The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data

Figures & data

Table 1. description of the immunopathogenic features of pediatric neurodegenerative disorders

Immune molecule involved in the pathogenesis	Disease in which it has been recognized	Innate vs Acquired immune system (IS)	Mechanism of Action	References
TLR2, 3, 4	PD, ALS, AD	Innate IS	Trigger to start innative immune response	Okun E. et al, 2009 (6); Letiembre M et al, 2009 (7); Jackson AC et al., 2006 (8)
TLR4, 9	MS, EAE	Innate IS	Trigger to start innative immune response	Bsibsi M et al, 2002 (4); Prinz M et al, 2006 (11); van Noort JM, 2007 (12)
NLRs	AD	Innate IS	Recognition of intracellular invaders	Visser L et al, 2006 (14)
RAGE	MS	Innate IS	Increased activity following oxidative stress, immune and/or inflammatory responses, and upon altered cell functions	Qin J et al, 2008 (16); Sternberg Z, 2008 (17)
Adenosine receptors	AD	Innate IS	Regulation of inflammation by modulation of cytokine release	van der Putten C, 2009 (19); Salminen A, 2009 (20)
Complement fragment C1q, C3, C4	PD, ALS, AD, MS, Traumatic brain injury, SLE, Huntington's chorea	Innate IS	Opsonization, activation of acquired immune system, contribution in inflammatory processes leading to gliosis, axonal death and basal gangla abnormalities	Bonifati DM, 2007 (21); Gasque P, 2000 (22)
ABGA	PANDAS, SC, TS	Acquired IS	Molecular mimicry, cross-reaction with neuronal antigens	Church A, 2004 (58); Pavone P et al, 2004 (59); Gause C et al, 2009 (60); Morer A et al, 2008 (61)
aPL	SLE, APS	Acquired IS	Molecular mimicry, cross-reaction with neuronal antigens	Peluso S et al, 2012 (88); Lazurova I et al, 2007 (89)
anti-MOG	ADEM	Acquired IS	Molecular mimicry, cross-reaction with neuronal antigens	O'Connor KC et al, 2007 (98)
T-lymphocytes subsets B-lymphocytes anti-MOG	MS	Innate IS and Acquired IS	Production of proinflammatory cytokines; Interaction with metalloproteinases (MMPs); Activation of proinflammatory humoral immunity; Molecular mimicry, cross-reaction with neuronal antigens	Frohman EM et al, 2006 (141); Charo IF et al, 2006 (142); Hemmer B et al, 2006 (143); Baranzini SE et al, 1999 (144); Colombo M et al, 2000 (145); Krumbholz M et al, 2005 (146); Cepok S et al, 2005 (147); Genain CP et al, 1999 (148); Berger T et al, 2003 (149); Reindl M et al (150)
Anti-gangliosides antibodies T-lymphocytes subsets	GBS	Acquired IS	Molecular mimicry, cross-reaction with neuronal antigens; Production of proinflammatory cytokines	Kuwabara S et al, 2004 (211); Magira EE et al, 2003 (212); Hartung HP et al, 2002 (213)

* PD: Parkinson Disease.

** ALS: Amyotrophic Lateral Sclerosis.

° AD: Alzheime Disease.

" MS: Multiple Sclerosis.

¨ EAE: Experimental autoimmune encephalitis.

^$ NLRs; Nucleotide-binding oligomerization domain-like receptors.

^% RAGE: Receptor for advanced glycation end products.

^¢ SLE: Systemic lupus erythematosus.

°° ABGA: Anti basal ganglia antibodies.

^¥ PANDAS: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

^£ SC: Sydenham's Chorea.

^€ TS: Tourette syndrome.

^₠ aPL: Antiphospholipid antibodies.

^¶ APS: Antiphospholipid syndrome.

^⌘ anti-MOG: autoantibodies against the tetrameric myelin oligodendrocyte glycoprotein (MOG).

^⌥ ADEM: Acute disseminated encephalomyelitis.

^ GBS: Guillan-Barré syndrome.

Table 2. Resume of the immunotherapeutic approaches used for the treatment of the most frequent pediatric neurodegenerative disorders

Type of movement disorder	Study Design	Number of patients	Drugs and dosages	Efficient/not efficient	Author, years of study, reference number
SC	Randomized clinical trial (RCT)	22 patients, 15 controls	Methylprednisolone 2 mg/kg, 4 weeks	Efficient	Paz et al, 2005, (72)
SC	Retrospective, observational	584 cases of rheumatoid fever, 177 SC patients, 32 prednisone-treated patients vs 14 untreated	Methylprednisolone	Efficient	Walker et al, 2007, (73)
SC	Prospective, observational	10 patients with severe paralytic SC	Methylprednisolone tapered with oral Deflazocort	Efficient	Fusco et al, 2012, (74)
SC	RCT	18 patients	4 patients IVIG, 6 patients methylprednisolone, 8 PE	IVIG more efficient than PE, more efficient than methylprednisolone	Garvey et al, 2005, (75)
SC	Case report	2 patients	IVIG 0.4 mg/kg/day for 5 days	Efficient	Van Immerzeel, 2010, (76)
SC	RCT	10 patients, 10 controls	IVIG 2 g/kg, vs standard treatment	Efficient	Walker et al, 2012, (77)
PANDAS	RCT	30 patients	10 patients PE 5 exchanges for 2 weeks, 9 patients IVIG 1g/kg for 2 days, 10 patients placebo saline solution	PE more effiecient than IVIG than placebo.	Perlmutter et al, 1999, (79)
TS	Case study	1 TS, 1 OCD, 2 both	IVIG in one patients, prednisolone in 1 and PE in one	Efficient	Allen et al, 1995, (81)
TS	Prospective, Observational	7 patients with neuroleptic resistant TS among 60 TS patients	IVIG 1 g/kg	Efficient	Zykov et al, 2009, (83)
TS	Case report	1 patient	Celecoxib	Efficient	Muller, 2004, (85)
ADEM	Case report	3 patients	IVIG 400 mg/kg/day for 5 days	Efficient	Nishikawa et al, 1999, (111)
ADEM	Observational	4 steroid-resistant patients	IVIG 400 mg/kg/day for 5 days	Efficient	Pradhan et al, 1999, (112)
ADEM	Case report	1 steroid refractory patient	IVIG 400 mg/kg/day for 5 days	Efficient	Hahn et al, 1996, (115)
ADEM	Case report	1 steroid refractory patient	IVIG 400 mg/kg/day for 5 days	Efficient	Imataka et al, 2014, (114)
ADEM	Case report	2 patients	PE	Efficient	Kanter et al, 1995, (117)
ADEM	Case report	1 patient	PE 4 times (after methylprednisolone and IVIG with no results)	Efficient	Miyazawa et al, 2001, (123)
ADEM	Retrospective, observational	13 patients	PE 5 sessions (in 12 patients who did not respond to methylprednisolone and IVIG)	Efficient	Khurana et al, 2005, (126)
MS	Retrospective, observational	4 patients	Mitoxantrone with cumulative dose of 36, 68, 84 and 120 mg/m	Efficient	Kornek et al, 2011, (164)
MS	Retrospective, observational	19 patients	Mitoxantrone 20 mg	Efficient	Etemadifar et al, 2014, (165)
MS	Retrospective, observational	17 patients	Cyclophosphamide	Efficient	Makhani et al, 2009, (166)
MS	Case report	3 patients	Natalizumab, 3–5 mg/kg every 4 weeks, after no response to IFN-βand steroid	Efficient	Huppke et al, 2008, (167)
MS	Case report	1 patient	Natalizumab, 3–5 mg/kg every 4 weeks, after no response to IFN-βand steroid	Efficient	Borriello, 2009, (168)
MS	Prospective, observational	19 patients	Natalizumab, 300 mg every 4 weeks	Efficient	Ghezzi et al, 2010, (169)
NMO	Case report	1 patient	4 courses of rituximab, 375 mg/m^2, every other week	Efficient	Dembinski et al, 2013, (192)
NMO	Retrospective, observational	5 patients	Rituximab	Efficient	Longoni et al, 2014, (193)
NMO, Devic's disease	Case report	1 patient	Mycofenolate mofetil, 2 g/day, after no response to methylprednisolone and azathioprine	Efficient	Falcini et al, 2006, (200)
GBS	RCT	18 patients; 9 cases, 9 controls	IVIG 1 g/kg/ day for 2 d and supportive treatment	Efficient	Gurses et al, 1995, (239)
GBS	Comparative study, prospective	7 patients 8 comparable children receiving PE	IVIG 0.4 g/kg/day for 5 days, PE in comparison group	Efficient	Abd-allah et al, 1997, (242)
GBS	Comparative study, prospective cases, retrospective controls	33 patients with very severe GBS; 22 cases, 11 controls	IVIG 0.4 g/kg/day for 5 d and supportive treatment for the other group	Efficient	Singhi et al, 1999, (240)
GBS	RCT- 2 parts	21 patients in study 1 51 patients in study 2	IVIG 1 g/kg for 2 d vs no treatment in study 1 IVIG 1g/kg for 2 d vs 0.4 g/kg for 5 days	Efficient, study 2: no difference	Korinthenberg et al, 2005, (241)
GBS	RCT	20 cases received IVIG, 21 patients received PE	IVIG 0.4 g/kg/days for 5 d in cases, 5 day courses of 1 volume of PE in the second group	In children requiring mechanical ventilation (MV), PE is better than IVIG regarding the duration of MV but not PICU stay or the short term neurological outcome	El-bayoumi et al, 2011, (243)

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