Movement disorders: Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor features. The prevalence is estimated at about 120 per 100,000 persons and the peak age of onset is between 55-60 years. The parkinsonian brain is characterized by a dopaminergic cell loss, of unknown origin, particularly in the substantia nigra pars compacta (SNc). The resulting dysregulation of the functioning of the basal ganglia loops (motor, cognitive and limbic) leads to motor and non-motor symptoms. The clinical team aims at better understanding the pathophysiology underlying theses signs, and at improving patients’ care.
In addition to the well-known cardinal symptoms of the disease (the tremor, rigidity and bradykinesia triad), most patients present with so-called axial symptoms affecting speech, posture, and gait. While current treatments, whether medication or brain surgery, can satisfactorily alleviate the segmental triad, axial symptoms are more resistant to treatment. In some cases, they can even be worsened by treatment. Their underlying pathophysiology is poorly understood, and clinical management of the patients is a challenge. Our current research projects specifically target gait disorders on one hand and postural abnormalities on the other hand.
Regarding gait, we are particularly interested in Freezing of Gait (FOG), an unpredictable and sudden inability to start or continue walking. It often occurs as a start hesitation, when the patient’s attention is shifted, or during a directional change. It can be responsible for falls as the upper body continues moving forward while the feet remain glued to the ground. It is therefore very disabling, affecting the patients’ autonomy and quality of life. Some forms of FOG are improved by levodopa (levodopa-responsive FOG), while others are not (levodopa-resistant FOG). The neurosurgical treatment of PD includes stimulation of three brain targets including the Ventral intermediate thalamic nucleus (Vim), the Globus Pallidus internus (GPi), and the Subthalamic Nucleus (STN). The best benefits on the cardinal PD symptoms seem to be obtained with bilateral STN stimulation. STN stimulation also alleviates levodopa-responsive FOG and gait disorders, improving stride length and velocity. Yet, the efficacy wanes over time.
Levodopa- and STN stimulation- resistant gait disorders suggest the involvement of non-dopaminergic circuits. Considering the influence of external sensory cues and that of motivation and emotion on FOG, these structures are likely linked to the sensory and limbic systems in addition to the basal ganglia loop. Animal data pointed at the pedunculopontine nucleus (PPN), a structure localized within the brainstem and showing reciprocal connections with the basal ganglia. Clinical trials of PPN area stimulation have brought mitigated results so far. In our own cohort, FOG was improved, or disappeared altogether, in about half of the patients operated on. While pursuing our investigations on the influence of PPNa stimulation on gait, speech, as well as the neural circuits recruited by the stimulation, we are also turning back to STN stimulation and its potential for alleviating FOG via an improvement in gait symmetry. Indeed, for those patients not responding to PPNa stimulation, additional therapeutic approaches need to be sought. We specifically focus on long term effects in the patients’ daily life.Ferraye MU, Debû B, Fraix V, Xie-Brustolin J, Chabardès S, Krack P, Benabid AL, Pollak P. (2008) Effects of subthalamic nucleus stimulation and levodopa on freezing of gait in Parkinson disease. Neurology. 70(16):1431-7. Ferraye M., Debû B., Fraix V., Goetz L., Chabardès S., Ardouin C., Seigneuret E., Benabid AL., Pollak P. (2010) Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson Disease. Brain, 133(1), 205-14. Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, Lozano AM. (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain. 133(1):215-24.
Postural abnormalities such as postural deviations affect nearly all patients with advanced Parkinson’s disease and represent an important source of disability. The clinical phenotype of the abnormal posture is variable, with some patients bending forward, others leaning to one side, and most cases presenting with a combination of the two directions of deviation. The management of these deviations, whether by medication, deep brain stimulation, or physiotherapy, remains a challenge. Pisa syndrome is a marked lateral tilt of the trunk, typically reducible by passive mobilization or when the patient lies down. The onset of Pisa syndrome may be sub-acute, after a change in antiparkinsonian treatment, or slow, with patients unable to date back the onset of the tilting as they initially did not notice their leaning to one side. Several hypotheses have been put forward to try and explain the underlying mechanisms: central hypotheses, which refer to basal ganglia dysfunction, abnormal integration of sensory information, or dystonic processes, and peripheral hypotheses, which advocate an alteration of the musculoskeletal system, such as myopathy of the paraspinal muscles. We are currently examining the influence of asymmetry of the basal ganglia output and abnormal integration of sensory input in the genesis of Pisa syndrome.