| Considering IVIG therapy for your child's condition? |
| You can contact Dr. Kovacevic by e-mail and ask for his opinion on the applicability of IVIG treatment in your child's case. If you would prefer to meet with the Doctor you can call our offices and arrange an appointment. If you decide to make the appointment, please make sure that copies of your child's' pertinent medical records arrive to our offices at least 1 week in advance of the appointment. Dr. Kovacevic insists on examining the medical records beforehand, so that the meeting can be more efficient and fruitful. |
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| Intravenozni imunoglobulin u terapiji neuropsihijatrijskih oboljenja dje~je dobi |
Dr. Kovacevic has had a vast experience in use of IVIG (intravenous immune globulin) therapy for various medical conditions in children, including Guillain-Barre syndrome, Kawasaki syndrome, Opsoclonus -Myoclonus syndrome, Dermatomyositis, Juvenile Rheumatoid Arthritis, PANDAS & PITAND, post-infectious Encephalitis, ADEM, Autism, etc. While extremely successful in Guillain-Barre, Kawasaki and Dermatomyositis, IVIG therapy has also shown great deal of promise in PANDAS and PITAND syndromes, post-infectious Encephalitis and ADEM (into this group belongs vaccine induced brain damage), and Opsoclonus-Myoclonus (without Neuroblastoma). The experience with use of IVIG in Autism has been less satisfactory, however, in carefully chosen cases a significant benefits can be achieved.
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| Najnovija medicinska istra`ivanja potvr|uju da bi infektivni vektori (bakterije, virusi) mogli igrati va`nu ulogu u patofiziologiji izvjesnih neuropsihijatrijskih bolesti dje~je dobi1,11,17,19,20. Postoji osnovana sumnja da su beta-hemoliti~ki streptokok grupe A (GABS), te (vjerojatno) neke druge bakterije i virusi, uzro~nici barem nekih slu~ajeva obsesivno-kompulzivnog sindroma1,8,19,20, neuropsihijatrijskih bolesti koje se manifestiraju "tikovima" (npr. Tourette sindrom)1,18,19,20 , autizma i bolesti tzv. "autisti~kog spektruma"10, te anoreksije nervoze17. Vjerojatan patofiziolo{ki mehanizam se temelji na neuronskom o{te}enju od strane autoimunih antitijela20. |
| Intravenozni imunoglobulin (IVIG) se pokazao korisnim u lije~enju autoimunih oboljenja4,6,7,9,13,15,18,21 i navedene se beneficije pokazuju i u lije{enju izvjesnih dje~jih neuropsihijatrijskih oboljenja1,3,8,10,14. Iako se precizan na~in djelovanja IVIG-a u neuropsihijatrijskim bolestima ne zna, predlo`eni mehanizam po kojem IVIG sprije~ava vezivanje autoimunih antitijela u tijelu ili smanjuje stvaranje autoimunih antitijela izgleda prihvatljiv3,4,21. Jo{ zanimljivija je nedavno predlo`ena teorija po kojoj IVIG mo`e biti od pomo}i u "ozdravljenju" ve} o{te}enih neurona (`ivaca)5,16. |
| Terapija sa intravenoznim imunoglobulinom u upotrebi je ve} niz godina i ista se pokazala jednostavnom i relativno sigurnom13. Izvjesne manje nuzpojave terapije, kao npr. povi{ena temperatura, bolovi u mi{i}ima, glavobolja, mu~nina ili povra~anje, vrtoglavica i ubrzani puls (tahikardija) primije}eni su u manje od 5% pacijenata i uglavnom ne zahtijevaju bilo kakovu terapiju. Rijetko (jedan u tisu}u pacijenata ili rje|e) ozbiljnije alergi~ne reakcije su primije}ene u pacijenata, no ukoliko su iste pravilno i pravovremeno lije~ene opasnosti od dugotrajnijih posljedica nije bilo. |
| Tehni~ki opis terapije s intravenoznim imunoglobulinom |
| Trenuta~no se proporu~uje slijede}e: IVIG u dozi od 750 mg/kg tjelesne te`ine dnevno kroz dva dana. Uobi~ajeno je pacijenta primiti na odjel rano ujutro, te ga po zavr{etku infuzije (koja obi~no traje izme|u 3 - 5 sati) otpustiti ku}i. Ukoliko se poka`e potrebnim, dodatne infuzije IVIG-a kao jednodnevna terapija (1.5 grama/kg tjelesne te`ine) mogu se davati u vremenskim razmacima od 28 dana. |
| Intravenozni imunoglobulin se pokazao korisnim u pacijenata sa slijede}im dijagnozama: Kawasaki sindrome, Guillain-Barre sindrome, dermatomiositis, PANDAS, PITAND, opsoclonus-myoclonus, neurolo{ke posljedice viralnog encefalitisa (posebice slu~ajeva uzrokovanim Herpes simplex virusom, enterovirusima, npr. Enterovirus 71), Stevens-Johnson sindrom, toksi~na epidermalna nekroliza, post-infekciozni encephalitis (akutni diseminirani encephalitis - ADEM; isti mo`e biti posljedicom izvjesnih viroza ili mo`e biti rezultatom reakcije na izvjesne vakcinacije), refractorna (neizlje~iva) epilepsija* , te u izvjesnom broju pa`ljivo izabranih slu~ajeva autizma i anoreksije nervoze. Budu}i da najnoviji podaci iz Izraela potvr|uju mogu}u korist upotrebe IVIG-a u pacijenata s izvjesnim malignim tumorima, u vrlo skoroj budu}nosti indikacije za upotrebu IVIG-a }e se pro{iriti. |
| *Vagal nerve stimulation might be another possibility in these patients; recent studies have shown very encouraging results. |
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| *Another potential benefit of IVIG treatment has been reported from Israel, and may be the most important one to date: large animal studies as well as limited studies on patients with cancer are indicating that treatment with IVIG significantly reduces metastatic spread of certain cancers, particularly melanoma, carcinoma and sarcoma in these patients. Possibility of IVIG as an adjunct therapy in Neuroblastoma and Nesidioblastosis appears a tempting prospect. |
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| Recent studies have found IVIG therapy beneficial in STEVENS-JOHNSON SYNDROME and TOXIC EPIDERMAL NECROLYSIS, two of the most severe skin reactions known in children. |
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| Treatment with IVIG (Intravenous Immunoglobulin) in neuropsychiatric disorders in children is still not considered a standard treatment for these diseases and might not be covered by some health insurance carriers. It is costly and there are no guarantees that it will be successful in any particular patient. Even if the desired effect has been achieved, it is still unknown how long would the benefit last and when and if additional treatment(s) might be needed. |
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Criteria for Admission to Treatment for PANDAS and PITAND syndromes and ADEM
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PANDAS
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(1) At some time in his or her life, the patient must have met diagnostic criteria (DSM IV) for one of the following neuropsychiatric disorders: Obsessive Compulsive Disorder, Tic Disorder (including Tourette's), Autism, (or Autistic Spectrum Disorder).
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(2) Pediatric onset: symptoms of the disorder first become evident between 18 months of age and the beginning of puberty.
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(3) The onset of clinically significant symptoms must be sudden (with or without a sub clinical prodrome), and/or there must be a pattern of sudden, recurrent, clinically significant symptom exacerbation and remissions ("wax and waning pattern"). Onset of a specific episode typically can be assigned to a particular day or week, at which time symptoms seem to "explode" in severity, and they are frequently associated with an infectious episode.
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(4) There must be evidence of an antecedent or concomitant infection. Such evidence might include a positive throat culture, positive streptococcal serologic findings (e.g. anti-streptolysin O or anti-streptococcal DNAse B), or a history of illness (e.g. pharyngitis, sinusitis, infection with Epstein-Barr virus, influenza, ?recurrent otitis media), and possibly recent exposure to childhood vaccination.
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(5) Presence of auto antibodies (anticardiolipin, antineuronal, antibody/antigen complexes, etc.)
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(6) During the exacerbation, the majority of patients will have an abnormal neuropsychiatric examination, frequently with hyperactivity and adventitious movements ("choreiform" movements).
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(7) Measurable clinical improvement following "Steroid Burst".
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PITAND
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(1) Current presence of symptoms (DSM IV) of Obsessive Compulsive Disorder, Tic Disorder (including Tourette's), Autism or Autistic Spectrum Disorder, and Anorexia Nervosa*.
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(2) Symptom onset between 18 months of age and puberty.
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(3) Episodic course of symptom severity characterized by the abrupt onset of symptoms and/or frequent, dramatic symptom exacerbation.
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(4) Symptom exacerbation associated with GABS infection.
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(5) Presence of abnormal neuropsychiatric examination, including motor hyperactivity, adventitious movements, tics, etc.
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(6) Measurable clinical improvement following "Steroid Burst".
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| DISQUALIFYING FACTORS (absolute): Presence of symptoms before 1 year of age. |
| DISQUALIFYING FACTORS (relative): Confirmed Dg. of Autism and/or Autistic Spectrum Disorder in sibling(s). |
| (*) Male patients with Anorexia Nervosa should be of a particular interest. |
| Modified "Allen criteria" (from Albert J. Allen Group A Streptococcal Infections and Childhood Neuropsychiatric Disorders CNS Drugs Oct. 1997 8(4) 267-275 |
| POST - INFECTIOUS ENCEPHALITIS (ADEM): |
| (1) Patient's history compatible with Acute Disseminated Encephalitis (symptoms appearing 2-3 weeks following a non-specific upper respiratory infection caused by virus or certain bacterial agents (Mycoplasma pneumoniae), MMR or influenza vaccination. |
| (2) Exclusion of viral encephalitis (by laboratory, and/or clinically). |
| (3) Presence of characteristic asymmetrical, bilateral hyperintense lesions of the same age in the white matter and deep gray matter (T2-weighted or FLAIR images) on MRI of the brain. |
| (4) Significant multifocal neurologic abnormalities. |
| (5) Steroid therapy failure |
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Criteria for IVIG Treatment for Autism
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Absolute Criteria
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(1) At some time in his or her life, the patient must have met diagnostic criteria (DSM IV) for Autistic Spectrum Disorder.
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(2) Patient has been diagnosed as a "classical" autism, PDD or PDD NOS.
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| (3) Patient has been classified as "Essential" Autism (after Miles, J. et al.). Patients must NOT have facial dysmorphism, an abnormal MRI study, and must have a normal to increased head circumference. |
| (4) Patient must have normal levels of IgA in quantitative immunoglobulin assay. |
| (5) Patient's age is between 2 and 10 years of age. |
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Contributing Major Criteria
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(1) Patient had an illness within six weeks before the onset of symptoms
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(2) Patient received a viral vaccine within 6 weeks before the onset of symptoms.
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(3) Patient’s symptoms have followed a period of apparently normal psychological development.
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(4) The onset of symptoms was SUDDEN (over period of days to weeks) or INTERMEDIATE (weeks to up to three months).
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| Contributing Minor Criteria |
| (1) Positive immunodeficiency battery (lymphocyte phenotyping). |
| (2) Abnormal complement studies (C3, C4, CH50). |
| (3) Abnormal cytokine levels (IL-1-alpha, IL-2, IL-6, IFN-gamma and TNF-alpha). |
| (4) Presence of serum myelin basic protein antibody and/or neuro-axon filament protein antibody. |
| Patient must meet ALL FIVE Absolute Criteria, and at least TWO Contributing Major Criteria and ONE Contributing Minor Criteria to be considered for the IVIG treatment. |
| Listed criteria are reproduced from Dr. Kovacevic's upcoming study on long-term IVIG use in autism. |
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