In this prospective, blinded, case-control study of children who met published diagnostic criteria for PANDAS, there was no temporal association between clinical exacerbations and antecedent GABHS infections documented by microbiologic and/or immunologic criteria. The number of “hits” was higher in the non-PANDAS cases than in the PANDAS cases, although this difference was not statistically significant. Our findings support those from an earlier prospective, blinded, case-control study in which greater than 75% of clinical exacerbations were not temporally related to infections. However, in that study, the only “hits” occurred in the PANDAS cases, and PANDAS cases were significantly more likely to meet criteria for a new GABHS infection.7
The basis for this apparent difference is unlikely to be due to methodological differences, as each of six sites participating in this study were also sites for the earlier study7
and a virtually identical protocol was used in selecting and monitoring the PANDAS and non-PANDAS cases. Taken together, the implication from these two intensive, prospective studies (involving more than 160 unique subjects) is that there is no convincing evidence for an ongoing causal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.
Given the binary nature of exacerbations (Yes or No), secondary analyses designed to determine if symptom severity worsening occurred following a newly diagnosed GABHS infection were also conducted. These analyses also failed to support a link between any documented GABHS infections and symptom exacerbations (See Supplement 1
, available online). The one significant difference was that the PANDAS cases were significantly more likely to receive a course of antibiotics during episodes of pharyngitis from their primary care clinicians compared to the non-PANDAS cases. This may reflect the practice of many community-based practitioners to prescribe antibiotics once a diagnosis of PANDAS has been made.50
On average, the use of these antibiotics did not influence subsequent changes in tic or OC symptom severity (see Table S3
, available online).
Contrary to projections based on the retrospective
study of Swedo et al.3
the PANDAS cases identified in this study experienced a lower rate of clinical exacerbations and documented bona fide
new GABHS infections than expected. In addition, they did not typically show (during periods of tic or OC symptom exacerbation) a sudden increase in the severity of neuropsychiatric comorbidity including: emotional lability, intense anxiety, cognitive deficits, oppositional behaviors, motoric hyperactivity, choreiform movements, jerks of the hands, arms or legs, clumsiness, slurred speech, impaired dexterity or more difficulty drawing.
Another important potentially confounding issue in almost all of the earlier prospective longitudinal studies5,8
is that the criteria used to determine whether or not a new GABHS infection had occurred may have been flawed. In-depth analysis of prospectively and frequently collected culture and antibody data from this study, in conjunction with the earlier Kurlan et al. study7
has revealed that a single point or widely spaced cultures and/or only “elevated” ASO or ADB titers are often times misleading.49
Indeed, some cases had repeated positive throat cultures for the same strain of GABHS and their titers remained elevated over the entire 25 months of this study.49
These findings must be interpreted in light of several limitations of the study.37
First, although the expert clinical evaluators were blinded to the results of streptococcal laboratory tests and the decisions made by the patients’ primary care clinicians to treat or not to treat GABHS infections, they were not blinded to the presumptive PANDAS status of the case. This lack of blindness could have influenced the clinical ratings leading to more or fewer exacerbations being detected.
Second, out of respect for the well being of the subjects in the study the primary healthcare providers were informed of the results of throat cultures. As a result, the patients’ primary clinicians were free, if they chose to prescribe antibiotics for symptomatic or asymptomatic patients with positive cultures. This practice could have potentially limited the number of exacerbations observed.6
Third, we did not systematically monitor whether a child was referred for cognitive behavioral therapy (CBT) for either their tic or OC symptoms. This may have affected our results.51
However, only two of the sites were based in child psychiatry programs where tic and OC patients are routinely referred for CBT so that actual number of such cases is likely to have been relatively small.
Fourth, both the total number of clinical exacerbations and the total number of GABHS infections were lower than that had been estimated, raising the possibility that this study was underpowered.
Fifth, although the investigators in both this study and the earlier Kurlan et al. study7
prospectively identified PANDAS cases based on the published criteria, only a small minority of the clinical exacerbations recorded were consistent with the descriptions of PANDAS exacerbations in which the period of increased tic or OC symptom severity was associated with a sudden increase in the severity of psychiatric comorbidity.3
Consequently, if indeed PANDAS exists as a valid clinical entity, the diagnostic criteria may need to be strengthened. One set of proposed suggestions include (James Leckman, personal communication, July 2010): (1) eliminating cases where there was a sudden onset of a tic disorder in the absence of the sudden onset of OCD; (2) specifying that the acuity of symptom onset/exacerbation must be severe, dramatic, and proceeded from no/minimal symptoms to maximum severity within 24–48 hours; and (3) requiring that the onset/exacerbation of OC symptoms is accompanied by at least three (rather than just one) of the seven PANDAS associated symptoms (markedly increased level of anxiety; emotional lability, irritability, aggressive behavior; sudden difficulties with concentration or learning; developmental regression (loss of abilities); sleep disorder; sudden onset of motor dysfunction [dysgraphia, motoric hyperactivity, tics]; and/or urinary frequency or an increased urge to urinate) and that the acuity of the co-occurring symptoms must occur in the same sudden time interval as the OC symptoms.
Next, it is also worth noting that true PANDAS cases may be relatively rare so that it may be necessary to use a national referral base to recruit an adequate number of PANDAS cases as was true of the earlier studies conducted at NIH Clinical Center. 3,27,28
In our view, future studies should focus in part on the new onset cases as this was not addressed in this study and it is a key element of the PANDAS hypothesis. However, if the focus is just on the treatment of new onset cases, this may leave in doubt whether PANDAS is chronic relapsing and remitting polyphasic illness if the intervention is efficacious. It will also be critical to exclude cases of SC.
Finally, although GABHS infections have been postulated as the main initial autoimmune response-inciting event contributing to the sudden onset
of severe neuropsychiatric symptoms in a subgroup of patients, it is well documented that sudden OC and tic symptom onset or worsening can be triggered by other infectious agents (e.g. herpes simplex virus, varicella zoster virus, human immunodeficiency virus, Borrelia burgdorferi, Mycoplasma pneumoniae, as well as sinusitis, and the common cold).24,52–58
It will be important for clinicians and scientists to continue to work together across the disciplines of pediatrics, family medicine, neurology, child and adolescent psychiatry and immunology and microbiology to advance our knowledge and improve our understanding and care of these children regardless of the diagnostic label they carry.
This intensive study provides important additional and convincing evidence about the course of tic and OC symptoms in two groups of pediatric age subjects after these symptoms are established. During the prospective course of two years of intensive observation and care, no documentable differences emerged to suggest that GABHS infections were temporally related to either ongoing tic or OC symptoms or to exacerbations. The implication of this finding for patient care is that clinicians who see children who meet the published diagnostic criteria for PANDAS,3
particularly those whose exacerbations are limited to just tics or OC symptoms, typically do not need to perform throat cultures in the absence of symptoms of pharyngitis nor is there a convincing rationale for the use of prophylactic antibiotics. That said, further intensive longitudinal and treatment studies are warranted in younger children, at or close to the onset of their illness where there is clinical evidence of the abrupt onset or sudden worsening of OC and other neuropsychiatric symptoms.