. 2022 Jun 3;14(1):35.

doi: 10.1186/s11689-022-09446-w.

Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder

Jonathan D Santoro^{1

2}, Rebecca Partridge³, Runi Tanna⁴, Dania Pagarkar⁴, Mellad Khoshnood⁵, Mustafa Rehmani⁶, Ryan M Kammeyer⁷, Grace Y Gombolay^{8

9}, Kristen Fisher¹⁰, Allison Conravey¹¹, Jane El-Dahr¹², Alison L Christy¹³, Lina Patel¹⁴, Melanie A Manning¹⁵, Heather Van Mater¹⁶, Michael S Rafii^{17

18}, Eileen A Quinn¹⁹

Affiliations

¹ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd, MS82, Los Angeles, CA, 90027, USA. jdsantoro@chla.usc.edu.
² Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. jdsantoro@chla.usc.edu.
³ Down Syndrome Program at Virginia Mason, Seattle, WA, USA.
⁴ Keck School of Medicine at the University of Southern California, Los Angeles, USA.
⁵ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd, MS82, Los Angeles, CA, 90027, USA.
⁶ Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Colorado, Aurora, CO, USA.
⁸ Department of Neurology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁹ Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Division of Neurology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
¹¹ Ochsner Health, Department of Pediatrics, New Orleans, LA, USA.
¹² Section of Pediatric Allergy, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
¹³ Providence Health, Portland, OR, USA.
¹⁴ Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁵ Division of Medical Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
¹⁶ Division of Rheumatology, Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁷ Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
¹⁸ Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine at the University of Southern California, San Diego, CA, USA.
¹⁹ Department of Pediatrics, University of Toledo College of Medicine and Life Science, Toledo, OH, USA.

PMID: 35659536
PMCID: PMC9164321
DOI: 10.1186/s11689-022-09446-w

Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder

Jonathan D Santoro et al. J Neurodev Disord. 2022.

. 2022 Jun 3;14(1):35.

doi: 10.1186/s11689-022-09446-w.

Authors

Affiliations

¹ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd, MS82, Los Angeles, CA, 90027, USA. jdsantoro@chla.usc.edu.
² Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. jdsantoro@chla.usc.edu.
³ Down Syndrome Program at Virginia Mason, Seattle, WA, USA.
⁴ Keck School of Medicine at the University of Southern California, Los Angeles, USA.
⁵ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd, MS82, Los Angeles, CA, 90027, USA.
⁶ Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Colorado, Aurora, CO, USA.
⁸ Department of Neurology, Children's Healthcare of Atlanta, Atlanta, GA, USA.
⁹ Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Division of Neurology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
¹¹ Ochsner Health, Department of Pediatrics, New Orleans, LA, USA.
¹² Section of Pediatric Allergy, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
¹³ Providence Health, Portland, OR, USA.
¹⁴ Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁵ Division of Medical Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
¹⁶ Division of Rheumatology, Department of Pediatrics, Duke University, Durham, NC, USA.
¹⁷ Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
¹⁸ Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine at the University of Southern California, San Diego, CA, USA.
¹⁹ Department of Pediatrics, University of Toledo College of Medicine and Life Science, Toledo, OH, USA.

PMID: 35659536
PMCID: PMC9164321
DOI: 10.1186/s11689-022-09446-w

Abstract

Background: Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention.

Methods: A retrospective, multi-center, case-control study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living, and/or a new movement disorder) and no other explanation for symptoms.

Results: Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04-1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64-37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88-9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective.

Conclusions: This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.

Keywords: Cerebrospinal fluid; Down syndrome; Encephalopathy; Immunotherapy; Regression.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Histogram of symptom onset by age

**Fig. 2**
Number of patients with neurodiagnostic study abnormalities (n). None: n = 43 (60%)

**Fig. 3**
Axial T2 FLAIR sequence demonstrating T2 signal prolongation along the gray, white junction bilaterally

**Fig. 4**
Axial GRE sequence demonstrating symmetric hypodensities in the bilateral deep gray nuclei consistent with calcification

See this image and copyright information in PMC

References

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Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder

Affiliations

Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical