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 Brittle Response to Levodopa as a Marker of Parkinson’s Disease Phenotype Characterized by Heavy Motor and Non Motor Burden
Filomena Abate1orcid, Roberto Erro1orcid, Alfonso Fasano2,3,4,5orcid, Paolo Barone1orcid, Marina Picillo1corresp_iconorcid
Journal of Movement Disorders 2025;18(1):31-34.
DOI: https://doi.org/10.14802/jmd.24182
Published online: November 11, 2024

1Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno (SA), Italy

2Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN. Division of Neurology, University of Toronto, Toronto, Canada

3Krembil Brain Institute, Toronto, Canada

4Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada

5Department of Parkinson’s Disease & Movement Disorders Rehabilitation, Moriggia-Pelascini Hospital–Gravedona ed Uniti, Como, Italy

Corresponding author: Marina Picillo, MD, PhD Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno (SA) 84131, Italy / Tel: +1-00393497725402 / Fax: +1-00393497725402 / E-mail: mpicillo@unisa.it
• Received: August 26, 2024   • Revised: October 6, 2024   • Accepted: November 7, 2024

Copyright © 2025 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Owing to differential motor and non motor involvement, Parkinson’s disease (PD) patients can exhibit various clinical phenotypes [1,2]. Such stratification is useful for determining patient prognosis and progression rate. Sex and body weight also play roles in the exhibition of motor and non motor symptoms as well as in individual responses to dopaminergic therapy [3,4]. As such, a brittle response (BR) to levodopa, i.e., the development of highly disabling dyskinesia following low doses of levodopa, has been described as typical of young women with low body weights [5]. To date, a deep characterization of motor and non motor burdens as well as recommendations about the management of PD with a BR is lacking [5].
The aim of the present case series is to characterize the motor and non motor features of PD patients with a BR and describe their management. In our patients, low body weight and size were associated with a heavy disease burden in terms of both motor and non motor symptoms, especially in terms of cognitive and behavioral symptoms. All patients in our case series were women and presented disabling motor fluctuations characterized by dyskinesia and/or dystonia and profound cognitive and/or behavioral issues, including dementia, severe anxiety with panic attacks, and suicide attempts. Despite the substantial disease burden and the known efficacy of advanced therapies, most of these patients were referred to device-aided therapies late. We believe that better knowledge of this phenotype, which affects mainly women, may accelerate the referral of those patients to advice-aided therapies.
The present case series included seven patients with BR, defined as those who were taking 100 mg or less of levodopa per dose and who developed highly disabling dyskinesia and/or dystonia. Consistent with previous reports [5], our definition only included patients who could not tolerate more than 100 mg of levodopa for any administration during the day; if they could tolerate a higher alternating dose, they were not considered to have a BR.
Demographic information, disease history, and clinical features (including body weight, presence of peak-dose or off dystonia, clinically significant dementia, non motor fluctuations, and non motor symptoms, such as depression, anxiety, and panic attacks) were extracted from patients’ charts.
All patients were women with early age disease onset (42–60 years old), low body weight (mean 52.25 kg, range: 48–56 kg), size (mean height: 161 cm, range: 158–163 cm; body mass index [BMI]: 19.9, range: 19.1–21.1), and a heavy motor and non motor burden (Table 1).
Severe non motor fluctuations and dementia, as anticipated by early changes in executive and visuospatial abilities affected two out of six patients (patient 1 and patient 2). The motor burden was mild, and disabling dyskinesias were managed by reducing the daily dosage of levodopa and introducing amantadine (100 mg three times per day). The most bothersome complaint from both the patients and caregivers was the presence of non motor fluctuations (Supplementary Video 1 in the online-only Data Supplement). These patients spent more than a quarter of their wakening hours moaning and complaining about pain with frequent panic attacks and agitation. The implementation of continuous intrajejunal infusion of levodopa/carbidopa intestinal gel (LCIG) for 14 hours/day at a relatively low dosage (patient 1: morning dose 3 mL, continuous dose 2.8 mL, extra dose 1.5 mL; patient 2: morning dose 7 mL, continuous maintenance dose 3 mL/h, extra dose 1.5 mL) resulted in a dramatic improvement in both motor and non motor burdens.
The remaining four patients did not present with any significant cognitive deficits, but they all presented with relevant behavioral disturbances. Patient 3 experienced severe depression and attempted suicide by drowning. She experienced mild improvement and stabilization of depressive symptoms with prolonged release pramipexole (1.05 mg/day) and escitalopram (10 mg/day) and was treated with continuous LCIG infusion for motor fluctuations and painful dystonia (Supplementary Video 2 in the online-only Data Supplement). This patient also presented with a particular shoulder dystonia described as “Malevich’s shoulder. [6]” LCIG infusion dramatically improved motor symptoms (morning dose: 7 mL; continuous maintenance dose 2.6 mL/h; extra dose: 1 mL). In accordance with current practices, pramipexole was tapered off, and an equivalent dose of levodopa/carbidopa gel was introduced. Despite improvements in motor condition, depression, and apathy dramatically worsened and improved again only after the reintroduction of pramipexole (Supplementary Video 3 in the online-only Data Supplement). After approximately 2 years, the patient developed granulation tissue around the insertion site of the percutaneous endoscopic gastrostomy (PEG) tube, with pain exacerbated by feeding. She was desperate to try any mechanical intervention, but neither PEG tube substitution nor granuloma endoscopic removal was effective. Eventually, pain reduction was only achieved with duloxetine 60 mg daily.
Patient 4 successfully underwent bilateral subthalamic nucleus deep brain stimulation (STN DBS), which improved motor fluctuations. As per current practice, during programming the dosage of levodopa was reduced, and pramipexole treatment was tapered off. As a result, a dramatic worsening of depression and apathy threatened to compromise the deep brain stimulation (DBS) outcome. Similar to patient 3, the behavioral disturbances completely resolved after the reintroduction of pramipexole (Supplementary Video 4 in the online-only Data Supplement).
Patient 5 never accepted the diagnosis of PD and consistently refused to take an appropriate levodopa dosage, which was also due to the development of painful dystonia at a low dosage. She developed a striatal hand, i.e., a hand deformity with flexion of the metacarpophalangeal joint and hyperextension of the interphalangeal joints (Supplementary Video 5 in the online-only Data Supplement), which was painful and disabling enough to warrant a distal tenotomy. She refused any proposed device-aided therapy. Suboptimal dopaminergic therapy led to the worsening of parkinsonism, dystonia, and related disability over the years. Despite the use of suboptimal dopaminergic therapy, a PD clinical diagnosis according to current criteria has been confirmed by an improvement in the Unified Parkinson’s disease rating scale part III score greater than 30% during a subsequent visit at the beginning of her story; the presence of nigrostriatal deficits shown with the SPECT DaTscan; and a negative PARK genetic panel.
Patients 6 and 7 presented BRs and severe motor fluctuations, and thus, STN DBS was performed with suboptimal outcomes. Both patients experienced significant improvement in dyskinesia, but profound motor and non motor fluctuations persisted. In our center, reprogramming was attempted with no improvement in the outcome. In patient 6, motor and non motor fluctuations, including depression and panic attacks, eventually improved after we proceeded with subcutaneous infusion of apomorphine (Supplementary Video 6 in the online-only Data Supplement). Patient 7 was lost to follow-up.
Herein, we described the motor and non motor symptoms of a series of PD patients with BR and their management. All our patients were women with low body weight and a heavy disease burden, which was characterized by disabling dyskinesia/dystonia and severe non motor involvement, especially in terms of neuropsychiatric symptoms and pain (Table 1). Such an association between a small body size and serious PD-related symptoms could be considered a distinct phenotype associated with a BR.
In fact, thin women are more likely to develop disabling dyskinesia early in the disease course [5]; however, little is known about their specific phenotype in terms of cognitive and behavioral involvement or their management [7]. All patients presented a severe non motor burden, ranging from non motor fluctuations to a wide range of neuropsychiatric disturbances (suicidal ideation and attempts, depression, anxiety, rejection of PD diagnosis and appropriate treatment) and dementia (in 2 out of 7 patients). Additionally, all patients exhibited disabling motor fluctuations, such as dyskinesia and/or painful dystonia, associated with low doses of levodopa (the classical hallmark of a BR) with significant impacts on activities of daily living. In detail, when patients and caregivers were asked about the most important complaint, neuropsychiatric symptoms were as important as motor symptoms. Martinez-Ramirez and colleagues5 previously characterized the motor profile of such a population, reporting an overall benefit from DBS, but they did not report an increased incidence of depressive symptoms compared with other patients. Additionally, insufficient data about the management of BR with the remaining device-aided therapies are available.
Indeed, low body weight may account in part for higher plasma and tissue concentrations of levodopa, explaining the BR in these patients [8]. Moreover, disease duration is known to be related to a greater degree of dopaminergic nigrostriatal depletion and to greater pulsatile stimulation of dopaminergic receptors. Both factors may contribute to the development of disabling dyskinesia with low doses of levodopa [5]. However, our case series demonstrated that patients with a BR also present with specific non motor features, further supporting our description of a specific phenotype. Such evidence also suggests that distinct neuronal plasticity and maladaptive responses to levodopa may in part account for BRs [5].
Consistent with the available evidence [3,9], neuropsychiatric disturbances and non motor fluctuations were highly disabling in our series and often represented barriers to accessing device-aided therapies (dementia or suicide attempts prevented DBS in patients 1, 2, and 3; rejection of both diagnosis and appropriate treatment in patient 6). However, DBS of both the STN and globus pallidus pars interna has been reported to be beneficial for patients with a BR [5]. In fact, fewer than half of our cohort were deemed good candidates for STN DBS. In addition, our report offers new insights into the medical management of patients with BR. First, in patients with dementia with prominent non motor fluctuations, LCIG infusion resulted in a dramatic improvement in disability that was perceived by both patients and caregivers (patients 1 and 2). Second, withdrawal of dopamine agonists after DBS or intrajejunal infusion of levodopa/carbidopa gel should be carefully considered due to the possible worsening of depression and apathy, which can compromise the outcome perceived by the patient (patients 3 and 4) [10]. Finally, subcutaneous continuous infusion of apomorphine can be considered a rescue therapy after a suboptimal outcome from STN DBS, especially because it may ameliorate the non motor burden due to the stimulation of dopamine receptors other than D1.
Our case series also emphasized the need to anticipate referral to device-aided therapies for such patients. Among the seven patients, one refused to undergo any advanced treatment, while the others accepted either DBS or infusional therapies after a mean of 9.3 years. Indeed, women with PD are less likely to undergo advanced therapies [11].Addressing these disparities requires increasing patient awareness and education with the implementation of diverse and inclusive initiatives within the health care system.
We recognize that our report is based on few patients; thus, the generalizability of our findings may be limited. Furthermore, we defined our patients as those who presented with low body weight and size, whereas no patient was categorized as underweight according to BMI. Indeed, all but one of the patients in our series came from Italy, and their mean weight and height were both below the mean values reported for Italians (mean weight for Italian women: 52.25 kg; mean height for Italian women: 164.6 cm) [12]. Since we did not perform a formal statistical analysis, we may not conclude that body weight is the major determinant of disability in these patients. Finally, although patients in this report presented a BR to levodopa, patients 2 and 3 were able to tolerate higher levodopa dosages in the morning. Indeed, the definition of a BR includes the use of oral levodopa, and a corresponding definition of a BR with the use of intrajejunal levodopa/carbidopa is lacking. These patients were selected for the present report because they exhibited a BR to oral levodopa, and their motor and non motor symptoms improved after switching to intrajejunal levodopa/carbidopa, which has a different pharmacokinetic profile than oral levodopa.
However, we argue that the motor and non motor features we encountered in our series may represent a prototypical PD phenotype that is characterized by a BR to levodopa and a heavy motor and non motor burden. Additionally, we believe that our experience in the management of the disease burden of such patients with a combination of device-aided therapies and dopamine agonists may be informative for clinicians.
In conclusion, we described seven women with PD with a similar phenotype characterized by low body weight and size, a peculiar sensitivity to low doses of levodopa and a heavy motor and non motor burden of disease. We also report our experience in the therapeutic management of such complex patients.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24182.
Video 1.
Patient 1 presents with moaning as sign of non-motor fluctuation. Of note, this is not associated to a motor block.
Video 2.
Painful dystonia with left shoulder elevation (Malevich’s shoulder).
Video 3.
The patient 3 explains how pramipexole improved her perception of disease burden, with particular regard to apathy and depression.
Video 4.
The patient 4 explains how pramipexole improved her perception of disease burden, with particular regard to apathy and depression.
Video 5.
A fixed painful deformity in patient’s left hand (ie, striatal hand).
Video 6.
In the first segment, the patient presents with motor and non motor block after bilateral subthalamic nucleus deep brain stimulation and before starting apomorphine infusion. In the second segment, the patient explains how apomorphine improved her perception of disease burden.

Ethics Statement

The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The patient signed written informed consent.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Marina Picillo. Data curation: Marina Picillo, Filomena Abate. Investigation: all authors. Methodology: all authors. Project administration: all authors. Resources: all authors. Supervision: Marina Picillo. Validation: Marina Picillo. Visualization: all authors. Writing—original draft: Filomena Abate. Writing—review & editing: all authors.

The authors thank all patients who gave consent to share their data.
Table 1.
Patients’ demographics, disease history, clinical features and management
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
Sex Female Female Female Female Female Female Female
Age at onset (yr) 60 58 49 60 47 42 52
Disease duration (yr) 10 11 13 7 10 12 13
Weight (kg) 49 52 56 50 48 52 55
Height (cm) 160 161 163 160 158 162 163
BMI (kg/m2) 19.1 20.1 21.1 19.5 19.2 19.8 20.7
Dementia Yes Yes No No No No No
Motor fluctuations Mild Mild Moderate Severe Moderate Severe Severe
Dyskinesia Mild Mild Severe Severe None Severe Severe
Non motor fluctuations Pain, moaning, panic attacks Pain, moaning, panic attacks No No No Pain, panic attacks Anxiety, depression
Dystonia No No Peak dystonia of the shoulder No Striatal hand Peak dystonia of the right foot No
Depression Present Present Present* Present* Present Present Present
Suicide attempt No No Yes No No No No
Device-aided therapy (LCIG–STN DBS–CSAI) LCIG LCIG LCIG STN DBS None STN DBS and CSAI STN DBS
Disease duration at start of device-aided-therapy 9 10 10 6 N/A 10 11

* worsened with pramipexole taper off and improved with pramipexole reintroduction, in keeping with a diagnosis of dopamine agonist withdrawal syndrome.

BMI, body mass index; LCIG, levodopa-carbidopa intestinal gel; STN DBS, subthalamic nucleus deep brain stimulation; CSAI, continuous subcutaneous infusion of apomorphine; N/A, not applicable.

  • 1. Erro R, Vitale C, Amboni M, Picillo M, Moccia M, Longo K, et al. The heterogeneity of early Parkinson’s disease: a cluster analysis on newly diagnosed untreated patients. PLoS One 2013;8:e70244.ArticlePubMedPMC
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  • 4. Olanow WC, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord 2013;28:1064–1071.ArticlePubMedPDF
  • 5. Martinez-Ramirez D, Giugni J, Vedam-Mai V, Wagle Shukla A, Malaty IA, McFarland NR, et al. The “brittle response” to Parkinson’s disease medications: characterization and response to deep brain stimulation. PLoS One 2014;9:e94856.ArticlePubMedPMC
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  • 11. Bishay AE, Hughes NC, Zargari M, Paulo DL, Bishay S, Lyons AT, et al. Disparities in access to deep brain stimulation for Parkinson’s disease and proposed interventions: a literature review. Stereotact Funct Neurosurg 2024;102:179–194.ArticlePubMedPDF
  • 12. Parkinson’s UK. Improving life through research [Internet]. Parkinson’s UK. London: Parkinson’s UK; 2019 [accessed on 2024 Aug 15]. Available at: https://www.parkinsons.org.uk/research/improving-life-through-research.

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      Brittle Response to Levodopa as a Marker of Parkinson’s Disease Phenotype Characterized by Heavy Motor and Non Motor Burden
      Brittle Response to Levodopa as a Marker of Parkinson’s Disease Phenotype Characterized by Heavy Motor and Non Motor Burden
      Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
      Sex Female Female Female Female Female Female Female
      Age at onset (yr) 60 58 49 60 47 42 52
      Disease duration (yr) 10 11 13 7 10 12 13
      Weight (kg) 49 52 56 50 48 52 55
      Height (cm) 160 161 163 160 158 162 163
      BMI (kg/m2) 19.1 20.1 21.1 19.5 19.2 19.8 20.7
      Dementia Yes Yes No No No No No
      Motor fluctuations Mild Mild Moderate Severe Moderate Severe Severe
      Dyskinesia Mild Mild Severe Severe None Severe Severe
      Non motor fluctuations Pain, moaning, panic attacks Pain, moaning, panic attacks No No No Pain, panic attacks Anxiety, depression
      Dystonia No No Peak dystonia of the shoulder No Striatal hand Peak dystonia of the right foot No
      Depression Present Present Present* Present* Present Present Present
      Suicide attempt No No Yes No No No No
      Device-aided therapy (LCIG–STN DBS–CSAI) LCIG LCIG LCIG STN DBS None STN DBS and CSAI STN DBS
      Disease duration at start of device-aided-therapy 9 10 10 6 N/A 10 11
      Table 1. Patients’ demographics, disease history, clinical features and management

      worsened with pramipexole taper off and improved with pramipexole reintroduction, in keeping with a diagnosis of dopamine agonist withdrawal syndrome.

      BMI, body mass index; LCIG, levodopa-carbidopa intestinal gel; STN DBS, subthalamic nucleus deep brain stimulation; CSAI, continuous subcutaneous infusion of apomorphine; N/A, not applicable.

      Table 1.

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