Journal of the Neurological Sciences 320 (2012) 66–71

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Risk factors for freezing of gait in Parkinson's disease

Ana Contreras, Francisco Grandas ⁎Movement Disorders Research Unit, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain

⁎ Corresponding author at: Servicio de Neurología,Gregorio Marañón, C/ Doctor Esquerdo 46, 28007915868339.

E-mail address: fgrandas.hgugm@salud.madrid.org (

0022-510X/$ – see front matter © 2012 Elsevier B.V. Aldoi:10.1016/j.jns.2012.06.018

a b s t r a c t

a r t i c l e i n f o

Article history:Received 23 January 2012Received in revised form 7 May 2012Accepted 27 June 2012Available online 15 July 2012

Keywords:Parkinson's diseaseFreezing of gaitRisk factorsFallsAge at onsetDisease duration

Freezing of gait is an episodic gait disorder that may occur in patients with Parkinson's disease. The risk factorsfor this disorder are poorly understood.To determine the relevant risk factors for this condition, we screened 160 consecutive patients with Parkinson'sdisease for freezing of gait and assessed 36 potentially related variables.Freezers and non-freezers were compared using statistical univariate analysis, followed by bivariate and multi-variate logistic regression, receiver operating characteristics curves and Kaplan–Meier estimates.Seventy-one patients (44.4%) reported freezing of gait. At onset, the mean disease duration was 8.1±6.3 years.Freezers experienced falls more frequently than non-freezers (57.7% vs 23.6%, pb0.001). Disease duration wasthe independent variable most associated with freezing of gait (OR=1.10, 95% CI=1.01–1.19, p=0.020). Itsspecificity was 77%, but its sensitivity was low, and Hoehn and Yahr staging and the UPDRS (part III) scoreshowed similar accuracy to that of disease duration in predicting freezers. Previous antiparkinsonian treatmentsand predominant motor signs (tremor/akinesia-rigidity subtypes) at the onset of Parkinson's disease were notrelated to freezing of gait. Patients who developed Parkinson's disease before the age of 60 years experiencedfreezing of gait earlier than older patients (log-rank, pb0.005).Freezing of gait is a common and disabling motor complication of Parkinson's disease that is related to theprogression of the disease. It is not primarily associated with dopamine replacement therapy andmay occurearly in young patients.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Freezing of gait (FOG) is a short-lasting episodic inability to generateeffective stepping in the absence of any known cause other than parkin-sonism or high-level gait disorders. It is most commonly experiencedduring turning and step initiation and also when the patient is facedwith spatial constraints, stress, and distraction. Focused attention andexternal stimuli (cues) can help the patient overcome the episode [1].Patients usually described FOG as the sensation of their feet beingglued to the floor [2].

FOG is common in Parkinson's disease (PD) and in atypical par-kinsonism such as progressive supranuclear palsy, vascular parkinson-ism and normal pressure hydrocephalus [3]. FOG is one of the causes offalls in patients with PD [4].

Despite the increasing awareness and interest in this disablingphenomenon, the risk factors for developing FOG in PD remain poorlyunderstood. FOG frequently occurs in advanced stages of the disease[5,6], although some patients may experience mild FOG episodes inrelatively early stages of PD [3]. Prevalence of FOG ranges from 7%

Hospital General UniversitarioMadrid, Spain. Tel./fax: +34

F. Grandas).

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in the early stages to 60% in the more advanced stages of the disease[5–7]. FOG has been related to the duration of PD symptoms, the du-ration of levodopa therapy, and the akinetic‐rigid form of PD [2,7].However, FOG seems not to correlate with bradykinesia [8] and haseven been considered a different subtype in PD patients with posturalinstability and gait disturbance [9].

The relationship between FOG and antiparkinsonian medicationsis somewhat controversial. Although levodopa is effective in reducingFOG occurring during off periods, it has been shown to induce FOGduring on periods in some cases. In addition, treatment with MAO-Binhibitors has been associated with a lower frequency of FOG (7),whereas dopamine agonists can produce a higher incidence of FOGthan levodopa in the early years of PD [10,11].

We performed a cross-sectional study of a group of unselectedpatients of different ages and disease duration in order to determinerisk factors for FOG in patients with PD. Our study took into accountmost of the clinical variables potentially associated with FOG.

2. Methods

2.1. Subjects

The study sample comprised consecutive patients with PD whoattended the Movement Disorders Clinic of Hospital UniversitarioGregorio Marañón, Madrid, Spain during a 9-month period. These

67A. Contreras, F. Grandas / Journal of the Neurological Sciences 320 (2012) 66–71

patients were regularly followed with visits to the clinic every 3 to4 months. The diagnosis of PD was confirmed according to the UnitedKingdom Parkinson's Disease Brain Bank [12]. Patients who under-went functional stereotactic surgery for PD were excluded. The localethics committee approved the study and all participants gave theirinformed consent. All patients were interviewed and examined bythe authors. A survey of falls in this set of patients has been publishedelsewhere [13].

2.2. Assessment of FOG

Patients with FOG were identified using the freezing of gait ques-tionnaire [14] by asking them “do you feel that their feet were gluedto the floor while walking, making a turn or when trying to initiatewalking?” (item 1.3). Patients who answered affirmatively were sub-sequently administered the freezing of gait questionnaire in full andquestioned about the time of appearance of FOG episodes since theonset of PD, as well as the circumstances related to the occurrenceof FOG (gait initiation, turning, or on walking) and their relationshipwith on or off states in the case of patients suffering from motorfluctuations. The information obtained from the patients was checkedwith relatives, caregivers and clinical records to ensure accuracy of data.

2.3. Variables

We recorded gender, age, age at onset of PD, initial predominantsymptom (tremor or akinetic-rigid syndrome), disease duration, pres-ence of motor fluctuations and dyskinesias, and the existence of falls.Fallers were specifically questioned about falls precipitated by freezing.

We also recorded treatments with antiparkinsonian drugs includingL-dopa (L-dopa/carbidopa, L-dopa/benserazide, controlled-releaseL-dopa formulations), COMT inhibitors (entacapone, tolcapone), MAO-Binhibitors (selegiline, rasagiline), amantadine, anticholinergics, anddopa-mine agonists (bromocriptine, pergolide, cabergoline, pramipexole,ropinirole, transdermal rotigotine, subcutaneous apomorphine) untilthe onset of FOG or the date of the survey in patients without FOG.Only sustained treatment for more than 2 months at recommendeddoses was considered.

Treatment with benzodiazepines, antidepressants, atypical neuro-leptics (quetiapine, clozapine) and cholinesterase inhibitors was alsorecorded in the same manner.

History of symptoms of orthostatic hypotension (light-headedness,dizziness, weakness on standing from a sitting or lying position)[15] was recorded as was past history of stroke, hypertension, anddiabetes.

All patients underwent neuroimaging studies (cranial computed to-mography, brain magnetic resonance, or both), which were reviewed bya neuroradiologist to identify cases with moderate/severe leukoaraiosisand infarcts of any size and location.

The motor function subscale (part III) of the Unified Parkinson'sDisease Rating Scale (UPDRS) [16] was administered, as were theSchwab and England activities of daily living [17], Hoehn and Yahrstaging [18], Mini Mental State Examination [19], and Tinetti's gaitand balance functional test [20].

The timed get-up-and‐go test [21] was performed and a 10-meterwalk at the preferred speedwas timed, videotaped, and used to calculategait velocity, and step length and cadence.

In fluctuating patients, the UPDRS, Schwab and England andHoehn and Yahr scales and timed tests were administered in off situa-tion to evaluate the possible influence of disease severity.

2.4. Statistical analysis

Mean differences between freezers and non-freezers were assessedusing the t test for independent samples or the Mann–Whitney test forcontinuous variables with a parametric or non-parametric distribution

respectively. The chi-square test was used to assess associations be-tween categorical variables.

Variables with statistically significant differences between freezersand non-freezers were entered into bivariate and stepwise multivariatelogistic regression analyses with the dichotomous criterion of FOG asthe common regressor to determine the best explanatory independentvariables. Several stepwisemultivariate logistic regressionswere tested,evaluating all possible combinations of variables. Up to five variableswere considered in each model.

Receiver operating characteristic (ROC) curves were performed toassess the sensitivity and specificity of each variable in predictingfreezers. The point that simultaneously maximized sensitivity andspecificity was selected as the cut-off value. Accuracy was calculatedbased on the proportion of correctly classified cases using cut-offvalues.

Kaplan–Meier curveswere used to evaluate the relationship betweentime to onset of FOG and disease duration. The log-rank test stratified byage at onset of PDwas performed to evaluate the effect of age at onset ofPD on the occurrence of FOG during the course of the disease. A pvalueb0.05 was considered significant in all tests.

Data were analyzed using the Statistical Package for the SocialSciences (SPSS) version 15.0 for Windows. The statistical methodsand data analysis were reviewed by an independent biostatistician,who confirmed the validity of the methods and the interpretation ofthe results.

3. Results

The study sample comprised 160 patients with PD (72 men, 88women, mean age 72±9.5 years). Demographic and disease charac-teristics are described in Table 1. Seventy-one patients (44.4%)reported FOG. FOG at the initiation of gait was reported by 67 patients(94.4% of freezers), FOG on turning by 43 patients (60.6% of freezers)and FOG while walking, particularly in narrow spaces, was reportedby 20 patients (28.2% of freezers). All patients with FOG and motorfluctuations experienced FOG during off states and 11 patients (35.5%of freezers with motor fluctuations) also experienced FOG during onstates. Forty patients with FOG (56.3%) did not experience classicmotor fluctuations (wearing-off or on–off phenomena) and, besidesFOG episodes, showed a stable motor response during the day. Sixteenpatients with FOG reported gait festination (22.5% of freezers).According to the FOGquestionnaire (item1.3), the frequency of FOGep-isodes was as follows: a) very rarely, about one a month: 6 patients(8.4%); b) rarely, about once a week: 18 patients (25.3%); c) often,about once a day: 45 patients (63.4%); and d) always, whenever walk-ing: 2 patients (2.9%). The duration of FOG episodes (item 1.4 of FOGquestionnaire) was: a) 1–2 s: 35 patients (49.3%); b): 3–10 s: 32 pa-tients (45.1%); c) 11–30 s: 3 patients (4.2%); and d) >30 s: 1 patient(1.4%).

At the onset of FOG, mean age was 69.9±9.8 years and the meandisease duration was 8.1±6.3 years. In the group of freezers themean score of FOG questionnaire was 10.6±4.1.

Thirty-two patients (seven non-freezers and twenty-five freezers)were unable to perform the timed tests because they could not walkunaided (Hoehn and Yahr stages IV and V).

3.1. Comparison between patients with FOG and without FOG (Tables 1and 2)

There was no difference in age and gender between freezers andnon-freezers. However, onset of PD was earlier in freezers. Freezershad longer disease duration and increased disease severity accordingto the UPDRS (part III), Hoehn and Yahr and Schwab andEngland activ-ities of daily living scores. In addition, freezers scored worse in theMini-Mental State Examination and had a higher frequency of motorfluctuations and dyskinesias. Freezers experienced fallsmore frequently

Table 1Demographics and disease characteristics.a

All patients (n=160) Non-freezers (n=89) Freezers (n=71) Testb p value

Age (year) 72.0 (9.5) 71.6 (9.7) 72.6 (9.3) 1 0.506Male (%) 52.5 48.3 57.7 2 0.267Age at onset (year) 63.9 (11.2) 65.7 (9.9) 61.7 (12.4) 1 0.025Disease duration (year) 8.1 (6.4) 5.8 (4.5) 10.8 (7.3) 3 b0.001PD subtype at onset 1 0.324

TDT (n, %) 100 (62.5) 59 (66.3) 41 (57.7)ART (n, %) 60 (37.5) 30 (33.7) 30 (42.2)

Motor fluctuations (n, %) 46 (28.8) 16 (17.9) 31 (43.7) 2 0.001Dyskinesias (n, %) 42 (26.3) 13 (14.6) 29 (40.8) 2 b0.001Hoehn and Yahr 2.6 (1.0) 2.2 (0.9) 3.1 (0.9) 3 b0.001Hoehn and Yahr (n, %) I 21 (13.1) I 20 (22.5) I 1 (1.4)

II 63 (39.4) II 44 (49.3) II 19 (26.7)III 44 (27.5) III 18 (20.2) III 26 (36.6)IV 23 (14.4) IV 2 (2.3) IV 21 (29.6)V 9 (5.6) V 5 (5.7) V 4 (5.7)

UPDRS III 28.8 (15.7) 22.9 (13.6) 36.4 (15.0) 3 b0.001Falls (n, %) 62 (38.8) 21 (23.6) 41 (57.7) 2 b0.001Activities of daily living 73.7 81.5 (19.4) 64.0 (28.5) 3 b0.001MMSE 26.9 (4.8) 27.7 (3.9) 25.9 (5.6) 3 0.013Hypertension (n, %) 62 (38.8) 39 (43.8) 23 (32.4) 2 0.146Diabetes (n, %) 16 (10.0) 9 (10.1) 7 (9.8) 2 1.000Stroke (n, %) 6 (3.8) 2 (2.2) 4 (5.6) 2 0.407Neuroimaging of CVD (n, %) 35 (21.9) 18 (20.2) 17 (23.9) 2 0.701Symptomatic orthostasis (n, %) 58 (36.2) 33 (37.1) 25 (35.2) 2 0.547

Abbreviations: PD = Parkinson disease; UPDRS = Unified Parkinson's Disease Rating Scale; MMSE = Mini-Mental State Examination; TDT = tremor-dominant subtype; ART:akinetic-rigid subtype; CVD = cerebrovascular disease.

a Data are mean (SD); range or absolute numbers and percentages.b Test 1=Mann–Whitney U test; test 2=χ2 test; test 3=independent sample t test.

Table 2Functional tests, gait parameters, and drug treatments.a.

All patients(N=160)

Non-freezers(N=89)

Freezers(N=71)

Testb p value

TinettiBalance 10.9 (5.7) 13.3 (4.6) 8.2 (5.8) 1 b0.001Gait 8.6 (4.6) 10.3 (3.4) 6.6 (5.0) 1 b0.001Total 19.5 (10.2) 23.7 (7.8) 14.8 (10.6) 1 b0.001

Timed up andgo (s)

11.4 (8.1) 9.3 (2.9) 14.8 (11.9) 1 0.001

Velocity (m/s) 1.2 (0.3) 1.2 (0.3) 1.1 (0.4) 1 b0.001Step length (m) 0.82 (0.21) 0.84 (0.31) 0.71 (0.32) 1 b0.001Cadence (steps/s) 1.55 (0.71) 1.57 (0.30) 1.53 (0.41) 1 0.01Levodopa use(n, %)

139 (86.8) 74 (83.1) 65 (91.5) 2 0.158

Levodopa dose(mg/day)

557.8 (254.1) 474.6 (193.5) 650.1 (282.1) 1 b0.001

Dopamine agonistuse (n, %)

98 (61.2) 50 (56.1) 48 (67.6) 2 0.146

MAO-I use (n, %) 49 (30.6) 23 (25.8) 26 (36.6) 2 0.168COMT-I use (n, %) 25 (15.6) 10 (11.2) 15 (21.1) 2 0.124

68 A. Contreras, F. Grandas / Journal of the Neurological Sciences 320 (2012) 66–71

than non-freezers (57.7% vs 23.6%, pb0.001). Thirteen patients reportedfalls directly related to FOG episodes (31% of freezers with falls).

No differences were observed between freezers and non-freezersin the initial predominant symptom, symptoms of orthostatic hypo-tension or cerebrovascular disease (clinical, neuroimaging and riskfactors). Moderate leukoaraiosis with or without subcortical lacunarinfarcts were detected in 18 non-freezers (20.2%) and 23 freezers(23.9%). There was no statistically significant difference betweengroups (χ2 test; p=0.701). These findings did not lead to retrospectiveexclusion of cases.

Freezers were treated with higher doses of levodopa and more fre-quently received amantadine, atypical neuroleptics (quetiapine) andcentral cholinesterase inhibitors (Table 2). Patients treated with centralcholinesterase inhibitors (rivastigmine) had dementia associated withPD and those treated with quetiapine had hallucinations. Amantadinewas used in patients with disabling dyskinesias.

Freezers scoredworse in the balance and gait subscales of the Tinettifunctional test and showed reduced gait velocity, cadence and steplength and increased timed get-up-and-go test (Table 2).

Amantadine use(n, %)

13 (8.1) 2 (2.2) 11 (15.5) 2 0.003

Anticholinergic use(n, %)

2 (1.2) 0 (0) 2 (2.8) 2 0.195

Polytherapy (n, %) 83 (51.8) 42 (47.1) 41 (57.7) 2 0.395Benzodiazepineuse (n, %)

22 (13.7) 8 (8.9) 14 (19.7) 2 0.065

Antidepressantuse(n, %)

18 (11.2) 7 (7.8) 11 (15.5) 2 0.140

Neuroleptic use(n, %)

8 (5.0) 1 (1.1) 7 (9.8) 2 0.022

Cholinesteraseinhibitor use(n, %)

7 (4.3) 1 (1.1) 6 (8.4) 2 0.045

Abbreviations: MAOI = inhibitor of monoamine oxidase B; COMTI = inhibitor ofcatechol-O-methyl transferase.

a Data are mean (SD), absolute numbers or percentage.b Test 1=independent samples t test; test 2=χ2 test.

3.2. Regression analysis

The independent variables identified as significantly associatedwith falls in the bivariate logistic regression were the same as thosethat had been found to be statistically different in the previous ap-proach, except for anticholinesterase use, which lost its statisticalsignificance (Table 3).

When the variables were included in a stepwise multivariatemodel of logistic regression, only disease duration was independentlyassociated with FOG (OR=1.10, 95% CI=1.01–1.19, p=0.020). Therest of variables lost their statistical significance once disease durationentered into the regressionmodel. In Table 3 appear themost favorableOR obtained for the other variables, which did not reach in any case thethreshold of statistical significance.

Table 3Logistic regression analysis.

Bivariate analysis Multivariate analysis

Oddsratio

95%CI p value Oddsratio

95%CI p value

Age at PD onset 0.97 0.94–0.99 0.028 0.98 0.94–1.02 0.333Disease duration 1.17 1.09–1.26 b0.001 1.10 1.01–1.19 0.020Motor fluctuations 3.33 1.63–6-84 0.001 0.93 0.35–2.48 0.890Dyskinesia 4.03 1.89–8.58 b0.001 2.18 0.82–5.80 0.116Hoehn and Yahr 2.62 1.79–3.82 b0.001 1.21 0.57–2.58 0.614UPDRS 1.07 1.04–1.09 b0.001 1.00 0.95–1.05 0.848Falls 4.43 2.24–8.72 b0.001 1.61 0.63–4.00 0.297Activities of daily livinga 0.97 0.95–0.98 b0.001 1.02 0.97–1.03 0.821MMSEa 0.92 0.85–0.99 0.018 0.98 0.89–1.08 0.711Tinetti balancea 0.84 0.77–0.90 b0.001 0.92 0.80–1.04 0.216Tinetti gaita 0.82 0.75–0.89 b0.001 0.95 0.82–1.10 0.953Tinetti totala 0.90 0.87–0.94 b0.001 0.95 0.88–1.02 0.208Step length 0.11 0.09–0.30 b0.001 0.20 0.06–6.75 0.378Velocity 0.24 0.13–0.49 b0.001 1.46 0.07–27.9 0.801Cadence 0.41 0.24–0.70 0.001 1.04 0.29–3.71 0.946Levodopa dose 1.04 1.02–1.06 b0.001 1.02 1.00–1.04 0.090Amantadine use 7.98 1.70–37.2 0.008 4.42 0.83–23.4 0.080Neuroleptic use 9.62 1.15–80.1 0.036 1.25 0.16–12.6 0.854Cholinesterase inhibitoruse

8.12 0.95–69.1 0.055 1.11 0.23–11.7 0.756

Abbreviations: PD = Parkinson disease; UPDRS = Unified Parkinson's Disease RatingScale; MMSE = Mini-Mental State Examination.

a Functional tests: higher scores mean normality.

Fig. 1. Kaplan–Meier curve showing that the risk of freezing of gait increases with theduration of Parkinson's disease.

69A. Contreras, F. Grandas / Journal of the Neurological Sciences 320 (2012) 66–71

3.3. ROC analysis

Table 4 shows the outcomes of the ROC analysis for thenon-dichotomous variables associated with FOG in the bivariate logisticregression. Tinetti score, UPDRS, Hoehn and Yahr stage, disease durationand levodopa dosewere the best independent predictors of FOG. Amongthem, disease duration had the highest specificity (77%) although itssensitivity was low (59%).

3.4. Kaplan–Meier curves

Survival curves show that the risk of FOG increased with the dura-tion of the disease (Fig. 1). About 40% patients developed FOG after10 years of PD. Six per cent of freezers experienced FOG in the firstyear of the disease and 17% between the second and the third year ofPD. The combined effect of age at onset of PD and disease durationis illustrated in Fig. 2. Patients who developed PD before the age of60 years experienced FOGearlier thanolder patients (log-rank, pb0.005).

Among freezers, there was no statistically significant difference inthe FOG questionnaire score (10.3±4.1 vs 10.9±4.0; p>0.05) and inthe Tinetti score (19.9±10.0 vs 19.4±10.1; p>0.05) between pa-tients with age at onset of PDb60 and ≥60 years.

Table 4Receiver operating characteristic analyses.

Area under curve Sensitivity Specificity Accuracy

Tinetti total 0.78 0.76 0.75 0.75UPDRS 0.77 0.74 0.72 0.72Hoehn andYahr 0.76 0.72 0.72 0.72Disease duration 0.73 0.59 0.77 0.70Levodopa dose 0.72 0.83 0.60 0.74Step length 0.70 0.58 0.74 0.77Velocity 0.68 0.58 0.76 0.69Activities of day living 0.68 0.76 0.75 0.50Cadence 0.63 0.67 0.57 0.52Age at PD onset 0.60 0.58 0.65 0.40MMSE 0.58 0.52 0.62 0.40

4. Discussion

We confirm that FOG is a common phenomenon in PD; it wasreported by nearly half of the patients in this series. This result is con-sistent with those of previous studies [5,6].

In this cross-sectional study, multivariate logistic regression re-vealed that the independent variable most related to FOG was durationof PD. The prevalence of FOG increased progressively as the disease ad-vanced. Approximately 40% of patients developed FOG after 10 years ofPD. Although disease duration showed a specificity of 77%, its sensitivitywas low, and other variables such as Hoehn and Yahr stage, the UPDRS(part III), Tinetti test, and levodopa dose showed similar accuracy inpredicting freezers. Disease duration, Hoehn and Yahr staging, andhigh scores in the UPDRS reflect the progression of the disease, whichthus appears as the main cause of FOG in PD in our series. Diseaseseverity has also been associated with FOG in previous studies[6,22].

The reduced gait velocity, cadence and step length, increasedtimed get-up-and-go test and poor scores in the Tinetti test observedin patients with FOG were probably related to gait abnormalities,

Fig. 2. Kaplan–Meier curve showing the effect of age at onset of Parkinson's disease onthe occurrence of freezing of gait. Patients with age at onsetb60 years experiencedfreezing of gait earlier than older patients (log-rank pb0.005).

70 A. Contreras, F. Grandas / Journal of the Neurological Sciences 320 (2012) 66–71

which are present between freezing episodes and occur in advancedPD. In fact, most of the freezers did not experience FOG episodes duringthe timed tests performed in the clinic.

In our series, falls were more frequent in freezers, confirming pre-vious observations [4]. We found that more than 70% of patients withFOG were in Hoehn and Yahr stages ≥3 and scored worse in theTinetti balance test, suggesting that the combination of FOG and pos-tural instability may be responsible for the high prevalence of falls inparkinsonian freezers.

Mini Mental State Examination scores were worse in patients withFOG, although their statistical relevancewas overcome by disease dura-tion andwas not a predictor of freezers. This associationmay reflect theinteraction between cognitive function and FOG [23,24], although exec-utive function and attention were not specifically assessed in our study.Executive dysfunction, particularly set-shifting and conflict resolutionimpairments, have been associated with FOG in PD patients [25,26].Nevertheless, it cannot be completely ruled out that cognitive declinemight be an epiphenomenon related to more advanced disease in pa-tients with FOG.

Patients with FOG received higher doses of levodopa and weretreated more frequently with amantadine and quetiapine. This may berelated to the more severe disease of patients with FOG, as suggestedby the finding that their individual statistical relevance was overcomeby disease duration in the multivariate approach. Amantadine wasadministered to patients with disabling dyskinesias and quetiapine wasadministered to patients with hallucinations. In contrast to previous re-ports [7,10,11], we observed no statistically significant difference in treat-mentswithMAO-B inhibitors or dopamine agonists between freezers andnon-freezers.

Therefore, dopamine replacement therapy does not seem to be re-sponsible for the occurrence of FOG in patients with PD, although itcan aggravate this phenomenon, as is the case of FOG during on pe-riods. However, in our series, all fluctuating patients with FOG duringon periods experienced FOG episodes in off situations as well. More-over, a small proportion of freezers (6%) developed FOG before anyantiparkinsonian treatment was started.

Interestingly, although FOG is common in patients with advancedPD, it is not an exclusive problem of late stages of the disease. Wefound that FOG already occurred in 17% of freezers within the firstthree years of the disease. Furthermore, half of the patients withFOG did not show classic motor fluctuations, and nearly 30% offreezers were in Hoehn and Yahr stages I and II. These observationssupport the hypothesis that FOG may not correlate with some of thecardinal parkinsonian motor signs [8]. FOG has been related to theakinetic-rigid form of PD [7], although we could not replicate thisfinding, since we found no association between FOG and any particu-lar subtype of motor symptoms at the onset of PD. It has beensuggested that freezers may be a different subtype among PD patientswith postural instability and gait disturbance [9]. Structural changesin the midbrain, including gray matter atrophy of the mesencephaliclocomotor region [27] and reduced connectivity between thepedunculopontine nucleus and the cerebellum [28] have been foundin parkinsonian patients with FOG.

It is noteworthy that, in our study, younger patients developedFOG earlier in the course of PD. Young onset of PD may be a factorof susceptibility to early occurrence of FOG, even in the absence ofother gait and balance disorders. Perhaps these patients have differ-ent disease progression with early impairment of non-dopaminergicmidbrain structures.

A limitation of this study is the retrospective assessment of FOG.However, episodes of FOGare often rare or absent in the clinic, so historiesor questionnaires are often better indicators than clinical observations ofthe presence and severity of the phenomenon [29].

In conclusion, FOG is a frequent and disablingmotor complication ofPD associated with the progression of the disease and it is not primarilyrelated to dopamine replacement therapy. Nevertheless, FOGmay occur

early in young patients with PD. The appearance of FOG could be aclinical hallmark for the assessment of PD progression.

Conflict of interest

The authors declare that they have no conflict of interest.F. Grandas received consultancy honoraria from Abbott and Allergan.

Acknowledgments

Dr. A. Contreras holds a Fellowship Grant in Movement Disordersfrom the Fundación de Investigación Biomédica del Hospital GregorioMarañón (Madrid, Spain) and the Spanish Society of Neurology.

Dr. F. Grandas is partially supported by the Programa deIntensificación de la Actividad Investigadora en el Sistema Nacionalde Salud (Programa I3SNS).

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