Upper Limb Nerve Cryoneurolysis is Non Inferior to the Usual Care and Has Therapeutic Add Value in Dealing With Shoulder Pain and Functional Problems Caused by Spasticity and Motor Impairment

Hypothesis and state of the art Spasticity is a common clinical feature in several central nervous system conditions (stroke, traumatic brain injury, spinal cord injury, multiple sclerosis cerebral palsy, etc.). Strictly, spasticity refers to the increased excitability of the phasic and tonic muscular stretch reflexes in the absence of volitional activity observed in patients with upper motor neuron lesion.

Gracies has eloquently explained that spasticity is one of the presentations of the pathological stretch-sensitive muscle overactivity in spastic paresis, the other two being spastic dystonia and muscle cocontraction. The muscle overactivity is a neurophysiological consequence of the motor command disruption and sensorimotor privation which, associated with muscle hypo-mobilization in short position is also responsible for the spastic myopathy . Nevertheless, in the literature, experts use interchangeably these concepts and spasticity is often employed as an umbrella term, a synonym of all the positive signs of the corticospinal (pyramidal) pathway disorder, referring to a broad spectrum of clinical manifestations as disorganization of motor volitional command, loss of motor selectivity, muscle overactivity with co-contractions, muscular synkinesis, aberrant synergic patterns, increased muscular tone, abnormal postures, clonus, deep tendon hyperreflexia, spasms and spastic dystonia.

Spasticity is often associated with sensory impairment. Long lasting spasticity left untreated leads to irreversible anatomical structural changes, including muscular tendon shortenings and imbalances, joint stiffness, or other musculoskeletal deformities as well as pain. For instance, in stroke survivors (2017: 9,53 million persons in EU) spastic paralysis and associated functional loss, along with cognition limitations are the most dramatic consequences that these persons, their caregivers and relatives must deal with. The number of people living with stroke is estimated to increase by 27% between 2017 and 2047 in the European Union, mainly because of population ageing and improved survival rates.

Spastic paresis and muscle hypertonia of the limbs caused by spasticity, expresses in different rigid postures, which, added to sensory impairment and motor control loss, is a source of dysfunction, pain and discomfort, leading to trophic deterioration, skin lesions and disrupted body image with negative impact in self-esteem. In these cases, it can even interfere with providing care for basic daily live activities (transfers, being dressed, hygienic care), and preclude fully social participation of persons having spasticity.

Quantifying the impact of spasticity at the organ level is a well-known issue and controversy still exists in non-instrumental measurements of spasticity and its treatment efficacy. Different scales are widely used with diverse intra and inter examiner variability. The challenge is even greater when there are several joints involved and a composite metric is needed. When evaluating the effects of a specific spasticity treatment, it is pertinent to consider the patients and therapeutic team's treatment goals. Likewise, the changes the treatment strategy might provoke in other dimensions as pain, trophic changes, social participation, self-esteem, caregiver burden, self-care, autonomy, and quality of life should be take into account.

Nowadays, there are several therapeutic interventions to manage functional and structural problems caused by spasticity. These options are usually applied in sequential combined protocols to achieve a balanced outcome between negative and positive functional outputs of a spastic limb. In the framework of the therapeutic escalation, the reversibility of the treatment must be considered. Invasive procedures that act directly or indirectly on the uninhibited muscle stretch reflex loop and are reversible to some degree include: (1) minimally invasive procedures such as intramuscular BoNT-A or chemical peripheral nerve denervation (chemodenervation) with alcohol and phenol, percutaneous tenotomies and (2) more invasive procedures such as neurosurgery (peripheral nerve neurotomy and neurectomy, selective dorsal rhizotomy, intrathecal baclofen pump implantation, and neuromodulation.

Other major invasive and irreversible procedures such as neuro-orthopaedic surgery (tendon transfers, soft tissue lengthening, correction of secondary skeletal deformities, and arthrodesis) may also be performed. Finally, non-invasive interventions exist such as physiotherapy, plaster casts, orthoses, functional electrical stimulation, neuroplasticity interventions, and pharmacological agents .

Most of those therapeutic options are costly in term of health resources (human, financial, operating theatre workflows, expensive pharmacological agents, risk exposure, hospital backlogs), not widely available and, should be addressed in an era of hospital staff shortages, supply chain bottlenecks and strained delivery of care.

In the therapeutical decision-making discussion, weighing the contribution to the active and passive loss of mobility, between the dynamic overactivity of the muscle versus the passive elements is crucial. This can be accomplished by a diagnostic nerve block (DNB). This intervention will knock-off temporarily the uninhibited myotatic stretch reflex, therefore, while the block lasts, the resulting resistance to movement is related to the altered passive viscoelastic properties of the muscle-fascia-tendon unit, and/or to the joint. Therefore, diagnostic motor block rules out structural and rheologic causes of stiffness. and at the same time it can simulate the result of a spasticity therapeutic intervention that targets muscle overactivity.

In a general population of stroke survivors, the prevalence of hemiplegic shoulder pain is approximately 22-23% and in a rehabilitation setting it is 54-55%, a majority of patients present moderate to severe pain and it correlates with reduction in quality of life . The etiology of post stroke hemiplegic shoulder pain is often not clear but it seems that spasticity of muscles controlling the shoulder plays an important role. Pectoralis major, teres major and subscapularis muscles are targets for BoNT-A injection as a treatment for hemiplegic shoulder pain.

Cryoneurolysis (also named cryoablation, cryoneurotomy, cryodenervation) is a biophysical controlled lesion of a peripheral nerve, provoked by focused cold generated by a specific medical device. The lowering of temperature between -30 to -40, is provoked by a cryoprobe creating an ice ball, from surrounding tissular water molecules, around the nerve in a specific location. The procedure is guided by ultrasound, and the cryoprobe can also make sensory and/or motor stimulation to finetune the selection of the targeted nerve.

This technology is indicated in peripheral nerves to create a long lasting locoregional anaesthesia in defined painful conditions. It creates a controlled damage by inducing ischemia in the nerve, leading to an axonotmesis leaving intact the perineurium and epineurium (2nd degree nerve lesion according to Sunderland) and therefore, allowing for a reparative process to undergo without a random proliferation of fibrotic scar and avoiding the neuroma formation. In interventional pain settings, a cryoneurolysis therapeutic session lasts about 30-45 minutes/patient and can be performed in an outpatient clinic.

There are some published preliminary applications of cryoneurolysis in spasticity in humans but still many unanswered questions persist, such as treatment efficacy and tolerance, defining the profile of cryoneurolysis indications and patient selection criteria in spasticity, establishing ideal biophysical parameters (number, duration of freezing cycles, ice ball size and distance from the targeted nerve), interest in targeting mixed peripheral nerves (sensory, motor, vegetative), risk exposure, etc, claiming further clinical investigation. As in interventional pain treatment, cryoneurolysis therapeutic effects in spasticity may wane, at an unknown rate, and it might be needed to repeat the procedure.

In a recent paper analysing adverse effects of cryoneurolysis in the treatment of spasticity in 113 patients (277 nerves), Winston et al state that cryoneurolysis has the potential to be a safe method of treating spasticity. Nevertheless in 7 out of 99 cryoneurolysed mixed motor/sensory nerves, patients developed dysesthesia that lasted a maximum of 3 months. Considering these findings, the investigators use exclusively motor nerves or motor nerve branches on our clinical trial protocol.

The American Academy of Physical Medicine \& Rehabilitation (AAPM\&R) recently published a consensus guidance on spasticity assessment and management, authored by Monica Verduzco-Gutierrez, M.D. et al. This paper eloquently summarizes the current state of the art in spasticity assessment and treatment. Notably, the authors mention cryoneurolysis as a potentially safe treatment for spasticity, though they emphasize that further studies are needed.

Our hypothesis is that ultrasound guided peripheral nerve cryoneurolysis, as a minimal invasive technique acting at the pathologically uninhibited myotatic loop, can be integrated in the therapeutic protocols to treat the shoulder functional limitations and pain caused by spasticity and that cryoneurolysis is not inferior in terms of therapeutic value and is safe and the therapeutic effects might last longer when compared to a standard of care in this condition (BoNT-A intramuscular injection).Risks/Benefits trade-off.

Cryoneurolysis of peripheral nerves offers several advantages for treating spasticity when compared to other therapeutic options. Unlike neurotomy-a surgical procedure-ultrasound-guided cryoneurolysis can be performed in an outpatient setting. This frees up operating theatre availability and reduces the need for specialized staff.

The research team has identified some distinct advantages of cryoneurolysis over intramuscular BoNT-A injections. First, cryoneurolysis has an immediate therapeutic effect and tends to last longer. Moreover, for complex spastic conditions, a systematic, step-by-step approach can be adopted. This involves sequencing cryoneurolysis procedures spaced about a week apart. Such a protocol lets patients witness the outcomes of one cryoneurolysis treatment, undergo further functional evaluation in real-world conditions or a movement laboratory, and if necessary, receive another treatment shortly thereafter to optimize results. This flexibility contrasts with BoNT-A injections, which require a minimum of a three-month interval between sessions. And finally, cryoneurolysis per se is a biophysical phenomenon not implying administration of drugs, without the risks of allergic reactions or antibody formation.

Compared to neurolysis using alcohol and phenol for spasticity treatment, cryoneurolysis offers a distinct advantage as it doesn't cause destruction or induce necrosis in neighbouring tissues such as fascia, muscles, and blood vessels. Moreover, phenol can lead to allergic reactions, neuroma formation, and exhibits caustic properties that can harm tissues.

Like all minimally invasive procedures, cryoneurolysis comes with inherent risks and potential side effects. However, when all safety protocols are diligently followed, these risks are substantially reduced. It's imperative that patients with certain conditions, including cryoglobulinemia, paroxysmal cold haemoglobinuria, cold urticaria, Raynaud's disease, or those with open and/or infected skin wounds, abstain from this treatment. Winston et al75 have highlighted potential complications from cryoneurolysis such as skin infections, bruising, swelling, and dysesthesia.

Dysesthesia, which persists for 4-6 weeks, is exclusively reported in approximately 7% of mixed nerves subjected to cryoneurolysis75. This sensation may arise

• Change in muscle tone muscles controlling the shoulder [Time frame: Baseline, week 1, 4, 12, 24]
• Change in nociceptive pain: Visual analogue scale [Time frame: Baseline, week 1,4,12,24]
• Upper limb fonction - Fugl-Meyer Assessment (FMA) [Time frame: Baseline, Week 24]
• change in Quality of Life [Time frame: Baseline, Week 24]
• Tardieu Modified scale [Time frame: baseline, week 1, 4, 12 and 24]
• Change in neuropathic pain - Douleur Neuropathique 4 (DN4) [Time frame: baseline, week 1, 4, 12 and 24]
• Change in upper limb function - Box and Block Test [Time frame: Baseline, Week 24]