Drugs https://doi.org/10.1007/s40265-020-01310-2 REVIEW ARTICLE Therapeutic Strategies to Treat or Prevent Of Episodes in Adults with Parkinson’s Disease Nirosen Vijiaratnam1,2 · Thomas Foltynie1,2 © Springer Nature Switzerland AG 2020 Abstract Parkinson’s disease is a chronic, neurodegenerative disease, which manifests with a mixture of motor, cognitive and behav- ioural symptoms. Levodopa is the most efective antiparkinsonian treatment to date, although chronic use engenders a mixture of complications in a substantial proportion of patients. Amongst these is the occurrence of episodes of worsening symptoms—‘of’ phenomena. These episodes can manifest with either motor or non-motor symptoms or a combination of these features and have been found to have profound impacts on patients’ quality of life. Although preventative measures are poorly evidenced, avoiding excessive total daily levodopa intake in selected populations that are deemed to be of a higher risk for developing these episodes warrants further exploration. Methods to improve levodopa bioavailability and delivery to the brain are currently available and are of value in addressing these episodes once they have become established. These include modifcations to levodopa formulations as well as the use of complimentary agents that improve levodopa bioavailability. The deployment of device-assisted approaches is a further dimension that can be considered in addressing these debilitating episodes. This review summarises the clinical manifestations of ‘of’ phenomena and the current approaches to treat them. Although we briefy discuss clinical advances on the horizon, the predominant focus is on existing, established treatments. 1 Introduction Key Points Parkinson’s disease (PD) is the second most highly preva- ‘Of’ phenomena in Parkinson’s disease commonly occur lent neurodegenerative condition and results in substan- as a result of long-term levodopa use and can have a tial patient morbidity and care-giver burden [1]. Although profound impact on patients’ quality of life. motor features such as bradykinesia, rigidity, postural Avoiding inappropriately high total levodopa daily dos- instability and rest tremor have become synonymous with age in high-risk cohorts could potentially mitigate their the disease, patients with PD also experience a range of risk of occurrence. non-motor symptoms (NMS), which also impose nega- tively on quality of life (QOL) [2, 3]. In patients sufering from ‘of’ phenomena, fractionating Dopaminergic defciency remains a key aspect of the levodopa dosages, the addition of adjunctive agents (e.g. pathogenesis and clinical manifestations of the disease dopamine agonists, monoamine oxidase-B inhibitors, [4], therefore treatment approaches targeting replacement Catechol-O-methyltransferase inhibitors) or the introduc- of dopamine remain paramount. L-dopa (3, 4-dihydroxy- tion of device-assisted therapies (apomorphine infusion, L-phenylalanine), was engineered to achieve this outcome deep brain stimulation, levodopa-carbidopa intestinal over 50 years ago and still remains the gold standard for gel) can signifcantly improve symptom burden. symptomatic management of PD today [5, 6]. This mol- ecule is converted to dopamine by the enzyme aromatic amino acid-decarboxylase (AADC) largely upon cross- * Thomas Foltynie [email protected] ing the blood–brain barrier. This increases presynaptic dopamine concentrations, synaptic release of dopamine 1 Department of Clinical and Movement Neurosciences, UCL and therefore post-synaptic dopamine receptor stimula- Queen Square Institute of Neurology, London, UK tion in the basal ganglia with resultant improvements to 2 The National Hospital for Neurology and Neurosurgery, symptoms [7–9]. Queen Square, London, UK Vol.:(0123456789) N. Vijiaratnam, T. Foltynie The benefcial efects of L-dopa replacement, although The occurrence of slowness or immobility in a patient’s substantial, tend to wane as the disease progresses. The waking hours prior to the frst medication dose is considered numerous explanations for this will be discussed in detail an early morning ‘of’ state (EMO). This is related to low later. The net result is of an increasing frequency of rapid plasma levodopa levels from a lack of overnight medication. and, at times, unpredictable cycles between good therapeu- The term delayed ‘on’ is a further term often used to tic motor responses (‘on’ states), poorly controlled symp- describe the lengthy latency for a levodopa dose to start toms (‘of’ states)- known as motor fuctuations (MF) and working and can commonly occur with the frst morning involuntary movements (dyskinesia), collectively consid- dose or after a meal [14]. ered as motor complications. There is an increasing aware- In contrast, a dose failure or no ‘on’ refers to times when ness that non-motor fuctuations (NMF) can also occur and the medication fails to work. mirror levels of dopamine release, which can be harder to When the symptoms experienced during ‘of’ states are of detect because they are less obviously manifest to carers a non-motor nature, these can be referred to as a non-motor or clinicians [10, 11]. ‘of’ state, or non-motor fuctuation (NMF) [15]. Fluctuations are a major source of disability and result The constellation of motor symptoms experienced by in a substantial reduction to QoL. Modifying treatment patients in the ‘of’ state is broad and variable. Although approaches to prevent or improve fuctuations have there- some report a mixture of slowness, stifness, incoordina- fore become a major focus of therapeutics in PD. Here, tion or reduced dexterity and muscle cramping, others expe- we aim to provide an overarching view of these occur- rience difculties in their ability to stand up, balance, or rences and the principles and specifc therapies currently even swallow. Patients can also sufer changes in their voice utilised in their management. This review will focus on and breathing while experiencing posturing (dystonia) in the ‘of’ state and does not encompass specifc techniques their hands, feet or legs. On occasion, a profound worsen- employed for the management of dyskinesia although the ing of tremor and the emergence of gait freezing can be majority of treatments described, potentially provide over- seen [16]. The non-motor symptoms commonly reported lapping benefts for both ‘of’ periods and dyskinesia. can be divided into neuropsychiatric, autonomic and sen- sory domains. Neuropsychiatric symptoms can manifest 1.1 Clinical Characteristics with fuctuations in cognition, attention, and mood (anxiety, depression, apathy). Autonomic symptoms on the other hand While subtle variations in PD motor severity are not uncom- comprise altered sweating, light headedness, abdominal mon, abrupt “On–Off” phases in the setting of chronic pain or bloating, and urinary urgency. Patients experiencing levodopa therapy are unique to patients with PD and were sensory symptoms report a mixture of visual disturbances, observed soon after the frst introduction of L-dopa therapy pain, dysaesthesia, akathisia and restless legs. A number into clinical practice [12]. A variety of terms have subse- of non-motor endo-phenotypes have also been described quently been coined to describe variations in their nature. and comprise subtypes of either a depressed, anxious, or These diferences are depicted in Fig. 1 and predominant anxious-depressed variety. Though neurobehavioural syn- underlying mechanisms in Fig. 2. dromes [impulse control disorders (ICDs), punding and First, the more gradual transitions in clinical symptom dopamine dysregulation syndrome] are not strictly consid- control noted towards the end of doses are described as ered NMFs, they can masquerade as such considering their ‘wearing of’ phenomenon or end-of-dose deterioration [13]. varying occurrences with L-dopa intake. The phenomenon of anticipation of an impending ‘of’ period-metacognition is a Fig. 1 Schematic depiction of diferent motor fuctuations and their relation to levodopa intake. EMO early morning ‘of’ Treating ‘Of’ Episodes in Parkinson’s Disease Fig. 2 Diferent ‘of’ phenom- ena and varying mechanisms Wearing off Random on-off resulting in their development. EMO = Early morning OFF change to levodopa half life, issues striatal plascity changes, dopamine with pre-synapc storage, post- receptor internalisaon, synapc transcripon abnormalies pharmacodynamic changes OFF Delayed on Dose failures or no 'on' gastric emptying delays, abnormal gastric emptying delays, abnormal intesnal absorpon intesnal absorpon, delays to transport across blood-brain barrier further non-motor manifestation and can worsen the distress commonly noted co-occurrence with MF, NMF can also and severity of the fuctuation [17, 18]. occur in an isolated and heterogeneous manner and pre- Although fuctuations become more prevalent as the date their motor counterpart. While anxiety, fatigue, pain, disease progresses, the frequency noted seems to vary and paraesthesia commonly complicate motor fuctuations, between cohorts, presumably in view of discrepancies their co-occurrence is also common with dyskinesia [28]. in ascertainment approaches. Broadly speaking however, Psychiatric symptoms and pain appear to frequently fuctu- 10% of patients will develop MF annually from the onset ate according to L-dopa replacement, while concentration of initiation of levodopa [19]. Over time, this results in difculties, fatigue, depression and anxiety can persist in a compounded average of approximately 40% of patients the on state