The Cunningham panel, my autoimmune dx

 

THE CUNNINGHAM PANEL™

Autoantibody testing for neuropsychiatric symptoms

The Cunningham Panel™ is a series of high complexity blood tests that assists clinicians in diagnosing infection-triggered autoimmune neuropsychiatric syndromes, such as Basal Ganglia Encephalitis and PANS/PANDAS.*

Elevated levels on one or more of these tests indicate that a person’s neuropsychiatric symptoms may be due to a treatable autoimmune disorder (potentially triggered by an infection(s), rather than a classic neurologic or psychiatric illness.

These test results can support a physician’s clinical diagnosis with laboratory evidence of an underlying autoimmune dysfunction, and assist the physician in determining an appropriate treatment regimen.

The Cunningham Panel™ is unique and based on over two decades of research. It is offered exclusively through Moleculera Labs, Inc. and has been utilized by clinicians worldwide.

* PANS – Pediatric Acute-onset Neuropsychiatric Syndrome; PANDAS – Pediatric Autoimmune Neuropsychiatric Disorder associated with Strep infections

THE CUNNINGHAM PANEL™ IS COMPRISED OF 5 INDIVIDUAL TESTS: 

1. Anti-Dopamine D1 Receptor
2. Anti-Dopamine D2L Receptor
3. Anti-Lysoganglioside-GM1
4. Anti-Tubulin
5. Calcium/calmodulin-dependent protein kinase II (CaMKII) – a cell stimulation test

Binding and Blocking Tests

Four (4) of the tests measure the levels of circulating autoantibodies in serum that are directed against and bind to, or block specific neuronal targets in the brain. 

Each of these autoantibody targets (Dopamine D1 and D2L receptors, Lysoganglioside-GM1 and Tubulin) have been associated with the presence of various neurologic and/or psychiatric symptoms.

When autoantibodies bind to or block these targets, they can disrupt normal neuronal functioning, resulting in the onset of neuropsychiatric symptoms.

Elevated levels on one or more of these tests indicate that a person’s neuropsychiatric symptoms may be due to a treatable autoimmune disorder (triggered by an infection(s), rather than a classic neurologic or psychiatric illness.

Cell Stimulation Test

Calcium/calmodulin-dependent protein kinase II (CaMKII) 

The CaMKII test is a cell stimulation assay. It measures the ability of a patient’s autoantibodies to stimulate the CaMKII enzyme in human brain cells. The CaMKII is involved in upregulating the production of neurotransmitters – dopamine, epinephrine, and norepinephrine.

In our patient population, elevated levels of CaMKII activity correlated with certain adrenergic symptoms (these include nerve cells in which certain neurotransmitters activate), as well as the likelihood of an active infection or reinfection.

Note: The Cunningham Panel™ does not directly identify infectious agents, but rather points to the likelihood of an infectious stimulus being present.

The Cunningham Panel™ is a metabolic test, the laboratory results represent the values at the time the patient’s blood was collected, which may vary over time, with treatment, and in conjunction with the presence or absence of symptoms.

The Cunningham Panel™ is available worldwide. Healthcare practitioners licensed or authorized to order laboratory tests may order the Cunningham Panel.™ Canadian prescribers can contact Moleculera Labs directly. For prescribers outside the US and Canada, please refer to our international ordering page. 

WATCH VIDEOS

The Cunningham Panel™

Autoantibodies Impact Behavior

LEARN MORE ABOUT THE CUNNINGHAM PANEL™

What does the Cunningham Panel™ measure?

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Cunningham Panel™ Sensitivity and Specificity

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Cunningham Panel™ Results and Symptom Correlation

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Laboratory Testing

• Resources
• Testing Overview
• The Cunningham Panel
• Ordering Lab Tests
• Laboratory Accreditation

Educational Brochures

Ongoing Research

PANS: Diagnostic Criteria

To be diagnosed with PANS, a patient must meet the following criteria, as developed by the PANDAS Physicians Network consortium 3: 

1. An abrupt, acute, dramatic onset of obsessive-compulsive disorder or severely restricted food intake

   “Approximately 1 in 5 children with PANS will have restricted intake of specific foods or all food groups, often with observable weight loss…” 3

   “The acuity of symptom onset and age at onset can distinguish PANS-related eating restrictions from more typical anorexia nervosa.” 3

2. Concurrent presence of additional neuropsychiatric symptoms with similarly severe and acute onset from at least 2 of the following categories:
   • Anxiety
   • Emotional Lability and/or Depression
   • Irritability, Aggression, and/or Severe Oppositional Behaviors
   • Behavioral (Developmental) Regression
   • Sudden Deterioration in School Performance
   • Motor or Sensory Abnormalities
   • Somatic Signs and Symptoms, including Sleep Disturbances, Enuresis, or Urinary Frequency

   “The presenting symptoms often change over the first weeks of illness.” 3

3. Symptoms are not better explained by a known neurologic or medical disorder
4. No age requirement

   “PANS has no age limitation, but symptoms typically begin during the grade-school years.” 3

PANS: Treatment Guidelines

Treatment guidelines for PANS and PANDAS were published in 2017 in the Journal of Child and Adolescent Psychopharmacology 6,7,8 The guidelines focused on three treatment areas: psychiatric and behavioral interventions, use of immunomodulatory therapies, and treatment and prevention of infections.

PANS/PANDAS treatment begins with identifying and treating any triggering infections, and addressing the immune dysfunction and inflammation with immune-modulating therapies. 4

“The general ‘principles’ used to treat other brain inflammatory diseases (AE [autoimmune encephalitis], NPSLE [neuropsychiatric lupus], etc.) likely apply to PANS (especially those presenting with severe symptoms):

1. Patients given immunotherapy do better and relapse less frequently than patients given no treatment;
2. Patients given early treatment do better;
3. When patients fail first-line therapy, second-line therapy improves outcomes and reduces relapses.” 6

Furthermore, “Immunomodulatory therapy should be considered early, because NSAIDs [non-steroidal anti-inflammatory drugs] or a short course of oral corticosteroids may be sufficient for symptom remission in recent-onset cases, whereas those with long-standing symptoms often require more intensive and prolonged immunotherapeutic interventions.” 6

 REFERENCES

PANS symptoms can be triggered by various infections and is not limited to strep. 

PANS and PANDAS are sometimes misdiagnosed as OCD, Tourette's syndrome, autism spectrum disorder (ASD), ADHD, anorexia, and other psychiatric disorders. The presence of obsessive rituals and interests, rigidity around routines, and impaired eye contact may be confused with ASD in young children.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS), considered by expert consortiums to be a type of Autoimmune Encephalitis (AE), is characterized by a dramatic onset of severe obsessive-compulsive symptoms or food restriction that presents along with two or more of the following which cause impairment to functioning:

• Behavioral/developmental regression (immature play, “baby talk,” afraid of the dark, wanting to sleep in parents’ bed, etc)
• Abnormal movements such as tics, jerking/involuntary muscle spasms, stereotyped movements
• Severe mood swings and depression
• Out of character rage, aggression, tantrums with or without self-injurious behavior or suicidal/homicidal ideation or gestures
• Changes to executive functioning (poor memory, impaired concentration/focus, slowed processing speed)
• Separation anxiety and panic attacks
• Psychosis
• Sensory amplification (aversion to certain textures, sensitivity to noise, lights, or repetitive sounds)
• Insomnia or other sleep disturbance (nightmares/night terrors)
• Changes to fine motor skills or muscle strength (for example, difficulty opening doors, using utensils or holding a pencil; changes to handwriting or drawing abilities)
• Urinary changes (bedwetting, daytime accidents, urgency/frequency of urination)

So what causes this?

While originally believed to be an unusual response to a Group A Strep infection (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS), we now understand that in susceptible individuals, PANS can be triggered by anything that activates the immune response – this can include infection, allergies, certain cancers, inflammatory conditions or injuries, and exposure to toxins. Like other autoimmune diseases, PANS occurs when the immune system mistakes our own cells and healthy tissue as foreign pathogens that need to be eradicated. More commonly-identified autoimmune diseases, such as rheumatoid arthritis, lupus, hashimoto’s thyroiditis, etc., present with primary physical symptoms that are associated with the type of cell that is mistakenly targeted by the inflammatory response. In the case of PANS/Autoimmune Encephalitis, however, it’s healthy tissue in certain areas of the brain that is the target of this autoimmune attack – the result being the array of severe neuropsychiatric symptoms described above.

Interestingly, since the start of the COVID19 pandemic, PANS/AE clinicians across the country have seen a significant increase in cases. In some instances, this is clearly related to infection with the COVID19 virus, itself; however, often the trigger is not straightforward, and while many theories currently center around the impact of extreme stress (which subsequently can increase inflammation and suppress the immune response which elevates the risk of reactivation of latent infection or acquiring illness from exposure), the overall etiology is not clear.

In general, the treatment of PANS entails a three-pronged approach:

• Initiate appropriate psychiatric interventions including psychotherapy and medications to target specific symptoms (SSRIs/SNRIs, Non-stimulant ADHD medication, Antipsychotics).
• Treat any underlying infection with appropriate antimicrobial medication, keeping in mind the importance of balancing this with pre/probiotics to ensure that gut flora is adequately maintained during therapy.
• Treat immune system dysregulation with anti-inflammatory medication and/or immunomodulatory therapy if indicated.

Once someone has gotten through the most severe part of their flare-up, we often transition to a “maintenance” phase of treatment which includes lifestyle and dietary changes along with selective use of supplements to support immune health and manage systemic inflammation. Psychiatric treatment is also maintained for as long as clinically indicated. These efforts, along with quick identification and treatment of signs/symptoms of future flare-ups, help to minimize the frequency/intensity of subsequent flares and can ultimately improve long-term prognosis.

What makes this such a controversial diagnosis? 

Our understanding of PANS and other neuroinflammatory conditions is still somewhat in its infancy. This means that much of the existing literature is based on empirical evidence gathered by expert consensus groups and clinicians with experience in assessing, diagnosing, and treating this special patient population. As with any emerging field of science or medicine, new research and expanded awareness of the disease have led to modifications to the original diagnostic criteria and theories associated with PANS/PANDAS – however, these updates (namely, that PANS/AE may not present as “acute” onset, but rather, as sub-acute or insidious; not limited to pediatrics – can also occur in adolescence and adulthood) are largely underrecognized, and as a result, the condition is prematurely “ruled out” in individuals who otherwise meet criteria based on their clinical presentation.

The complex and variable presentation of symptoms and potential triggers associated with PANS leads many clinicians to refute the connection between infection/immune dysfunction and psychiatric symptoms. Unfortunately, when seeking care, families often face judgment and experience repeated invalidation when they attempt to bring up their concerns for possible PANS/AE, as individual providers and occasionally even entire organizations maintain a firm stance against the assessment/diagnosis and treatment of PANS/PANDAS as a whole.

Final thoughts and resources:

PANS/AE can be a significant source of suffering not only for the individual impacted by the illness, but the entire family who is involved with their care. It’s important to strengthen your own support systems and build in time for self-care when faced with a loved one’s intense cognitive and behavioral manifestations of the disease.

Regardless of the underlying etiology, psychiatric treatment with psychotherapy and appropriate medication management is imperative for individuals with this diagnosis.

Below are a few of my favorite resources for patients, families, and clinicians who want to learn more about PANS/PANDAS/AE:

https://pandasnetwork.org/

https://www.pandasppn.org/

https://aspire.care/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779869/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193809/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784221/

In the treatment of mycoplasmal pneumonia, antimicrobials against M pneumoniae are bacteriostatic, not bactericidal. Tetracycline and erythromycin compounds are very effective. The second-generation tetracyclines (doxycycline) and macrolides are the drugs of choice. ^[54] Macrolide resistance has been reported in several areas of the world, but most experts agree that macrolides are the antibiotics of choice for treating M pneumoniae infections in adults and children. ^{[55, 56, 57, 58, 59]} If a patient does not respond appropriately to a macrolide, a fluoroquinolone should be added to the treatment regimen. ^[55, 56] Penicillins and cephalosporins are ineffective, because the organism lacks a cell wall.

Macrolide resistance has been increasing throughout the world, with 0-15% resistance in Europe and the United States, 30% in Israel, and 90-100% in Asia, ^[60] but macrolides remain the mainstay of treatment. If symptoms do not resolve, consider prescribing tetracyclines (doxycycline and minocycline) or fluoroquinolones (levofloxacin). ^[61] Doxycycline has been avoided in children younger than 8 years because of fear of tooth staining, but the US Centers for Disease Control and Prevention has stated that short courses of newer formulations of doxycycline do not cause tooth staining. ^[62] 

Antibiotic Therapy

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Erythromycin (E.E.S., Erythrocin, Ery-Tab)

• View full drug information

Erythromycin is a macrolide antibiotic that is used in the treatment of staphylococcal and streptococcal infections. This agent acts by inhibiting bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes and causing RNA-dependent protein synthesis to arrest. 

Azithromycin (Zithromax)

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Azithromycin is a macrolide antibiotic that is very effective against M pneumoniae and may be the most common agent used to treat M pneumoniae given its ease of administration. 

Clarithromycin (Biaxin, Biaxin XL)

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Clarithromycin is a macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating the dissociation of peptidyl tRNA from ribosomes, which results in bacterial growth inhibition. 

Doxycycline (Vibramycin, Vibra-Tabs)

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Doxycycline is a tetracycline antibiotic that is used to treat susceptible bacterial infections of both gram-positive and gram-negative organisms, as well as infections caused by Mycoplasma, Chlamydophilia, and Rickettsia organisms. This agent is as effective as erythromycin and other macrolides in the treatment of M pneumoniae infection. Doxycycline inhibits bacterial protein synthesis by binding with the 30S subunit and possibly the 50S ribosomal subunit of susceptible bacteria. 

Levofloxacin (Levaquin)

• View full drug information

Levofloxacin is a fluoroquinolone antibiotic that can be used to treat Mycoplasma infections. It works by inhibiting the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. 

Moxifloxacin (Avelox)

• View full drug information

Moxifloxacin is a fluoroquinolone antibiotic that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription.

PANS clinicians.

(Overview of Treatment of PANS, Swedo, MD et al, JCAP-Vol27, #7, 2017)

Treating of PANS PANDAS involves a three-pronged approach that utilizes psychiatric medications when appropriate to provide symptomatic relief, antimicrobial treatments to eliminate the source of neuroinflammation, and anti-inflammatory and immune-modulating therapies to treat disturbances of the immune system.”

• Treat Symptoms: psychoactive medications, psychoactive therapies, and supportive therapies
• Remove Inflammatory Source:antimicrobial treatments
• Treat Immune System Dysregulation:anti-inflammatory and/or immunomodulating medications

“At A Glance”

Treatment Basics

Symptoms Treatment

1. Cognitive Behavior Therapy (CBT)
2. Psychotropic Medications: “start low & go slow’’ approach

Inflammatory Source Treatment

1. Antimicrobial Treatments: Therapeutic or prophylactic antibiotics
2. Other medications like anti-virals if the trigger is not a bacterial infection

Immune System Dysregulation Treatments

1. Anti-Inflammatories: NSAIDs, Corticosteroids
2. Intravenous Immunoglobulin (IVIG)
3. Plasmapheresis (PEX)/ Therapeutic Plasma Exchange (TPE)
4. Rituximab, Cellcept, and other immunomodulatory agents

Other Treatment Options

1. Tonsillectomy and Adenoidectomy
2. Antivirals
3. Antifungals
4. Antihistamines (H1 & H2 Blockers)
5. Vitamin D3, Omegas, etc
6. Dietary Changes

“At A Glance”

Guidelines for Treating PANS PANDAS

Establish Correct Diagnosis

Properly establish PANS PANDAS is the accurate diagnosis via a complete evaluation. PANS PANDAS is a clinical disorder and a diagnosis of exclusion defined by abrupt onset of obsessive-compulsive symptoms and/or severe eating restrictions and at least two concurrent cognitive, neurological, or behavioral symptoms.

   

Provide Symptomatic Relief

Provide symptomatic relief with behavioral interventions and psychiatric medications. Prioritize treatments based on which symptoms are the most immediately concerning. Treatments must be individualized and will require adjustment over time. Patients with mild to moderate symptoms may not require any pharmacological intervention. Psychiatric medications generally should be implemented with a ‘‘start low & go slow’’ approach. PANS patients may not be able to participate in CBT due to overwhelming symptoms during the acute stage of illness. However, caregivers should begin instruction on behavioral interventions to learn how to manage symptoms at home.

Treat Postinfectious Autoimmunity and/or Neuroinflammation

An Immunomodulatory treatment plan is based on disease trajectory and symptom severity; it must be an individualized protocol. Immune treatments are used only in PANS patients demonstrating signs of postinfectious autoimmunity and/or neuroinflammation, which are seen in at least 80% of patients. Guidelines for treating postinfectious autoimmunity and/or neuroinflammation in PANS are predicated on decades of treating other neuroinflammatory disorders and postinfectious autoimmune conditions.

Treat Source of Infection

For PANS PANDAS flares triggered by an infection, treat the underlying infection thoroughly. While GAS is the most studied inciting infection, there are many other infections known to trigger PANS flares such as various upper respiratory tract infections, Mycoplasma pneumoniae, influenza, etc. Even without a documented infection, a course of antibiotics is suggested at the time of diagnosis. Extended and/or prophylactic courses of antibiotics should be considered for strep-triggered PANS/PANDAS.

Assess Treatment Efficacy

When treating PANS PANDAS, periodically assess the efficacy of treatment protocols. Modify the plan according to symptom worsening or improvement

Taper/Cease Treatment

As symptoms resolve, taper or discontinue interventions. Treatments may need to be resumed, as PANS is often relapsing-remitting. PANS PANDAS can be relapsing-remitting, chronic-static, or chronic-progressive.

Three-Pronged Approach Treatment Strategies

Three-pronged treatment protocols are dependent on disease trajectory, symptoms, and severity as well as lab work and patient history.

1. Provide Symptomatic Relief 

2. Treat Postinfectious Autoimmunity and/or Neuroinflammation

3. Treat Source of Infection

 

 Provide Symptomatic Relief

PANS/PANDAS treatment is a three-pronged strategy; treat PANS PANDAS symptomatically while treating inflammation, immune system, and infections. Prioritize the behavioral, and psychiatric treatments based on which symptoms are the most immediately concerning, and creating the most interference. Treatments must be individualized and will require adjustment; symptomology and severity differ per child. Psychiatric medications, generally, should be implemented with a ‘‘start low & go slow’’ approach; beginning dosages for PANS PANDAS are typically ¼ or less typical doses. Patients with mild to moderate symptoms may not require any pharmacological intervention while those with more severe symptoms may require behavioral therapy, further education, and pharmacologic treatments. Treatments should be reviewed periodically and adjusted as per symptom severity; symptoms can change during a flare and from flare to flare. The disease trajectory and the efficacy of other treatments such as antibiotics, anti-inflammatories, and immunomodulators vary from patient to patient. Some patients react positively and quickly to medical interventions, while others experience less positive outcomes. Thus, mental health providers are advised to not always make quick changes with every symptom change. See more on Behavioral Health. 

Cognitive Behavior Therapy (CBT)/ Exposure Response Prevention (ERP)
CBT, when caregivers reinforce it in the home, is the most effective treatment for pediatric OCD. Often the patient is not ready to undergo CBT therapy themselves until medical treatment is well underway and producing favorable results. Thus, caregivers are encouraged to seek out the help of a CBT therapist immediately to learn techniques on how to not encourage OCD rituals and other behaviors, and setting limits while reinforcing good habits. Therapists can assist caregivers in finding ways to reduce unsafe episodes, such as limiting transitions, sensory overload, stressful situations, too many expectations, etc. During unsafe episodes, due to compulsions, and rages, the primary goal of any intervention is to keep the patient safe. Once that episode is over, caregivers are encouraged to resume the tools learned from the therapists. Utilizing CBT tools to minimize and discourage obsessions and compulsions in the home can help prevent them from getting worse and reduce stress in the long run.

Behavioral Interventions

OCD	Cognitive behavior therapy (CBT) Exposure/response prevention (ERP) Parent management techniques (PMT)
Anxiety	Cognitive behavior therapy (CBT) Exposure with response prevention (ERP) Occupational therapy (OT) interventions for fear management
Depression (Not Severe)	Family supportive therapy Individual therapy
Tics	Comprehensive behavioral intervention for tics (CBIT) Habit reversal training (HRT) ERP when severe Relaxation techniques and family reinforcement of HRT
Irritability & Aggression	Environmental interventions: reduced stimulation, sleep hygiene Distraction during outbursts

Psychoactive Medication
Controlled studies have not been done on psychoactive medications and PANS patients. However, clinical experience shows, with careful management, the same medications used for the individual symptoms can be beneficial. Clinicians believe most PANS patients are more prone to have adverse reactions to medications. It is crucial to “start low and go slow”; the general advisement is to begin doses at ¼ or even less of typical starting doses and slowly taper the dose up. Two factors make PANS patients clinically complex, which ultimately increases the difficulty in understanding responses to psychoactive medication:

1. Simultaneous multiple symptoms versus “just” anxiety.
2. Some medications take days to weeks to take effect, especially with a slow taper, making it hard to discern between reactions, positive or negative, caused by the medications versus those caused by treatments and/or the episodic nature of PANS.

A general, first psychoactive treatment for PANS/PANDAS may be benzodiazepines, which can help alleviate agitation, aggression, anxiety, and insomnia. However, some pediatric patients experience may experience severe disinhibition. Selective serotonin reuptake inhibitors (SSRI) are indicated for some symptoms. Side effects can match the symptoms they are being used for; careful attention must be paid to the timing of symptom change and dosage.  Patients placed on antipsychotics should have an EKG before and during treatment to rule out a prolonged QTc.

Inpatient Hospitalization
For patients with dangerous and/or life-threatening behaviors, inpatient hospitalization may be necessary to keep them safe. Ideally, a behavioral unit will have staff qualified to handle medical procedures as well as be trained in behavior modification techniques. Such units are extremely rare; thus, doctors often must choose between a psychiatric unit and a general pediatric hospital.

School Accommodations
Appropriate school accommodations are necessary for most students with PANS/PANDAS. Typically, a 504 plan or an individualized educational plan (IEP) is created. Planning teams should write accommodations based on the student’s worst exacerbation to be appropriately prepared. As PANS symptoms relapse and remit, the school must be able to move the patient in and out of services.  Over half of PANS patients miss a significant amount of school. There needs to be a consistent flow of information between the school, its various departments, and the caregivers. School support is part of treating PANS PANDAS. Learn more about PANS at School.

Family Support
PANS places a significant burden on the entire family. Families must remember to take care of themselves. Parents are encouraged to seek local support groupsboth in-person and online. Parents are also encouraged to find a CBT Therapist to work with to learn tools to incorporate into daily living.

For specific psychiatric and behavioral interventions for each specific symptom (OCD, anxiety, restricted food take, etc.), please refer to Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I–Psychiatric and Behavioral Interventions, Margo Thienemann, MD et al, Journal of Child and Adolescent Psychopharmacology Volume 27, Number 7, 2017, Mary Ann Liebert, Inc., Pp. 1–8

General Guidelines of Immunomodulatory Therapy for Treating PANS PANDAS

1.  New Onset/Acute Flare

• Mild: ‘‘tincture of time’’ along with CBT. If symptoms persist, add nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts
• Moderate-to-Severe: oral or intravenous corticosteroids may be sufficient.
• Extremely Severe: Long, tapered corticosteroid courses or repeated high-dose corticosteroids. TPE is the first-line therapy given with or without IVIG, high-dose intravenous corticosteroids, and/or rituximab.

2.  Relapsing-Remitting

• As above
• Look for recurrent or new triggers; treat accordingly
• If immunodeficient, IVIG may be warranted.

3.  Chronic-Static or Chronic-Progressive

• Mild-to-moderate and moderate-to-severe symptoms: Prescribe immunomodulatory therapies appropriate to severity
• Severe-to-extreme symptoms:Consider appropriate immunomodulatory therapies. Seek further evaluation.
• Refractory disease course: Seek further evaluation. Consider appropriate immunomodulatory therapies. Consider shifting to primary rehabilitation in cases with possible injured neurocircuitry.

 Treat Postinfectious Autoimmunity and/or Neuroinflammation

Immune treatments are only used in PANS/PANDAS patients demonstrating signs of postinfectious autoimmunity and/or neuroinflammation, which are seen in at least 80% of patients. Evidence to prescribe these treatments may be obtained from paraclinical assessments, lab work, and physical examination. Immunomodulatory treatment plans are based on disease trajectory and symptom severity; treatment plans must be individualized. The Treatment Guidelines are organized by severity: mild, moderate-to-severe, and extreme/life-threatening clinical presentations. For more information on Symptom Severity. There are supplementary guidelines based on disease trajectory because single disease and relapsing-remitting disease episodes are treated differently than those with a chronic-progressive and chronic-static course.

Overview of Immunomodulatory Therapy Based on Severity & Disease Trajectory for Treating PANS PANDAS

Mild Symptom Severity Treatment
Mild symptoms, once an infection is ruled out or treated, may only need ‘‘tincture of time’’ along with some CBT therapy. However, there may be a relapse.  If symptoms worsen or last longer than two weeks, nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for six weeks.  NSAIDs effects can decrease over time, so they should be stopped intermittently; if symptoms return, then another course of NSAIDs should be given.  Negative side effects should be watched for, even though two studies reveal no significant toxicities. A recent study reveals that 1/3 of PANS patients improved on NSAIDs and another 1/3 did worse once the NSAIDs were stopped. Another study confirms that NSAIDs are related to shorter flares.

For Mild-to-Moderate Treatment
For mild-to-moderate symptoms, short courses of oral corticosteroids are recommended. Risks are minimal, and if given within the first day of onset, the results can be remarkable. In a recent study, patients with an infectious illness did not have as much benefit from corticosteroids as those without an infectious illness, whose PANS symptoms lasted 6.4 weeks as versus 11.4 weeks. Those with an infectious illness may benefit from a repeated steroid burst if given at symptom onset, or by delaying the initial steroid burst. Patients who relapse or have a prolonged exacerbation may benefit from additional steroid bursts with or without a taper. Caution should be used in patients with rage or aggression as corticosteroids can aggravate these symptoms, but benefits may still outweigh the risks.

Moderate-to-Severe Symptom Severity Treatment
For moderate-to-severe symptoms, immunomodulatory treatments are usually necessary. As with mild symptoms, oral corticosteroids may be adequate if given early. Longer courses equal longer periods of symptom remittance in PANS but risks are increased. Corticosteroids are the standard of care for unexplained new-onset neuropsychiatric symptoms without infections, neurodegenerative disorders, and metabolic disturbances. Patients with chronic-static or chronic-progressive disease see reduced reactions. Due to symptoms returning after the effect of the steroids wears off, IVIG and immunomodulatory agents are often needed. IVIG trials for PANS have only been designed to use a single course of IVIG. However, the PRC members typically use repeated doses on patients who experienced positive results from the first round only to relapse once the IVIG has cleared the system. Since positive results from IVIG often are not seen for 2-3 weeks, additional gains may be seen in each cycle.

Extreme or Life-Threatening Symptom Severity Treatment
For extreme and life-threatening symptoms, TPE is a first-line therapy because it generates the fastest and most significant improvement. TPE will cause hypogammaglobulinemia; clinicians should consider including IVIG in the treatment plan. TPE, on its own, does not produce long-lasting symptom improvements, so a maintenance immunosuppression regimen like rituximab is usually needed.  This may be the case in chronic-static or chronic-progressive forms of PANS too. When TPE is not accessible, then IVIG along with IVMP pulses may serve as an alternative. Rituximab or mycophenolate mofetil may be an option in patients with autoimmunity, neuroinflammation or who have relapsed after a period of continued benefit from IVIG or IVMP. Clinicians must be well versed in these treatments. Patients must also be in the care of a psychiatrist who is qualified to manage worsening psychiatric symptoms seen during a treatment protocol.

For additional information on why immunomodulatory treatments are used for PANS, as well as specific considerations and treatment guidelines, see Clinical Management of PANS: Part II—Use of Immunomodulatory Therapies, Jennifer Frankovich, MD, MS, et al., Journal of Child and Adolescent Psychopharmacology Volume 27, Number 7, 2017, Mary Ann Liebert, Inc., Pp. 1–6.

 Treat Source of Infection

Current data shows that an infection is typically the inciting factor for PANS/PANDAS. As part of the three-pronged treatment approach for PANS, treat the underlying infections thoroughly for all PANS flares triggered by an infection. As indicated by emerging data, the PRC suggests a course of anti-streptococcal antibiotics at the time of diagnosis even without a documented GAS infection. Some patients have reported full recovery due to antibiotic treatment. All PANS/PANDAS patients should be closely examined for intercurrent infections. If positive for an infection, then treat according to standard guidelines.

GAS and PANDAS
40%-77% of PANS cases are associated with strep. The number of prior GAS infections correlates with the severity and frequency of PANDAS flares. The interval between exposure to an infectious organism and the appearance of PANS symptoms ranges from 1 to 3 days prior to strep throat symptoms to 30 plus days post infection.

Not all patients with a GAS infection will present with any GAS infection symptoms. GAS infections do not just occur in the throat; perianal dermatitis is known to trigger PANS symptoms, and impetigo and other forms of the disease are thought to as well. 15% of strep throat cases are missed on rapid strep tests; a culture must be done if negative. The PRC recommends that patients presenting with PANS symptoms be given a throat swab even if no strep throat symptoms are present. The PRC accepts that a 50% fall or rise in ASO and/or ADB titers to be significant. The PRC created guidelines to determine ‘‘adequate’’ or ‘‘not adequate’’ evidence of a past strep infection to diagnose PANDAS.

Antibiotic Treatment for PANDAS
Oral or intramuscular penicillin is the first line antibiotic to treat strep. Injectable antibiotics are used when patients refuse to take medications by mouth. Cephalexin, azithromycin, clindamycin, clarithromycin, and cefadroxil are recommended in patients with persistent or relapsing strep throat, as they may be more effective. Azithromycin may not be effective in some regions of the country but it is effective against mycoplasma and may have immunomodulatory results. Note it should be used with caution in patients with a prolonged QT interval or on medications that cause one like SSRIs.

The PRC recommends ordering a course of antibiotics for a strep infection at the time of PANS diagnosis whether or not a strep infection has been identified.  This is similar to the protocol for rheumatic fever. The goal of aggressively treating GAS is to lower the risk of neuronal injury. Some members of the PRC order a 3-week initial dose of an antibiotic to resolve neuropsychiatric symptoms. Although there is not enough data to firmly support long-term prophylactic antibiotic use for PANDAS, one study shows the frequency of GAS infections were reduced by 95%-96% and flares were reduced by 56% to 75% depending on the antibiotic. The PRC commonly order long-term prophylactic antibiotics for strep, especially in patients with severe symptoms and/or frequent PANDAS flares to try and reduce further infections, flares and thus reduce risk of neuronal injury. Guidelines established for the prevention of rheumatic fever are used for PANDAS patients. The precise duration of prophylactic antibiotics has not been established but due to late relapses, it is suggested that one to two years after the last flare may be needed. Patients in remission may be able to cease antibiotics during the summer when exposure is reduced. For severe cases, prophylactic antibiotics may be warranted until 18 years of age depending on severity, relapses, and exposure.

Antibiotic Treatment for PANS
As stated above, even with no signs that strep is the PANS trigger, an initial course of antibiotics is suggested at the time of diagnosis because there may be a hidden infection. Prophylactic antibiotic use is not recommended for patients with no signs of past or current strep infection. Close monitoring of the patient and close contacts is strongly recommended. Siblings between the ages of 3-12 must be especially closely monitored for strep infections and signs of PANS as they have a high genetic risk for having PANS too.  

Upper respiratory infections
Upper respiratory infections (common cold, sinusitis, middle ear infections) are associated with the initial onset and subsequent exacerbations of PANS; the specific organism is usually not identified. For acute sinusitis, Amoxicillin-clavulanate (Augmentin) is the preferred antibiotic, especially for those with severe PANS symptoms and/or for patients who have recently been on another antibiotic. For influenza, prevention is key during flu season. Anti-virals for influenza can be used; anti-viral treatment for children can be given after the first 48 hours of illness as they may shed the virus for longer than adults.

Mycoplasma pneumoniae
Mycoplasma pneumoniae has been anecdotally observed to be a PANS trigger. The most accurate diagnosis of M. Pneumonia utilizes the information from both polymerase chain reaction (PCR) and serologic testing. IgG titers can be raised for life, even with treatment. Mycoplasma is most often treated with azithromycin, macrolides, and tetracyclines.

Lyme borreliosis
At the time the Treatment Guidelines were published, the PRC did not know of any documented cases in which Lyme borreliosis was a trigger for PANS. OCD and many of the same neuropsychiatric symptoms seen in PANS occur in some Lyme disease patients. Established treatment protocols for Lyme disease should be referenced.

Other infections and triggers
In addition to the infections mentioned above, many other infections are associated with PANS onset and/or exacerbations, including but not limited to varicella, Epstein-Barr virus, enterovirus, dental infection, herpes simplex, gastrointestinal infections. All should be treated as per guidelines for those infections.

For specific more information on Treating PANS PANDAS that is triggered by an infection, please refer to Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part III—Treatment and Prevention of Infections, Michael S. Cooperstock, MD, MPH, et al, Journal of Child and Adolescent Psychopharmacology Volume 27, Number 7, 2017, Mary Ann Liebert, Inc., Pp. 1–4.

Highlights

• After primary infection, HSV-1 can reach the central nervous system where, in rare cases, it replicates and triggers an acute and inflammatory response resulting in herpes simplex encephalitis (HSE).
• The presence of the HSV-1 genome has been revealed in tissues of the peripheral and central nervous system of individuals with no clinical signs of HSE.
• In humans, levels of circulating anti-HSV immunoglobulins, considered as markers of HSV-1 reactivation, have been positively correlated with an increased risk of Alzheimer’s disease (AD).
• Experimental data show that HSV-1 infection of neurons activates neurotoxic pathways typical of AD, and repeated HSV-1 reactivations in the brain of infected mice produce an AD-like phenotype.
• Further studies are required to get greater mechanistic understanding of the causal links between recurrent HSV-1 infections in the brain and AD as well as to validate experimental findings in humans.

Herpes simplex virus-1 (HSV-1) establishes latency preferentially in sensory neurons of peripheral ganglia. A variety of stresses can induce recurrent reactivations of the virus, which spreads and then actively replicates to the site of primary infection (usually the lips or eyes). Viral particles produced following reactivation can also reach the brain, causing a rare but severe form of diffuse acute infection, namely herpes simplex encephalitis. Most of the time, this infection is clinically asymptomatic. However, it was recently correlated with the production and accumulation of neuropathological biomarkers of Alzheimer’s disease. In this review we discuss the different cellular and molecular mechanisms underlying the acute and long-term damage caused by HSV-1 infection in the brain.

Keywords

• herpes simplex virus-1
• HSV-1
• encephalitis
• Alzheimer’s disease
• neurodegeneration latency/reactivation

HSV-1 Infection

HSV-1 is a widely distributed neurotropic human pathogen that is transmitted mainly by intimate contact between infected and susceptible individuals, and it causes labial, ocular, or genital infections [

1.

]. Primary infection usually occurs during childhood: over 60% of individuals under 50 years of age are infected with HSV-1 worldwide [

2.

]. After primary infection of epithelial cells, the virus becomes latent in neurons of the peripheral nervous system (PNS) and can be periodically reactivated resulting in recurrent clinical or subclinical episodes throughout life [

1.

]. Although sympathetic neurons can be also affected, HSV-1 mainly infects sensory neurons close to the site of primary infection [

3.

,

4.

], subsequently traveling retrogradely along the axon to the cell body in the peripheral ganglia. Studies in animal models have shown that the virus can also reach the central nervous system (CNS) [

5.

, 

6.

, 

7.

, 

8.

, 

9.

, 

10.

, 

11.

, 

12.

, 

13.

, 

14.

] (Figures 1 and 2A ). In humans, viral replication in the brain may result in herpes simplex encephalitis (HSE) (reviewed in [

15.

]) or milder/asymptomatic infections eventually followed by latency [

16.

]. A growing body of evidence indicates that the cumulative effects of repeated 'mild' HSV-1 brain infections may result in neuronal damage similar to that found in neurodegenerative disorders such as Alzheimer’s disease (AD), the most common form of dementia in the elderly (Box 1) [

17.

]. Here, we review recent knowledge on the pathogenic mechanisms underlying neuronal damage caused by HSV-1 infection and discuss the effects of severe acute infection and repeated viral reactivations.

Figure 1Schematic Representation of Acute and Latent Herpes Simplex Virus-1 (HSV-1) Infection in Humans.

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