TRANSCRANIAL DIRECT CURRENT STIMULATION (t-DCS) AS ADD-ON TO NEUROREHABILITATION OF PISA SYNDROME IN PARKINSON DISEASE

TRANSCRANIAL DIRECT CURRENT STIMULATION (t-DCS) AS ADD-ON TO NEUROREHABILITATION OF PISA SYNDROME IN PARKINSON DISEASE: A RANDOMIZED CONTROLLED TRIAL

Pisa Syndrome (PS) is a lateral trunk flexion frequently associated to Parkinson's disease (PD). The management of PS is still a challenge for the clinician, because it poorly responds to anti-parkinsonian drugs, and the improvement achieved with neurorehabilitation or botulinum toxin injections tends to fade in 6 months or less. Transcranial direct current stimulation (t-DCS) is a non-invasive neuromodulation technique, with promising results in movement disorders. Aim of our study is to evaluate the role of bi-hemispheric t-DCS as add-on to neurorehabilitation in PS. Twenty-eight patients affected by PD and PS were managed with a 4-week hospital neurorehabilitation programme and randomized to: 1) t-DCS group: 5 daily sessions (20 minutes - 2 mA) with cathode over the primary motor cortex (M1) contralateral to PS, and anode over the M1 cortex ipsilateral to PS; or 2) sham group. Patients were tested with kinematic analysis of trunk movement in static and dynamic conditions, UPDRS-III, FIM, and VAS for lumbar pain rating at hospital admission (T0), at hospital discharge (end of neurorehabilitation - T1), and 6 months later (T2). At T0, the evaluations were completed by an EMG study of trunk muscles activation.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease; Pisa Syndrome
• Intervention / Treatment: Other: t-DCS group; Other: Sham group

Detailed Description

Axial disorders are frequent complications of Parkinson's Disease (PD) and they can lead to postural deformities and balance impairments. The most prevalent postural disorders of PD are represented by camptocormia, antecollis, scoliosis, and Pisa syndrome (PS).

The pathogenesis of these disorders has not yet been completely elucidated, and it is characterized by a complex interlacement between central and peripheral mechanisms.

The first report of PS dates back in 1972, when Ekobm described a case series of three patients who developed a lateral trunk flexion in close temporal relationship with neuroleptics assumption. The roster of drugs associated with an acute/subacute onset of PS is huge and constantly growing, and it includes: antidepressants (mirtazapine, sertraline), cholinesterase inhibitor (rivastigmine, galantamine, donepezil), neuroleptics (tiapride, clotiapine, clozapine, aipiprazole, butyrophenone, paliperidone, quetiapine), dopamine agonists, (pramipexolo, ropinirole, pergolide), lithium, valproic acid, and betahistine. Nonetheless, PS was described as well in patients with neurodegenerative disorders, and in particular in PD and parkinsonism without drugs exposure.

The prevalence of PS is around 8.3% (9.3% in women and 6.4% in men) when calculated in a psychogeriatric population, and it is 8 to 8.8% when populations of PD patients were considered.

Formal diagnostic criteria for PS are not available, indeed the diagnosis is based on the clinical features:

• presence of a lateral flexion of the trunk with a homogenous angle between sacrum and spinous process of the 7th cervical vertebra;
• association of an ipsilateral rotation of the trunk around the sagittal axis that leads to a higher and anterior position of the shoulder contralateral to the side of trunk deviation;
• the postural disorder worsens during standing position, sitting position and gait;
• the postural disorder improves in supine position;
• disregard of patients for the postural disorder.

The fluctuation of the postural alteration during static (supine position vs. upright standing position) and dynamic conditions appears to be crucial to differentiate PS from scoliosis.

A lateral trunk deviation of at least 10° is commonly accepted for the diagnosis, although higher or lower cut-offs were used in the past. According to the degree of the lateral trunk flexion, PS can be further divided in mild (less than 20°) or severe (more than 20°) phenotypes.

Patients with PD and PS showed some typical clinical and demographic features when compared to PD patients without postural alterations: they are older, PD is longer in duration, more severe and with a more pronounced asymmetry of motor symptoms. The parkinsonian symptoms involving the upper limbs as well as gait impairment are more severe in PD patients with PS. Moreover, they are characterized by a higher incidence of falls, arthrosis, osteoporosis, orthopedics diseases and pain, specifically lumbar and lower back pain, which is reported in up to 75% of patients with PD and PS.

The management of PS is still a challenge for the physician. PS poorly responds to antiparkinsonian drugs, although there aren't studies specifically designed to assess this topic.

Neurorehabilitation represents one of the fundamental approach to PD and to postural disorders in general, not only for the treatment of the motor symptoms itself but also to improve quality of life and autonomy in the activity of daily living.

The study was a randomized, double-blind, controlled trial aimed to assess the efficacy of five daily sessions of bi-hemispheric t-DCS in add-on to an in-hospital neurorehabilitation protocol in patients affected by PD and PS.

At hospital admission (T0 - baseline), all patients underwent complete neurological, general and functional examinations by a Neurologist with expertise in movement disorders and neurorehabilitation. Patients who fulfilled inclusion and exclusion criteria underwent a baseline kinematic analysis of trunk movement. Patients with at least 10° of lateral trunk flexion completed the baseline evaluations with a dynamic electromyographic (EMG) study of trunk muscles, and with administration of a set clinical scales for the evaluations of motor disability, functional independence, and lumbar pain.

After that, patients were randomly assigned to "t-DCS" or "sham" treatment, and they started the double-blind phase of the study. The 5-day t-DCS/sham treatment was delivered in 5 daily consecutive sessions, starting from the first Monday after hospital admission. In parallel to neuromodulation, all patients were treated with a standardized 4-week rehabilitation programme. The kinematic analysis of trunk movement as well as the administration of the set of questionnaires were repeated at the end of the 4-week rehabilitation programme (T1 - hospital discharge), and 6 months after discharge (T2).

The randomization was performed according to a block randomization method. A unique randomization list was generated before enrollment with the following parameters: 6 blocks; 6 patients per block (3 for t-DCS group, and 3 for sham group).

All the patients were treated with an optimized and individualized anti-parkinsonian therapy, which dose and regimen were kept stable during the overall study period. All the evaluations were performed in the morning, and always in an ON phase.

The specific and standardized in-hospital rehabilitation programme was focused on the rehabilitation of the trunk postural disorder. All patients were treated with 90-minute daily sessions, 6 days a week (Monday to Saturday) for four weeks.

Each session was structured as follow:

• 10 minutes of cardiovascular warm-up activities: intersegmental coordination exercises; exercises to release shoulder and pelvic girdle; pelvic anteversion and retroversion movements to improve diaphragmatic respiration (supine position); breathing exercises to promote expansion of the chest;
• 15 minutes of stretching exercises: exercises to stretch the muscles of the posterior kinematic chain; exercises to stretch the pectoralis muscles; exercises to stretch the ischio-cruralis muscles; assumption of the prone position, sitting on heels and stretching the arms out in front; the "bridge" exercise to stretch the muscles of the anterior abdominal wall, glutei, quadriceps and hamstring; exercises to stretch lumbar muscles (in the supine position, each knee, in turn, is brought to the chest);
• 15 minutes of strengthening exercises in a functional context: exercises to strengthen the dorsal muscles (arms extended and hands outstretched as though to take something); lateral bending (arms lying along the body and hands reaching down as though to pick up something); stretching using the wall bars;
• 20 minutes of gait training: overground gait training (forwards, backwards, and lateral); walking on the spot;
• 15 minutes of balance training: path with obstacles; balance exercises performed in order of difficulty (heel-to-toe walking, lateral walking crossing the legs, walking along a path on surfaces of different texture);
• 15 minutes of relaxation exercises: intersegmental coordination exercises; segmental passive mobilization (until maximum joint range of motion is reached); breathing exercises to promote expansion of the chest.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Pavia, Italy, 27100
    • Neurorehabilitation Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age between 18 and 80 years;
• Hoehn and Yahr stage between II and III;
• Mini-Mental State Examination score above 24;
• lateral trunk flexion of at least 10° at baseline.

Exclusion Criteria:

• history of major psychiatric or other neurological conditions;
• history of back surgery, tumors or infections of the spine, intradural or extradural hematoma, ankylosing spondylitis, spinal stenosis;
• history of idiopathic scoliosis;
• botulin toxin treatment in the previous year;
• any change in dose or regimen of the anti-parkinsonian therapy in the last month before enrolment.

Thirty patients affected by Parkinson' Disease (PD) and Pisa Syndrome (PS) were consecutive enrolled among those attending the Neurorehabilitation Department of the IRCCS Mondino Foundation (Pavia, Italy). Idiopathic PD was diagnosed according to the Movement Disorders Society clinical diagnostic criteria for PD. Pisa syndrome was clinically diagnosed according to the following criteria:

• a lateral flexion of the trunk with a homogenous angle between sacrum and spinous process of the 7th cervical vertebra;
• an ipsilateral axial rotation of the trunk around the sagittal axis, that leads to a higher and anterior position of the shoulder contralateral to the side of trunk deviation;
• the worsening of the postural disorder during standing position, sitting position and gait;
• the improvement of the postural disorder in supine position.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tDCS group; Patients randomized to the experimental group were treated with the following parameters: duration of stimulation of 20 minutes per session with a 2 mA intensity delivered at anodal and cathodal levels.	Other: t-DCS group; All the participants received daily stimulation sessions for 5 consecutive days, starting from the first Monday after hospital admission (Monday to Friday). The primary motor cortex (M1) was identified using the International 10-20 system for C3 (left M1) or C4 (right M1). For the stimulation, the anode was placed over the primary motor cortex (M1) ipsilateral to the side of trunk deviation, and the cathode was placed over the primary motor cortex (M1) contralateral to the side of trunk deviation (bi-hemispheric stimulation).
Sham Comparator: Sham Group; The stimulation setting was exactly the same of the experimental group but the stimulation intensity was set according to a ramping up/ramping down method and delivered only in the first and last 30 seconds of each session. This stimulation paradigm is insufficient to produce a meaningful therapeutic effect, but it is necessary to guarantee the blind condition as it mimics the possible initial tingling sensation associated with active stimulation.	Other: Sham group; The stimulation setting was exactly the same but the stimulation intensity was set according to a ramping up/ramping down method and delivered only in the first and last 30 seconds of each session. This stimulation paradigm is insufficient to produce a meaningful therapeutic effect, but it is necessary to guarantee the blind condition as it mimics the possible initial tingling sensation associated with active stimulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Stat Tot (Stat Bend + Stat Flex)	Total postural alteration in the upright standing position (Stat Tot): lateral trunk inclination in the upright standing position (Stat Bend) plus anterior trunk flexion in the upright standing position (Stat Flex).	Change from Baseline at 28 weeks (T2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Stat Bend	Lateral trunk inclination in the upright standing position	Change from Baseline at 28 weeks (T2)
Change of Stat Flex	Anterior trunk flexion in the upright standing position	Change from Baseline at 28 weeks (T2)
Change of ROM Ips	Range of Motion (ROM) of trunk bending ipsilateral to the side of trunk deviation	Change from Baseline at 28 weeks (T2)
Change of ROM Con	Range of Motion (ROM) of trunk bending contralateral to the side of trunk deviation	Change from Baseline at 28 weeks (T2)
Change of ROM flex	Range of Motion (ROM) of anterior trunk flexion	Change from Baseline at 28 weeks (T2)
Change of ROM Ext	Range of Motion (ROM) of posterior trunk extension	Change from Baseline at 28 weeks (T2)
Change of Total ROM of the trunk	ROM Ips + ROM Con + ROM Flex + ROM Ext	Change from Baseline at 28 weeks (T2)
Change of The Unified Parkinson's Disease Rating Scale - part III - Motor examination (UPDRS-III)	It consists of 18 items (score from 0 to 4). Higher scores are worst otcomes.	Change from Baseline at 28 weeks (T2)
Change of Functional Independence Measure (FIM)	The Functional Independence Measure (FIM) is an 18-item measurement tool that explores an individual's physical, psychological and social function. FIM scores range from 1 to 7 (1= total assist and 7= complete independence).	Change from Baseline at 28 weeks (T2)
Change of Visual analog scale (VAS).	Lumbar pain severity was rated according to a 0 to 10 visual analog scale. Zero is no pain and 10 is worst pain.	Change from Baseline at 28 weeks (T2)

Collaborators and Investigators

• Sponsor: IRCCS National Neurological Institute "C. Mondino" Foundation
• Investigators: Study Director: Cristina Tassorelli, MD, IRCCS Mondino Foundation, Pavia

Publications and helpful links

General Publications

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• Barone P, Santangelo G, Amboni M, Pellecchia MT, Vitale C. Pisa syndrome in Parkinson's disease and parkinsonism: clinical features, pathophysiology, and treatment. Lancet Neurol. 2016 Sep;15(10):1063-74. doi: 10.1016/S1474-4422(16)30173-9. Epub 2016 Aug 8. Review.
• Tinazzi M, Gandolfi M, Ceravolo R, Capecci M, Andrenelli E, Ceravolo MG, Bonanni L, Onofrj M, Vitale M, Catalan M, Polverino P, Bertolotti C, Mazzucchi S, Giannoni S, Smania N, Tamburin S, Vacca L, Stocchi F, Radicati FG, Artusi CA, Zibetti M, Lopiano L, Fasano A, Geroin C. Postural Abnormalities in Parkinson's Disease: An Epidemiological and Clinical Multicenter Study. Mov Disord Clin Pract. 2019 Jun 29;6(7):576-585. doi: 10.1002/mdc3.12810. eCollection 2019 Sep.
• Tinazzi M, Fasano A, Geroin C, Morgante F, Ceravolo R, Rossi S, Thomas A, Fabbrini G, Bentivoglio A, Tamma F, Cossu G, Modugno N, Zappia M, Volontè MA, Dallocchio C, Abbruzzese G, Pacchetti C, Marconi R, Defazio G, Canesi M, Cannas A, Pisani A, Mirandola R, Barone P, Vitale C; Italian Pisa Syndrome Study Group. Pisa syndrome in Parkinson disease: An observational multicenter Italian study. Neurology. 2015 Nov 17;85(20):1769-79. doi: 10.1212/WNL.0000000000002122. Epub 2015 Oct 21.
• Tassorelli C, Furnari A, Buscone S, Alfonsi E, Pacchetti C, Zangaglia R, Pichiecchio A, Bastianello S, Lozza A, Allena M, Bolla M, Sandrini G, Nappi G, Martignoni E. Pisa syndrome in Parkinson's disease: clinical, electromyographic, and radiological characterization. Mov Disord. 2012 Feb;27(2):227-35. doi: 10.1002/mds.23930. Epub 2011 Oct 13.
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• Etoom M, Alwardat M, Aburub AS, Lena F, Fabbrizo R, Modugno N, Centonze D. Therapeutic interventions for Pisa syndrome in idiopathic Parkinson's disease. A Scoping Systematic Review. Clin Neurol Neurosurg. 2020 Nov;198:106242. doi: 10.1016/j.clineuro.2020.106242. Epub 2020 Sep 18.
• Tinazzi M, Geroin C, Gandolfi M, Smania N, Tamburin S, Morgante F, Fasano A. Pisa syndrome in Parkinson's disease: An integrated approach from pathophysiology to management. Mov Disord. 2016 Dec;31(12):1785-1795. doi: 10.1002/mds.26829. Epub 2016 Oct 25.
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• DaSilva AF, Volz MS, Bikson M, Fregni F. Electrode positioning and montage in transcranial direct current stimulation. J Vis Exp. 2011 May 23;(51):2744. doi: 10.3791/2744.
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Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2019
• Primary Completion (Actual): August 15, 2020
• Study Completion (Actual): September 15, 2020

Study Registration Dates

• First Submitted: October 26, 2020
• First Submitted That Met QC Criteria: November 6, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): November 13, 2020
• Last Update Submitted That Met QC Criteria: November 11, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Parkinson Disease; Transcranial direct current stimulation; Pisa Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Syndrome; Parkinson Disease
• Other Study ID Numbers: Pisa-tDCS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No