by Stefania Brotini, MD

Dr. Brotini is with the Movement Disorder Center, Department of Neurology, San Giuseppe Hospital in Empoli, Florence, Italy

FUNDING: No funding was provided for this study. 

DISCLOSURES: The author has no conflicts of interest relevant to the content of this article. 

Innov Clin Neurosci. 2021;18(10–12):12–14.

ABSTRACT: Background. Camptocormia is a complication in which the spine bends forward while walking or standing. This axial postural deformity is common in Parkinson’s disease (PD), with prevalence ranging from 3 to 18 percent; it is generally associated with a more severe disease and longer duration of symptoms. Camptocormia in PD typically responds poorly to levodopa. Other treatment options are limited and are often not effective.

Case Presentation. We describe an unusual case of PD presenting with camptocormia that only emerged during the “off” state of PD. The patient was treated with classical dopaminergic anti-Parkinson’s therapy plus a new formulation of palmitoylethanolamide co-ultramicronized with luteolin (Lut) termed um-PEALut. We observed that the addition of um-PEALut to acute treatment with carbidopa/levodopa resulted in improved dyskinesia and reduced camptocormia. The patient continued treatment for four months, resulting in a complete resolution of leg and trunk dyskinesia and a marked reduction in the onset of camptocormia during the “off” states.

Conclusion. um-PEALut shows potential as an efficacious adjuvant therapy for patients with PD receiving carbidopa/levodopa to treat both dyskinesia and camptocormia in acute and chronic fashion.

Keywords: Ultra-micronized palmitoylethanolamide/luteolin, camptocormia, neurodegeneration, adjuvant therapy, Parkinson’s disease (PD), neuromuscular complications

Camptocormia is an axial postural deformity characterized by abnormal thoracolumbar spinal flexion. It is relatively common during the course of Parkinson’s disease (PD) and is thought to be related to the clinical severity of the neurodegenerative disease. Camptocormia also occurs in other neurodegenerative diseases, such as myopathies with axial involvement, all forms of myositis, and dystonia, and it can also occur as a pharmacological side effect or as a functional disorder.1 Camptocormia causes marked impairment to quality of life and often leads to social isolation.2 The prevalence of camptocormia in PD ranges from 3 to 18 percent.3 The pathogenesis of camptocormia is not clearly understood, and central and peripheral mechanisms have both been proposed.3 The evidence so far suggests that postural deformities have a multifactorial pathophysiology;4 however, recent findings suggest the occurrence of a focal myopathy of the paravertebral muscles in PD-associated camptocormia5 and the interaction between muscle innervation, Golgi tendon organ, and the central nervous system (CNS) as a key player in regulating muscle tone.1 PD-associated camptocormia typically shows poor response to levodopa but might be alleviated to some extent with botulinum toxin therapy and deep brain stimulation.6,7

In a previous study,8 investigators observed that a one-year adjuvant treatment with ultramicronized palmitoylethanolamide (um-PEA) in patients with advanced PD receiving levodopa therapy led to significantly improved motor symptoms associated with the disease, as well as improved performance of activities of daily living. PEA is an endogenous, anti-inflammatory, analgesic, and neuroprotective mediator acting at several molecular targets in both central and peripheral nervous systems. Preclinical and human studies suggest that um-PEA, when co-micronized together with antioxidants, has potential as a therapeutic tool in the treatment of pathologies characterized by neurodegeneration, neuroinflammation, pain, and neuromuscolar conditions.9–12 

Certain new formulations containing um-PEA also contain luteolin (Lut). Lut is a flavonoid that has been shown to protect the dopaminergic neurons in a PD model; this protective effect is thought to be elicited through a reduction in oxidative damage, neuroinflammation, and microglial activation.13 In addition, Lut has been shown to improve the morphology and stability of PEA.14 In patients following stroke, treatment with a formulation of co-ultramicronized palmitoylethanolamide/luteolin (um-PEALut) demonstrated improvements in cognitive abilities, spasticity, pain, and independence in daily living activities.15

Here we describe a case of a 68-year-old man with PD with marked axial rigidity and bilateral cogwheel rigidity in all extremities and marked camptocormia in the “off” state. The addition of um-PEALut to the patient’s treatment regimen of carbidopa/levodopa (CD/LD) appeared to elicit a marked reduction of the camptocormia onset in the “off” states and induce a complete resolution of dyskinesia involving his legs and trunk.

Case Presentation

A 68-year-old right-handed man who had been diagnosed with PD five years earlier was evaluated at our movement disorders center (Department of Neurology, San Giuseppe Hospital, Empoli, Florence, Italy). Before PD diagnosis, the patient had noticed progressive slowing of movement in his right side and eventual loss of shoulder motion when raising his arm over his head. He was treated for presumed arthritis, but derived no benefit. Approximately one year after PD diagnosis, he developed similar slowing of movement on his left side. Over the following year, his handwriting became smaller and less legible. He had not yet developed resting tremor or postural instability. 

The patient responded well to CD/LD in the first year of treatment following PD diagnosis. Subsequently higher CD/LD doses were required, and ropinirole was added to provide additional motor benefit. Disabling motor fluctuations with painful right-foot dystonia began to emerge during wearing-off periods between subsequent CD/LD intake. His gait became characterized by camptocormia (marked forward bending of the trunk), and frequent freezing episodes, in which his feet felt glued to the ground, occurred. The camptocormia commonly emerged within 60 minutes before his next scheduled CD/LD dose and was reported as uncomfortable but not painful. He also developed peak-dose dyskinesias involving his legs and trunk.

At the time of presentation, the patient was on sustained-release CD/LD (25mg/100mg) three times a day, with prolonged-release ropinirole (16mg) once a day, supplemented with CD/LD (25mg/100mg) once a day, as needed. A gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain was performed one month before his initial visit to our clinic, and the results were unremarkable.

Neurological examination in the “off” state. The patient scored 30 out of 30 on the Folstein Mini-Mental State Examination. Frontal release signs were not present. Unified Parkinson’s Disease Rating Scale was used to assess the patient’s clinical motor picture. Extraocular movements were normal. Hypomimia and marked bilateral bradykinesia, with more involvement of his right side than his left in finger tapping, fist opening, rapid pronation-supination, and foot tapping, were observed. He could not abduct his right shoulder, but otherwise his strength was normal. No resting, postural, or action tremor was evident. The patient had marked axial rigidity and bilateral cogwheel rigidity in all extremities, which were more evident on his right side. His gait was characterized by marked camptocormia. When standing, he was able to correct his camptocormia slightly. The patient’s arm swing was diminished bilaterally. His pull test was normal.

Treatment and outcome. Neurological examination in the “on” state after intake of CD/LD. After administration of a regular dose of CD/LD (25mg/100mg) plus prolonged-release ropinirole (16mg), the patient showed an improvement of bradykinesia within 50 minutes and recovered the full range of motion in his right shoulder. The gait had a normal rhythm with diminished residual arm swing on the right side, and his camptocormia was improved.

Neurological examination in the “on” state after receiving a regular dose of CD/LD plus um-PEALut. um-PEALut at a dose of 700+70mg was added to his regular dose of CD/LD. The patient showed an improvement of bradykinesia within 35 minutes of the drug intake and complete resolution of the camptocormia. The patient’s therapy was then modified by adding um-PEALut to regular CD/LD. After four months, the patient was still experiencing some associated symptoms of PD during “off” periods, but with less intensity and duration. The “off” states were not associated with the relapse of his camptocormia, and a complete resolution of his dyskinesia involving his legs and trunk was observed.

Discussion

Camptocormia is a well-known clinical phenomenon in patients with generalized neuromuscular disorders, including polymyositis, myasthenia gravis, and motor neuron diseases, and it is also described in the context of movement disorders, such as PD. PD-associated camptocormia occurs most typically in late stages of the disease. Currently, there are three main hypotheses on the pathogenesis of camptocormia in PD: a focal myopathy of the trunk muscles, axial dystonia, and a drug-induced etiology.16,17

In the present case, the gradual progression of the clinical course (over 5 years), asymmetric onset of bradykinesia and rigidity, preserved postural reflexes and cognition, and excellent response to LD supported the diagnosis of PD. The unusual clinical feature in this patient was the occurrence of camptocormia only during the “off” state. Complete resolution of camptocormia was achieved with a combination of CD/LD and um-PEALut. Such an effect was unexpected in PD-associated camptocormia since axial symptoms of PD generally show little to no response to dopaminergic therapy. This lack of response suggests that nondopaminergic mechanisms controlling gait and posture have a prominent pathogenic role in the majority of camptocormia cases, although this role remains poorly understood. The addition of um-PEALut appears to have contributed to camptocormia remission in our patient. 

The camptocormia remission observed after um-PEALut treatment was added to CD/LD is thought to be due to the neuroprotective properties of um-PEALut, which result from its ability to modulate the neuroinflammatory processes and stimulate the autophagic pathways, aiding in the elimination of neurotoxic accumulations involved in PD.18,19 In neurodegenerative disease pathogenesis, such as in PD, Alzheimer’s disease, and depressive disorders, the neuroinflammatory processes are important components that impair tissue homeostasis.

PD animal models have demonstrated that neuroinflammation is the key mechanism underlying dopaminergic cell death.20 Dopaminergic neuron death can trigger the activation of glial cells, particularly microglia, which instigate inflammatory processes at the site of neuronal cell injury. um-PEA, a fatty acid ethanolamide, has demonstrated strong anti-inflammatory activity in preclinical models of inflammatory pain and CNS injury and has also shown efficacy in pain relief in humans. PEA prevents peripheral inflammation and mast cell degranulation, as well as exerts neuroprotective and antinociceptive effects in rodents.21–23 Experimental evidence suggests PEA has neuroprotective properties in MPTP models of PD.24 um-PEA, the main constituent of um-PEALut, is a pleiotropic molecule that can slow down disease progression and disability in patients with PD.8 In particular, the co-ultramicronization of PEA with Lut allows the stabilization of the two molecules, enhancing their pharmacological activities.25

um-PEA has been reported to provide rapid and noteworthy improvements, as measured both by electromyography and by performance of daily living activities, in single cases of sporadic and familial amyotrophic lateral sclerosis (ALS).10 In patients with ALS, treatment with um-PEA also demonstrated improved muscle force and respiratory efficacy.11 In these patients, um-PEA is thought to decrease acetylcholine (ACh) current rundown by stabilizing a portion of the ACh current that desensitizes when the ACh receptors (AChR) are repetitively stimulated. um-PEA has also shown efficacy as a symptomatic add-on treatment in myasthenia gravis patients.12 In these patients, the um-PEA effect was achieved over a period of only one week, suggesting a direct action on the AChRs. 

The effectiveness of um-PEA in patients affected by neuromuscular diseases, conditions characterized by camptocormia, suggests that um-PEALut might exert a similar effect at muscular level in PD-associated camptocormia.

The clear limitation of the study is that the evidence was observed in only one patient. It is necessary to reproduce the result in a double-blind clinical study with an adequate sample size.

Conclusion

The camptocormia of the reported case represents a rare form of “off” dystonia that was responsive to both acute and chronic therapy, including dopaminergic-PEALut therapy. This case report suggests that um-PEALut might be an efficacious adjuvant therapy for camptocormia in PD. Large controlled studies are needed to confirm this hypothesis.

Ethics Approval

Approval for case report by the institutional ethics committee is not required.

Consent for Publication

Written informed consent was obtained from the patient for publication of this case report

Author’s Contribution

SB fulfilled the criteria and should qualify for authorship. SB: conception and design, data acquisition, drafting the manuscript. The author has managed the manuscript submission process.

Availability of Data and Materials

Available on request.

References

  1. Schulz-Schaeffer WJ. Camptocormia in Parkinson’s disease: a muscle disease due to dysregulated proprioceptive polysynaptic reflex arch. Front Aging Neurosci. 2016;8:128. 
  2. Vorovenci RJ, Biundo R, Antonini A. Therapy-resistant symptoms in Parkinson’s disease. J Neural Transm (Vienna). 2016;123(1):19–30. 
  3. Doherty KM, van de Warrenburg BP, Peralta MC, et al. Postural deformities in Parkinson’s disease. Lancet Neurol. 2011;10(6):538–549. 
  4. Ali F, Matsumoto JY, Hassan A. Camptocormia: etiology, diagnosis and treatment response. Neurol Clin Pract. 2018;8(3):240–248.
  5. Margraf NG, Wrede A, Rohr A, et al. Camptocormia in idiopathic Parkinson’s disease: a focal myopathy of the paravertebral muscles. Mov Disord. 2010;25(5):542–551. 
  6. Bertram KL, Stripe P, Colosimo C. Treatment of camptocormia with botulinum toxin. Toxicon. 2015;107((Pt A)):148–153.
  7. Lyons M, Boucher O, Patel N, et al. Long-term benefit of bilateral subthalamic deep brain stimulation on camptocormia in Parkinson’s disease. Turk Neurosurg. 2012;22(4):489–492.
  8. Brotini S, Schievano C, Guidi L. Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson’s disease. CNS Neurol Disord Drug Targets. 2017;16(6):705–713.
  9. Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 2017;174(11):1349–1365.
  10. Clemente S. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report. CNS Neurol Disord Drug Targets. 2012;11(7): 933–936.
  11. Palma E, Reyes-Ruiz JM, Lopergolo D, et al. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. Proc Natl Acad Sci U S A. 2016;113(11):3060–3065
  12. Onesti E, Frasca V, Ceccanti M, et al. Short-term ultramicronized palmitoylethanolamide therapy in patients with myasthenia gravis: a pilot study to possible future implications of treatment. CNS Neurol Disord Drug Targets. 2019;18(3):232–238.
  13. Patil SP, Jain PD, Sancheti JS, et al. Neuroprotective and neurotrophic effects of apigenin and luteolin in MPTP induced parkinsonism in mice. Neuropharmacology. 2014;86:192–202.
  14. Adami R, Liparoti S, Di Capua A, Set al. Production of PEA composite microparticles with polyvinylpyrrolidone and luteolin using supercritical assisted atomization. J Supercrit Fluids. 2019;143:82–89.
  15. Caltagirone C, Cisari C, Schievano C, et al. Co-ultramicronized palmitoylethanolamide/luteolin in the treatment of cerebral ischemia: from rodent to man. Transl Stroke Res. 2016;7(1):54–69.
  16. Ponfick M, Gdynia HJ, Ludolph AC, Kassubek J. Camptocormia in Parkinson’s disease: a review of the literature. Neurodegener Dis. 2011;8(5):283–288.  
  17. Srivanitchapoom P, Hallett M. Camptocormia in Parkinson’s disease: definition, epidemiology, pathogenesis and treatment modalities. J Neurol Neurosurg Psychiatry. 2016;87(1):75–85.
  18. Siracusa R, Paterniti I, Impellizzeri D, et al. The association of palmitoylethanolamide with luteolin decreases neuroinflammation and stimulates autophagy in Parkinson’s disease model. CNS Neurol Disord Drug Targets. 2015;14(10):1350–1366.
  19. Cordaro M, Cuzzocrea S, Crupi R. An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of  neuroinflammatory events. Antioxidants (Basel). 2020;9(13):216.
  20. Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8(4):382–397.
  21. De Filippis D, D’Amico A, Iuvone T.  Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. J Neuroendocrinol. 2008;20(Suppl 1):20–25.
  22. Koch M, Kreutz S, Bottger C, et al.  Palmitoylethanolamide protects dentate gyrus granule cells via peroxisome proliferator-activated receptor-alpha. Neurotox Res. 2011;19(2):330–340. 
  23. Sasso O, Russo R, Vitiello S, et al. Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. Pain. 2012;153(1):33–41. 
  24. Esposito E, Impellizzeri D, Mazzon E, et al. Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson’s disease. PLoS One. 2012;7(8):e41880.
  25. Bertolino B, Crupi R, Impellizzeri D, et al. Beneficial effect of  co-ultramicronized palmitoylethanolamide/luteolin in a mouse model of autism and in a case report of autism. CNS Neurosci Ther. 2017;23(1):87–98.