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Case Report
Revised

Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol

[version 2; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 23 Oct 2020
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Abstract

Drug abuse may damage basal ganglia that are essential for planning and execution of movements. We report a 38-year old patient with ischemic lesions of the basal ganglia presenting with bilateral painful dystonia and parkinsonism caused by polyintoxication. Dronabinol resulted in improvement of pain and gait disturbance, suggesting a novel therapeutic strategy in these challenging patients.

Keywords

dronabinol, secondary parkinsonism, dystonia, intoxication, ischemic stroke

Revised Amendments from Version 1

We thank the reviewer for his  assessment. In response, we have made the following changes:
We have also submitted the new version of the manuscript in the effort to address your comments. 

As for other cases of the movement disorders treated with cannabis based medicine, there is already extensive evidence in this area, reporting also about the side effects. We discuss it in the paper, but have included more references and more extensive description, as suggested.

When it comes to the exact mechanism of ischemia in this case, it is not entirely clear. However, we suspect it was both toxic and secondary due to vasoconstriction. 

We have updated the information about the gait improvement, as the patient experienced less falls after treatment with dronabinol. 

We would like to comment on the time of assessments. The first follow-up was performed after two months and we do not consider it too long, taking into consideration previous reports, this is an adequate time of evaluation. 

We have checked the manuscript for the timing and updated it accordingly. 

Finally, we have included more references reporting about the use of CBM in treatment of movement disorders.

See the authors' detailed response to the review by Jose Luis Lopez-Sendon Moreno
See the authors' detailed response to the review by Giovanni Defazio and Tommaso Ercoli

Introduction

Drug abuse is an important health issue, not only affecting the social surrounding of a patient but also the cerebral integrity. Besides a number of different somatic abnormalities provoked by an intoxication, certain drugs may damage areas of the brain, such as basal ganglia or cortex, which are essential for the movement onset and coordination1,2.

In this case report, we present a 38-year-old male patient with a long-lasting drug history, including the abuse of cocaine, cannabinoids, benzodiazepines, opiates, methadone and amphetamines. As a result of the multi-intoxication induced bilateral ischaemic lesions to the basal ganglia, the patient presented with secondary bilateral dystonia and parkinsonism. It is not certain whether the cause of ischemia could be related to any specific drug or combinations thereof. Cocaine and its metabolites are known to cause cerebral vasospasm that could lead to ischemic infarctions in the whole brain1,3,4 or can provoke haemorrhagic stroke2. Heroin causes ischemia more often in the globus pallidus5. Amphetamines are known as the second most frequent cause of ischemia after cocaine, especially in younger patients due to their vasoconstrictive effect1,6. Although it is not clear whether cannabinoids and its metabolites can cause cerebrovascular events, there is evidence that cannabis can increase the risk for haemorrhagic stroke1,7. Opioids may not have a direct toxic impact on the neurons, but ischaemic lesions or necrosis can be triggered by recurrence of drug-induced hypoxia1.

The aim of this case report is to show the possible use of dronabinol for a multi-intoxicated patient with ischemia of the basal ganglia in order to temper his pain and improve gait.

Case report

We present a case of a 27-year-old Caucasian man who was admitted to the Intensive Care Unit (ICU) after multi-intoxication. Drug screening on admission identified the following substances: opiates, benzodiazepines, cannabinoids, crack cocaine, methadone and amphetamine. Due to the history of drug abuse he was unemployed. During the first days the patient was in coma, with Glasgow Coma Scale of 5 points. After slow amelioration of his status he presented with severe dysarthria, dysphagia, as well as bilateral parkinsonism and dystonia of his extremities. The neurological examination showed a bilateral positive Babinski sign, global rigidity in all extremities as well as symmetrical hyperreflexia. Furthermore, he suffered from high fever that resolved after treatment with benzodiazepines. Therefore, vegetative symptoms accompanying the patient on submission were interpreted as drug withdrawal syndrome. Both, CT and MRI showed bilateral hypoxemic infarction of the basal ganglia and boundary zone (Figure 1). Those changes could be the consequence of the mixed intoxication or could be attributed to only one harmful substance, especially crack cocaine or amphetamine. During the hospitalization he developed a tracheobronchitis and respiratory insufficiency due to acute respiratory distress syndrome (ARDS). Moreover, because of severe dysphagia he was nourished via percutaneous endoscopic gastrostomy. Further consequences of his primary condition included post ischemic epilepsy treated with levetiracetam (1000mg). After six months of intensive care, the patient was discharged from hospital.

a413b2df-0ac5-47e3-9f88-b4afb3204e52_figure1.gif

Figure 1. MRI images showing bilateral post-ischaemic lesions of the basal ganglia.

During the next five years the patient was treated with levodopa (titrated up to 800mg/day), apomorphine (up to 100 mg/day), selegiline (10mg/day) and baclofen (75mg/day). Further up-titration of levodopa was not possible because of subsequent side effects, such as hallucinations. Due to sleeping problems and agitation he was treated with trazodone (150mg/day) and quetiapine (250mg/day). The substitution dose of buprenorphine 20mg/day was tapered off constantly to keep the patient in a drug naive state. Nonetheless, he showed aggressive behaviour under the influence of alcohol and was admitted to psychiatric ward several times due to delusional disorder and recurrent addictive behaviours. After several months of psychiatric treatment, his addiction and hallucinations resolved. In spite of intense treatment, both parkinsonism as well as dystonia persisted for years and additional symptoms such as generalized pain as well as gait disturbances occurred.

During the examination in our outpatient clinic, 11 years after the hospitalization in the ICU, the patient was still experiencing moderate dysarthria, bilateral dystonia of all extremities, bilateral akinetic-rigid parkinsonism, camptocormia and freezing. Due to those symptoms and increased anxiety as well as painful dystonia as well as unsuccessful treatment with evidence-based agents the patient was treated with dronabinol by his psychiatrist (capsules slowly up titrated to 20mg/day).

After two months of dronabinol treatment, the patient reported subjective improvement of the dystonic pain and a moderate improvement of freezing of gait as well as less falls. We examined the patient at two timepoints: after two months and after two months of dronabinol therapy. Importantly, the medication used at both timepoints remained stable, which excludes confounding contribution of other agents. Results of clinical assessments after two and six months of dronabinol administration are shown in Table 1. The baseline Unified Parkinson’s Disease Rating Scale and Unified Dystonia Rating Scale results cannot be provided as the data were not collected. Although the patient reported the subjective improvement of his symptoms, this was not confirmed in the neurological examination or in the UPDRS and UDRS assessments. Particularly, there was no minimal clinically important differences for UPDRS nor UDRS, although there was an improvement in sleep quality according to ESS. It can therefore be concluded that dronabinol had major analgesic and calming effect and, as a consequence, also improved sleep and general performance. Although he self-reported gait amelioration, it is not clear whether the patient exhibited any motor improvement.

Table 1. Results of clinical assessments two and six months after therapy with dronabinol.

ScaleExamination after
two months
Examination
after six months
UPDRS I00
UPDRS II1814
UPDRS III2624
UPDRS IV00
H-Y2.52.5
Schwab and
England
80%90%
UDRS22
PDSS-2112
ESS15
BDI1110

UPDRS, Unified Parkinson’s Disease Rating Scale; H-Y, Modified Hoehn and Yahr Staging; PDSS-2, Parkinson Disease Sleep Scale-2; UDRS, Unified Dystonia Rating Scale; ESS, Epworth Sleepiness Scale; BDI, Beck Depression Inventory.

Discussion

While there is some evidence that cannabis-based medicine (CBM) could improve both motor and non-motor symptoms in Parkinson’s disease (PD)8,9, the effectiveness of CBM in secondary parkinsonism as well as dystonia is unknown. Recently, Peball et al.10 reported the potential efficacy of nabilone for PD patients with disturbing non-motor symptoms, which appears to be driven by positive effects on anxious mood and night-time sleep problems. Moreover, a number of other open label studies and case reports demonstrated efficacy of CBM in treatment of movement disorders1113. Small randomized trials in Tourette syndrome confirmed efficacy of tetrahydrocannabinol (THC) for tic reduction14,15. Therefore, CBM might be a useful therapeutic alternative for therapy resistant patients with movement disorders. However, systematic reviews and meta-analysis in this group of patients demonstrated conflicting results, due to methodological limitations of studies with CBM16,17.

In the case of our patient, his condition improved only subjectively, but this was not confirmed with objective neurological testing. Moreover, the use of cannabinoids in this case is controversial as the patient had a positive medical history for cannabis misuse. Additionally, long-term effectiveness should also be investigated with accuracy. Potential psychotic effects could be dangerous, therefore the dosage in our patient was slowly increased. Nevertheless, safety profile of CBM in movement disorders reported in previous studies was favorable, with the most common side effects being sedation, dizziness and sensation of “being high”16,17. Finally, no baseline assessments, prior to dronabinol administration, were available. Results of international randomized, double-blind controlled trials with CBM in PD might offer more scientific rationales for discussion of potential usefulness of CBM in other movement disorders.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

Consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

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Version 3
VERSION 3 PUBLISHED 21 Sep 2020
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Szejko N, Burger F, Sidoroff V and Wenning GK. Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2020, 9:1162 (https://doi.org/10.12688/f1000research.26476.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 23 Oct 2020
Revised
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Reviewer Report 28 Jul 2021
Giovanni Defazio, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy 
Tommaso Ercoli, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy 
Approved with Reservations
VIEWS 12
The authors reported an interesting and challenging case of secondary bilateral parkinsonism and dystonia. Treatment with dronabinol resulted in improvement of pain and gait disturbance. 

Major concerns:
  1. Pain improvement was not supported by
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Defazio G and Ercoli T. Reviewer Report For: Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2020, 9:1162 (https://doi.org/10.5256/f1000research.30251.r89189)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 09 Aug 2021
    Natalia Szejko, Department of Bioethics, Medical University of Warsaw, Warsaw, 02091, Poland
    09 Aug 2021
    Author Response
    Thank you so much for reviewing our manuscript. We provide answers to reviewer’s suggestions below:

    Major points:
    • Pain improvement was not supported by score change in a
    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 09 Aug 2021
    Natalia Szejko, Department of Bioethics, Medical University of Warsaw, Warsaw, 02091, Poland
    09 Aug 2021
    Author Response
    Thank you so much for reviewing our manuscript. We provide answers to reviewer’s suggestions below:

    Major points:
    • Pain improvement was not supported by score change in a
    ... Continue reading
Views
7
Cite
Reviewer Report 27 Oct 2020
Jose Luis Lopez-Sendon Moreno, Neurology Department, Hospital Ramón y Cajal, Madrid, Spain 
Approved
VIEWS 7
I believe that the amendments are correct ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Lopez-Sendon Moreno JL. Reviewer Report For: Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2020, 9:1162 (https://doi.org/10.5256/f1000research.30251.r73627)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 21 Sep 2020
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Cite
Reviewer Report 05 Oct 2020
Jose Luis Lopez-Sendon Moreno, Neurology Department, Hospital Ramón y Cajal, Madrid, Spain 
Approved with Reservations
VIEWS 26
The authors describe an interesting case about a patient with secondary dystonia and parkinsonism and an aparent improvement with dronabinol. 
The case is relevant since it provides insight into the treatment of a disabling condition. Also, the use of ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Lopez-Sendon Moreno JL. Reviewer Report For: Case Report: Secondary bilateral parkinsonism and dystonia treated with dronabinol [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2020, 9:1162 (https://doi.org/10.5256/f1000research.29232.r71804)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 23 Oct 2020
    Natalia Szejko, Department of Bioethics, Medical University of Warsaw, Warsaw, 02091, Poland
    23 Oct 2020
    Author Response
    Thank you so much for your valuable comments, we would like to address them below. We have also submitted the new version of the manuscript in the effort to address ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 23 Oct 2020
    Natalia Szejko, Department of Bioethics, Medical University of Warsaw, Warsaw, 02091, Poland
    23 Oct 2020
    Author Response
    Thank you so much for your valuable comments, we would like to address them below. We have also submitted the new version of the manuscript in the effort to address ... Continue reading

Comments on this article Comments (0)

Version 3
VERSION 3 PUBLISHED 21 Sep 2020
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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