PANDAS

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Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) is defined as rapid, episodic onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms after a group A β-hemolytic streptococcal infection (GABHS).^[1] The current hypothesis for the pathology of PANDAS is that a streptococcal infection occurring in a vulnerable host causes antibody production and these antibodies cross-react with the cellular components of the basal ganglia. This process, known as molecular mimicry, is believed to be the process that causes the OCD and tic disorder symptoms in the PANDAS subgroup of patients. There is controversy in the medical field over the reality of this disease, as studies have failed to prove or disprove its existence.^[2] PANDAS became popular in the late 1990s and continues to be a highly researched and controversial topic in the field of pediatric neuroscience.

Contents 1 Identification 1.1 Definition 1.2 Association studies 1.3 Comparing PANDAS to Sydenham’s Chorea 1.3.1 Similarities 1.3.2 Differences 1.4 Hypothesized post-streptococcal disorders affecting the central nervous system 2 Adult-onset potential 3 Pathophysiology 3.1 Proposed mechanism 3.1.1 Antineuronal antibodies 3.1.2 Genetic predisposition 3.2 Echocardiogram studies 4 Potential/experimental treatment 4.1 Treat symptoms 4.2 Antibiotic prophylaxis 4.3 Plasmapheresis 4.4 Intravenous immunoglobulin 4.5 Risks 5 Controversy 6 Research 6.1 Pathology 6.2 Treatment and prevention 7 References 8 External links

Identification

Definition

PANDAS is not an officially recognized diagnosis. A paper published in 1998 introduced five criteria for diagnosing PANDAS:^[3]

1. Presence of OCD and/or a tic disorder
2. Prepubertal symptom onset
3. Episodic course of symptom severity
4. Association with GABHS infection
5. Association with neurological abnormalities

During the exacerbation periods, symptoms have been reported to sustain peak severity for several weeks before gradually sinking into remission.^[1] The patients generally remain free of OCD and/or tic disorder symptoms until they are infected with GABHS again, at which time the cycle repeats.

Other symptoms of PANDAS include emotional instability, difficulty with attention, separation anxiety, motoric hyperactivity, bed-wetting, and the frequent need to urinate.^[1] The most obvious symptom to notice is choreiform movements, rapid and well-performed but unintentional movements. Choreiform movements, which are thought to be linked with dysfunction of the caudate nucleus and putamen of the basal ganglia, has been noted as one the most dependable and distinguishing feature to be used in identifying a child with PANDAS.

Association studies

Numerous studies have been completed to show the association between GABHS infections and the onset of OCD and tic disorders. In Rhode Island in 1989, after a GABHS outbreak a 10-fold increase of motor tics was identified.^[2] A 2005 case study of 144 patients concluded that a streptococcal infection within 3 months more than doubles a child’s odds of developing a neuropsychiatric disorder, indicated by an odds ratio (OR) of 2.22.^[4] Furthermore, this study found that a GABHS infection within 12 months increases a child’s likelihood of developing OCD or a tic disorder by almost double (OR 1.91). The risk of developing OCD or a tic disorder was also found to be greatly elevated after multiple GABHS infections within a 12-month period.

Comparing PANDAS to Sydenham’s Chorea

PANDAS and Sydenham's chorea (SC) have the potential to be mistaken for each other during diagnosis. Sydenham’s chorea, found in 20–30% of rheumatic fever (RF) patients, is caused by a GABHS infection.^[5] Since GABHS infection is also hypothesized to cause PANDAS, the similarities of the two can lead to a misdiagnosis. Studies on SC have shown that antibodies produced to fight against streptococcal antigens associated with the M-protein of GABHS cross-react with the epitopes, a component of the cell wall, on brain tissue.^[1] PANDAS is thought to be misdiagnosed as Sydenham’s chorea more than normal in underdeveloped countries due to the greater prevalence of rheumatic fever.

Similarities

PANDAS and Sydenham’s chorea are similar in that they both have prepubertal onset ages (SC has an onset range of 5–15 years of age, while onset age range of PANDAS is 3 to puberty).^[5] Studies of both diseases have also shown increased expression of the D8/17 monoclonal antibody in various studies. Some studies also report similar anti-basal ganglia antibodies found in both diseases; 40, 45, and 60 kDa molecular weights were found to be dominant in SC and 60 kDa molecular weight was dominant in PANDAS. Both conditions also show similar volumetric increases in the caudate, putamen, and globus pallidus of the brain without exhibiting overall increases in cerebral, prefrontal, midfrontal, or thalamic volumes.

Differences

PANDAS is dominant in males (2.6:1), while SC is more prevalent in females.^[5] Studies have indicated a genetic link in PANDAS, but SC does not show similar trends. The movement types caused by the two diseases also differ. PANDAS causes choreiform movements, such as soft signs that generally do not cause functional impairment, while SC results in choreatic movements that are more irregular and cause functional impairment.

Hypothesized post-streptococcal disorders affecting the central nervous system

Other diseases are hypothesized as being linked with a streptococcal infection.^[6] Some of these diseases are:

• Sydenham's chorea
• Tourette syndrome
• Dystonia
• Myoclonus
• Parkinsonism
• Paroxysmal Dystonic Choreoathetosis
• Motor Stereotypies
• Encephalitis lethargica

Adult-onset potential

One of the criteria for PANDAS is a prepubertal onset age. However, there have been some case studies of adults who have the other four criteria for a PANDAS diagnosis. A 25-year-old male was reported as developing OCD after having a sore throat.^[7] Tests indicated that he had been infected with GABHS, demonstrated by elevated levels of anti-streptolysin O and antideoxyribonuclease B titers. The patient’s globus pallidus, generally enlarged in PANDAS patients, was found to have a minor abnormality in his MRI results. This patient was also found to have increased levels of D8/17 monoclonal antibody, positive antistriatal antibodies, and positive anticytoskeletal antibodies, all of which are often found in children diagnosed with PANDAS. These clinical findings support a post-streptococcal process in the OCD development of this adult patient. Other studies have shown similar results^[8], indicating that PANDAS-related OCD and tic disorders may occur in adults as well as children.

Pathophysiology

Proposed mechanism

Magnetic resonance imaging studies have shown that the average size of the basal ganglia (specifically the caudate, putamen, and globus pallidus) of PANDAS patients is significantly larger than that of normal patients.^[9] However, no overall increase in volume of cerebral, prefrontal, midfrontal, or thalamic was identified.

Antineuronal antibodies

The proposed mechanism of PANDAS involves a pathogenic role of autoantibodies as the cause of the OCD and/or tic disorders. However, not all of the criteria to confirm the pathology of PANDAS have been proven. The five criteria, all of which need to be present to confirm an autoimmune pathogenesis in a disease, are:^[2]

1. Identification of autoantibodies
2. Presence of autoantibodies at the pathologic site
3. Induction of symptoms with autoantigens
4. Passive transfer of the disorder to animal models
5. Positive response to immunomodulatory therapy

A study researching the association between repeated GABHS infection and onset of OCD found that children with OCD have a greater than normal population of both B-lymphocytes positive for a D8/17 specific antigen and antineuronal antibody titers.^[10] This study supports the hypothesis that antibodies that develop during the GABHS infection cross-react with the brain tissue of children, leading to the onset of OCD and/or tic disorders. Another study found antineuronal antibodies in 63.6% of PANDAS patients, as compared the only 9% of control patients (those with GABHS infections but not diagnosed with PANDAS).^[11] This study also found increased levels of anti-streptolysin O and antideoxyribonuclease B in the PANDAS subgroup patients. These results support that GABHS infection alone cannot account for the increased levels of antineuronal antibodies in PANDAS patients and suggest that they play a role in the development of the neuropsychiatric disorders.

However, not all studies have been consistent with showing an antineuronal antibody link between GBAHS and neuropsychiatric symptom exacerbations. If antineuronal antibodies act via molecular mimicry to cause the neuropsychiatric symptoms associated with PANDAS, it is hypothesized that these levels should increase after a streptococcal infection. A 2008 study failed to find a statistically significant association between immunoflourescent reactivity and clinical severity or elevated anti-streptococcal titers.^[6] Another study in which antineuronal antibodies were injected into rodent striatum at high and low concentrations failed to find any behavioral differences between the two test groups.^[12] This contradicts the idea that increased levels of antineuronal antibodies will cause more sever neuropsychiatric symptoms.

Genetic predisposition

Steptococcus is relatively abundant, especially amongst school-aged children. The fact that many children are exposed to GABHS and (1) do not get infected or (2) get infected but do not develop a neuropsychiatric disorder, this indicates a genetic vulnerability of PANDAS.^[1] Further support of a genetic predisposition is that the occurrences of OCD and tic disorders have been shown to be higher in first-degree relatives of patients included in the PANDAS subgroup.

Echocardiogram studies

Echocardiogram studies on PANDAS patients have shown mixed results. One study of 60 PANDAS patients found no evidence of significant aortic valve regurgitation.^[13] A solitary patient (1.67%) in this study was found to have only mild mitral regurgitation. Furthermore, all patients were reported as having standard left, atrial, and ventricular size and standard left ventricular function. Another study on children with post-streptococcal tic disorders found dissimilar results. This study reported that patients who had a sign of streptococcal infection produced much higher rates of echocardiographic abnormalities (58% had abnormalities) compared to the control group that did not show signs of a past streptococcal infection (22%).^[14] The authors of this study concluded that these results suggest a post-streptococcal pathogenesis to the heart abnormalities.

Potential/experimental treatment

This article's factual accuracy is disputed. Please see the relevant discussion on the talk page. (December 2008)

Treat symptoms

The tic disorder symptoms of PANDAS have been successfully treated with α-adrenergic agonists and dopamine blockers.^[15] Behavioral therapies have also been successfully implemented to treat the symptoms associated with PANDAS patients. Since the efficacy and efficiency of other methods of treatment have not been proven, this is often the chosen form of treatment.

Antibiotic prophylaxis

The use of antibiotic prophylaxis has been studied as a preventative measure to PANDAS symptom exacerbations. Since the GABHS infections are hypothesized to be the trigger of the OCD and tic disorder symptoms in the PANDAS subgroup patients, then preventing these infections would be predicted to decrease the occurrence or exacerbations of these symptoms. These studies, like many surrounding PANDAS, have resulted in varying results. The results of a 1999 study indicated that penicillin did not adequately prevent GABHS infections in patients.^[16] In this study, 14 of the 35 GABHS infections occurred in the patients given penicillin.

However, a more recent study (2005) indicated that both penicillin and azithromycin might decrease the occurrence of GABHS infections.^[17] In this study, the 23 participants were asked to recall their symptoms in the previous year, and these reports then compared to the level of symptoms during antibiotic treatment. The azithromycin treatment was compared to a control group that were given penicillin. This study reported a 61% reduction in overall OCD and tic disorder symptoms and a 94% reduction in GABHS infection-triggered symptoms, compared to the previous year. However, no significant difference was seen between the "control" penicillin group and the azithromycin group. The authors of this study suggested that their results supported the etiologic role of GABHS infections in children with OCD and tic disorders. In letters to the journal after this article was published, two groups of scientists raised serious concerns about the small size of the sample, the design of the study, and the interpretation and reliability of the data obtained; with one letter stating that "fundamental aspects of the study design are flawed" and arguing that the results could not be used to guide medical decision-making.^[18][19]

Plasmapheresis

Plasmapheresis is the process of exchanging plasma in which the patient’s blood is sent through a machine, additional donor plasma is added, and then the blood is returned to the patient. Studies on using this method for treating PANDAS have resulted in mixed conclusions. A case study of a 10-year old boy indicated improved symptom conditions after his first few plasma exchange sessions.^[15] Another study indicated that plasmapheresis can reduce symptoms severity by 55%.^[1] Opposing this study is a 2000 study that found that plasma exchange did not provide benefits to PANDAS patients.^[20]

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) treatment, a procedure in which antibodies from the plasma of many donors is collected and inserted into the patient, has been shown to have varying degrees of effectiveness in PANDAS patients. One study indicated that IVIG treatment reduced the neuropsychiatric symptoms severity by 45%, and 82% of these patients had prolonged effects.^[1]

Risks

These treatments have not been entirely proven for efficacy and efficiency. Both plasmapheresis and IVIG are invasive surgical procedures, thus they carry the risk of infection involved with such treatments. In addition, negative side effects, such as vomiting and headaches, have been seen with patients treated with these procedures. The NIH suggests that these treatments be “reserved for severely ill patients, and administered by a qualified team of health care professionals.”^[21]

Controversy

PANDAS is currently a very controversial subject in the medical field. Various studies completed on the disease have been found to contradict each other. Many factors, such as stress, can initiate exacerbations of neuropsychiatric symptoms. Thus, it may be that GABHS infections are a trigger, but not the cause, of the symptom exacerbations.^[4] Skeptics^[vague] also point out that the co-concurrence of a GABHS infection and OCD/tic disorder symptoms could be a random coincidence. Of school-aged children, 1–2% have OCD and 10–25% are diagnosed with a tic disorder.^[1] Many children are infected when there is a regional GABHS outbreak, thus indicating the possibility that the overlap of neuropsychiatric disorders and a GABHS infection could be pure coincidence. Select researchers also believe that PANDAS symptoms may not be totally associated with GABHS infections, but could have links to a wide array of other infections.^[22] On the other hand, researchers report an increasing volume of evidence to support the existence of PANDAS and an etiologic role for molecular mimicry.^{[dubious – discuss]} The studies previously mentioned in this article have reported finding evidence to support the existence and pathology behind PANDAS.

Research

Pathology

Clinical diagnosis and epidemiological uncertainties of PANDAS still exists. Questions about regional specificity and the cellular basis of the autoimmune portion of the disease are also present and need to be addressed in future research. Further studies on the link between GABHS antibodies and the potential for molecular mimicry to cause the neuropsychiatric symptoms of PANDAS are currently underway.

Treatment and prevention

The differing results of antibiotic prophylaxis studies indicate a need for further research in this area. Various groups are carrying out studies to determine the efficacy and effectiveness of treatment for children hypothesized to have PANDAS.

References

External links

• Pediatrics and Developmental Neuropsychiatry Branch of the National Institute of Health
• List of Internet Resources

v • d • e Topics related to Tourette syndrome Main Causes and origins · History · Sociological and cultural aspects · Treatment Terms Coprolalia · Copropraxia · Echolalia · Echopraxia · Palilalia · PANDAS · Sensory phenomena · Tic · Tic disorder · Tourettism History Jean-Martin Charcot  · Georges Gilles de la Tourette  · Jean Marc Gaspard Itard  · Arthur K. Shapiro Organizations Tourette Syndrome Association · Tourette Syndrome Foundation of Canada · Tourettes Action Media I Have Tourette's but Tourette's Doesn't Have Me · John's Not Mad · The Tic Code · "Le Petit Tourette" · Motherless Brooklyn Notable people Mahmoud Abdul-Rauf · Howard Ahmanson, Jr · Basshunter · Pete Bennett · Brad Cohen · Jim Eisenreich · Tim Howard · Samuel Johnson · André Malraux · Tobias Picker · Nick van Bloss · Michael Wolff