What is PANS and PANDAS?

“If your child is fine one day and needs psychiatric treatment then next … think about brain on fire or PANS and or PANDAS. Despite over three decades of research the pathogenesis of this condition is still debated, but the clinical phenotype has shown consistent features and evidence that the dramatic symptoms cause substantial impairment in the child and in family

functioning. The implications of this disease impact on families is staggering as many physicians are either not aware of this disease or refuse to acknowledge that PANS and PANDAS exist. Clearly we need more awareness of and education about these diagnoses.”
 
PANS and PANDAS are treatable, but a child’s response to therapy depends on a number of factors and early intervention is absolutely a key component in any treatment plan.
 
Pediatric autoimmune neuropsychiatric disorders loosely defined as a sudden onset of acute anxiety and mood variability accompanied by OCD (Obsessive Compulsive Disorder) and/or tics associated with streptococcus infections (PANDAS). These disorders originated from the observational work of Dr. Susan Swedo at the National Institute of Mental Health (NIMH) and collaborators who formalized in 1998 both a definition and established set of operational criteria. In looking back at the Sydenham Chorea (SC) data this showed that children with rheumatic heart disease didn’t have any difficulties, but roughly two out of three children with SC would have obsessions and compulsions and the behaviors could actually start before classic signs such as involuntary movements were even exhibited.
 
PANDAS stands for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. With PANDAS, the onset of symptoms is typically preceded by streptococcal -A infection (“strep throat”). However, in some cases, children may not have presented with a full-blown, acute strep throat infection. PANDAS is included in the larger umbrella of PANS, Pediatric Acute-onset Neuropsychiatric Syndrome.  PANS, almost by definition, has to be multi-factorial and may have multiple causes. We know that there are infectious triggers and we know there are non-infectious triggers that may include anything from child abuse to environmental factors, genetics, metabolic disorders, brain trauma, concussion and other traumatic brain injuries.
 
Recent statistics indicate that roughly one in 200 children in the United States is affected with PANS or PANDAS. In the United States approximately 500,000 children are diagnosed with OCD and 138,000 have Tourette’s Syndrome. In addition, 1.5 million American children are diagnosed with anxiety, phobias, OCD and/or bipolar disorder. Nearly 55% of children in America have a chronic disease vs in 1970 it was just 4%.
 
Typically, PANS and PANDAS are accompanied by an acute onset of extreme behavioral and emotional symptoms although it is not uncommon for the onset to be gradual, which can contribute to difficulties in making the initial diagnosis.
 
Symptoms may include, but are not limited to:
•   OCD (Obsessive Compulsive Disorder)
•   Excessive anxiety, especially separation anxiety
•   Depression
•   ODD (Oppositional Defiant Disorder)
•   Tics such as hair or eyelash pulling, motor tics, repetitive or compulsive throat clearing in the absence of other illness or allergies
•   Excessive temper tantrums
•   Mood swings
•   Behavioral regression
•   Developmental regression
•   Sensory processing difficulties including pain amplification
•   Sleep problems are very common ( many have REM motor disihibition
•   Gastrointestinal pain
•   Bedwetting
•   Severe food restriction
•   Anorexia
•   Decline in handwriting skills
•   Decline in math skills
•   Hyperactivity
•   Inability to concentrate
•   Head banging
•   Aggression
•   Refusal to go to school
•   Increased desire to be left alone
•   Seizures
 
Children diagnosed with PANS or PANDAS are typically between one and 13 years of age, with 60% of diagnoses for children between the ages of four and nine.
Please note that there is an overlap of general symptoms between PANS and PANDAS, and that PANS usually results in severely restricted food intake as well as at least two of the symptoms described above.   Clinical diagnosis of PANDAS is defined as the presence of significant OCD behavior and/or tics in addition to the above symptoms. In addition, your child may have a combination of both PANS and PANDAS.
 
Pathophysiology: Anti-Dopamine Receptor Antibodies
In PANDAS, the cross-reactive antibodies created in response to strep attack the dopamine receptors in the basal ganglia of the brain because of a blood-brain barrier breach.  The basal ganglia form a major center in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). The basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well.  Animal models of SC and PANDAS point to an essential role of the adaptive immune response (cellular and humoral) in disease pathogenesis, including Th17 cells and autoantibodies, which is consistent with the molecular mimicry hypothesis.
 
However, these antibodies can be also be created in response to microbes other than streptococcus as well as to environmental toxins, which is why the umbrella term of PANS more accurately describes these disorders.
The basal ganglia are a group of nuclei located at the base of the brain and are linked to the thalamus.
Basal ganglia have traditionally been associated with movement disorders, such as Huntington’s and Parkinson’s disease.
In addition to voluntary movement control, the basal ganglia are also associated with procedural learning, eye movements, cognitive function and emotional function.
The basal ganglia are also the site of two dopamine receptors.
Dopamine is a neurotransmitter associated with attention, movement and the pleasure/reward centers of the brain.
•   The D1 receptor is a direct pathway in the basal ganglia that facilitates movement.
•   The D2 receptor is an indirect pathway that inhibits movement.
When the cross-reactive antibodies associated with strep or other antigens attack the dopamine receptors in the basal ganglia of the brain, it causes a fluctuation in dopamine, which results in OCD, tics and other neuropsychiatric symptoms.
Some doctors also refer to this as autoimmune-mediated basal ganglia dysfunction.
Differential Diagnosis for Youth with PANS
Obsessive compulsive disorder
Anorexia nervosa
Avoidant/restrictive food intake disorder (ARFID)
Tourette syndrome
Transient tic disorder
Bipolar disorder
Sydenham chorea
Autoimmune encephalitis
Systemic autoimmune disease
Wilson’s disease
Kryptopyrroluria (KPU) is a condition in which zinc and pyridoxine (vitamin B6) are excreted in high amounts into the urine. Elevated kryptopyrroles (HPL) are found in the urine due to abnormality in the synthesis of heme (hemoglobin) in the body. Pyrroles have also been found to have an affinity to zinc and pyridoxine (vitamin B6) and may excrete these nutritional molecules into the urine in high amounts.  Some estimates suggest the incidence of KPU to be as high as 80% in autism and between 40% and 70% in those with learning difficulties, ADHD, depression and bipolar disorders.
 
Diagnosis
As there are no disease-specific laboratory tests available, the diagnosis of PANS PANDAS is a clinical diagnosis based on established medical criteria for same. There are however a number of labs that can be used to aid physicians in making the diagnosis and may include:
- MRI / NeuroQuant / PET / EEG
- CBC w differential
- ESR 
- CMP
- ANA comprehensive panel  and complement levels C3 and C4
- Thyroid profile including thyroglobulin antibodies
- Anticardiolipin AB, Lupus Anticoagulant ,  Antiphospholipid antibodies
- ACE
- Anti DNAse B  - repeat in 2–6 weeks for antibody rise or fall
- ASO titer - repeat in 2–6 weeks for antibody rise or fall
- Mycoplasma IgG and IgM 
- Serum IgG and IgG subsets 
- serum copper and Zinc  
- Viral titers (HHV 6, EBV acute and chronic, HSV1 and 2, Coxsackievirus, CMV) 
- Vit D level 
- Throat Swab for GAS rapid strep and throat culture
- Throat or nasopharyngeal swab for M. pneumoniae PCR
- Magnesium
- CD 57
- Western Blot 
 
Other considerations for diagnostic purposes:
1. Mold Evaluation (through Great Plains lab urine)
2. Evaluate for KPU urine
3. Check for Folate receptor antibodies (through http://iliadneuro.com)
4. Test for Lyme
5. Consider nutritional evaluation
6. Consider Food Sensitivity
7. Testing Serum to Mayo for AE panel and paraneoplastic panel
8.  Heavy Metal evaluation
9.  Gut Analysis (stool sample ) 
10. Evaluate close contacts as asymptomatic strep carriers  
 
It is important to note in regard to lab testing or results:
-Throat cultures frequently result in false negatives because of the technique used in obtaining the specimen, mishandling of the specimen and the fact that the strep bacteria may be harbored in other parts of the body than the throat.
-ASO begins to rise at about 1 week and peaks at 3–6 weeks after infection  ADB begins to rise at 1–2 weeks and peaks at 6–8 weeks  It should be noted that even properly timed serial assays have failed to show a rise in as many as 38% of new pharyngeal GAS acquisitions
-If GAS was diagnosed and treated, repeat culture 2–7 days
-After treatment is complete, it is recommended to retreat if still positive.
 
To help guide treatment of both conditions, and to which Gazda Integrative Neurology ascribes, the PANS Research Consortium of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and other scientists published the three-part recommendations online July 19 in a special issue of the Journal of Child and Adolescent Psychopharmacology, the first part of which discusses psychiatric and behavioral interventions for the syndromes’ symptoms (2017 Jul 19. doi: 10.1089/cap.2016.0145).
Part II of the guidelines covers immunomodulators.
Part III of the guidelines covers infections.
 
Dr. Gazda follows the PANS/PANDAS consortium guidelines for treatment, the basic principles of which include:   
1.  Clean up the environment (chemicals, toxins, plastics, eliminate fluoride, aluminum-free deodorants, mold) 
2.  Diet should be autoimmune paleo diet with elimination of gluten, dairy and sugar. Eat non-GMO, organic foods whenever possible and eliminate artificial sweeteners, nitrites, sulfites, artificial dyes and preservatives, high fructose corn syrup and MSG (which stimulates glutamate that is an excitatory neurotransmitter).
3.  Heal the gut            
4.  Treat underlying infections
5.  Modulate glutamate 
6.  Modulate the immune system  
7.  Neuro-rehab therapies - starting Cognitive Behavioral Therapy (CBT), an exposure-response prevention protocol, has the best chance of halting OCD behaviors.  
8.  Neurofeedback training can be helpful in learning new ways to deal with stress, external triggers and other influences.
9.  Remove the source of Inflammation and or infection
10.  Family support – provide education about these disorders and opportunities for support on an ongoing basis. Unfortunately, because PANDAS and PANS are not well understood, children are often misdiagnosed, causing enormous stress to families that are already in crisis. With the right support system and treatment, we believe children can recover from these conditions.
 
Key Things to Consider in PANS/PANDAS
 
Recognizing there are a great many items and concepts presented here, these are some of the primary takeaways and considerations for patients and practitioners alike:
 
1.  PANS patients exhibit additional immune abnormalities including comorbid autoimmune or inflammatory conditions and/or below normal or low-normal levels of immunoglobulins, in addition to having neuroactive autoantibodies.
2.  Is PANS a form of AE (Autoimmune Encephalitis)? Dr. Swedo believes it is, given the clinical presentation that fits all the requirements along with MRI and PET scans showing evidence of inflammation in the basal ganglia, EEG, CSF with pleocytosis, CSF IgG, and CSF with cross-reactive antibodies acute vs convalescent and improvement in immune therapies.
3.  Roughly 30-50% of children with autism, ADD/ADHD and Sensory Processing Disorder (SPD) also have PANS PANDAS.
4.  It is very common for younger siblings of children diagnosed with autism, ADD/ADHD or Sensory Processing Disorder to be diagnosed themselves with PANS and PANDAS.
5.  A child with PANDAS can present with signs and behaviors very similar to autism. They withdraw socially. They can lose their speech. They may become mute, even completely mute. They are bothered by lights and sounds and manifest compulsive rituals that really cannot be distinguished from those of a child with OCD.
6.  PANS can be seen in adults.
7.  Two studies suggest that up to 10% of children have transient tics during strep season, meaning that subclinical PANDAS is probably quite or more common than we may realize.
8.  In PANS, identification of the causal events (including infections, immune dysfunction, and/ or environmental events) is not always found.
9.  There is a high rate of immune deficiency in PANS.
10.  Those who are positive for the autoantibodies against the dopamine receptor(s) and have a positive CaMKII or other antibody in the panel respond to immunodulating treatment.
 
What is the Cunningham Panel?  
The Cunningham Panel is a series of tests that was developed by Madeleine Cunningham, PhD to help physicians diagnose and treat infection-induced neuropsychiatric disorders.
These tests measure circulating levels of auto-antibodies directed against specific neuronal antigens, including:
-Dopamine D1 receptor (DRD1)
-Dopamine D2L receptor (DRD2L)
-Lysoganglioside GM1
-Tubulin
-CaM kinase
If any of these antibodies is elevated, this is an indication of autoimmunity. Also, please note that the Cunningham panel only establishes autoimmunity, not what is causing the autoimmunity. Additional testing is necessary to determine the cause of autoimmunity.       
*  The autoantibodies against the dopamine receptors indicate an autoimmune dopamine receptor encephalitis while autoantibodies against lysoganglioside or tubulin suggest a basal ganglia encephalitis if they are not positive when tested against the dopamine receptors
*  A negative test does not necessarily rule out PANS or PANDAS.
*  Advise testing during a flare.  
 
Neuroimaging 
MRI may be normal. Imaging studies on occasion can show enlargement of the caudate .   Positron emission tomography (PET) imaging studies of patients with PANDAS suggest that they have a higher degree of microglial activation compared with controls.
 
 
Please visit our Resources section of our website for more information and links to relevant organizations and support groups.
 
Citations and sources:
Journal of Child and Adolescent Psychopharmacology, the first part of which discusses psychiatric and behavioral interventions for the syndromes’ symptoms (2017 Jul 19. doi: 10.1089/cap.2016.0145). https://www.liebertpub.com/doi/full/10.1089/cap.2016.0145
 
Part II of the guidelines covers immunomodulators: https://www.liebertpub.com/doi/full/10.1089/cap.2016.0148
 
Part III of the guidelines covers infections: https://www.liebertpub.com/doi/full/10.1089/cap.2016.0151