Download PDF
J Hand Microsurg
DOI: 10.1055/s-0043-1764161
Case Report

Ultramicronized Palmitoylethanolamide and Luteolin: Drug Candidates in Post-COVID-19 Critical Illness Neuropathy and Positioning-Related Peripheral Nerve Injury of the Upper Extremity

Luca Roncati 
1   Department of Surgery, Medicine, Dentistry, and Morphological Sciences with interest in Transplantation, Oncology and Regenerative Medicine, Institute of Pathology, University of Modena and Reggio Emilia, Polyclinic Hospital, Modena, Italy
,
Caterina Marra
2   Department of General Surgery and Surgical Specialties, Unit of Plastic and Reconstructive Surgery, University Hospital of Modena, Modena, Italy
,
Davide Gravina
3   Department of Musculoskeletal System, Unit of Orthopedics and Traumatology, University Hospital of Modena, Modena, Italy
,
Gianluca Di Massa
1   Department of Surgery, Medicine, Dentistry, and Morphological Sciences with interest in Transplantation, Oncology and Regenerative Medicine, Institute of Pathology, University of Modena and Reggio Emilia, Polyclinic Hospital, Modena, Italy
,
Norman Della Rosa
4   Department of Musculoskeletal System, Unit of Hand Surgery and Microsurgery, University Hospital of Modena, Modena, Italy
,
Roberto Adani
4   Department of Musculoskeletal System, Unit of Hand Surgery and Microsurgery, University Hospital of Modena, Modena, Italy
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium and patients with serious infection can stay in intensive care unit (ICU) for weeks in a clinical scenario of systemic inflammatory response syndrome, likely related to the subsequent development of critical illness polyneuropathy (CIP). It is in fact now accepted that COVID-19 ICU surviving patients can develop CIP; moreover, prone positioning-related stretch may favor the onset of positioning-related peripheral nerve injuries (PNI). Therefore, the urgent need to test drug candidates for the treatment of these debilitating sequelae is emerged even more. For the first time in medical literature, we have successfully treated after informed consent a 71-year-old Italian man suffering from post-COVID-19 CIP burdened with positioning-related PNI of the left upper extremity by means of ultramicronized palmitoylethanolamide 400 mg plus ultramicronized luteolin 40 mg (Glìalia), two tablets a day 12 hours apart for 6 months. In the wake of our pilot study, a larger clinical trial to definitively ascertain the advantages of this neuroprotective, neurotrophic, and anti-inflammatory therapy is advocated.

Keywords

coronavirus disease 2019 - critical illness polyneuropathy - positioning-related peripheral nerve injury - palmitoylethanolamide - luteolin

Authors' Contributions

LA and RA were involved in conceptualization and investigation. DG and GDM helped in bibliographic resources. LR and CM contributed to data curation and writing—original draft preparation. NDR and RA supervised the study. All authors have read and agreed to the published version of the manuscript.


Ethical Approval

The study was conducted in accordance with the ethical standards and the Declaration of Helsinki of 1975, as revised in 2008.


Informed Consent

Informed consent was obtained from the subject involved in the study; sensitive data and images have been entirely anonymized.


Data Availability

The data presented in this study are available on request from the corresponding author.




Publication History

Article published online:
13 March 2023

© 2023. Society of Indian Hand Surgery & Microsurgeons. All rights reserved.

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry 1984; 47 (11) 1223-1231
    CrossrefPubMedGoogle Scholar
  • 2 Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol 2011; 10 (10) 931-941
    CrossrefPubMedGoogle Scholar
  • 3 Maramattom BV, Wijdicks EF. Acute neuromuscular weakness in the intensive care unit. Crit Care Med 2006; 34 (11) 2835-2841
    CrossrefPubMedGoogle Scholar
  • 4 Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008; 12 (06) 238
    CrossrefPubMedGoogle Scholar
  • 5 Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med 2014; 370 (17) 1626-1635
    CrossrefPubMedGoogle Scholar
  • 6 Visser LH. Critical illness polyneuropathy and myopathy: clinical features, risk factors and prognosis. Eur J Neurol 2006; 13 (11) 1203-1212
    CrossrefPubMedGoogle Scholar
  • 7 Schweickert WD, Hall J. ICU-acquired weakness. Chest 2007; 131 (05) 1541-1549
    CrossrefPubMedGoogle Scholar
  • 8 Hermans G, Wilmer A, Meersseman W. et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 2007; 175 (05) 480-489
    CrossrefPubMedGoogle Scholar
  • 9 Johnson KL. Neuromuscular complications in the intensive care unit: critical illness polyneuromyopathy. AACN Adv Crit Care 2007; 18 (02) 167-180 , quiz 181–182
    PubMedGoogle Scholar
  • 10 Roncati L, Corsi L. Nucleoside-modified messenger RNA COVID-19 vaccine platform. J Med Virol 2021; 93 (07) 4054-4057
    CrossrefPubMedGoogle Scholar
  • 11 Boehme AK, Doyle K, Thakur KT. et al. Disorders of consciousness in hospitalized patients with COVID-19: the role of the systemic inflammatory response syndrome. Neurocrit Care 2022; 36 (01) 89-96
    CrossrefPubMedGoogle Scholar
  • 12 Roncati L, Nasillo V, Lusenti B, Riva G. Signals of Th2 immune response from COVID-19 patients requiring intensive care. Ann Hematol 2020; 99 (06) 1419-1420
    CrossrefPubMedGoogle Scholar
  • 13 Roncati L, Ligabue G, Nasillo V. et al. A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients. Platelets 2020; 31 (08) 1085-1089
    CrossrefPubMedGoogle Scholar
  • 14 Roncati L, Corsi L, Barbolini G. Abnormal immunothrombosis and lupus anticoagulant in a catastrophic COVID-19 recalling Asherson's syndrome. J Thromb Thrombolysis 2021; 52 (04) 1043-1046
    CrossrefPubMedGoogle Scholar
  • 15 Roncati L, Ligabue G, Fabbiani L. et al. Type 3 hypersensitivity in COVID-19 vasculitis. Clin Immunol 2020; 217: 108487
    CrossrefPubMedGoogle Scholar
  • 16 Bawiskar N, Talwar D, Kumar S, Acharya S. Critical illness polyneuropathy as a sequela of COVID-19. J Glob Infect Dis 2022; 14 (02) 90
    CrossrefPubMedGoogle Scholar
  • 17 Intiso D, Marco Centra A, Giordano A, Santamato A, Amoruso L, Di Rienzo F. Critical illness polyneuropathy and functional outcome in subjects with Covid-19: report on four patients and a scoping review of the literature. J Rehabil Med 2022; 54: jrm00257
    CrossrefPubMedGoogle Scholar
  • 18 Stoian A, Bajko Z, Maier S. et al. High-dose intravenous immunoglobulins as a therapeutic option in critical illness polyneuropathy accompanying SARS-CoV-2 infection: a case-based review of the literature (Review). (review) Exp Ther Med 2021; 22 (04) 1182
    CrossrefPubMedGoogle Scholar
  • 19 Kayim Yildiz O, Yildiz B, Avci O, Hasbek M, Kanat S. Clinical, neurophysiological and neuroimaging findings of critical illness myopathy after COVID-19. Cureus 2021; 13 (03) e13807
    PubMedGoogle Scholar
  • 20 Bax F, Lettieri C, Marini A. et al. Clinical and neurophysiological characterization of muscular weakness in severe COVID-19. Neurol Sci 2021; 42 (06) 2173-2178
    CrossrefPubMedGoogle Scholar
  • 21 Novak P, Cunder K, Petrovič O. et al. Rehabilitation of COVID-19 patients with respiratory failure and critical illness disease in Slovenia: an observational study. Int J Rehabil Res 2022; 45 (01) 65-71
    CrossrefPubMedGoogle Scholar
  • 22 Bocci T, Campiglio L, Zardoni M. et al. Critical illness neuropathy in severe COVID-19: a case series. Neurol Sci 2021; 42 (12) 4893-4898
    CrossrefPubMedGoogle Scholar
  • 23 Hokkoku K, Erra C, Cuccagna C. et al. Intensive care unit-acquired weakness and positioning-related peripheral nerve injuries in COVID-19: a case series of three patients and the latest literature review. Brain Sci 2021; 11 (09) 1177
    CrossrefPubMedGoogle Scholar
  • 24 Fernandez CE, Franz CK, Ko JH. et al. Imaging review of peripheral nerve injuries in patients with COVID-19. Radiology 2021; 298 (03) E117-E130
    CrossrefPubMedGoogle Scholar
  • 25 Malik GR, Wolfe AR, Soriano R. et al. Injury-prone: peripheral nerve injuries associated with prone positioning for COVID-19-related acute respiratory distress syndrome. Br J Anaesth 2020; 125 (06) e478-e480
    CrossrefPubMedGoogle Scholar
  • 26 Miller C, O'Sullivan J, Jeffrey J, Power D. Brachial plexus neuropathies during the COVID-19 pandemic: a retrospective case series of 15 patients in critical care. Phys Ther 2021; 101 (01) pzaa191
    CrossrefPubMedGoogle Scholar
  • 27 Gugliandolo E, Peritore AF, Piras C, Cuzzocrea S, Crupi R. Palmitoylethanolamide and related ALIAmides: prohomeostatic lipid compounds for animal health and wellbeing. Vet Sci 2020; 7 (02) 78
    CrossrefPubMedGoogle Scholar
  • 28 Aloe L, Leon A, Levi-Montalcini R. A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions 1993; 39 (Spec No): C145-C147
    CrossrefPubMedGoogle Scholar
  • 29 D'Amico R, Impellizzeri D, Cuzzocrea S, Di Paola R. ALIAmides update: palmitoylethanolamide and its formulations on management of peripheral neuropathic pain. Int J Mol Sci 2020; 21 (15) 5330
    CrossrefPubMedGoogle Scholar
  • 30 Cordaro M, Scuto M, Siracusa R. et al. Effect of N-palmitoylethanolamine-oxazoline on comorbid neuropsychiatric disturbance associated with inflammatory bowel disease. FASEB J 2020; 34 (03) 4085-4106
    CrossrefPubMedGoogle Scholar
  • 31 López-Lázaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 2009; 9 (01) 31-59
    CrossrefPubMedGoogle Scholar
  • 32 Ashaari Z, Hadjzadeh MA, Hassanzadeh G. et al. The flavone luteolin improves central nervous system disorders by different mechanisms: a review. J Mol Neurosci 2018; 65 (04) 491-506
    CrossrefPubMedGoogle Scholar
  • 33 Fan X, Du K, Li N. et al. Evaluation of anti-nociceptive and anti-inflammatory effect of luteolin in mice. J Environ Pathol Toxicol Oncol 2018; 37 (04) 351-364
    CrossrefPubMedGoogle Scholar
  • 34 Cordaro M, Cuzzocrea S, Crupi R. An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events. Antioxidants 2020; 9 (03) 216
    CrossrefPubMedGoogle Scholar
  • 35 Bertolino B, Crupi R, Impellizzeri D. et al. Beneficial effects of co-ultramicronized palmitoylethanolamide/luteolin in a mouse model of autism and in a case report of autism. CNS Neurosci Ther 2017; 23 (01) 87-98
    CrossrefPubMedGoogle Scholar
  • 36 Peritore AF, D'Amico R, Siracusa R. et al. Management of acute lung injury: palmitoylethanolamide as a new approach. Int J Mol Sci 2021; 22 (11) 5533
    CrossrefPubMedGoogle Scholar
  • 37 Roncati L, Lusenti B, Pellati F, Corsi L. Micronized / ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation. Prostaglandins Other Lipid Mediat 2021; 154: 106540
    CrossrefPubMedGoogle Scholar
  • 38 Fessler SN, Liu L, Chang Y, Yip T, Johnston CS. Palmitoylethanolamide reduces proinflammatory markers in unvaccinated adults recently diagnosed with COVID-19: a randomized controlled trial. J Nutr 2022; 152 (10) 2218-2226
    CrossrefPubMedGoogle Scholar
  • 39 Raciti L, De Luca R, Raciti G, Arcadi FA, Calabrò RS. The use of palmitoylethanolamide in the treatment of long COVID: a real-life retrospective cohort study. Med Sci (Basel) 2022; 10 (03) 37
    PubMedGoogle Scholar
  • 40 Albanese M, Marrone G, Paolino A. et al. Effects of ultramicronized palmitoylethanolamide (um-PEA) in COVID-19 early stages: a case-control study. Pharmaceuticals (Basel) 2022; 15 (02) 253
    CrossrefPubMedGoogle Scholar
  • 41 Del Re A, Corpetti C, Pesce M. et al. Ultramicronized palmitoylethanolamide inhibits NLRP3 inflammasome expression and pro-inflammatory response activated by SARS-CoV-2 spike protein in cultured murine alveolar macrophages. Metabolites 2021; 11 (09) 592
    CrossrefPubMedGoogle Scholar
  • 42 Fonnesu R, Thunuguntla VBSC, Veeramachaneni GK. et al. Palmitoylethanolamide (PEA) inhibits SARS-CoV-2 entry by interacting with S protein and ACE-2 receptor. Viruses 2022; 14 (05) 1080
    CrossrefPubMedGoogle Scholar
  • 43 De Luca P, Camaioni A, Marra P. et al. Effect of ultra-micronized palmitoylethanolamide and luteolin on olfaction and memory in patients with long COVID: results of a longitudinal study. Cells 2022; 11 (16) 2552
    CrossrefPubMedGoogle Scholar
  • 44 Versace V, Ortelli P, Dezi S. et al. Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome. Clin Neurophysiol 2023; 145: 81-88
    CrossrefPubMedGoogle Scholar
  • 45 Roncati L, Gianotti G, Gravina D. et al. Carpal, cubital or tarsal tunnel syndrome after SARS-CoV-2 infection: a causal link?. Med Hypotheses 2021; 153: 110638
    CrossrefPubMedGoogle Scholar
  • 46 Roncati L, Gravina D, Marra C, Della Rosa N, Adani R. Cubital tunnel syndrome temporally after COVID-19 vaccination. Trop Med Infect Dis 2022; 7 (04) 62
    CrossrefPubMedGoogle Scholar
  • 47 Impellizzeri D, Bruschetta G, Cordaro M. et al. Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain. J Neuroinflammation 2014; 11: 136
    CrossrefPubMedGoogle Scholar
  • 48 Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O, van Riel D. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci 2022; 45 (05) 358-368
    CrossrefPubMedGoogle Scholar
  • 49 Paternostro-Sluga T, Grim-Stieger M, Posch M. et al. Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 2008; 40 (08) 665-671
    CrossrefPubMedGoogle Scholar
  • 50 Shooter D. Use of two-point discrimination as a nerve repair assessment tool: preliminary report. ANZ J Surg 2005; 75 (10) 866-868
    CrossrefPubMedGoogle Scholar
  • 51 Arnaout A, Fontaine C, Chantelot C. Sensory recovery after primary repair of palmar digital nerves using a Revolnerv(®) collagen conduit: a prospective series of 27 cases. Chir Main 2014; 33 (04) 279-285
    CrossrefPubMedGoogle Scholar