Background and objective: Parkinson’s disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.
Parkinson’s disease (PD) is a complex disorder with a wide variety of symptoms that have a negative impact on patients’ quality of life (QoL) and independence for activities of daily living (ADL) [1]. Importantly, PD is clinically heterogeneous, since symptoms and prognosis can be very different among patients [2], so that having a simple classification, which could properly inform about key symptoms at different stages of the disease, would be of great importance. Based on the classic motor symptoms of the disease, the Hoehn and Yahr (H&Y) scale is used to describe the progression of PD [3]. The scale was originally described in 1967 and included stages 1 through 5. It has been modified with the addition of stages 1.5 and 2.5 to help describe the intermediate course of the disease [4]. However, although H&Y is frequently used in clinical practice, in part because it is very simple and easy to interpret, the information it provides is limited to the motor stage. The importance of non-motor symptoms (NMS) has increased over the last years because they are frequent and disabling, and impact negatively on patients’ QoL independently of other variables [5]. Recently, a new classification combining the H&Y and the non-motor symptoms scale (NMSS) has been suggested [6]. According to this scale (H&Y-NMSS), patients with a greater global NMS burden but a lower H&Y stage can have a worse QoL than patients with a higher H&Y stage but a lower NMS burden [7]. Therefore, NMS are frequent even in early stages of PD and impact significantly on QoL.
Ideally, a classification for a neurodegenerative disease should include key symptoms and biomarkers that, if present, imply an important therapeutic decision or have a great prognostic value [8]. Some key symptoms in PD are motor fluctuations, dyskinesia, dysphagia, freezing of gait (FOG), falls, cognitive impairment, psychosis, impulse control disorder, major depression, or autonomic symptoms [9]. In particular, many of these symptoms are present in what has been called advanced PD [10]. However, the definition of advanced PD is too broad and includes patients starting with disabling motor fluctuations at one extreme and patients with dementia in an advanced palliative stage at the other. The CDEPA questionnaire is a valid, reliable, and useful instrument for screening advanced PD [11]. In practice, however, it is somewhat complex and takes time to use, given the controversial, high variability in the definition of advanced PD. Moreover, labeling a patient with advanced PD could have a negative connotation in certain circumstances, such as the COVID pandemic [12]. Alternatively, 5-2-1 criteria (≥5 times oral levodopa tablet taken/day; ≥2 h of OFF time/day; ≥1 h/day of troublesome dyskinesia) is a simple and useful tool for early identification of advancing disease [13,14] but its applicability in all PD patients is uncertain (e.g., older PD patients without clear fluctuations but axial or cognitive symptoms). More recently, MANAGE-PD has been proposed as a simple, clinician-reported, screening web-based tool to identify patients with PD inadequately controlled on oral medications [15]. Again, the application of this tool takes time and does not provide a straightforward clinical picture of a patient’s condition, which limits its value in routine clinical practice.
In this context, we propose a new simple classification that makes it possible to identify key symptoms and monitor the evolution of the disease in patients with PD, including the definition of different stages.
Sixteen movement disorders specialists from Spain participated in this project. A first classification proposal was developed by one of them (DSG) in May 2021. It was initially reviewed by the rest of the neurologists. On 21 June 2021, a telematic meeting of about 2 h was held in which all the points of the project and the classification were discussed by the neurologists. A second version of the classification was proposed and finally, it was consensually approved in October 2021.
The main points approved by all the participants are shown in Table 1. Importantly, it was considered that the purpose of this new classification is to provide a quick visual interpretation of a patient’s condition, both for the doctor who follows him/her regularly and for any other specialist. Moreover, the classification may be used at each clinical visit to monitor the evolution of the patient in terms of symptoms control and disease progression, with a staging established on this basis. Specifically, the TNM classification [16] and the National Institutes of Health Stroke Scale (NIHSS) [17] used in oncology and in vascular neurology, respectively, were considered in the design as models.
The project was planned in two phases. The first phase consisted of reporting a new classification and staging of PD agreed upon by expert neurologists in movement disorders through scientific publication in 2021. The second part would contemplate the development of a study to apply the new classification in patients in clinical practice from the year 2022. A timeline of the project development deadlines is shown in Figure 1.
In the proposed classification, 4 major axes were considered: (1) Motor symptoms; (2) N on-motor symptoms; (3) Cognition; (4) Dependency for ADL. Using the TNM classification as a model, the classification was named as MNCD, such that each letter is the first letter of each major axis.
The first axis considered was Motor symptoms (M), subdivided into 4 defined sub axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor.
For each of the axes, the presence or absence of the symptom is established. Each sub-axis is scored as 1 when symptoms are present and are clinically relevant at the discretion of the neurologist and 0 if there are no symptoms or they are quite minor and not relevant. In the MNCD classification, the number, from 0 to 4, is placed as a subscript next to M: M 0 (no sub-axis with symptoms); M 1 (1 sub-axis with symptoms); M 2 (2 sub-axes with symptoms); M 3 (3 sub-axes with symptoms); M 4 (all sub-axes with symptoms). All types of motor fluctuations (wearing-off, early-morning akinesia, sudden-off, on-off, no-on, delayed-on) and dyskinesia (peak-dose, benefit of dose, diphasic, off period dystonia) should be considered [18]. Axial symptoms for taking in care include FOG, postural instability, trunk posture alterations, dysphagia and dysarthrophonia [19]. Any type of significant disabling tremor (resting, postural, etc.) should be scored as 1.
Using the NIHSS as a model, it is indicated which axis is showing symptoms: e.g., M 2 (1100), a patient with motor fluctuations and dyskinesia but neither significant axial symptoms nor significant tremor; M 1 (0010), a patient with at least one significant axial symptom (e.g., FOG) but without motor fluctuations, dyskinesia and significant tremor; M 1 (0001), a patient with only tremor as a significant disabling motor symptom. In summary, the information about axis 1 would be displayed as M 0-4 (_ _ _ _).
The second axis considered was Non-motor symptoms (N), subdivided into 4 defined sub axes: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders.
Again, for each of the axes the presence or absence of relevant symptoms is established. In the MNCD classification, the number, from 0 to 4, is placed as a subscript next to N: N 0 (no sub-axis with symptoms); N 1 (1 sub-axis with symptoms); N 2 (2 sub-axes with symptoms); N 3 (3 sub-axes with symptoms); N 4 (all sub-axes with symptoms). Each sub-axis is scored as 1 when symptoms are clinically relevant at the discretion of the neurologist; in sub-axis 1 (neuropsychiatric symptoms), depression, anxiety, apathy, visual hallucinations, psychosis, impulse control disorder, etc. [20]; in sub-axis 2 (autonomic dysfunction), cardiovascular (orthostatic hypotension, syncope, supine hypertension, postprandial hypotension), gastrointestinal (constipation, obstipation, nausea, vomiting, early satiety), urinary (urgency, frequency, noctoria, urinary retention, incontinence), sexual (sexual dysfunction, impotence) and other dysautonomic symptoms (anhidrosis, compensatory hyperhidrosis, venous pooling, acral color changes, dry mouth, etc.) [21]; in sub-axis 3 (sleep disturbances and fatigue), physical fatigue, insomnia, fragmented sleep, excessive daytime sleepiness (EDS), periodic limb movements in sleep (PLMS), restless legs syndrome (RLS), sleep apnea, rapid eye movement sleep behavior disorder (RBD), etc. [22]; in sub-axis 4 (pain and sensory disorders), pain and related symptoms, abnormal sensations, vestibular deficits, hyposmia, color vision deficits, etc. [23].
Again, using the NIHSS as a model, MNCD classification would indicate which axis is showing symptoms: e.g., N 2 (1100), a patient with at least one neuropsychiatric symptom (e.g., depression) and one dysautonomic symptom (e.g., orthostatic hypotension) but without relevant symptoms regarding fatigue, sleep, pain and sensory symptoms; N 2 (1001), a patient with anxiety and pain but no other significant NMS; N 3 (1110), a patient with visual hallucinations, constipation, and EDS such as disabling NMS. In summary, the information about axis 2 would be displayed as N 0-4 (_ _ _ _).
The third axis considered was Cognition (C). Cognition was considered by itself as a single axis (without sub-axes) with 3 excluding options (only one option is possible): 0, normal cognition; 1, mild cognitive impairment; 2, dementia. In clinical and research settings, the term ‘mild cognitive impairment’ is applied to PD patients who present cognitive complaints and whose neuropsychological examinations confirm the deficits, but PD dementia criteria cannot be fulfilled due to the lack of overt functional decline related to cognitive impairment [24]. In broad terms, mild cognitive impairment can be defined as a cognitive decline from a previous performance baseline, that is considered abnormal for the patient’s age, but with retention of normal daily functioning [25]. In the MNCD classification, the number, from 0 to 2, is placed as a subscript next to C: C 0 (normal cognition); C 1 (mild cognitive impairment); C 2 (dementia). The information about axis 3 would be presented as C 0-2 (_).
The fourth axis considered was Dependency for ADL (D). Two major groups of ADL have been reported: ‘basic’ activities related to self-care, such as bathing, dressing, eating, voluntary control of sphincters, grooming and walking; and ‘instrumental’ activities, such as light housework, preparing meals, taking medications, shopping for groceries or clothes, using the telephone and managing money [26,27]. Dependency was considered by itself as a single axis (without sub-axes) with 3 excluding options (only one option is possible): 0, independence for ADL; 1, dependency for instrumental but not for basic ADL; 2, dependency for basic ADL.
