Adrenomyeloneuropathy, Hereditary Spastic Paraplegia
Conditions
Keywords
Hereditary spastic paraplegia, repetitive transcranial magnetic stimulation, disturbed gait, Adrenomyeloneuropthy
Brief summary
Hereditary spastic paraplegia (HSP) is the group of inherited disorders, characterized by progressive gait disturbance. There is no established therapy. Adrenoleukodystrophy (AMN) is an x-linked hereditary disease. One of its form, the adrenomyeloneuropathy has the same symptoms as HSP. Current therapeutic options for AMN are very limited. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity. The purpose of this study is to compare the effectiveness of rTMS in improving the HSP- and AMN-related gait disturbance and other symptoms with sham stimulation. Intervention will include five daily sessions. In each session 1500 magnetic pulses will be administered to each of both primary motor areas for lower extremities. Assessment of gait and of strength and spasticity of lower extremities will be made before and after therapy, as well as two weeks later.
Detailed description
Hereditary spastic paraplegia (HSP) is a group of inherited disorders, characterized by progressive gait disturbance with weakness and spasticity, which predominate in lower extremities. There is no established therapy. Adrenoleukodystrophy (AMN) is an x-linked hereditary disease. One of its form, the adrenomyeloneuropathy has the same symptoms as HSP. Current therapeutic options for AMN are very limited. Repetitive Transcranial Magnetic Stimulation (rTMS), a noninvasive method of modulation of brain plasticity proved to be effective in improving the gait performance in several conditions such as Parkinson Disease, vascular Parkinsonism, partial spinal cord injury and in post-stroke paresis. Previous studies documented also altered cortical excitability in HSP patients. The purpose of this study is to compare the effectiveness of 10 hertz (Hz) rTMS over the primary motor cortices in improving the gait and strength and spasticity of lower extremities with sham stimulation in HSP and AMN patients. Intervention will include five daily sessions. In each session 1500 magnetic pulses will be administered to each of both primary motor areas for lower extremities. Assessment of gait and of strength and spasticity of lower extremities will be made before and after therapy, as well as two weeks later.
Interventions
DEVICErTMS
high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities
Sponsors
Jakub Antczak
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Sham stimulation will be provided by holding the stimulating coil perpendicularly to the scalp, which assures similar impression as during active stimulation but prevents significant magnetic field to reach the brain tissue.
Intervention model description
16 patients with HSP or AMN will receive either active and sham stimulation in random order
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* diagnosis of hereditary spastic paraplegia - confirmed genetically, on the basis of family history or on exclusion or diagnosis of adrenomyeloneuropathy - confirmed genetically or by the elevated plasma very long chain fatty acid or on family history * Gait disturbances affecting daily activities * Ability to walk 10 meters without assistance or with crutches or with rollator walker
Exclusion criteria
* Presence of signs or symptoms indicating other than HSP or AMN ethiology of gait disturbances * Contraindications for rTMS as listed by the Guidelines of the International Federation of Clinical Neurophysiology (IFCN 2009) i.e. seizure in the past, epilepsy, presence of magnetic material in the reach of magnetic field, pregnancy, likelihood to get pregnant, intracranial electrodes, cardiac pacemaker or intracardiac lines, frequent syncopes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS | Before rTMS, directly (on the same day) after rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and directly after rTMS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Timed up and go Test | Baseline, directly (on the same day) after rTMS and 14 days later | Time of standing up from a chair, walking three metres to cross a line drawn 3 meters ahead and going back to sit down on the chair. |
| Change in Medical Research Council Scale (MRC) | Baseline, directly (on the same day) after rTMS and 14 days later | Change in bilateral assessment of the strength of following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) MRC scale, with higher values representing stronger movements, which is better outcome. Values are averaged from all movements tested. |
| Modified Ashworth Scale | Baseline, directly (on the same day) after rTMS and 14 days later | Bilateral assessment of spasticity in following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) Modified Ashworth Scale, with higher values representing more severe spasticity, which is worse outcome. Values are averaged from all movements tested. |
| Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS | Baseline, 14 days after rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and 14 days after finishing rTMS therapy. |
Countries
Poland
Participant flow
Recruitment details
We recruited 15 patients meeting inclusion criteria. One patient dropped out due to seizure, when he was in active treatment.
Participants by arm
| Arm | Count |
|---|---|
| Active rTMS, Then Sham rTMS First intervention:
10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited.
The washout period will last at least one month.
Second intervention:
Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue.
rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities | 8 |
| Sham rTMS, Then Active rTMS First intervention:
Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue.
The washout period will last at least one month.
Second intervention:
10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited.
rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Active rTMS, Then Sham rTMS | Sham rTMS, Then Active rTMS | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 7 Participants | 15 Participants |
| Age, Continuous | 45.5 years STANDARD_DEVIATION 11.9 | 41.7 years STANDARD_DEVIATION 7.5 | 44.8 years STANDARD_DEVIATION 10.1 |
| Amplitude of motor evoked potentials | 1.1 millivolts STANDARD_DEVIATION 0.6 | 0.7 millivolts STANDARD_DEVIATION 0.5 | 0.9 millivolts STANDARD_DEVIATION 0.5 |
| Central motor conduction time | 18.2 milliseconds STANDARD_DEVIATION 3.4 | 20.3 milliseconds STANDARD_DEVIATION 6.6 | 19.1 milliseconds STANDARD_DEVIATION 5.2 |
| Motor threshold for left abductor hallucis | 64.1 percentage of the maximal stimulator out STANDARD_DEVIATION 7.5 | 63.5 percentage of the maximal stimulator out STANDARD_DEVIATION 8 | 63.9 percentage of the maximal stimulator out STANDARD_DEVIATION 7.7 |
| Motor threshold for the right abductor hallucis | 61.4 Percentage of the max stimulator output STANDARD_DEVIATION 12.1 | 62.8 Percentage of the max stimulator output STANDARD_DEVIATION 8.3 | 62.0 Percentage of the max stimulator output STANDARD_DEVIATION 10.6 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Poland | 8 participants | 7 participants | 15 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 4 / 15 | 0 / 15 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 |
Outcome results
Primary
Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS
Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and directly after rTMS.
Time frame: Before rTMS, directly (on the same day) after rTMS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active rTMS | Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS | -5.41 seconds | Standard Deviation 16.42 |
| Sham rTMS | Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS | 1.70 seconds | Standard Deviation 8.52 |
Secondary
Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS
Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and 14 days after finishing rTMS therapy.
Time frame: Baseline, 14 days after rTMS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active rTMS | Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS | -5.84 seconds | Standard Deviation 17.52 |
| Sham rTMS | Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS | 0.93 seconds | Standard Deviation 6.54 |
Secondary
Change in Medical Research Council Scale (MRC)
Change in bilateral assessment of the strength of following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) MRC scale, with higher values representing stronger movements, which is better outcome. Values are averaged from all movements tested.
Time frame: Baseline, directly (on the same day) after rTMS and 14 days later
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active rTMS | Change in Medical Research Council Scale (MRC) | Baseline vs. directly after rTMS | 0 score on a scale | Standard Deviation 0 |
| Active rTMS | Change in Medical Research Council Scale (MRC) | Baseline vs. 14 days later | 0.09 score on a scale | Standard Deviation 0.27 |
| Sham rTMS | Change in Medical Research Council Scale (MRC) | Baseline vs. directly after rTMS | 0.06 score on a scale | Standard Deviation 0.22 |
| Sham rTMS | Change in Medical Research Council Scale (MRC) | Baseline vs. 14 days later | 0 score on a scale | Standard Deviation 0.32 |
Secondary
Change in Timed up and go Test
Time of standing up from a chair, walking three metres to cross a line drawn 3 meters ahead and going back to sit down on the chair.
Time frame: Baseline, directly (on the same day) after rTMS and 14 days later
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active rTMS | Change in Timed up and go Test | Baseline vs. after rTMS | -4.72 seconds | Standard Deviation 13.9 |
| Active rTMS | Change in Timed up and go Test | Baseline vs. 14 days later | -2.92 seconds | Standard Deviation 7.29 |
| Sham rTMS | Change in Timed up and go Test | Baseline vs. after rTMS | 0.18 seconds | Standard Deviation 4.83 |
| Sham rTMS | Change in Timed up and go Test | Baseline vs. 14 days later | 0.78 seconds | Standard Deviation 7.24 |
Secondary
Modified Ashworth Scale
Bilateral assessment of spasticity in following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) Modified Ashworth Scale, with higher values representing more severe spasticity, which is worse outcome. Values are averaged from all movements tested.
Time frame: Baseline, directly (on the same day) after rTMS and 14 days later
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active rTMS | Modified Ashworth Scale | Baseline vs. after rTMS | -0.36 score on a scale | Standard Deviation 0.5 |
| Active rTMS | Modified Ashworth Scale | Baseline vs. 14 days later | -0.27 score on a scale | Standard Deviation 0.46 |
| Sham rTMS | Modified Ashworth Scale | Baseline vs. after rTMS | 0 score on a scale | Standard Deviation 0.46 |
| Sham rTMS | Modified Ashworth Scale | Baseline vs. 14 days later | -0.11 score on a scale | Standard Deviation 0.53 |