Dystonia in children

Dystonia is a motor disorder characterized by sustained muscle contractions producing twisting, repetitive, and patterned movements or abnormal postures. Dystonia is among the most commonly observed motor disorders in clinical practice in children. Unlike dystonia in adults that typically remains focal or spreads only to nearby muscle groups, childhood dystonia often generalizes. Classification of dystonia has direct implications for narrowing down the differential diagnosis, choosing the diagnostic work-up, predicting the prognosis, and choosing treatment options. The etiology of pediatric dystonia is quite heterogeneous. The etiological classification distinguishes primary dystonia with no identifiable exogenous cause or evidence of neurodegeneration and secondary syndromes. Dystonia can be secondary to any pathological process that affects the basal ganglia. The treatment options of childhood dystonia include several oral pharmaceutical agents, botulinum toxin injections, and deep brain stimulation therapy. Botulinum toxin treatment is the first choice treatment for most types of focal dystonia. In children it is less used because dystonic forms are mainly generalized, but it might also be helpful in controlling the most disabling symptoms of segmental or generalized dystonia. Long-term electrical stimulation of the globus pallidum internum is now established as an effective treatment for various types of movement disorders including dystonia. However, this method has not yet found its application in Russia due to the difficulty of implementation and the lack of patient routing. To increase the effectiveness of complex therapy of dystonia in children, new pathogenetic methods of treatment of common forms of primary dystonia and dystonic syndromes in the structure of degenerative diseases of the central nervous system are needed, as well as the development of optimal algorithms for the diagnosis and treatment of these patients.

Contribution:
Pak L.A., Lyalina A.A. — study concept and design, text writing;
Lyalina A.A., Kondakova O.B. — collection and treatment of materials, statistical processing;
Fisenko A.P., Smirnov I.E. — text editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Informed consent. Informed consent was received from the patients’ parents.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: April 20, 2021
Accepted: April 22, 2021
Published: May 14, 2021

1. Jinnah H.A., Neychev V., Hess E.J. The anatomical basis for dystonia: the motor network model. Tremor. Other Hyperkinet. Mov. (NY). 2017; 7: 506. https://doi.org/10.7916/d8v69x3s

2. de Oliveira-Souza R. The human extrapyramidal system. Med. Hypotheses. 2012; 79(6): 843–52. https://doi.org/10.1016/j.mehy.2012.09.004

3. Zhang H.Y., Tang H., Chen W.X., Ji G.J., Ye J., Wang N., et al. Mapping the functional connectivity of the substantia nigra, red nucleus and dentate nucleus: A network analysis hypothesis associated with the extrapyramidal system. Neurosci. Lett. 2015; 606: 36–41. https://doi.org/10.1016/j.neulet.2015.08.029

4. Gonzalez-Latapi P., Marotta N., Mencacci N.E. Emerging and converging molecular mechanisms in dystonia. J. Neural. Transm. (Vienna). 2021. https://doi.org/10.1007/s00702-020-02290-z

5. Lerner R.P., Niethammer M., Eidelberg D. Understanding the anatomy of dystonia: determinants of penetrance and phenotype. Curr. Neurol. Neurosci. Rep. 2013; 13(11): 401. https://doi.org/10.1007/s11910-013-0401-0

6. Bressman S.B. Dystonia: phenotypes and genotypes. Rev. Neurol. (Paris). 2003; 159(10): 849–56.

7. Balint B., Bhatia K.P. Dystonia: an update on phenomenology, classification, pathogenesis and treatment. Curr. Opin. Neurol. 2014; 27(4): 468–76. https://doi.org/10.1097/WCO.0000000000000114

8. Shtok V.N., Levin O.S. Classification of extrapyramidal disorders. In: Shtok V.N., Ivanova-Smolenskaya I.A., Levin O.S., eds. Extrapyramidal Disorders. Guidelines for Diagnosis and Treatment [Ekstrapiramidnye rasstroystva. Rukovodstvo po diagnostike i lecheniyu]. Moscow: MEDpress-inform; 2002: 16–56. (in Russian)

9. Bhatia K.P, Bain P., Bajaj N., Elble R.J., Hallett M., Louis E.D., et al. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov. Disord. 2018; 33(1): 75–87. https://doi.org/10.1002/mds.27121

10. Zech M., Jech R., Boesch S., Škorvánek M., Weber S., Wagner M., et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet. Neurol. 2020; 19(11): 908–18. https://doi.org/10.1016/S1474-4422(20)30312-4

11. Spatola M., Wider C. Overview of primary monogenic dystonia. Parkinsonism Relat. Disord. 2012; 18:158–61. https://doi.org/10.1016/S1353-8020(11)70049-9

12. Moghimi N., Jabbari B., Szekely A.M. Primary dystonias and genetic disorders with dystonia as clinical feature of the disease. Eur. J. Paediatr. Neurol. 2014; 18(1): 79–105. https://doi.org/10.1016/j.ejpn.2013.05.015

13. Artusi C.A., Dwivedi A., Romagnolo A., Bortolani S., Marsili L., Imbalzano G., et al. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry. 2020; 91(4): 426–33. https://doi.org/10.1136/jnnp-2019-322169

14. Defazio G. The epidemiology of primary dystonia: current evidence and perspectives. Eur. J. Neurol. 2010; 17: 9–14. https://doi.org/10.1111/j.1468-1331.2010.03053.x

15. Müller U. The monogenic primary dystonias. Brain. 2009; 132(Pt. 8): 2005–25. https://doi.org/10.1093/brain/awp172

16. Shaikh A.G., Beylergil S.B., Scorr L., Kilic-Berkmen G., Freeman A., Klein C., et al. Dystonia and tremor: a cross-sectional study of the dystonia coalition cohort. Neurology. 2021; 96(4): e563–74. https://doi.org/10.1212/WNL.00000000000110

17. Skogseid I.M. Dystonia – new advances in classification, genetics, pathophysiology and treatment. Acta. Neurol. Scand. Suppl. 2014; (198): 13–9. https://doi.org/10.1111/ane.12231

18. Vidailhet M., Grabli D., Roze E. Pathophysiology of dystonia. Curr. Opin. Neurol. 2009; 22(4): 406–13. https://doi.org/10.1097/WCO.0b013e32832d9ef3

19. Jinnah H.A., Albanese A., Bhatia K.P., Cardoso F., Da Prat G., de Koning T.J., et al. Treatable inherited rare movement disorders. Mov. Disord. 2018; 33(1): 21–35. https://doi.org/10.1002/mds.27140

20. Kuipers D.J.S., Mandemakers W., Lu C.S., Olgiati S., Breedveld G.J., Fevga C., et al. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann. Neurol. 2021; 89(3): 485–97. https://doi.org/10.1002/ana.25973

21. Pak L.A., Kuzenkova L.M., Fisenko A.P., Naydenko A.V. Genetically determined diseases in the structure of cerebral palsy in children. Rossiyskiy pediatricheskiy zhurnal. 2018; 21(6): 324–30. https://doi.org/10.18821/1560-9561-2018-21-6-324-330 (in Russian)

22. Hernández I.H., Cabrera J.R., Santos-Galindo M., Sánchez-Martín M., Domínguez V., García-Escudero R., et al. Pathogenic SREK1 decrease in Huntington’s disease lowers TAF1 mimicking X-linked dystonia parkinsonism. Brain. 2020; 143(7): 2207–19. https://doi.org/10.1093/brain/awaa150

23. Rachad L., El Kadmiri N., Slassi I., El Otmani H., Nadifi S. Genetic aspects of myoclonus-dystonia syndrome (MDS). Mol. Neurobiol. 2017; 54(2): 939–42. https://doi.org/10.1007/s12035-016-9712-x

24. Hellberg C., Alinder E., Jaraj D., Puschmann A. Nationwide prevalence of primary dystonia, progressive ataxia and hereditary spastic paraplegia. Parkinsonism Relat. Disord. 2019; 69: 79–84. https://doi.org/10.1016/j.parkreldis.2019.10.028

25. Berman B.D., Groth C.L., Sillau S.H., Pirio Richardson S., Norris S.A., Junker J., et al. Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study. J. Neurol. Neurosurg. Psychiatry. 2020; 91(3): 314–20. https://doi.org/10.1136/jnnp-2019-321794

26. Petrucci S., Valente E.M. Genetic issues in the diagnosis of dystonias. Front. Neurol. 2013; 4: 34. https://doi.org/10.3389/fneur.2013.00034

27. Mencacci N.E., Reynolds R., Ruiz S.G., Vandrovcova J., Forabosco P., Sánchez-Ferrer A., et al. Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain. 2020; 143(9): 2771–87. https://doi.org/10.1093/brain/awaa217

28. Jinnah H.A. The Dystonias. Continuum. 2019; 25(4): 976–1000. https://doi.org/10.1212/CON.0000000000000747

29. Carecchio M., Mencacci N.E. Emerging monogenic complex hyperkinetic disorders. Curr. Neurol. Neurosci. Rep. 2017; 17(12): 97. https://doi.org/10.1007/s11910-017-0806-2

30. Casper C., Kalliolia E., Warner T.T. Recent advances in the molecular pathogenesis of dystonia-plus syndromes and heredodegenerative dystonias. Curr. Neuropharmacol. 2013; 11(1): 30–40. https://doi.org/10.2174/157015913804999432

31. Kawarai T., Morigaki R., Kaji R., Goto S. Clinicopathological Phenotype and Genetics of X-Linked Dystonia-Parkinsonism (XDP; DYT3; Lubag). Brain. Sci. 2017; 7(7): 72. https://doi.org/10.3390/brainsci7070072

32. Haggstrom L., Darveniza P., Tisch S. Mild parkinsonian features in dystonia: Literature review, mechanisms and clinical perspectives. Parkinsonism Relat. Disord. 2017; 35: 1–7. https://doi.org/10.1016/j.parkreldis.2016.10.022

33. Pak L.A., Zherdev K.V., Kuzenkova L.M., Kurenkov A.L., Bursagova B.I. Therapeutic methods in cerebral palsy from the standpoint of evidence-based medicine. Rossiyskiy pediatricheskiy zhurnal. 2018; 21(3): 168–74. https://doi.org/10.18821/1560-9561-2018-21-3-168-174 (in Russian)

34. Junker J., Berman B.D., Hall J., Wahba D.W., Brandt V., Perlmutter J.S., et al. Quality of life in isolated dystonia: non-motor manifestations matter. J. Neurol. Neurosurg. Psychiatry. 2021. https://doi.org/10.1136/jnnp-2020-325193

35. Klein C., Münchau A. Progressive dystonia. Handb. Clin. Neurol. 2013; 113: 1889–97. https://doi.org/10.1016/B978-0-444-59565-2.00059-9

36. Blanchard A., Roubertie A., Frédéric M.Y., Claustres M., Collod-Béroud G. Monogenetic dystonia: revisiting the dopaminergic hypothesis. Rev. Neurol. (Paris). 2010; 166(4): 389–99. https://doi.org/10.1016/j.neurol.2009.09.007

37. Rossi M., Balint B., Millar Vernetti P., Bhatia K.P., Merello M. Genetic dystonia-ataxia syndromes: clinical spectrum, diagnostic approach, and treatment options. Mov. Disord. Clin. Pract. 2018; 5(4): 373–82. https://doi.org/10.1002/mdc3.12635

38. Bragg D.C., Armata I.A., Nery F.C., Breakefield X.O., Sharma N. Molecular pathways in dystonia. Neurobiol. Dis. 2011; 42(2): 136–47. https://doi.org/10.1016/j.nbd.2010.11.015

39. McClelland V.M. The neurophysiology of paediatric movement disorders. Curr. Opin. Pediatr. 2017; 29(6): 683–90. https://doi.org/10.1097/MOP.0000000000000547

40. Tarakad A., Jankovic J. Recent advances in understanding and treatment of Parkinson’s disease. Fac. Rev. 2020; 9: 6. https://doi.org/10.12703/b/9-6

41. Pearson T.S., Pons R. Movement disorders in children. Continuum. 2019; 25(4): 1099–120. https://doi.org/10.1212/CON.0000000000000756

42. Sun Y., Tsai P.J., Chu C.L., Huang W.C., Bee Y.S. Epidemiology of benign essential blepharospasm: A nationwide population-based retrospective study in Taiwan. PLoS One. 2018; 13(12): e0209558. https://doi.org/10.1371/journal.pone.0209558

43. Sławek J., Jost W.H. Botulinum neurotoxin in cervical dystonia revisited – recent advances and unanswered questions. Neurol. Neurochir. Pol. 2021. https://doi.org/10.5603/PJNNS.a2021.0029

44. Perez D.L., Edwards M.J., Nielsen G., Kozlowska K., Hallett M., LaFrance W.C. Jr. Decade of progress in motor functional neurological disorder: continuing the momentum. J. Neurol. Neurosurg. Psychiatry. 2021. https://doi.org/10.1136/jnnp-2020-323953

45. Stoessl A.J., Lehericy S., Strafella A.P. Imaging insights into basal ganglia function, Parkinson’s disease, and dystonia. Lancet. 2014; 384(9942): 532–44. https://doi.org/10.1016/S0140-6736(14)60041-6

46. Hauser R.A., Meyer J.M., Factor S.A., Comella C.L., Tanner C.M., Xavier R.M., et al. Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice. CNS Spectr. 2020; 1–10. https://doi.org/10.1017/S109285292000200X

47. Lallemant-Dudek P., Darios F., Durr A. Recent advances in understanding hereditary spastic paraplegias and emerging therapies. Fac. Rev. 2021; 10: 27. https://doi.org/10.12703/r/10-27

48. Oczkowska A., Kozubski W., Lianeri M., Dorszewska J. Genetic variants in diseases of the extrapyramidal system. Curr. Genomics. 2014; 15(1): 18–27. https://doi.org/10.2174/1389202914666131210213327

49. Mikhaylova S.V., Zakharova E.Yu., Petrukhin A.S. Neurometabolic Diseases of Children and Adolescents. Diagnostics and Approaches to Therapy [Neyrometabolicheskie zabolevaniya u detey i podrostkov. Diagnostika i podkhody k lecheniyu]. Moscow: Litterra; 2011. (in Russian)

50. Bragg D.C., Sharma N., Ozelius L.J. X-Linked Dystonia-Parkinsonism: recent advances. Curr. Opin. Neurol. 2019; 32(4): 604–9. https://doi.org/10.1097/WCO.0000000000000708

51. Roze E., Lang A.E., Vidailhet M. Myoclonus-dystonia: classification, phenomenology, pathogenesis, and treatment. Curr. Opin. Neurol. 2018; 31(4): 484–90. https://doi.org/10.1097/WCO.0000000000000577

52. Downs A.M., Roman K.M., Campbell S.A., Pisani A., Hess E.J., Bonsi P. The neurobiological basis for novel experimental therapeutics in dystonia. Neurobiol. Dis. 2019; 130: 104526. https://doi.org/10.1016/j.nbd.2019.104526

53. Stahl C.M., Frucht S.J. Focal task specific dystonia: a review and update. J. Neurol. 2017; 264(7): 1536–41. https://doi.org/10.1007/s00415-016-8373-z

54. Draganski B., Bhatia K.P. Brain structure in movement disorders: a neuroimaging perspective. Curr. Opin. Neurol. 2010; 23(4): 413–9. https://doi.org/10.1097/WCO.0b013e32833bc59c

55. Hess C.W., Ofori E., Akbar U., Okun M.S., Vaillancourt D.E. The evolving role of diffusion magnetic resonance imaging in movement disorders. Curr. Neurol. Neurosci. Rep. 2013; 13(11): 400. https://doi.org/10.1007/s11910-013-0400-1

56. Christensen C.K., Walsh L. Movement disorders and neurometabolic diseases. Semin. Pediatr. Neurol. 2018; 25: 82–91. https://doi.org/10.1016/j.spen.2018.02.003

57. Ebrahimi-Fakhari D., Van Karnebeek C., Münchau A. Movement disorders in treatable inborn errors of metabolism. Mov. Disord. 2019; 34(5): 598–613. https://doi.org/10.1002/mds.27568

58. Brüggemann N., Klein C. Genetics of primary torsion dystonia. Curr. Neurol. Neurosci. Rep. 2010; 10(3): 199–206. https://doi.org/10.1007/s11910-010-0107-5

59. Jinnah H.A. Medical and surgical treatments for dystonia. Neurol. Clin. 2020; 38(2): 325–48. https://doi.org/10.1016/j.ncl.2020.01.003

60. Segawa M. Segawa disease. Brain Nerve. 2008; 60(1): 5–11. (in Japanese)

61. Kulshreshtha D., Maurya P.K., Singh A.K., Thacker A.K. Dopa-responsive dystonia in a child misdiagnosed as cerebral palsy. J. Pediatr. Neurosci. 2017; 12(2): 172–3. https://doi.org/10.4103/jpn

62. Nagatsu T., Nakashima A., Ichinose H., Kobayashi K. Human tyrosine hydroxylase in Parkinson’s disease and in related disorders. J. Neural. Transm. 2019; 126(4): 397–409. https://doi.org/10.1007/s00702-018-1903-3

63. Factor S.A. Management of Tardive Syndrome: Medications and Surgical Treatments. Neurotherapeutics. 2020; 17(4): 1694–712. https://doi.org/10.1007/s13311-020-00898-3

64. Saranza G.M., Whitwell J.L., Kovacs G.G., Lang A.E. Corticobasal degeneration. Int. Rev. Neurobiol. 2019; 149: 87–136. https://doi.org/10.1016/bs.irn.2019.10.014

65. Jabbari E., Holland N., Chelban V., Jones P.S., Lamb R., Rawlinson C., et al. Diagnosis across the spectrum of progressive supranuclear palsy and corticobasal syndrome. JAMA Neurol. 2020; 77(3): 377–87. https://doi.org/10.1001/jamaneurol.2019.4347

66. Boy N., Mühlhausen C., Maier E.M., Heringer J., Assmann B., Burgard P., et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J. Inherit. Metab. Dis. 2017; 40(1): 75–101. https://doi.org/10.1007/s10545-016-9999-9

67. Kuzenkova L.M., Pak L.A., Kondakova O.B., Lyalina A.A., Tsygankova P.G., Kanivets I.V., et al. Infantile parkinsonism-dystonia, type 1 (case report). Nevrologicheskiy zhurnal imeni L.O. Badalyana. 2020; 1(4): 232–41. https://doi.org/10.17816/2686-8997-2020-1-4-232-241 (in Russian)

68. Berardelli A., Conte A. The use of botulinum toxin for treatment of the dystonias. Handb. Exp. Pharmacol. 2021; 263: 107–26. https://doi.org/10.1007/164_2019_339

69. Singh M., Agrawal M. Deep brain stimulation for tremor and dystonia. Neurol. India. 2020; 68: 187–95. https://doi.org/10.4103/0028-3886.302472

70. Dressler D., Altavista M.C., Altenmueller E., Bhidayasiri R., Bohlega S., Chana P., et al. Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity. J. Neural. Transm. 2021; 128(3): 321–35. https://doi.org/10.1007/s00702-021-02312-4

71. Sui Y., Tian Y., Ko W.K.D., Wang Z., Jia F., Horn A., et al. Deep brain stimulation initiative: toward innovative technology, new disease indications, and approaches to current and future clinical challenges in neuromodulation therapy. Front. Neurol. 2021; 11: 597451. https://doi.org/10.3389/fneur.2020.597451

72. Anandan C., Jankovic J. Botulinum toxin in movement disorders: an update. Toxins. 2021; 13(1): 42. https://doi.org/10.3390/toxins13010042

73. Ahmed R., Griffiths B., Lumsden D.E. Dystonia in paediatric intensive care: a retrospective prevalence study. Arch. Dis. Child. 2020; 105(9): 912–4. https://doi.org/10.1136/archdischild-2018-316421