It may sound improbable that strep throat can be a cause of obsessive-compulsive disorder. However, for the first time, large-scale research coming out of Denmark seems to support this causal relationship.

Background

Bacteria are responsible for between 5 and 10 percent of sore throats. The most common bacterial agent responsible for sore throat is group A beta-hemolytic streptococci (GAS or “strep”).

In 1998, researchers at the National Institute of Mental Health (NIHM) observed that some children abruptly develop obsessive-compulsive disorder, tics, and other neuropsychiatric symptoms after being infected with GAS and other types of bacteria and viruses. These symptoms are rapid onset, and peak in intensity within 24 to 48 hours.

Usually, OCD begins more gradually. Furthermore, the initial presentation of OCD can be hidden for months by a child secondary to anxiety or embarrassment about irrational worries and behaviors.

In the beginning, the NIMH chose to focus its initial research efforts on the association between streptococcal infection and sore throat. They came up with a working hypothesis titled Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections or PANDAS.

The PANDAS hypothesis describes how infection with GABS potentially causes OCD through an autoimmune process.

The PANDAS hypothesis is controversial, and for years, there was limited support for it because all the studies examining the relationship between streptococcal infection, OCD, and tics involved only small numbers of participants.

However, in a May 2017 issue of JAMA Psychiatry, Orlovska and co-authors detail a large study examining the link between GAS—as well as other types of infection—and OCD and tics. They looked at the records of more than one million Danish children spanning 17 years.

PANDAS Diagnosis

There is no laboratory test that diagnoses PANDAS. Instead, a diagnosis of PANDAS is based on a detailed history and physical examination.

Here are the five criteria used to diagnose PANDAS:

Presence of either OCD, tic disorder, or both. The explosion in the onset of OCD, tics, or both that occurs abruptly and can wax and wane following subsequent streptococcal infections. Subsequent exacerbations similarly present with dramatic symptoms. Onset between 3 years and 11 years (the beginning of puberty). (This criterion is arbitrary, and adolescents can rarely be diagnosed with PANDAS.) Association with the sudden onset of symptoms suggestive of other neuropsychiatric illness, including concentration difficulties, general anxiety, bed-wetting, irritability, and developmental regression. A temporal association with a streptococcal infection needs to be established by either throat culture or blood tests (i.e., elevated anti-GAS antibody titers).

Sydenham chorea, which also results in rapid, involuntary movements resembling tics, must also be ruled out to diagnose PANDAS. Like PANDAS, Sydenham chorea and, more generally, rheumatic fever have autoimmune underpinnings and occur secondary to streptococcal infection.

How Does PANDAS Occur?

Genetics, development, and immunity contribute to the development of PANDAS:

First, certain children seem susceptible to PANDAS, and these children may share genetic similarities with those who experience rheumatic fever and Sydenham chorea.

Second, PANDAS is developmental in nature because it usually affects children who have not yet experienced puberty, with the peak age being 6 or 7.

Third, as with Syndenham chorea, those with PANDAS are hypothesized to develop antibodies that attack nerve cells in the brain.

Streptococcal bacteria are a hardy and primeval organism that can mimic the cellular appearance of various body tissues to evade the body’s immune system.

When GABS mimic the appearance of brain cells, antibodies to brain tissue are thought to form. These antibodies end up attacking the basal ganglia, and instead of causing Sydenham chorea, result in OCD, tics, and so forth.

PANS Diagnosis

Because it is often hard to pinpoint an exact temporal relationship between strep infection and OCD or tics, in 2010, clinicians and researchers expanded the classification of PANDAS so that it falls under the umbrella of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS).

Instead of explicitly tying diagnosis to only streptococcal infection, PANS is more generally described by the abrupt onset of OCD and can be associated with nonstreptococcal infection, too, including influenza and varicella (chicken pox). Specifically, here are the diagnostic criteria for PANS:

The abrupt and dramatic onset of OCD Concurrent presence of two additional neuropsychiatric symptoms similar to those seen in PANDAS Symptoms which can’t be better explained by another neurological or motor disorder, such as Sydenham chorea, lupus, or Tourette disorder

Notably, by formulating the PANS diagnosis, these clinicians and researchers hope to facilitate the diagnosis and treatment of abrupt-onset OCD.

The relationship between PANDAS and PANS is analogous to the relationship between melanoma and cancer. In other words, just like melanoma is a subset of cancer, PANDAS is a subset of PANS. Of note, a diagnosis of PANS is also based on a detailed history and physical exam.

New Research

Orlovska and colleagues examined Danish patient records spanning 17 (1996 to 2013) years and representing 1,067,743 children (defined as fewer than 18 years old). This study is by far the highest-powered analysis of the PANDAS hypothesis to date, and results support fundamental elements of this hypothesis.

Here is a more specific breakdown of the patient records:

519,821 girls

547,922 boys

638,265 children received a streptococcal test

349,982 had at least one positive streptococcal test

The researchers found that children with a positive strep test result were more likely to exhibit mental disorders—in particular, OCD and tic—compared with those children without a strep test.

More specifically, children with a positive strep test had an 18 percent higher risk of developing any mental disorder, a 51 percent higher risk of developing OCD, and a 35 percent higher risk of developing tic disorders.

The researchers also found that children who had a nonstreptococcal throat infection (i.e., negative streptococcal test) also were at increased risk for mental disorders, OCD, and tic disorders. However, the magnitude of this risk was lower than that for streptococcal infection.

The researchers found that, as defined by PANDAS criteria, children between age 3 and 11 had the greatest increased risk of OCD and tic disorders.

According to the researchers, the results of the study support the PANDAS hypothesis to some extent. With regards to nonstreptococcal infection, they write the following:

"Our findings that the risk of mental disorders is only slightly less elevated after a nonstreptococcal throat infection than after a streptococcal infection suggest that other, possibly viral, infectious agents are also linked with the development of OCD and tic disorders. This finding might instead support the recently proposed concept of pediatric acute-onset neuropsychiatric syndrome … Pediatric acute-onset neuropsychiatric syndrome offers an alternative to PANDAS with wider diagnostic criteria; it is primarily thought to be a postinfectious condition but without restriction to streptococcal infections."

PANDAS Treatment and Prevention

As described in Fegin and Cherry’s Textbook of Pediatric Diseases:

"This proposed disorder [PANDAS] is currently a hypothesis, and it remains a controversial topic. Several authors believe in this disorder as a separate entity and recommend treatment and prophylaxis. Others argue that it is only a hypothesis and that further evidence with double-blind studies is needed before recommending treatment and prevention for children given a diagnosis of PANDAS."

In other words, some experts view PANDAS (and PANS) as conjecture. Others, however, consider PANDAS diagnosis and will treat it accordingly.

Recommendations

Of note, the NIMH does recommend certain treatment options for those who are thought to have the condition:

Children with PANDAS-related obsessive-compulsive symptoms will benefit from cognitive behavioral therapy (CBT) and/or anti-obsessional medications. Studies show that the best results are produced from the combination of CBT and an SSRI medication (such as fluoxetine, fluvoxamine, sertraline, or paroxetine). Children with PANDAS appear to be unusually sensitive to the side-effects of SSRIs and other medications, so it is important to “START LOW AND GO SLOW!!” when using these medications.

By starting children on low dosages of psychotropic medications, the number and severity of negative side effects are minimized. If a child ends up experiencing negative side effects while on medication, the dosage should be decreased immediately. Of note, psychotropic medications should not be stopped abruptly because doing so could be dangerous.

Antibiotics

The NIMH stresses that if the strep infection is still present, the best treatment for PANDAS is antibiotics, including amoxicillin, penicillin, azithromycin, and cephalosporins. With positive throat cultures, a single course of antibiotics should be sufficient. Other measures include replacing toothbrushes and testing family members for strep to limit the risk of re-infection.

Based on a small number of case reports, some clinicians treat patients who demonstrate symptoms of PANDAS with antibiotics even when streptococcal tests are negative. This practice requires further investigation.

Immune-based therapies, including plasma exchange (i.e., plasmapheresis) and intravenous immunoglobulin, have also shown been used to effectively treat symptoms related to PANDAS.

Steroids

Steroids have also been used to treat PANDAS. However, the results of steroid treatment are mixed, with only some reports of benefit and other reports of worsening tics. Furthermore, steroids should be used only for a short period of time because they can be dangerous when used long-term. Finally, patients with PANDAS who receive steroids can experience a rebound effect which results in PANDAS symptoms that are even worse than when the steroids were started. For these reasons, steroids are usually not recommended for treatment in children who have PANDAS.

Of note, sometimes a brief treatment with steroids can help clinicians gauge which patients will be responsive to plasma exchange and intravenous immunoglobulin.

On a related note, the preceding treatment guidance primarily applies to PANDAS not PANS, because PANS is a newer diagnosis with no tested treatments. Nevertheless, if PANS appears to be triggered by an infectious agent, treatment of the infection may attenuate the symptoms of OCD and other neuropsychiatric symptoms. Additionally, treatments that work for PANDAS, such as immune-based therapies, as well as preventive strategies, may also be useful when treating symptoms related to PANS.

In two small clinical trials, prophylactic treatment with antibiotics—or treatment before the occurrence of streptococcal throat infection and PANDAS symptoms—proved effective in preventing strep infections and reducing recurrences of PANDAS symptoms.

Specifically, some children who previously experienced PANDAS-related symptoms several months a year experienced far fewer exacerbations once given prophylactic antibiotics. These children were treated with either penicillin or azithromycin.

Analogously, treatment with prophylactic antibiotics has proven useful with other streptococcal sequelae that have autoimmune origins, such as rheumatic fever and Sydenham chorea thus providing further support for this intervention.