Can Spasticity Be Prevented? Insights from Preclinical and Clinical Evidence

Spasticity is a common and disabling consequence of central nervous system injury that evolves progressively over time. Although traditionally viewed as an unavoidable sequela, emerging preclinical and clinical evidence suggests that spasticity may be preventable or mitigated through early, targeted interventions. This article explores the pathophysiology and natural history of spasticity across multiple conditions (stroke, spinal cord injury, traumatic brain injury, cerebral palsy, and multiple sclerosis), reviews early identification strategies, and critically examines preclinical and clinical data supporting spasticity prevention.

Key points

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Spasticity is a maladaptive response to an upper motor neuron injury but may be modifiable with early interventions.
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Early identification of individuals at high risk for developing problematic spasticity enables timely, early, targeted intervention.
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Preclinical studies in spinal cord injury and stroke models demonstrate that early pharmacologic, neuromodulation, and activity-based treatments can reduce or prevent spasticity.
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Clinical evidence supports early use of botulinum toxin, neuromuscular electrical stimulation, and transcranial magnetic stimulation to mitigate poststroke spasticity.
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Multimodal strategies, initiated during the acute or subacute phase of injury, may prevent long-term complications such as contractures, pain, and impaired mobility.

Abbreviations

AAPM&R	American Academy of Physical Medicine and Rehabilitation
BoNT-A	botulinum toxin type A
CNS	central nervous system
CP	cerebral palsy
ITB	intrathecal baclofen
MAS	Modified Ashworth Scale
MS	multiple sclerosis
NMES	Neuromuscular electrical stimulation
rTMS	repetitive transcranial magnetic stimulation
SCI	spinal cord injury
SMD	standardized mean difference
SSRI	selective serotonin reuptake inhibitor
TBI	traumatic brain injury
TENS	transcutaneous electrical nerve stimulation
VR	virtual reality

Introduction/background

Our understanding that spasticity develops progressively following central nervous system (CNS) injury can be traced to the very origins of medical thought. As early as the 5th century BCE, Hippocrates described in On the Sacred Disease a constellation of symptoms that resemble what we now recognize as spasticity—progressive muscle stiffness and abnormal posturing following brain insult. Centuries later, with the emergence of modern medicine in the 19th century, Dr. William John Little provided one of the first formal clinical accounts of spasticity evolving over time in children with perinatal complications. His description of what was then termed “Little’s Disease”—now recognized as a form of spastic cerebral palsy (CP)—highlighted a pattern of delayed-onset rigidity and contractures following early CNS injury. Since then, literature has continued to elucidate the dynamic nature of spasticity development after CNS insults, particularly in stroke and spinal cord injury (SCI) populations.

Pathophysiology and Natural History of Spasticity

Spasticity is a common consequence of upper motor neuron injury and arises from a shared set of pathophysiological mechanisms across neurologic conditions ( Table 1 ). ^,^,^,^,^,^,^,^, Central to its development is the loss of supraspinal inhibitory control, particularly from the corticospinal and reticulospinal tracts, which leads to increased excitability of spinal motoneurons and interneurons. This disinhibition enhances reflex responsiveness, promotes persistent inward currents, and facilitates maladaptive plasticity within spinal circuits. ^,^,^,^,^,^,^,^,^, Over time, secondary musculoskeletal changes such as muscle shortening, increased collagen deposition, and joint contractures further exacerbate tone. ^,^,^,^,^,^,^,^, Despite these shared mechanisms, the natural history of spasticity varies depending on the condition. In stroke, spasticity typically develops within days to weeks due to damage to the corticospinal tract and compensatory hyperactivity of the reticulospinal system, resulting in abnormal motor synergies and segmental hyperexcitability. ^,^, Spasticity following traumatic brain injury (TBI) typically develops within days to weeks after the initial insult, often following a brief period of flaccidity or hypotonia. Its severity and distribution vary based on the extent and location of the brain injury. In multiple sclerosis (MS), spasticity evolves over months to years, with its severity fluctuating in relation to disease activity and lesion location. ^, In SCI, spasticity typically emerges weeks to months after an initial phase of spinal shock characterized by flaccidity and areflexia and often stabilizes within a year. ^,^, In CP, spasticity develops in early childhood following static brain injury and may worsen with growth due to secondary biomechanical changes. While all these conditions share a final common pathway involving hyperexcitable spinal circuits and impaired descending control, their distinct timelines, progression, and distribution patterns necessitate individualized assessment and early intervention strategies.

Table 1

Comparison of spasticity characteristics across neurologic conditions

	Stroke	TBI	SCI	MS	CP
Onset	Days to weeks	Days to weeks	Weeks to months	Months to years	Infancy
Progression	May persist or evolve	Variable; may persist or worsen	Stabilizes within 1 y	Fluctuating chronic	Static injury, progressive tone
Distribution	Hemiparetic pattern	Focal or multifocal; often asymmetric	Below the lesion level, variable presentation	Variable (often legs>arms)	Bilateral often symmetric

Early Identification and Risk Stratification

It is important to recognize that not all spasticity is inherently detrimental. In some cases, mild or optimally controlled spasticity may provide functional benefits, such as assisting with standing or transfers, particularly in individuals with profound weakness. However, when spasticity becomes severe, painful, or poorly controlled, it can significantly impair functional independence and quality of life. Problematic spasticity contributes to joint contractures, skin breakdown, pain, sleep disturbance, urinary dysfunction, and increased caregiver burden. ^,^, Despite these consequences, current clinical approaches are largely reactive, initiating treatment only after spasticity becomes problematic in most instances. To reduce long-term morbidity, early identification of high-risk individuals and timely intervention are critical. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) Consensus Guidance on Spasticity Assessment and Management emphasizes the importance of systematic, repeated assessments starting at the time of diagnosis or injury, using standardized measures of muscle tone, range of motion, reflex activity, and functional ability. In stroke, TBI, and MS, risk increases with greater initial motor impairment, sensory deficits, and lesion locations involving the internal capsule, corona radiata, thalamus, or basal ganglia. Additional predictors of stroke include hemorrhagic etiology, left-sided weakness, reduced activity in daily living, and lower Barthel Index scores. ^,^, In MS, the risk is increased with higher lesion burden, progressive disease course, and spinal cord involvement. ^, The AAPM&R consensus guideline emphasizes that immobility and limb immobilization are modifiable contributors to spasticity across all etiologies, and that exacerbating comorbidities, such as infections, pain, and skin injuries, can trigger or worsen spasticity. Risk factors for developing clinically significant or problematic spasticity in patients with SCI include cervical and upper thoracic lesions, motor-incomplete injuries, early return of hyperreflexia or clonus, asymmetric motor involvement, immobility, and the presence of exacerbating factors such as infections, pain, or skin injuries. ^, In CP, early tone abnormalities, delayed motor milestones, and progressive musculoskeletal changes are recognized indicators of evolving spasticity, prompting the need for early interventions. ^,

Ultimately, the goal is not to eliminate all spasticity but to prevent the development of severe, painful, or function-limiting spasticity that compromises rehabilitation and recovery efforts and leads to secondary complications. Early, individualized interventions, before the onset of fixed contractures, offer the best chance to optimize outcomes. With a growing ability to recognize individuals at risk during the acute or subacute phase of neurologic injury, a critical question emerges: can early, targeted therapies modify the course of spasticity before it begins?

Preclinical Evidence: Can Spasticity Be Prevented?

Preclinical studies increasingly suggest that spasticity is not an inevitable outcome of CNS injury, but a modifiable process, particularly when targeted early through mechanistically guided interventions. The most compelling evidence comes from SCI models. In a landmark study by Marcantoni and colleagues (2020), early and sustained administration of nimodipine, an L-type calcium channel blocker targeting CaV1.3, completely prevented the development of spasticity in mice. When initiated within 24 hours of SCI and continued for 6 weeks, nimodipine abolished tonic overactivity and spasms, with effects persisting even after drug withdrawal, suggesting durable remodeling of spinal circuits. In another study, gabapentinoids have been shown to modulate voltage-gated calcium channels, reducing neuronal excitability and inflammation in SCI models. ^, Warner and colleagues reported that early administration of gabapentin promoted motor recovery and reduced spasticity-like features in a rodent SCI model, possibly by altering excitatory synapse formation and central sensitization. Similarly, selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, have been shown to reduce spasticity by modulating serotonergic tone and downregulating 5-HT receptor expression on spinal motoneurons in animal models. In a controlled study using a closed-head TBI rat model, acute intrathecal baclofen (ITB) treatment initiated 1 week post-injury and continued for 4 weeks was shown to block the early onset of spasticity and significantly attenuate late-onset spasticity by reducing velocity-dependent ankle torque and electromyography measures of motoneuron hyperactivity. Additionally, early activity-based therapies have been shown to preserve spinal inhibitory circuits and mitigate reflex hyperactivity, particularly when initiated in the subacute phase in animal models of SCI. ^,^, Although most robust findings stem from SCI models, the shared pathophysiological mechanisms across stroke, TBI, and SCI highlight that early, sustained, and mechanism-targeted interventions can prevent or reduce the severity of spasticity across multiple CNS injury models.

Clinical Evidence: Early Clinical Interventions to Mitigate Spasticity

Preclinical research has firmly established that spasticity is not an unavoidable consequence of CNS injury, but a modifiable process, particularly when addressed early through targeted interventions. These findings raise an important translational question: Can the timing and mechanisms identified in animal models be leveraged to alter the clinical trajectory of spasticity in humans?

Although much of contemporary clinical practice remains focused on managing spasticity after it becomes functionally limiting, there is increasing recognition that earlier intervention may offer substantial benefits. A growing number of studies have begun to investigate whether proactive strategies, initiated during the acute or subacute phases of CNS injury, can delay, attenuate, or even prevent the development of severe spasticity.

In the following sections, we examine the existing literature on early interventions implemented after human CNS injuries to reduce or prevent the development of spasticity.

Early Interventions in Stroke

Given the heightened neuroplastic potential in the early poststroke period, this phase presents a critical window for therapeutic intervention aimed at preventing or minimizing spastic hypertonia. Several modalities, including pharmacologic agents, neuromodulation techniques, and rehabilitation-based strategies, have been investigated for their potential to mitigate early spasticity and its associated complications. The following section summarizes key evidence for early interventions targeting spasticity within the first 3 months after stroke.

Botulinum t oxin t ype A

Early administration of Botulinum Toxin Type A (BoNT-A) (within 2–12 weeks post-stroke) consistently and significantly reduces spasticity, as measured by the Modified Ashworth Scale (MAS) or electromyography, and is more effective than late administration for both spasticity reduction and prevention of secondary complications such as contractures and pain. ^,^,^, Early BoNT-A also slows contracture formation, increases passive range of motion, and reduces the need for splinting, without interfering with recovery of arm function. The American Stroke Association recommends BoNT-A as an important tool in the comprehensive management of poststroke spastic hypertonia, particularly for focal or multifocal involvement. Early, goal-oriented, multidisciplinary intervention is associated with better outcomes and fewer secondary complications. ^,

Neuromuscular and p eripheral e lectrical s timulation

Neuromuscular electrical stimulation (NMES) and transcutaneous electrical nerve stimulation (TENS) offer modest but clinically meaningful reductions in poststroke spasticity when initiated within the first three months after stroke. Meta-analyses indicate that NMES significantly reduces spasticity, as measured by the MAS (standardized mean difference [SMD]: −0.30), and improves joint range of motion. In contrast, TENS yields greater reductions in spasticity (SMD: −0.71) and enhances static balance and gait speed. ^,^,^, Electrical stimulation is most effective when combined with conventional rehabilitation, such as physiotherapy or kinesiotherapy, with the greatest benefits observed in the subacute phase (within 1–8 weeks poststroke). ^, Targeted muscles for NMES include the wrist flexors and extensors, as well as the ankle dorsiflexors and plantar flexors. TENS is commonly applied over peripheral nerves, such as the median and ulnar nerves at the wrist for upper limb spasticity, and the peroneal nerve at the fibular head for lower limb involvement. Some protocols also stimulate antagonistic muscle groups to enhance reciprocal inhibition and promote voluntary movement. ^,^,^,^,

Repetitive transcranial magnetic stimulation

Early repetitive transcranial magnetic stimulation (rTMS), when initiated within the first 3 months after stroke, using typical protocols of 10 to 15 daily sessions and combined with conventional rehabilitation, has been shown to reduce upper limb spasticity and improve motor function. ^,^,^, High-frequency rTMS (eg, 10 Hz) over the ipsilesional motor cortex and low-frequency rTMS (eg, 1 Hz) over contralesional cortex have both demonstrated significant reductions in MAS scores and improvements in Fugl–Meyer Assessment for upper extremity scores compared to sham stimulation, with effects observed after 15 sessions in the early poststroke period. Meta-analyses confirm that the benefits of rTMS on upper limb motor function and spasticity are most pronounced when treatment is started in the acute or early subacute phase, and that regimens of at least 10 sessions are associated with greater efficacy. ^,^,^, One systematic review and meta-analysis by Xu and colleagues included randomized controlled trials where rTMS was initiated within the first 3 months poststroke and using 10 to 15 daily sessions. In this analysis, rTMS did not reach statistical significance for MAS reduction compared to sham, but within-group analyses showed a significant pre–post reduction in MAS (weighted mean difference −0.27), indicating a small but clinically relevant effect on spasticity in the early poststroke period.

ITB is effective for severe, generalized spasticity refractory to other treatments, but its use is generally reserved for the subacute or chronic phase. The American Heart Association/American Stroke Association and the AAPM&R Consensus Guidelines both state that ITB can be considered as early as 3 to 6 months poststroke in refractory cases, but robust evidence for ITB in the early phase (within the first weeks) is lacking. ^,

Other

Newer interventions being tested for their potential role in early spasticity management include the use of virtual reality (VR). One example is the RHOMBUS II feasibility trial, in which stroke survivors in the acute and subacute phases were randomized to receive either usual care or usual care plus a 7 week home-based VR intervention. The gamified rehabilitation system aimed to promote upper limb recovery through self-directed, repetitive movement practice. While the intervention was found to be safe, feasible, and well accepted, it did not demonstrate a measurable effect on spasticity. Specifically, there were no significant differences in MAS scores between the intervention and control groups at follow-up, suggesting that the VR platform did not reduce spasticity more than usual care alone. Participants in the intervention group used the platform for a median of 11 hours over 7 weeks, approximately 94 minutes per week, training an average of 3.2 days per week and completing a median of 10,276 upper limb movements. However, only 12.5% of participants met the recommended rehabilitation dose of 45 minutes per day, 5 days per week, which may have limited the intervention’s overall impact.

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Tags: Physical Medicine and Rehabilitation Clinics of North America Volume 37 Issue 2

Jul 12, 2026 | Posted by drzezo in PHYSICAL MEDICINE & REHABILITATION | Comments Off