Nonmotor fluctuations in Parkinson’s disease

Methods.

Our inclusion criteria were patients with PD (according to diagnostic criteria of the United Kingdom Parkinson’s Disease Society Brain Bank4) with an MF response to levodopa. The motor complications included end-of-dose akinesia with an “off” period lasting at least 1 hour, “on-off” phenomenon, peak-of-dose and diphasic dyskinesia, and dystonia. Patients with only morning akinesia were not included. The other criteria were the absence of significant intellectual impairment as defined by a Mini-Mental State Examination (MMSE) score ≤24 and correct language comprehension. Sixty-two patients were screened for this prospective study. Twelve were excluded because of either cognitive dysfunction or language barrier. All the patients were interviewed and examined by two neurologists who both examined the initial cohort of patients together in order to ensure the homogeneity of the interview. The severity of the disease was assessed using the Unified PD Rating Scale (UPDRS) including Hoehn and Yahr staging during “on” and “off” states. MMSE and Mattis Dementia Rating Scale were used to evaluate cognitive functions. Beck Depression Inventory was used to assess mood state. Each patient was interviewed with a structured questionnaire about the NMF. This interview consisted of 54 questions about NMF manifestations: 26 dysautonomic, 21 mental, and seven sensory symptoms. These symptoms were reported in several studies and were collected to create the questionnaire.2,3,5-9⇓⇓⇓⇓⇓⇓ For each symptom, the link with the motor state was specified: the patients were asked whether the fluctuating manifestation seemed to coincide with the “on,” pre-“on,” “off,” pre-“off,” dyskinetic state or whether it did not seem to depend on the motor state (e.g., “Have you experienced any transient episodes of drenching sweats during the day in the course of the last few months?”). If the answer was yes, the patient was asked, “Might this fluctuating sweating depend on your motor state?” Prior to these questions, the exact meanings of “on,” “off,” and “dyskinetic state” were defined with the patient. At the end of the questionnaire, the patients were asked to grade the level of disability in each fluctuation subgroup (motor, dysautonomic, mental, or sensory) from 0 (no disability) to 4 (maximum discomfort) and they were asked which fluctuation category—motor or nonmotor—was the most incapacitating. The questionnaire was administered during the “on” state for the sake of the patients’ comfort. The frequency of each NMF was determined. Statistical analysis was performed using nonparametric tests. First, a Spearman rank test was performed to determine whether there existed a correlation between the level of disability and the number of symptoms in each of the NMF subgroups. A Mann-Whitney test was then performed to determine whether there existed a correlation between the presence of one specific symptom and the level of disability. Lastly, the correlation between the main characteristics of the population (age, sex, pattern of the disease (akineto-rigid, tremor, or mixed), duration of the disease, duration of dopatherapy, levodopa-equivalent daily dose calculated as outlined in the literature,10 Hoehn and Yahr state, Schwab and England score, UPDRS part III score during “on” and “off” states, MMSE, Beck Depression Inventory, Mattis Dementia Rating Scale), and the number of NMF and the disability engendered were analyzed in each NMF subgroup using Mann-Whitney, Kruskall Wallis, and Spearman rank tests. Two-sided p values < 0.05 were considered significant.

Results.

Details of the main characteristics of the population are given in table 1. Table 2 gives the various types of motor complications. The mean duration time for the interview was 2 hours. All the patients declared that they had NMF and most of them had had a combination of symptoms belonging to two or more NMF subgroups. Three patients (6%) had no dysautonomic fluctuation and five had no sensory symptom. All the patients described mental fluctuations. The most frequent NMF were anxiety (66%), drenching sweats (64%), slowness of thinking (58%), fatigue (56%), akathisia (54%), and irritability (52%) (table 3).

Discussion.

In this prospective study based on a structured questionnaire, all the patients with motor complications had experienced NMF of various kinds, including dysautonomic, cognitive/psychiatric, and sensory/pain according to a recognized threefold system of classification.2 Although NMF have been described for >20 years,1 they tend to be underassessed. In addition, few data are available about their prevalence in general. To our knowledge, only one previous study has been conducted on the prevalence of NMF.3 The authors reported that only 17% of the patients with fluctuant PD studied had NMF. These results are not in line with ours, but they were obtained using different methods, based on the use of a single question with an open answer (“Tell us about any symptoms that are associated with the ‘off’ state”).

Here we administered a structured questionnaire about a wide range of symptoms that can be experienced in any type of motor state. This difference between the approaches used may explain the discrepancy between the results obtained.

It is not easy to compare our results with other data in the literature, because most studies on nonmotor symptoms in PD, whether fluctuant or not, were based on one nonmotor sign of a specific kind, such as mood fluctuations, fatigue, pain, or dyspnea.11-14⇓⇓⇓ However, as regards the NMF most frequently described by the patients, our results are in agreement with those of other studies. Anxiety was the NMF most frequently reported here by the patients (66%). Similar results were obtained in a study based on anxiety in patients with PD with “on-off” MF.15 Fluctuant anxiety is preferentially associated with the “off” state (91%) as previously reported by other authors.16 Its presence is correlated with the grade of disability generated by NMF. As other authors have noted, anxiety and mood fluctuations can be more impressive than MF.2

Parkinson himself in 1817 reported autonomic dysfunction in PD, and a variety of fluctuating symptoms has been described since then.17 These include changes in blood pressure,7 dyspnea,14,18⇓ stridor,19 abdominal bloating,3 anismus,20,21⇓ facial flushing,3 bladder dysfunction,22 and drenching sweats.8,23⇓ These fluctuations are mainly associated with the “off” state but also with peak-of-dose dyskinesia.8 Drenching sweats were the second most frequent NMF reported (64%). As described by other authors, this symptom occurred mostly during the “off” state (62%) but could also occur during severe dyskinetic states (18%).8,24⇓ In this study, patients with severe disease who were taking a high dose of levodopa reported a significantly higher level of disability induced by dysautonomic fluctuations.

Concerning cognitive fluctuations, 58% of the patients we studied described cognitive slowing occurring during the “off” state. A variety of cognitive fluctuations have been reported so far, but their analysis has given rise to controversy.25-29⇓⇓⇓⇓ Furthermore, in our study, patients described only subjective symptoms that are difficult to measure. Further studies are therefore required to correlate these subjective signs with a pathologic cognitive process on the basis of neuropsychological methods of assessment.

Fatigue is a common symptom in PD. Fifty-six percent of our population reported a fluctuating sensation of fatigue during the “off” state. This result is in agreement with other studies describing the high frequency of this symptom and the disability it entails.12,30⇓

Among the sensory fluctuations, akathisia was reported to be the most frequent by 54% of the patients. Another study found a prevalence of 43% (pure akathisia and restlessness), but akathisia did not depend on any specific motor state.31 Our group of patients reported having akathisia mostly during the “off” state, as in another study.13 Sensory phenomena may cause greater distress than motor symptoms.32 In our study, six patients reported that the most incapacitating type of fluctuations was the sensory ones.

NMF are generally linked to MF. Very few patients stated that some NMF, such as pyrosis, could also occur regardless of their motor state. The level of disability induced by NMF, especially in the dysautonomic and sensory subgroups, was found to be correlated with the severity of the disease. It thus emerges that patients are likely to have more NMF if they have severe PD. This raises questions as to the physiopathology of these NMF. The fact that they are linked to the MF and the generally good response to dopaminergic treatment reported by the patients suggest that the dopaminergic system may be strongly involved. The dopaminergic system is known to either directly mediate or modulate some nondopaminergic systems such as the serotoninergic system in the case of mood fluctuations33 and the adrenergic system in that of dysautonomic fluctuations.23

The aim of this study was to quantify the frequency as well as the severity of NMF in patients with PD. Unexpectedly, 28% of the patients stated that NMF resulted in a greater level of incapacity than MF. Similar results were obtained in a preliminary study on 35 patients.34 This high percentage points to the need for NMF to be more widely recognized. In addition, some symptoms such as dyspnea, abdominal pain, or chest pain can mimic respiratory, gastrointestinal, or cardiac emergencies. Recognition of these fluctuations as part of PD has important implications. It would help to avoid unnecessary investigations and useless treatments, as most of these severe NMF respond to levodopa or subcutaneous injections of apomorphine.

This study has methodologic shortcomings that must be considered when interpreting the findings. Because it was based on the use of a questionnaire, the symptoms described were subjectively assessed. However, the two neurologists who administered the interview could assist to some “off” state and were thus able to assess whether the patients’ descriptions were accurate. During some “off” periods, e.g., one patient had severe dyspnea associated with precordialgia and high blood pressure. All the cardiac and respiratory test result results were still negative. These disabling symptoms disappeared with apomorphine injection. This patient had previously been admitted three times to an intensive care unit. He stated that dysautonomic fluctuations produced a greater degree of disability than MF. Further studies are now required on a larger population in order to confirm the validity of these results, and the assessment of NMF should become part of regular clinical practice.

The findings obtained in this study show a high prevalence (100%) of NMF involving a wide range of symptoms in patients with PD with MF. To optimize our care, recognition of these NMF is important because they are responsible for a greater level of disability than MF in 28% of all patients with parkinsonism.