How effective is current pharmacotherapy for motor recovery after stroke?

KEYWORDS:

• Clinical trials
• motor recovery
• neural plasticity
• pharmacotherapy
• stroke recovery

1. Introduction

Stroke is one of the main causes of death and disability worldwide [1,2]. Although the number of stroke survivors has increased thanks to the improvement in acute and subacute management, this has not been paralleled by any significant decrease of the consequences of stroke, including motor function deficit, cognitive impairment, overall disability, and poor quality of life (QoL) [3]. Thus, there is a substantial need for developing novel therapies to improve motor learning and motor recovery, which both represent two main issues in neurorehabilitation.

Targeting brain plasticity after stroke by means of rehabilitation is essential for function recovery [4,5]. Strategies aimed at inducing brain plasticity and modulating brain activity in order to achieve functional goals are essential as well. Despite post-stroke cures and cares made great strides, there is no clear evidence on the role of pharmacological treatment in post-stroke recovery [6–12]. Drugs specifically aimed at acting onto neuroplasticity-based recovery mechanisms may indeed have a significant role in this field. Thus, conjugating rehabilitation and pharmacological treatments may help in better managing stroke survivors and achieving better functional outcomes [8]. Indeed, specific drugs may favor the recovery of the neural pathways and neuroplasticity mechanisms related to cognitive and motor learning (including modulation of central neurotransmitters, synaptic long-term potentiation/depression mechanisms, sprouting and synaptogenesis, dendritic length and density, with synaptic connectivity improvements) [11], thus facilitating the commonly shared mechanisms of action of neurorehabilitation. In other words, drugs can be used as a primer to other treatment strategies, including neurorehabilitation, and non-invasive neuromodulation [8].

The neurotransmitter cascade mediating anti-inflammatory effects, angiogenesis, neurogenesis, and axon and dendritic re-growth may represent an interesting target for post-stroke drugs, taking into account that recovery mostly occurs within the first 3 months following stroke [12]. Specifically, these drugs (including antidepressants, e.g., SSRI, glutamate antagonists, cholinomimetics, e.g., cholinesterase inhibitors, amphetamines, and dopamine agonists, amphetamines and monoamine oxidase inhibitors) can increase motor cortex excitability, as well as LTP-like plasticity magnitude and duration [12]. However, the currently available data show either positive or lacking effects on motor and cognitive improvement in post-stroke individuals [12,13]. In particular, it has been shown that 100 mg LDopa/day significantly boosted motor recovery, also influencing several different non-motor neural systems (including motivation and reward ones), in addition to physical therapy [13]. On the other hand, ropinirole seems to be less effective [13]. Norepinephrine strengths the overall arousal level, with a modulatory effect on executive functions. Modulation of nicotinic cholinergic neurotransmission alters attention, whereas muscarinic receptors play a greater role in cognitive flexibility [14].

There is growing interest for the dietary supplementation or therapy with free radical scavengers in order to protect against post-stroke ischemia-reperfusion injury and modulate the intracellular redox-sensitive pathways. Among the numerous phytonutrients (including flavonoids – quercetin, genistein, and resveratrol- and organosulfur compounds), promising results have been reported when harnessing the antiinflammatory effects of palmitoylethanolamide (a nuclear-factor agonists, endogenous fatty-acid amide), and the anti-inflammatory and antioxidant properties of the flavonoid luteolin, in order to counteract the neuroinflammation mechanisms related to stroke, which limit stroke recovery [15,16]. The contradicting results of the different drugs on post-stroke recovery may depend on the small samples enrolled, the variable time of inclusion, the non-homogeneous clinical outcome criteria and supporting outcome criteria (including transcranial magnetic stimulation and functional neuroimaging) [6]. Nonetheless, SSRI have proven effective to reduce disability and neurological impairment scores in people with stroke [10]. In particular, the Fluoxetine for Motor Recovery After Acute Ischemic Stroke (FLAME) study [6] showed a significant gain on the primary end-point (improvement in the arm/leg Fugl-Meyer motor score) in the patients treated with fluoxetine (20 mg/d). However, results that are more recent do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote functional recovery [17]. However, further studies are required to demonstrate the usefulness, feasibility, and safety of pharmacotherapy to augment post-stroke recovery.

2. Expert opinion

There is growing evidence suggesting that brain plasticity after stroke is the basis for function recovery and rehabilitation. Several pharmacological approaches and non-invasive brain stimulation, as well as physiotherapy and rehab innovation technology, have been demonstrated to induce brain plasticity and modulate brain activity in order to achieve functional goals. However, pharmacological treatments, including amphetamines, dopamine agonists, cholinomimetics, and, above all, SSRI have proven effective in boosting post-stroke functional recovery in experimental setups. Thus, future trials might be able to confirm the external generalizability of these findings to the different stroke populations, as well as to identify those subgroups that may benefit from pharmacotherapy.

It is our opinion that pharmacotherapy for post-stroke recovery should be based on the pathophysiology of the disease. Indeed, the knowledge of both adaptive and maladaptive neuroplasticity mechanisms at individual level (measured using EEG, TMS, and fMRI, inflammatory mediators or neurotrophin levels) should be mandatory in order to identify the most appropriate drug and treatment strategy. About that, the knowledge of the potential brain plasticity reservoir after brain damage constitutes a prerequisite for an optimal pharmacological and rehabilitation strategy. A neurophysiologic assessment focusing on a bimodal balance–recovery model (using a rapid paired associative stimulation protocol) to more objectively predict functional motor outcome and personalize robotic rehabilitation training may be helpful [18].

Pharmacotherapy for post-stroke recovery should be started as soon as possible and last up to, at least, the first 3 months after stroke onset. In fact, the most significant neuroplasticity changes occur within this temporal window. Whether treatment duration should be tailored proportionally to the deficit degree in order to avoid any ceiling effect remains to be clarified.

Moreover, as non-invasive brain stimulation have shown to enhance physical therapy for stroke motor rehabilitation, combining this neurophysiological approach with psychoactive drugs may further improve functional recovery. However, the possibility of a mutually enhancing effect, and the issue of ‘who primes who’, is still a matter of debate, given that more information is needed to determine what is the real process behind the possible summatory effect.

Last, identifying commonly used outcome measures is central to build valid clinical trials to assess the usefulness of pharmacotherapy. We believe that scales aimed at estimating the global changes in the daily life of the patients, such as the Functional Independence Measure or Stroke Specific Quality of Life Scale, should be preferred. In fact, the ultimate goal of rehabilitation is the functional outcome and QoL improvement, as well as family, social, and work reintegration.

Thus, we encourage the development of a holistic approach to stroke recovery that conjugates stroke neuroprotection (i.e., acute and subacute pharmacotherapy) with neurorehabilitation and neuroplasticity pharmacotherapy. This could lead to greater benefits for the patients who are prone to such combined approach based on their neurophysiological profile.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.