Hypokinetic gait and festinations in PD

Dopa responsive gait and balance alterations are frequent in PD and encompass distinct patterns. Hypokinetic rigid gait is mainly characterised by a reduction of gait speed,6 with a reduction of the step amplitude but an unchanged or slightly increased cadence. In early studies of gait at imposed speed, PD patients were able to increase their cadence but the step length remained systematically lower whatever the speed.7 This observation suggests that gait akinesia was mainly related to a deficit in internal generation of adapted step length rather than an inability to increase the cadence. Conversely, cadence increase may be viewed as a compensatory mechanism. In line with this concept, external visual cues help to increase the step length, suggesting that only internal programming of amplitude is impaired, a finding that is consistent with general descriptions of akinesia. Postural disturbances related with hypertonia were also described in PD gait. They could be explained by a flexed and stiffened posture of the trunk throughout the gait cycle. The range motion of the hip was also reduced. All these changes are well improved by levodopa.6 Another typical and unique gait pattern observed in PD is festination. Festinating gait is described as rapid small steps done in an attempt to keep the centre of gravity in between the feet while the trunk is leaning forward involuntarily. The mechanisms of festination and its relationship with FOG are still debated. Although festination was found to be associated with FOG,8 it is difficult to find a unified view to include the issue of gait initiation in this particular symptom.9 Thus festination may also be considered as separate episodic gait impairment encountered in PD. Early in the course of PD tandem gait performance is generally normal although it is impaired in most atypical parkinsonism.10 However the most impairing gait disruptions are related with balance deficit and FOG episodes that tend to become resistant to levodopa, thus suggesting the involvement of extranigral lesions.1

Falls are a major milestone in the evolution of PD

In PD patients, falls induce an increased risk of mortality and morbidity mainly related to hip fractures and head injuries. Falls are a source of major disability leading to dependency, institutionalisation, poor quality of life and a residual fear of falling. The incidence of falls in PD is variable among the different available studies, with a 51–68% risk of having a fall in a year in PD patients.11 The frequency of recurrent falls is about 50% in 1 year.12 Once the first fall has occurred, the survival duration is similar in PD and in atypical parkinsonian syndromes which usually have a more severe course.13 Clinical predictive factors of falls are a previous fall, fear of falling, disease duration and severity, abnormal axial posture and tone, cognitive impairment, decrease in arm swing (uni- or bilateral), presence of dyskinesia and antiparkinsonian treatment.14 Most falls are unrelated to extrinsic factors, such as sliding or a collision, but are dependent upon intrinsic deficits of balance control. Falls occur mainly during posture changes, in particular during a half-turn, or while performing activities that require a double task demand (cognitive or motor).11 The more the second task is difficult, the more the balance control is altered and fall risk increased.11 Lastly, some authors reported proprioceptive and vestibular deficits in PD, which can participate in the occurrence of balance disturbances.15

At bedside, postural instability is routinely evaluated with the pull-retropulsion test (item 30 of the Unified Parkinson's Disease Rating Scale-part III). However, variability exists in its execution and the reproducibility is low and so is its sensitivity to the early detection of fallers.15 In the recently validated Movement Disorders Society-Unified Parkinson's disease rating scale (MDS-UPDRS),16 detailed instructions for the examiner may reduce the variability of this test. However, the outcome of clinical testing for postural instability is not related to the risk of falls.12 Other clinical tests such as the push and release test have recently been proposed with higher sensitivity for identifying fallers. Non-specific scales have also been proposed to evaluate balance and risk of falls in parkinsonian patients, such as the Berg Balance Scale, the Timed Up and Go test, and the Tinetti score, with a good sensitivity to detect fallers among PD patients.14 Recently, the Functional Gait Assessment, the Balance Evaluation System Test, and the Rapid Assessment of Postural Instability in PD have been proposed for PD patients with good test-retest and inter-rater reliability, good sensitivity to detect fallers versus non-fallers and good predictive value.17

Posturography for balance deficits in PD

Quantitative posturographic methods measure oscillations of the centre of pressure of the foot with force plates in static or dynamic position using mobile platforms. Measures include the limit of stability and the posture sway using the sensory organisation test.18 The perturbation can be a rotation, a translation, or both combined; then the changes in the centre of pressure position and the pattern and latencies of lower limb muscle activations can also be measured. In the literature, many studies report posturographic data in PD patients, but with contradictory results (online supplementary material). Even if significant differences exist between PD patients and healthy subjects at the group level, posturographic parameters are not well related to clinical postural instability or risk of falls. Their usefulness for the management of individual patients has yet to be clearly established, in particular for assessing the effects of therapeutic interventions on balance deficit in PD patients. Posturography studies may however provide insights in the mechanisms of falls. For example, Carpenter et al19 stressed the abnormalities of upper limb movements that could give no protection against falls in PD patients. Recently, a change in the vertical velocity of the centre of mass has been shown to be sensitive to postural instability and to the effects of treatment at the individual level.20 However, its utility in clinical practice as well as its predictive value needs to be further evaluated.

Freezing of gait

FOG is an episodic transient disruption of gait that typically lasts a few seconds and is associated with a unique sensation: patients feel that their feet are glued to the ground, causing them to remain in place despite making a concerted effort to overcome the motor block and move forward. FOG is not specific of PD. It may also be encountered in other degenerative disorders such as progressive supranuclear palsy, multisystem atrophy or dementia with Lewy bodies and in focal lesions of various brain structures (brainstem, basal ganglia, supplementary motor area, frontal lobes and subcortical regions).9

When FOG occurs during gait initiation, it is characterised by repeated ineffective anticipatory postural adjustments and leads to a failure of gait initiation and sometimes to a fall. FOG may also occur while patients are walking. There is an abrupt decrease of step length and increase of step frequency and step-to-step variability that precedes a complete blockade of gait and falls. Another important characteristic is the occurrence of an irregular rapid trembling in both knees.21 FOG is often triggered by characteristic circumstances such as a half or 360°-turn,22 obstacle (doorway) clearance, spaces with a narrow passage or unexpected visual or auditory stimuli. Fatigue, stressful situations, cognitive load23 anxiety and depression may also elicit FOG.24 Usually, FOG is improved by visual (eg, marks on the ground) or auditory cueing (rhythmic sounds). Paradoxically, running, cycling or climbing stairs are performed more easily than usual gait. Generally, freezing is defined as an abrupt difficulty in starting or continuing rhythmic and repetitive movements. Freezing is also observed in other motor plans such as in repetitive bimanual motor tasks (eg, writing) or during speech. In line with this concept, freezing (and FOG) may be viewed as an extreme form of akinesia. New tools for FOG assessment have recently been developed. For the purposes of objective evaluation, standardised tasks have been designed to elicit FOG during gait with imposed stressors, such as a fast cadence, a slow cadence or obstacle occurrence. An obstacle avoidance task during treadmill walking was also used to provoke FOG.25 Freezing episodes can be automatically detected by means of ambulatory devices.26 Given the difficulty in evaluating FOG, more sensitive and specific clinical and neurophysiological approaches need to be developed.

Because of its high variability, depending on environmental triggers, emotional state, cognitive inputs and medication, the frequency of FOG is difficult to measure in PD populations. In the Deprenyl and tocopherol antioxydative therapy for Parkinson's disease (DATATOP) study, FOG was infrequent (7.1%) and rarely led to fall in early PD. Its frequency rose to 23.6% after 18 months of observation. The risk of developing FOG was increased in patients that started the disease with gait disorders and had higher scores in postural instability, rigidity, bradykinesia and speech at baseline. In contrast, tremor at onset considerably decreased the risk of subsequent FOG. At the end of follow-up, FOG was no longer associated with akinesia and hypertonia but correlated with other midline signs (speech deficit and balance disorder) suggesting that these symptoms are, at least partially, independent of akinesia.27 After 6–10 years of evolution, FOG was retrospectively reported by 48–70% of PD patients.28 Cognitive deficits and, more specifically, low frontal test scores are also associated with FOG. FOG has a high impact on the quality of life of PD patients far beyond its motor components since quality of life measured on the Parkinson's disease questionnaire (PDQ) scale is affected in all its dimensions except stigma and social support.29

The cerebral mechanisms underlying FOG have not been elucidated but alterations observed during physiological analysis of gait may provide important clues. Alterations of gait rhythm, gait symmetry and bilateral coordination in stepping are observed in PD patients with FOG outside episodes of freezing.30 However, the question of whether these alterations are causative is still debated. Electromyographic studies also point to disruption of the central gait cycle timing: a consistent pattern of premature timing of lower limb muscle activity before freezing was observed that may contribute to deceleration and interruption of the movement.31 The role of perceptual stimuli (such as doorways) as a FOG trigger also suggests that a perceptual defect may contribute to the motor impairment. Conversely, the improvement of FOG by visual clues may reveal a double deficit: increased visual dependence to compensate impaired kinaesthetic feedback and increased attentional processing in order to bypass the deficit of internal generation of appropriate lower limb movement during the automated gait cycle.32 ,33

General organisation of the network involved in balance and locomotion

The neuronal networks involved in locomotion have been extensively studied in animals. They are hierarchically organised and include: (1) the lower effector levels, including the musculoskeletal system and the peripheral nervous system; (2) the central locomotion pattern generators composed of organised groups of interneurons automatically generating rhythmic and alternating limb activity34 (3) several locomotor areas located at various levels in the brainstem, which control the central locomotion pattern generators and are characterised by their ability to produce locomotor action when electrically or pharmacologically stimulated. These are the subthalamic locomotor region, the MLR and the dorsal and ventral tegmental field of the caudal pons. The MLR, composed of the PPN and cuneiform nucleus (CN), is the locomotor area known to be the most relevant in PD, and we will focus on the MLR and will not review data on the structures located in the posterior midbrain; (4) finally, these locomotor areas are modulated by higher level control systems, including the dopaminergic and other modulatory systems, the basal ganglia and the prefrontal cortex. These locomotor circuits are modulated by sensory feedback via sensory afferent systems (somesthetic, vestibular and visual systems) (figure 1A).

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Figure 1

(A) Anatomy and connectivity of the pedunculopontine (PPN) and cuneiform nuclei (CN) in primates. Both nuclei have reciprocal connections with the basal ganglia (GP, globus pallidus; Pu, putamen; SN, substantia nigra; STN, subthalamic nucleus). They also receive inputs from the cerebellum and motor cortices. The existence of inputs from the spinal cord remains to be demonstrated in monkeys. The PPN and CN have major outputs to the descending reticulospinal pathway and the ascending thalamocortical pathway through the thalamic centromedian nucleus. Cholinergic neurons in the PPN visualised using Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry are also represented in a transverse brainstem section (lower right panel). (B) Anterior view of surgical targets for Parkinson's disease. Targets are defined in a three-dimensional histological atlas, with axial and coronal sections of the corresponding postmortem T1-weighted MRI. The usual targets are visualised on the right hemisphere: GPi, internal globus pallidus; STN, subthalamic nucleus; Vim, ventral intermediate thalamic nucleus. New targets are visualised on the left hemisphere: CM, thalamic centromedian nucleus; CN, cuneiform nucleus; PPN, pedunculopontine nucleus; SNr, substantia nigra pars reticulata.

MLR in gait control

Medication options and rehabilitation

The response of gait and balance disorders to levodopa is inconstant and decreases over time. Only a few trials have tested drugs targeting extradopaminergic systems for FOG or balance deficits in PD. A recent study demonstrated that a central cholinesterase inhibitor reduced the number of falls by 0.12 falls/day in comparison with placebo (0.25 falls/day, p=0.049).58 Thus, the number of patients to treat to avoid one fall was 8.3 in this study. Another trial suggested that methylphenidate could improve OFF-dopa FOG whereas a beneficial effect on FOG persisting ON-dopa was less obvious.59 However, these results remain controversial since a recent study reported that methylphenidate was not effective and could even worsen the severity of PD symptoms.60 Finally, rehabilitation programs targeting gait and balance are widely used in clinical practice although scientific evidence for choosing the optimal method is still lacking. Interestingly, an experimental study in mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine suggested that treadmill exercise could improve balance/locomotion and increase the DA level in the dorsal striatum.61 In PD patients, various rehabilitation approaches were evaluated in controlled trials (see online supplementary material). Nearly all types of rehabilitation methods are beneficial in comparison with no intervention. Interestingly, home based exercise programs could also be efficient to reduce the risk of injurious falls and recurrent near falling.62

Given the seminal importance of the cholinergic lesion of the PPN in the pathophysiology of gait disorders, drugs targeting this system should be further explored. Despite the relative lack of response to inhibitors of cholinesterase, this strategy should not be discarded, since the procholinergic effect could be hampered by the degeneration of terminations within the targets of PPN cholinergic neurons. From a pathophysiological standpoint, there is evidence to support the use of direct cholinergic agonists. Nicotine would be convenient to use and its effects on gait and balance parameters could be tested. However, as nicotine is not specific to the PPN cholinergic system, its potential effects could be masked by the action on other targets such as cerebral cortex and striatal interneurons. Thus, further research aimed at identifying the subtypes of cholinergic receptors involved in gait and balance may help with the process of screening new drugs. Interestingly, a recent study performed in the lamprey63 suggested that muscarinic cholinergic receptors could be critical for driving activation of the reticulospinal pathway from the MLR. Thus, further study focused on the role of muscarinic receptors in mammals could provide new therapeutic options for gait disorders in PD. Similar approaches could be applied to the noradrenergic system, which could also be involved in gait and balance disorders in PD patients. Even though an improvement of gait has been reported in PD patients after administration of the 5-HT2 serotonin receptor antagonist ritanserin (an anxiolytic substance),64 the specific effect of serotoninergic drugs on gait has never been studied.

Functional surgery