PANDAS

Clinic

• Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is a controversial hypothetical diagnosis for a subset of children with rapid onset of obsessive-compulsive disorder (OCD) or tic disorders.
• Symptoms are proposed to be caused by group A streptococcal (GAS), and more specifically, group A beta-hemolytic streptococcal (GABHS) infections.
• OCD and tic disorders are hypothesized to arise in a subset of children as a result of a post-streptococcal autoimmune process.
• The proposed link between infection and these disorders is that an autoimmune reaction to infection produces antibodies that interfere with basal ganglia function, causing symptom exacerbations, and this autoimmune response results in a broad range of neuropsychiatric symptoms.

Characteristics

• Abrupt onset of symptoms, including motor or vocal tics, obsessions, or compulsions. This abrupt onset is thought to be preceded by a strep throat infection

Other symptoms

• Emotional lability
• Enuresis
• Anxiety
• Deterioration in handwriting: (Sudden loss of fine motor skills)

There may be periods of remission.

• As the clinical spectrum of PANDAS appears to resemble that of Tourette syndrome / disorder (TS or TD), some researchers hypothesized that PANDAS and TS may be associated; this idea is challenged and a focus for research.

PANS

• Pediatric acute-onset neuropsychiatric syndrome (PANS) is a hypothesized disorder characterized by the sudden onset of OCD symptoms or eating restrictions, concomitant with acute behavioral deterioration or neuropsychiatric symptoms.
• PANDAS hypothesis is unconfirmed and unsupported by data, and two new categories have been proposed: PANS (pediatric acute-onset neuropsychiatric syndrome) and CANS (childhood acute neuropsychiatric syndrome).
• CANS and PANS hypotheses include different possible mechanisms underlying acute-onset neuropsychiatric conditions, but do not exclude GABHS infections as a cause in a subset of individuals. PANDAS, PANS, and CANS are the focus of clinical and laboratory research, but remain unproven. Whether PANDAS is a distinct entity differing from other cases of tic disorders or OCD is debated.
• PANS eliminated tic disorders as a primary criterion and placed more emphasis on acute-onset OCD, while allowing for causes other than streptococcal infection.

Classification

• PANDAS is hypothesized to be an autoimmune disorder that results in a variable combination of tics, obsessions, compulsions, and other symptoms with sudden or abrupt onset that may be severe enough to qualify for diagnoses such as chronic tic disorder, OCD, and TS.
• PANS, CANS and PITANDs are also hypothesized to be autoimmune disorders.

Cause

The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are disputed and unconfirmed. The cause is thought to be akin to that of Sydenham's chorea (SC), which is known to result from childhood group A streptococcal (GAS) infection leading to the autoimmune disorder rheumatic fever of which SC is one manifestation. Like SC, PANDAS is thought to involve autoimmunity to the brain's basal ganglia.

To establish that a disorder is an autoimmune disorder, the Witebsky criteria require

1. that there be a self-reactive antibody,
2. that a particular target for the antibody is identified (autoantigen)
3. that the disorder can be caused in animals and
4. that transferring antibodies from one animal to another triggers the disorder (passive transfer).

Results of studies investigating an autoimmune cause that meet Witebsky's criteria are inconsistent, controversial, and subject to methodological limitations.

To show that a microorganism causes a disorder, the Koch postulates would require one show that the organism is present in all cases of the disorder, that the organism can be extracted from those with the disorder and be cultured, that transferring the organism into healthy subjects causes the disorder, and the organism can be re-isolated from the infected party. Giavanonni notes that the Koch postulates are not useful in substantiating PANDAS a post-infectious disorder because the organism may no longer be present when symptoms emerge, multiple organisms may cause the symptoms, and the symptoms may be a rare reaction to a common pathogen.

Some studies support acute exacerbations associated with streptococcal infections among clinically defined PANDAS subjects; others studies have found no association between abrupt onset or exacerbation with infection. The PANS hypothesis, then, expands the causes beyond streptococcal infection and postulates that the cause can be genetic, metabolic, or infectious.

Among children with PANS or PANDAS, studies are inconsistent, and the hypothesis that antibodies trigger symptoms is unproven; some studies showed antibodies in children with PANS/PANDAS, but those results were not replicated in other studies. A large multicenter study (EMTICS—European Multicentre Tics in Children Studies) showed no evidence in children with chronic tic disorders of strep infections leading to tic exacerbation, or specific antibodies in children with tics, and a study of the cerebrospinal fluid of adults with TS similarly found no specific antibodies. The antibodies that were found by one group were collectively named the "Cunningham Panel"; subsequent independent testing showed this panel of antibodies did not distinguish between children with and without PANS, and its reliability is unproven. A consensus statement from the British Paediatric Neurology Association (BPNA), states that a "causal infection (rather than coincidental infection) or an inflammatory or autoimmune pathogenesis" has not been confirmed, and that "no consistent biomarkers have been identified that accurately diagnose PANDAS or are reliably associated with brain inflammation".

Mechanism

The mechanism is hypothesized to be similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions. The molecular mimicry hypothesis is a proposed mechanism for PANDAS: this hypothesis is that antigens on the cell wall of the streptococcal bacteria are similar in some way to the proteins of the heart valve, joints, or brain. Because the antibodies set off an immune reaction which damages those tissues, the child with rheumatic fever can develop Sydenham's. In a typical bacterial infection, the body produces antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. In some rheumatic fever patients, autoantibodies may attack heart tissue, leading to carditis, or cross-react with joints, leading to arthritis. In PANDAS, it is believed that tics and OCD are produced in a similar manner. One part of the brain that may be affected in PANDAS is the basal ganglia, which is believed to be responsible for movement and behavior. It is thought that similar to Sydenham's, the antibodies cross-react with neuronal brain tissue in the basal ganglia to cause the tics and OCD that characterize PANDAS.

Whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism (pathophysiology) than seen in other people diagnosed with TS is unclear. Studies of this hypothesis are inconsistent: the strongest supportive evidence comes from a controlled study of 144 children (Mell et al., 2005), but prospective longitudinal studies have not produced conclusive results, and other studies do not support the hypothesis.