excitability of gamma and alpha neurons.

NICE clinical guidance recommends the use of physiotherapy, as it provides an approach centred on how the current functional problems impact on the participation at home, school life and community. Nowadays, CP is not fully curable, and physiotherapy should be used in conjunction with other interventions such as oral drugs, botulinum toxin type A, continuous pump-administered intrathecal baclofen, orthopaedic surgery and selective dorsal rhizotomy. However, a recent Cochrane Systematic Review (CSR) concludes that there is low evidence that BoNT-A is more effective than placebo or a non-placebo control in children with CP. Another recent CSR determines that there is short-term evidence of the Intrathecal Baclofen therapy. Furthermore, there is not a CSR for orthopaedic surgery and selective dorsal rhizotomy.

Non-invasive brain stimulation Repetitive Transcranial Magnetic Stimulation (rTMS) is a type of neuromodulator technique in which trains are emitted from multiple magnetic pulses. The effect of rTMS depends on the emitted electromagnetic field frequency; low frequencies (≤1 Hz) lead to an inhibition of neural electrical activity at the stimulation site, while high frequencies (≥3 Hz) cause neuronal depolarization. It has been reported that rTMS stimulation of prefrontal and motor cortical areas gives rise to trans synaptic activation of subcortical circuits which are responsible for motor activity and reduction of muscle spasticity. That is, an increase in the activity in the motor cortex, increases the inhibitory input to the corticospinal tract and reduces the hyperactivity of the gamma and alpha neurons.

In terms of scientific evidence, some researchers have already studied the effect of rTMS over standard therapy in decreasing muscle tone in CP patients, such as Gupta et al. who demonstrated better results on the group who carried out the treatment compared to the control group. Lal Rajak et al. studied how the number of therapy sessions of rTMS would improve the motor development by reducing muscle spasticity in children with CP, and concludes that the group which carried out more sessions, showed better improvements. Gupta and Lal Rajak also studied the efficacy of different pulses by a constant frequency. They found that in diplegic patient's, the gross motor function improved by 3.04%, 4.62% and 5.95% in groups of 1500 pulses, 2000 pulses and 2500 pulses, respectively.

However, all the randomized controlled trials (RCTs) conducted as of yet, showed limitations on the methodological quality. They all presented a very small sample size, which makes difficult to conclude that the therapy is effective. Moreover, neither did an evaluation in the middle of the treatment, only at the beginning and at the end, so it is not known if the therapy begins to produce effect sooner, and none of them conducted long-term monitoring results. Additionally, they only used one evaluation measure, the Modified Ashworth scale. Besides, none of the RCTs took into account the family or carers, which have a main role on making decisions and care planning.

Eligibility criteria: Inclusion Criteria:

* Primary school children with diagnose of Spastic Diplegia CP
* \> 1 on Mas in hip flexors, adductors and tibialis anterior of both lower extremities.
* Parents/legal guardians signed the Informed consent

Exclusion Criteria:

* Severe mental retardation
* Present epilepsy
* Present any remedial surgery/medication
* Less than 1 year post orthopaedic surgery
* Less than 6 months post botulinum toxin type A injection
* Present metallic implants
* Present any comorbidity unfit for the study
* Congenital disorders such as Down's syndrome, fragile-x syndrome or congenital anomalies

Primary outcomes:
measure: Change in Gross Motor Function by the Gross Motor Function-66
timeFrame: baseline, one month, two months, three months and six months.
Secondary outcomes:
measure: Change in Functional Strength by the Functional Strength Measure
timeFrame: baseline, one month, two months, three months and six months.
measure: Change in Quality of Life by the Cerebral Palsy Quality of Life-Child
timeFrame: baseline, one month, two months, three months and six months.
measure: Change in Spasticity by the Modified-Modified Ashworth Scale.
timeFrame: baseline, one month, two months, three months and six months.
measure: Change in Impact on family by the Revised Impact on Family questionnaire
timeFrame: baseline, one month, two months, three months and six months.
measure: Cortex excitability
timeFrame: Enrollment, 1st month, 2nd month, 3rd month and 4th month
Other outcomes:
Locations:
city: Lleida
country: Spain
facility: Claudia Arumi
Study officials:
References: