The clinical syndrome, described by James Parkinson in his 1817 ‘Essay on the shaking palsy’, and commonly referred to as ‘Parkinson’s disease’ (PD), is characterised by the cardinal features of rest tremor, bradykinesia, rigidity and postural instability, and a variety of other motor and non-motor symptoms.
With ageing and increasing life span of the global population, age-related diseases like PD are receiving increased attention from the scientific community. Neurological disorders are now the leading source of disability in the world, and PD is the fastest growing of these disorders.
The Global Burden of Disease Study estimates that the number of PD case will double from about 7 million in 2015 to about 13 million in 2040, suggesting a potential ‘PD Pandemic’.
While this extrapolation based on future growth of population is just an estimate, it highlights the enormous burden that PD and related neurodegenerative conditions can pose for society.
Clinical syndrome
The clinical criteria of the UK Parkinson’s Disease Society Brain Bank for probable PD require the presence of bradykinesia and one of the following features: rigidity, 4–6 Hz rest tremor, or postural instability; in addition, 3 supportive features are required.
In addition to a variety of clinical rating scales, particularly the Unified Parkinson’s Disease Rating Scale (UPDRS) used to assess severity of the disease, reliable diagnostic, pre-symptomatic and progression biomarkers are being developed to support the diagnosis and to track the course of the disease.
The term ‘prodromal’ PD refers to a phase (up to 15–20 years before onset of motor symptoms) during which clinical signs of disease are not evident but underlying neurodegeneration has started and progressed.
Clinical studies have shown that rapid eye movement sleep behaviour disorder (RBD), depression, olfactory dysfunction, constipation and autonomic dysfunction may be present during this period.
Course of PD from prodromal phase to clinical phase, including levodopa- related complications. PD, Parkinson’s disease; PIGD, postural- instability- gait- disorder; RBD, rapid eye movement sleep behaviour disorder.
Causes of PD
Biologic interaction between genetic, epigenetic and environmental factors. PD, Parkinson’s disease; REM, rapid eye movement.
Pathogenesis of PD
A variety of cellular mechanisms on the background of oxidative stress, coupled with again, lifestyle/environmental and genetic factors contribute to the PD- related neurodegeneration. PD, Parkinson’s disease
Patients present with features of dopamine as well as non-dopamine deficiency syndromes.
Treatment
PD is a complex neurodegenerative disorder with a broad spectrum of motor and non-motor features that require individualised therapeutic approach.
Although a variety of clinical rating scales and other instruments have been utilised in assessing response to various therapies, the UPDRS is used most frequently as the primary outcome measure in various clinical trials.
Levodopa (Carbilev, Sinemet). Most people with Parkinson’s disease eventually need a medication called levodopa. Levodopa is absorbed by the nerve cells in your brain and turned into the chemical dopamine, which is used to transmit messages between the parts of the brain and nerves that control movement
Neuroprotective or disease-modifying therapies
In order to consider disease-modifying therapies, it is critical to recognise the variable slopes of progression in patients with PD, reflecting the clinical (and pathological) heterogeneity of the disease.
An increasing understanding of etiopathogenesis of PD has led to hypotheses about potential neuroprotective strategies that, when applied early (perhaps even in the prodromal phase), may favourably alter the progression of the disease. However, double-blind placebo-controlled trials of potential disease-modifying therapies have been thus far disappointing.
Photobiomodulation therapy, as Neuroprotective
Currently no neuroprotective agents (agents that slow down the disease progression), or drugs, exist for PD. Thus, PBMT can be considered a potential neuroprotective therapy, that may not be able to cure, but slow down progression, in patients with PD.
Why and how does light therapy offer neuroprotection in Parkinson’s disease? Neural Regeneration research, John Mitrofanis, Ph.D, 2017
Surgical treatment
Deep brain stimulation (DBS)
Despite optimal medical therapy, many patients with moderate to advanced disease have a poor quality of life because of fluctuating response, troublesome dyskinesia or levodopa-unresponsive symptoms.
Ablative surgical approaches such as stereotactic destruction of physiologically defined overactive brain nuclei (thalamotomy, pallidotomy) have been largely replaced by DBS using implanted pulse generators. The chief advantage of DBS over ablative lesioning is that the stimulation parameters can be customised to the needs of the patient in order to optimise the benefits.
Thalamic DBS is most frequently used to control high-amplitude tremor in patients with essential tremor, but STN or globus pallidus interna (GPi) are the most frequent targets for DBS treatment of patients with PD with disabling tremor and/or levodopa-related motor complications.
255 patients at seven Veterans Affairs and six university hospitals were enrolled in a randomised controlled trial designed to compare the effects of DBS (STN, n=60; or GPi, n=61) and ‘best medical therapy’ (n=134) after 6 months of treatment.
Patients treated with DBS gained a mean of 4.6 hours/day of on time without troubling dyskinesia, compared with 0 hours/day for patients who received best medical therapy (p<0.001). Furthermore, motor function improved by five or more points on the motor UPDRS in 71% of DBS and 32% of medical therapy patients. This was accompanied by improvements in the majority of PD-related health-related quality of life measures and only minimal decrement in neurocognitive testing.
The overall risk of experiencing a serious adverse event, however, was 3.8 times higher in the DBS than in the medical therapy group (40% vs 11%).
The Role of PhotoBioModulation Therapy (PBMT) in PD
The mechanism that underlies the observed beneficial outcomes of the transcranial photobiomodulation in the patients is not known, although there are 3 possibilities.
First, by direct stimulation, where photobiomodulation is applied directly on the distressed neurons themselves, activating mitochondrial function that then increases both adenosine triphosphate energy and the expression of stimulatory and/or protective genes (Hamblin, 2016; Johnstone et al., 2016; Mitrofanis, 2017).
Second, by indirect stimulation, where photobiomodulation triggers recruitment of a “middle man”, such as cells of the immune and/ or stem cell systems (Figure 1). These activated cells may swarm to the region of distressed neurons and helps them survive and function, by potentially increasing the expression of anti-inflammatory cytokines while decreasing the pro-inflammatory ones.
Third, rather than acting on the distressed neurons through either a direct or indirect stimulation as described above, photobiomodulation may act on other brain regions, for example motor cortex, that then stimulate the neural networks that underpin the behavioural improvements
Transcranial photobiomodulation can reach the rich network of blood vessels in the skin over the cranium and within the meninges to activate immune and/or other cells (Figure 1); indeed, photobiomodulation has been shown to influence immune and stem cell function in experimental animals .
Further, the transcranial photobiomodulation can also reach the motor cortex, which lies superficially in the brain, just underneath the cranial surface (~10 mm; Figure 1).
It is clear that further investigation is required as to which of these mechanisms are involved in generating the benefits of transcranial photobiomodulation in humans, in particular the identity of any circulatory cells that are activated and/or the neural circuits within the motor cortex that are stimulated.
The “hard” scientific evidence that photobiomodulation does indeed change neuronal activity and influence neuronal survival against insult has become irrefutable (Hamblin, 2016).
Photobiomodulation in Parkinson’s disease: A randomized controlled trial [February, 2019]
Luis Santos, Susana del Olmo-Aguado, Pedro L. Valenzuela, Kristian Winge, Eliseo
Iglesias-Soler, Juan Argüelles-Luis, Samuel Álvarez-Valle, Guillermo J. Parcero-
Iglesias, Ana Fernández-Martínez, Alejandro Lucia
Photobiomodulation, which uses non-thermal and non-ionizing light in the visible and infrared spectrum, has been proposed as a potential strategy for improving the symptoms of patients with Parkinson’s disease (PD)
The RCT was conducted from January 29 to the April 6th, 2018.
Patients were randomly assigned to a photobiomodulation or sham (control) group.
Eligibility criteria were: diagnosis of idiopathic PD; stage 1-2 on the Hoehn and Yahr Scale; no neurological condition other than PD; able to stand for 2min and walk 10m without assistance; and no severe dyskinesias or “ON-OFF” phases.
Participants were instructed to maintain their medication and usual activity routine during the study.
They received 18 photobiomodulation or sham sessions for 9 wks. During the sessions they were blindfolded, so that the light signal was not perceivable (the device emits no sound). Sessions lasted 9 min and were administered twice weekly on non-consecutive days.
Photobiomodulation was administered using red light-emitting diodes (LEDs) with a wavelength of 670 nm (which has been proven to penetrate the skull) in six 1-min blocks, alternating the LEDs between the right and left temples and with a 30-sec rest between blocks. This LED location aimed to reach one of the
substantia nigra pars compacta, with death of dopamine-producing neurons in this area being a proposed major pathological substrate associated with PD motor symptom.
Endpoint assessment was conducted by the same researchers the week prior to (i.e., baseline) and after the 9 wk intervention. Post-intervention tests were performed 72-96h after the last therapy session. Baseline and post-intervention tests were conducted while patients were in the medication ON-state (i.e., 1e2h hours after taking their morning or evening dose).
We found no changes over the 9-wk period in the sham group (all p > 0.1). Yet, the photobiomodulation group showed gait improvements (i.e., TMWT, fast rhythm), and a significant between-group difference was found for the mean change (post-intervention minus baseline) in this endpoint.
No other intervention effect was noted, although there was trend towards greater benefits in the TUG test after photobiomodulation
Photobiomodulation improved gait speed in the fast rhythm of the TMWT by 0.33 m/second on average, which is of potential clinical relevance as 0.23 m/second has been identified as the minimal detectable change.
Our Experience using PhotobioModulation therapy in Parkinsons disease
Our findings are in agreement with those of a previous study that reported gait improvements in PD patients after transcranial photobiomodulation, as well as with other preclinical studies that suggest that photobiomodulation could be a potential strategy against neurodegenerative diseases.
UPDRS scales, and clinical symptoms, gait, walking speed, and tremor improve over time, minimum duration, 6 weeks, after commencing therapy, depending on clinical picture, 2-3 times, per week, transcranial, and treatments over the abdomen, in keeping with the GIT-Brain Axis mechanism described.
Maintenance therapy is then commenced, once a week, for 4-6 weeks, then continued depending on individual clinical response, to therapy, thereafter 1 – 2 sessions, monthly.
We have seen improvements in multiple domains, including gait speed, dyskinesia, UPDRS scale, reduction in pain, improved mood, sleep, and less fatigue.
PBMT is aimed at Neuroinflammation, improving cerebral blood flow, mitochondrial function activation, release of Brain Derived Neurotrophic Factor (Stem cell), hence enhancing dopamine release, improving synaptogenesis and reducing neuronal excitotoxicity, all mechanisms of disease progressions, in PD.
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