Spastic Paresis: A Treatable Movement Disorder

If a movement disorder is a neurological condition that causes "excess movement or a paucity of voluntary and involuntary movements," we propose that spastic paresis represents an archetypical movement disorder and should be considered within this sphere.1 This relates not only to the sign of spasticity, which is defined as the enhancement of velocity-dependent stretch reflexes, measured at rest.2, 3 Spasticity is but the symptomatic hallmark of the syndrome of spastic paresis following lesions that involve pyramidal pathways. Spastic paresis comprises hypokinetic and hyperkinetic movement abnormalities from both muscular and neural causes, which constitute the spastic movement disorder (SMD).1 When considering brain lesions causing syndromes of spastic paresis (eg, stroke, trauma, tumors, inflammatory, or infectious brain disorders), the vast majority are not confined to the pathways of motor command execution, that is the pyramidal pathways. In most cases, neural damage extends to striatal-cortical areas involved in the preparation of motor command, which are extrapyramidal pathways. In some instances, causal lesions even include pathways involved in the conception or the motivation of motor command, causing superimposed symptoms of apraxia or abulia. Even when considering strictly spinal cord injuries, we suggest that the syndromes resulting from those lesions also represent true movement disorders, with hypokinetic and hyperkinetic components. Disruption of motor command execution causes paresis, that is, reduced voluntary motor unit recruitment.4 The resulting signs include insufficient movement acceleration or force.4 A paucity of movement ensues with low amplitude and speed. Paresis of the agonist is the only operative mechanism in the hyperacute stages of paresis. In subacute and chronic stages, agonist paresis becomes combined with increased antagonistic resistances, with muscle and then additional neural impairments, which also contribute to the hypokinetic movement disorder. The individualization of a muscle disorder because of immobilization in unstretched position in the context of paresis is relatively recent. Following stroke, lesion load in the brain and reduced active movement at 48 hours predict later hyper-resistance to stretch from some muscles, with risks of limb deformities and pressure sores.5-8 In his volume Internal Affections, Hippocrates emphasized the need to frequently mobilize the bed-ridden patient—regardless of brain lesion—and the poor prognosis of movement loss from insufficient mobilization.9 In the late 18th century, the anatomist Vicq d'Azyr reported fatty transformation inside immobilized muscles, the outside aspect of the muscle being unchanged.10 The concept of a condition later called disuse atrophy was born, with early measures showing reduction of muscle mass, but no report at the time on muscle extensibility changes.11 It was not immediately understood that disuse in the stretched position was partly protective for the muscle.11 Muscle extensibility may be defined as the amount of muscle lengthening obtained for a given stretching force.1, 4 The first animal studies specifically monitoring muscle extensibility after muscle immobilization in unstretched position were performed in the 1970s.12, 13 Within days of immobilization in unstretched position, muscle extensibility decreases in parallel with sarcomere loss.12-15 From a pathogenetic point of view, these muscle changes are initiated by profound modifications in gene transcription, with falling protein synthesis within 2 hours of the unstretched immobilization onset.16, 17 In parallel, centro-nucleation occurs within the diseased muscle fiber.18, 19 Surrounding collagen bundles stiffen, forming a modified muscle extracellular matrix (ECM) with thickened perimysial cables, enhanced collagen cross-links in endomysium, causing major losses of extensibility.15, 18-20 Of note, associated neurotomy or radicotomy partially protect the unstretched muscle from these changes.11, 13 Central neurophysiological consequences emerge later as any stretching forces are more readily transmitted through stiffer muscles, causing spindle stimulation enhancement and excitatory afferent bombardment that will later tend to increase motor neuronal excitability (see below).21 The bed rest that is generally prescribed in the setting of severe acute lesions of brain or spinal cord pathways induces sensori-motor restriction22 and leaves some muscles (eg, shoulder and knee extensors and plantar flexors) unused, but most importantly unstretched, that is immobilized in the short position.23 In the context of severe paresis of descending origin, no compensatory movement occurs, no peripheral nerve lesion preserves from these pathological muscle changes and muscle vulnerability to unstretched immobilization is maximal. Therefore, within the generic concept of disuse atrophy, a specific unstretched muscle stiffening is acutely operative for those muscles left in short, unstretched position in the context of paresis.12-15 Yet, this early evolving muscle disorder has long remained referred to as secondary muscle changes in the literature on spastic paresis, suggesting that these would be mere consequences of motor neuronal overactivity.1, 5 However, the acute muscle changes described above actually precede the emergence of spasticity or any other form of overactivity24; it is unfortunate that they will indeed be further exacerbated by the later emergence of motor neuronal overactivity.2, 25 In spastic paresis, rapidly developing muscle alterations and later emerging forms of motor neuronal overactivity eventually potentiate each other,21, 25, 26 therefore, the term spastic myopathy was coined to characterize the muscle disorder.27 Spastic myopathy increasingly contributes to movement reduction in subacute and chronic stages of spastic paresis.1, 4, 26 Importantly, spastic myopathy is genetically and biomechanically treatable by remobilization, that is by muscle stretch, particularly if applied early following the onset of unstretched immobilization.12, 14, 16, 17, 28 In the weeks following the onset of paresis and the development of spastic myopathy, plastic neural mechanisms occur, whereby stretch-sensitive muscle overactivity emerges to cause a third, general mechanism aggravating hypokinesis.1, 2, 5 Following damage to corticospinal pathways, there are alterations in spinal circuitry and increased involvement of diffusely projecting excitatory brainstem motor pathways together with aberrant sprouting onto motoneuronal membranes at each segmental level (see neurophysiological mechanisms below).1, 2, 29 Among the resulting forms of motor neuronal overactivity, a specific impairment of motor command deserves specific mention for its capacity to worsen movement hypokinesis and for its high degree of associated-disability. Spastic co-contraction, an antagonistic co-activation first noted by Nothnagel in the 19th century,30 has been defined as a misdirection of the volitional supraspinal drive during agonist command, which abnormally recruits antagonist motor units.2, 30, 31 In spastic co-contraction, abnormal antagonist recruitment occurs regardless of any stretch (or of any peripheral stimulation, ie, this is not a reflex) but is enhanced by stretch, hence the term spastic co-contraction.2, 30, 31 This form of overactivity directly impedes, and may sometimes reverse the desired voluntary movement, therefore, contributing to the hypokinetic component of the spastic movement disorder.30, 31 A number of other hyperkinetic movement abnormalities gradually emerge in spastic paresis. Spastic dystonia is a phenomenon observed at rest, first described and named by Denny-Brown following ablations of various areas of motor and premotor cortices in monkeys.32 This is another important form of motoneuronal overactivity, defined as an unwanted, prolonged, involuntary muscle activation at rest, in the absence of stretch or voluntary effort.32, 33 However, its level of severity is also impacted by how much tension is applied on the dystonic muscle.33 Spastic dystonia causes abnormal posturing with gradually increasing deformities.32, 33 Extra-segmental co-contractions are common in spastic paresis. They are known as synkinesis, dyssynergias, or associated reactions.29 Synkinesis has also been related to increased involvement of diffusely projecting excitatory brainstem motor pathways.29 Spasms are defined as sudden and brief involuntary muscle contractions at rest, related in particular to motor neuronal hyperexcitability34; they particularly develop following spinal cord lesions. Clonus is another form of hyperkinesis that may become troublesome in functional situations, in the context of severe spasticity that is major enhancement of stretch reflexes.1, 2, 33, 34 Spastic dystonia, synkinesis, spasms, and clonus increasingly become disabling and highly visible hyperkinetic components of the spastic movement disorder. Understanding the exact mechanisms of lesion-induced plasticity underlying the phenomena described above faces the fundamental challenge of connecting two fields: that of animal research—with data most often obtained from small quadrupedal animals—characterized by direct neurophysiological or ultrastructural investigation techniques, but usually rudimentary clinical analysis, and that of human research with opposite characteristics, in which disentanglement between the clinical phenomena of spastic paresis may be relatively advanced today, but where only indirect physiological investigations can be carried out, precluding direct demonstration of causal relationships between basic mechanisms and clinical events.34 In addition, the putative mechanisms mentioned below may be themselves causally related to one another. As a consequence, what follows are mostly hypotheses, which can be appreciated by their smaller or greater likelihood. These hypotheses may be classified into spinal and supraspinal mechanisms. In the months that follow a higher neural injury, neuronal circuits distal to the injury adapt to sudden disfacilitation and inactivity by mostly increasing intrinsic excitability. The time course of excitability recovery is increasingly protracted from simple to complex nervous systems, from frogs to small rodents to humans.35 At the spinal level, plastic changes that potentially contribute to spasticity, spastic dystonia, and spasms in humans include the recovery of mono-amine sensitive persistent inward currents (PICs) contributing to plateau potentials in α motoneurons,35-37 enhanced secondary spindle stimulation by stretch transmitted through stiffer muscles and increased facilitatory group II effects on the lower limb extensors,21, 38, 39 decreased presynaptic inhibition on Ia afferents,40-43 decreased homosynaptic depression,43-48 and decreased Ib inhibition.49-51 The spinal mechanisms that potentially contribute to spastic cocontractions are increased Renshaw inhibition and decreased Ia reciprocal inhibition during effort.52-55 As far as potentially increased input from γ motor neurons, this has not been confirmed in human studies that have used microneurography Ia recordings from nerves to non-shortened muscles only, such as the radial nerve in the upper limb and the peroneal nerve in the lower limb.56-58 Excitatory brainstem descending pathways such as the rubrospinal, vestibulospinal, and medial reticulo-propriospinal pathways, are phylogenetically older and characterized by more diffuse motor command and lesser capacity for rest than the corticospinal pathway.59-63 For the past few decades, studies after unilateral pyramidotomy or spinal hemisection in rodents have demonstrated plastic adaptive sprouting to motor neurons or to facilitatory interneurons—along group II pathways in particular—from excitatory brainstem descending pathways or from the contralesional cortex including with mid-line crossing axons and cues guiding and/or stabilizing newly formed sprouts in the adult, denervated spinal cord.59-63 Molecular changes in the spinal cord of stroke-affected corticospinal tracts comprise an early inflammatory phase with activated microglia in the target area of reinnervating corticospinal motor neurons and a late phase with upregulation of growth-promoting factors, which can influence sprouting response, arborization, and synapse formation, particularly from the contralesional motor cortex.63 Consistent findings have been obtained in human patients.29, 64 In some reviews, it has been suggested that suppression of descending inhibitions could contribute to motoneuronal overactivity in spastic paresis.65-67 Few inhibitory brainstem descending pathways, in particular the dorso-lateral reticulospinal pathway, may indeed exert inhibitory actions on stretch reflexes, as indicated in classic studies by Magoun, then by Lance in intact animals, showing that electrical stimulation of the medial medullary reticular formation indeed inhibits flexor and extensor as well as tonic vibration reflexes.68-70 However, the hypothesis that "spasticity" could emerge because of lesion-induced suppression of these inhibitory inputs from the corticoreticular pathways is more questionable. These assumptions rarely take the issue of time course into account. After the initial state of areflexia that follows a brain or a spinal cord lesion,71 the time course of reflex enhancements in humans is slower than in animals and protracted over weeks or months after most lesions,72 which points to a gradual, plastic phenomenon of sprouting and synaptic formation, as opposed to a lesion-induced disinhibition event.34 Beyond a certain threshold of severity, muscle shortening and stiffening on one side of each joint may "drive" impairments by tonically increasing excitatory spindle afferent activity to the homonymous motoneuron.2, 21 Such reverse muscle-central nervous system action might occur through synaptic sensitization at the spinal level by chronically increased intramuscular tension and, therefore, intensified muscle afferent firing.21, 73 On the side of the shortened and stiffened muscle, motoneuronal hyperexcitability may in turn enhance activation of that muscle, promoting phenomena such as spastic dystonia, synkinesis (causes of hyperkinesis), and spastic cocontraction (cause of hypokinesis). On the opposite side, chronic mechanisms of reciprocal inhibition from the more stiffened muscle may worsen paresis.74 In spastic paresis, all of the phenomena reviewed above—paresis, muscle stiffening, spastic co-contraction, synkinesis, spastic dystonia, and spasms—all coalesce to constitute a composite hypokinetic and hyperkinetic spastic movement disorder, asymmetric around joints, causing cosmetic and functional limitations.75 Classical teaching generally suggests that movement disorders are solely associated with dysfunction of non-pyramidal systems. However, we suggest that the concepts reviewed here provide further insight into the extent and complexity of the mixed hypokinetic and hyperkinetic movement disorder of spastic paresis. In practice, patients at risk (ie, with severe initial paresis) should be identified early and considered for multi-modal programs, involving wearable movement sensors and robotic, physical, medical, or surgical tools including blocking agents such as botulinum toxin, or procedures such as neuro-/radicotomies.6-8, 76 Among the physical strategies, alternating movement exercises reduce stretch reflexes and cocontractions in short-term studies.48, 77 As reviewed above, other techniques such as prolonged muscle remobilization (ie, long-term stretch programs) may partially reverse spastic myopathy, particularly if commenced early.12, 14, 16, 17, 28 Guided self-rehabilitation contracts combining chronic self-stretch and maximal alternating efforts have shown efficacy over the long term in controlled studies.78 We hope to have provided convincing arguments to support that spastic paresis is a movement disorder because it fits twice into the definition, being a neurological condition that causes both "excess movement" and "a paucity of voluntary and involuntary movements." We also briefly appraised the large number of potential therapeutic avenues for these patients. It is notable that study and care of patients with spastic paresis were predominantly conducted by neurologists until the 1960s when the emerging rehabilitation medicine gradually took ownership of the domain. Following the concept of the International Medical Society for Motor Disturbances (ISMD), a parent organization of the Movement Disorders Society (MDS),79 the MDS Spasticity Study Group was founded, involving neurorehabilitation specialists, movement disorders neurologists, neurophysiologists, and biomechanical engineers. We join in this collaborative group, animated by the commitment to exploring novel approaches to investigate, diagnose, and treat the spastic movement disorder. There is a logical synergy between these efforts and ongoing MDS teaching activities, on botulinum toxin therapy in particular. We also believe that the "Movement Disorders expertise" may prove precious in conjunction with the physiatry care of patients with this condition, and that it would be both a challenging and rewarding strategy for part of the Movement Disorders community to tackle again the complexity of the syndrome of spastic paresis. J.M.G. received consulting honoraria by Ipsen, Fastox, Merz, and AbbVie. J.W. received consulting honoraria by AbbVie, Ipsen, Medtronic, and Merz. D.S. received research grant support from Allergan/Abbvie and Merz, and consulting honoraria from Allergan/Abbvie, Merz, and Ipsen. D.D. received honoraria for services provided to Allergan, Ipsen, Merz, Lanzhou Institute of Biological Products, Medy-Tox, Revance, Desitin, Syntaxin, AbbVie, Medtronic, St Jude, Boston Scientific, Almirall, Bayer, Sun, Teva, UCB, and IAB-Interdisciplinary Working Group for Movement Disorders; and is a shareholder of Allergan and holds patents on botulinum toxin and botulinum toxin therapy. K.E.A. received royalties from Springer Publishing, Gul Coast Ultrasound; and honoraria from American Academy of Electrodiagnostic and Neuromuscular Medicine, Catalyst Medical Education, and The Cleveland Clinic Foundation. E.L. has received research grants from the National Medical Research Council, Singapore, the Singapore General Hospital, and the National University of Singapore. He receives royalties from McGraw-Hill and has done consulting work or received academic funds from Allergan, Revance, Novartis, and Ipsen. B.B.S. has received honoraria for lectures from Ipsen, Merz, Desitin, Allergan, AbbVie, UCB Pharma, Medtronic, Nordic Infucare, Berlin-Chemie AG, Orion Pharma, and Bial; received honoraria for participating in Advisory Boards from Ipsen, Medtronic, Allergan, Merz, Almirall Nordic, Innoventa Medica, and AbbVie; and received unconditional grants and funding for Investigator initiated clinical trials from Allergan, AbbVie, Nordic Infucare, Merz, Desitin, Toyota Foundation, and Danish Parkinson Association. (1) Writing of the First Draft; (2) Review and Critique. J.M.G., J.W., D.D.: 1, 2. All other co-authors: 2. Katharine Alter, Mount Washington Pediatric Hospital, An Affiliate of The University of Maryland System and Johns Hopkins Medical Institution, Baltimore, MD, USA Bo Biering-Sørensen, Movement Disorder Clinic, Spasticity clinic and Neuropathic Pain and CRPS Clinic, Neurological Department, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark Tae Mo Chung, Complexo Hospital das Clinicas, Instituto de Medicina Fisica e Reabilitação, São Paulo 04116-030, Brazil. Julius P.A. Dewald, Department of Physical Therapy and Human Movement Sciences, Department of Biomedical Engineering, Northwestern University, Chicago, IL, USA Dirk Dressler, Head of Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany Alberto Esquenazi, The John Otto Haas Endowed Chair and Professor Department of PM&R Chief Clinical Officer Jefferson Moss-Magee Rehabilitation, Director Gait and Motion Analysis Laboratory and Regional Amputee Center Jean-Michel Gracies, Service de Rééducation Neurolocomotrice, CHU Henri Mondor, APHP and UR BIOTN, Université Paris Est Créteil (UPEC), Créteil, France Jorge Hernandez Franco, National Institute of Neurology and Neurosurgery, CDMX, México Robert Jech, Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine Charles University and General University Hospital, Prague, Czech Republic Ryuji Kaji, Tokushima University Graduate School of Medicine, Tokushima, Japan Lingjing Jin, Department of Neurology, School of Medicine, Tongji Hospital and Shanghai Sunshine Rehabilitation Hospital, Tongji University School of Medicine, Shanghai, China Leonard Li, Division of Rehabilitation, Department of Medicine of Tung Wah Hospital Hong Kong, Hong Kong, Hong Kong Erle Chuen-Hian Lim, Division of Neurology, University Medicine Cluster, National University Hospital, Singapore Preeti Raghavan, Department of Physical Medicine and Rehabilitation and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland Raymond Rosales, Metropolitan Medical Center, Faculty of Medicine and Surgery, University of Santo Tomas Manila and Clinical Neurophysiology and Movement Disorders, St. Luke's Medical Center, Quezon City, Philippines John Rothwell, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom Ali Soliman Shalash, Ain Shams Movement Disorders Group, Department of Neurology, Ain Shams University, Cairo, Egypt Areerat Suputtitada, Department of Rehabilitation Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand – [email protected] David Martin Simpson, Clinical Neurophysiology Laboratories, Neuromuscular Disorders Division, Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA Jörg Wissel, Neurology and Psychosomatic at Wittenbergplatz, Berlin and University of Potsdam, Rehabilitation Science and Clinical Exercise Science, Germany Kenny Wong, Gait and Motion Analysis Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong Maximo Zimerman, Laboratory of Experimental Psychology and Neuroscience (LPEN), Institute of Cognitive and Translational Neuroscience (INCyT), INECO Foundation, Favaloro University Buenos Aires, Argentina Data sharing is not applicable to this article as no new data were created or analyzed in this study.