Researchers Submit Patent Application, “Diagnostic Method for Pediatric Acute-Onset Neuropsychiatric Syndrome (Pans) and Pediatric Autoimmune…
Researchers Submit Patent Application, "Diagnostic Method for Pediatric Acute-Onset Neuropsychiatric Syndrome (Pans) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococci Infection (Pandas)", for Approval (USPTO 201601
By a
No assignee for this patent application has been made.
News editors obtained the following quote from the background information supplied by the inventors: "The present invention provides a convenient and accurate diagnostic method for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS). The ability to reliably diagnose PANS and/or PANDAS using such a method allows treating clinicians to prescribe treatments in a more effective and timely manner than currently possible. Such ability to reliably diagnose PANS and PANDAS is expected to allow significant improvement in the outcomes of many patients with PANS and/or PANDAS.
"Pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS) is a sudden and severe onset obsessive-compulsive disorder (OCD) or tic disorder described in 1998 (Swedo et al., Am. J. Psychiatry 155:2, 264-271 (1998)). Such disorders generally have an onset between the ages of about 2 to 14. There are currently five diagnostic criteria required for a PANDAS diagnosis:
"(1) presence of OCD or tic disorder;
"(2) prepubertal symptom onset;
"(3) acute symptom onset and episodic (relapsing-remitting) course;
"(4) temporal association of Group A streptococcal infection and symptom onset/exacerbations; and
"(5) association with neuropsychiatric abnormalities (especially hyperactivity and choreiform movements). Swedo et al., Pediatr. Therapeut. 2012, 2:2 (http://dx.doi.org/10.4172/2161-0665.1000113).
"More recently, pediatric acute-onset neuropsychiatric syndrome (PANS) has been described based on three diagnostic criteria:
"(1) abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake;
"(2) concurrent presence of additional neuropsychiatric symptoms, with
"similarly severe and acute onset, from at least two of the following seven categories: (a) anxiety; (b) motional lability and/or depression; © irritability, aggression and/or severely oppositional behaviors; (d) behavioral (developmental) regression; (e) deterioration in school performance; (f) sensory or motor abnormalities; or (g) somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency; and
"(3) symptoms not better explained by a known neuropsychiatric or medical disorder (e.g., Sydenham chorea, systemic lupus erythematosus, Tourette disorder or the like). Id. Generally PANDAS, which has a temporal association of Group A streptococcal infection, is a subset of the more general PANS condition.
"Some of most striking aspects of PANS/PANDAS include its rapid onset and the severity and variability of its neuropsychiatric abnormalities. Many parents can point to a particular day or week when the condition began, often describing the event as 'falling off a cliff' or the 'day they lost their child.' A recent posting from the
"'My child was fine last week, last month--and now I have lost her. This is not my child; what has happened??? What do I do??'
"'For every parent of a child with an illness, especially a mental illness, there is a particular story. But when you meet a parent of a child with PANDAS (typically a child between ages 3-14), you will hear the same panicked story over and over. A child who was happy at home and at school, and was social and athletic, is now walking in circles for hours, washing hands until they bleed, asking the same questions over and over--and over. A child that used to be comforted by a hug is now inconsolable. They may be begging parents for help, begging for a way to end the horror that exists only in their minds. Imagine a child screaming in terror in a corner, and a parent unable to hold them. These parents will tell you in detail about the day or week that their child changed. Here is what life looks like now--children may exhibit some or all of these symptoms: Acute sudden onset of OCD Challenges with eating, and at the extreme end, anorexia Sensory issues such as sensitivity to clothes, sound, and light Handwriting noticeably deteriorates Urinary frequency or bedwetting Small motor skills deteriorate--a craft project from yesterday is now impossible to complete . . . Tics Inattentive, distractible, unable to focus and has difficulties with memory Overnight onset of anxiety or panic attacks over things that were no big deal a few days ago, such as thunderstorms or bugs Suddenly unable to separate from their caregiver, or to sleep alone Screaming for hours on end Fear of germs and other more traditional-looking OCD symptoms'
"'You will often find these parents on the computer every night, desperate for an explanation that makes sense. They are seeking specialists who can help--and finding no answers. They are starting to feel crazy themselves, because no one seems to believe what they are going through.' Jenike and Dailey,
"Thus, parents turning to the medical community are often at a loss since currently there are no clinical methods or tests to provide or confirm a diagnosis. Currently, only diagnosis based on existing observational clinical criteria are possible. Children presenting with neuropsychiatric symptoms would not generally be considered candidates for the most aggressive treatment options (e.g., autoimmune therapeutics or immune modulation treatments discussed below) without a diagnostic tool that shows autoimmune results. This is why there is significant difficulty in making a PANDAS/PANS diagnosis based upon symptoms alone; indeed, there is even difficulty in agreeing upon standard nomenclature for such conditions.
"Effective treatments for PANDAS/PANS are available. During the early stages with bacterial infections, antibiotic therapy, perhaps even for several months, is recommended. Antibiotics (e.g., amoxicillin, penicillin, azithromycin, and cephalosporins) can be used to treat the strep infection in PANDAS and often result in immediate improvement. Treatment with other anti-infective agents may also be useful in some cases depending on the specific infection observed in particular cases. For purposes of this invention, antibiotic therapy is to include treatment with both antibiotics and other anti-infective agents.
"Treatment with anti-inflammatory agents (including both steroids and non-steroidal anti-inflammatory drugs (NSAIDS)) may also be helpful. Treatment with prednisone or corticosteroids has been used with some reports of improvements. In some cases, however, tic conditions have actually worsened. Such treatments can only be used for short time periods due to possible serious long-term complications. And even where improvements are observed, symptoms often return after termination of treatment--sometimes to even worse levels. Nonetheless, since a 'steroid response' may be an indication that immune-based therapies may be helpful.
"Where symptoms lasting more than a year or very severe disease, intravenous immunoglobulin (IVIG) or plasmapheresis (i.e., plasma exchange to remove antibodies from the blood) may be helpful. A clinical study (http://clinicaltrials.gov/ct2/show/NCT01281969) is currently being conducted using IVIG therapy with Gamunex.RTM.-C (
"The lack of clinical methods or tests to provide or confirm a PANS or PANDAS diagnosis presents significant obstacles to providing effective therapies to children suffering from PANS or PANDAS and their parents seeking such therapies. A physician, without such clinical methods or tests, may be less likely to conclude such a diagnosis simply based on the currently existing observational clinical criteria. After all, such current treatments regimes can be uncertain in outcome, expose the patient to significant side effects as well as long term, painful, and difficult procedures, and expose the parents to very high economic costs. Clinical methods and procedures to more accurately diagnose PANS or PANDAS will more easily allow physicians to arrive at such diagnosis with confidence and will, over time, allow treatments to move out of the experimental phase and to achieve insurance coverage.
"Thus, there remains a need to provide such clinical methods and procedures. Indeed, this need has been unmet since the first identification of PANDAS/PANS in the 1980s and remains unmet today. The present invention provides such methods."
As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "The present invention provides for a convenient and accurate diagnostic method for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS). The ability to reliably diagnose PANS and/or PANDAS using such a method allows treating clinicians to prescribe treatments in a more effective and timely manner than currently possible. Such ability to reliably diagnose PANS and PANDAS is expected to allow significant improvement in the outcomes for many patients with PANS and/or PANDAS.
"Generally, the present diagnostic method can be applied to pediatric acute-onset neuropsychiatric syndrome (PANS) and similar diseases that may include autistic-like behaviors, anorexia nervosa, and deterioration in handwriting in addition to the typical contamination fears, obsessions and/or tics often associated with such conditions. Such similar diseases include pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS), rheumatic fever cases with Sydenham chorea, anorexia nervosa, autistic-like behaviors, obsessive compulsive disorder, Tourette's syndrome, Asperger's syndrome, and other related diseases with movement and neuropsychiatric symptoms. This present invention is especially adapted for the diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS) which is a subset of PANS. Unless otherwise specified, the term PANS is intended to include similar autoimmune-based diseases that may include autistic-like behaviors, anorexia nervosa, and deterioration in handwriting in addition to the typical contamination fears, obsessions and/or tics often associated with such conditions. The present invention is especially directed towards the diagnosis of PANDAS/PANS. The use of the present clinical diagnostic method avoids issues related to the many of conflicting names given to such conditions. If the present diagnostic method indicates the likelihood of such an underlying autoimmune disease presenting with neuropsychiatric symptoms, physicians can proceed more rapidly and with greater certainty to the determination of the appropriate treatment options (as discussed below).
"The present invention comprises a panel of at least five clinical analyses or tests (using serum samples) to determine the risk of pediatric acute-onset neuropsychiatric syndrome (PANS) and/or pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) in an individual. Serum samples include, for example, blood serum and cerebrospinal fluid (CSF). Generally blood serum is preferred whereby whole blood is collected from the patient and the red blood cells are centrifuged down to separate it from the serum. The serum is removed can be assayed immediately or stored for later assay.
"The first group of these clinical assays or tests include enzyme linked immunosorbent assays (ELISAs) to measure antibody titers against neuronal antigens present in the brain; these neuronal antigens include lysoganglioside, tubulin, dopamine receptor D1, dopamine receptor D2, human serotonin receptor 5HT2A, and human serotonin receptor 5HT2C. The present methods include at least four of these enzyme linked immunosorbent assays, preferably at least five of these enzyme linked immunosorbent assays, and more preferably all six of these enzyme linked immunosorbent assays. If only four assays are to be used from the first group, it is generally preferred that the neuronal antigens include lysoganglioside, tubulin, dopamine receptor D1, and dopamine receptor D2. The present methods also include a final assay to quantify calcium/calmodulin-dependent protein kinase activity using a neuronal cell line.
"The present invention provides a method for determining the likelihood of a PANS or PANDAS diagnosis in a patient, said method comprising
"(1) obtaining a serum sample from the patient;
"(2) in a first assay, measuring a first antibody titer against lysoganglioside in a first portion of the serum sample and comparing the measured first antibody titer to a first normal control titer against lysoganglioside;
"(3) in a second assay, measuring a second antibody titer against tubulin in a second portion of the serum sample and comparing the measured second antibody titer to a second normal control titer against tubulin;
"(4) in a third assay, measuring a third antibody titer against dopamine receptor D1 in a third portion of the serum sample and comparing the measured third antibody titer to a third normal control titer against dopamine receptor D1;
"(5) in a fourth assay, measuring a fourth antibody titer against dopamine receptor D2 in a fourth portion of the serum sample and comparing the measured fourth antibody titer to a fourth normal control titer against dopamine receptor D2; and
"(6) in a final assay, measuring calcium/calmodulin-dependent protein kinase activity using a neuronal cell line in a separate portion of the serum sample and comparing the measured calcium/calmodulin-dependent protein kinase activity to a normal control calcium/calmodulin-dependent protein kinase activity;
"whereby a PANS or PANDAS diagnosis is considered likely if any one of the first, second, third, or fourth antibody titers is significantly higher than the corresponding first, second, third, or fourth normal control titers, respectively; whereby the PANS or PANDAS diagnosis is considered highly likely if, independent of results from the first, second, third, and fourth assays, the measured calcium/calmodulin-dependent protein kinase activity is significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity; and whereby the PANS or PANDAS diagnosis is considered not likely if (1) none of the first, second, third, or fourth antibody titers are significantly higher than the corresponding first, second, third, or fourth normal control titers, respectively, and (2) the measured calcium/calmodulin-dependent protein kinase activity is not significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity.
"The present invention also provides a method for treating PANS or PANDAS in a patient, said method comprising (A) requesting an analysis of a serum sample from a patient suspected of having PANS or PANDAS, wherein the analysis is capable of determining whether the patient is likely or highly likely to have PANS or PANDAS and (B), should the analysis determine that the patient is likely or highly likely to have PANS or PANDAS, administering antibiotic therapy, anti-inflammatory therapy, intravenous immunoglobulin therapy, plasmapheresis therapy, or combinations thereof to the patient;
"wherein the analysis comprises the steps of:
"(1) obtaining the serum sample from the patient;
"(2) in a first assay, measuring a first antibody titer against lysoganglioside in a first portion of the serum sample and comparing the measured first antibody titer to a first normal control titer against lysoganglioside;
"(3) in a second assay, measuring a second antibody titer against tubulin in a second portion of the serum sample and comparing the measured second antibody titer to a second normal control titer against tubulin;
"(4) in a third assay, measuring a third antibody titer against dopamine receptor D1 in a third portion of the serum sample and comparing the measured third antibody titer to a third normal control titer against dopamine receptor D1;
"(5) in a fourth assay, measuring a fourth antibody titer against dopamine receptor D2 in a fourth portion of the serum sample and comparing the measured fourth antibody titer to a fourth normal control titer against dopamine receptor D2; and
"(6) in a final assay, measuring calcium/calmodulin-dependent protein kinase activity using a neuronal cell line in a separate portion of the serum sample and comparing the measured calcium/calmodulin-dependent protein kinase activity to a normal control calcium/calmodulin-dependent protein kinase activity;
"whereby the patient is considered likely to have PANS or PANDAS if any one of the measured first, second, third, or fourth antibody titers is significantly higher than the corresponding first, second, third, or fourth normal control titers, respectively; whereby the patient is considered highly likely to have PANS or PANDAS if, independent of results from the first, second, third, and fourth assays, the measured calcium/calmodulin-dependent protein kinase activity is significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity; and whereby the patient is considered not likely to have PANS or PANDAS if (1) none of the first, second, third, or fourth antibody titers are significantly higher than the corresponding first, second, third, or fourth normal control titers, respectively, and (2) the measured calcium/calmodulin-dependent protein kinase activity is not significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity.
"The present invention also provides a method for determining the likelihood of a PANS or PANDAS diagnosis in a patient, said method comprising
"(1) obtaining a serum sample from the patient;
"(2) carrying out at least four assays on the serum sample, wherein the at least four assays are selected from the group consisting of (A) a first assay wherein a first antibody titer against lysoganglioside is measured in a first portion of the serum sample and then is compared to a first normal control titer against lysoganglioside, (B) a second assay wherein a second antibody titer against tubulin is measured in a second portion of the serum sample and then is compared to a second normal control titer against tubulin, (C) a third assay wherein a third antibody titer against dopamine receptor D1 is measured in a third portion of the serum sample and then is compared to a third normal control titer against dopamine receptor D1, (D) a fourth assay wherein a fourth antibody titer against dopamine receptor D2 is measured in a fourth portion of the serum sample and then is compared to a fourth normal control titer against dopamine receptor D2, (E) a fifth assay wherein a fifth antibody titer against human serotonin receptor 5HT2A is measured in a fifth portion of the serum sample and then is compared to a fifth normal control titer against human serotonin receptor 5HTT2A, and (F) a sixth assay wherein a sixth antibody titer against human serotonin receptor 5HT2C is measured in a sixth portion of the serum sample and then is compared to a sixth normal control titer against human serotonin receptor 5HT2C; and
"(3) carrying out a final assay wherein calcium/calmodulin-dependent protein kinase activity is measured using a neuronal cell line in a separate portion of the serum sample and then is compared to a normal control calcium/calmodulin-dependent protein kinase activity;
"whereby a PANS or PANDAS diagnosis is considered likely if at least one of the measured first, second, third, fourth, fifth, or sixth antibody titers are significantly higher than the corresponding first, second, third, fourth, fifth, or sixth normal control titers, respectively; whereby the PANS or PANDAS diagnosis is considered highly likely if, independent of results from the first, second, third, fourth, fifth, or sixth assays, the measured calcium/calmodulin-dependent protein kinase activity is significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity; and whereby the PANS or PANDAS diagnosis is considered not likely if (1) none of the measured first, second, third, fourth, fifth, or sixth antibody titers are significantly higher than the corresponding first, second, third, fourth, fifth, or sixth normal control titers, respectively, and (2) the measured calcium/calmodulin-dependent protein kinase activity is not significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity. Preferably, step (2) involves carrying out at least five assays on the serum sample, wherein the at least five assays are selected from the group consisting of the first, second, third, fourth, fifth, and sixth assays. More preferable, step (2) involves carrying out all six assays on the serum sample from the group consisting of the first, second, third, fourth, fifth, and sixth assays.
"The present invention also provides a method for treating PANS or PANDAS in a patient, said method comprising (A) requesting an analysis of a serum sample from a patient suspected of having PANS or PANDAS, wherein the analysis is capable of determining whether the patient is likely or highly likely to have PANS or PANDAS and (B), should the analysis determine that the patient is likely or highly likely to have PANS or PANDAS, administering antibiotic therapy, anti-inflammatory therapy, intravenous immunoglobulin therapy, plasmapheresis therapy, or combinations thereof to the patient;
"wherein the analysis comprises the steps of:
"(1) obtaining the serum sample from the patient;
"(2) carrying out at least four assays on the serum sample, wherein the at least four assays are selected from the group consisting of (A) a first assay wherein a first antibody titer against lysoganglioside is measured in a first portion of the serum sample and then is compared to a first normal control titer against lysoganglioside, (B) a second assay wherein a second antibody titer against tubulin is measured in a second portion of the serum sample and then is compared to a second normal control titer against tubulin, (C) a third assay wherein a third antibody titer against dopamine receptor D1 is measured in a third portion of the serum sample and then is compared to a third normal control titer against dopamine receptor D1, (D) a fourth assay wherein a fourth antibody titer against dopamine receptor D2 is measured in a fourth portion of the serum sample and then is compared to a fourth normal control titer against dopamine receptor D2, (E) a fifth assay wherein a fifth antibody titer against human serotonin receptor 5HT2A is measured in a fifth portion of the serum sample and then is compared to a fifth normal control titer against human serotonin receptor 5HTT2A, and (F) a sixth assay wherein a sixth antibody titer against human serotonin receptor 5HT2C is measured in a sixth portion of the serum sample and then is compared to a sixth normal control titer against human serotonin receptor 5HT2C; and
"(3) carrying out a final assay wherein calcium/calmodulin-dependent protein kinase activity is measured using a neuronal cell line in a separate portion of the serum sample and then is compared to a normal control calcium/calmodulin-dependent protein kinase activity;
"whereby a PANS or PANDAS diagnosis is considered likely if at least one of the measured first, second, third, fourth, fifth, or sixth antibody titers are significantly higher than the corresponding first, second, third, fourth, fifth, or sixth normal control titers, respectively; whereby the PANS or PANDAS diagnosis is considered highly likely if, independent of results from the first, second, third, fourth, fifth, or sixth assays, the measured calcium/calmodulin-dependent protein kinase activity is significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity; and whereby the PANS or PANDAS diagnosis is considered not likely if (1) none of the measured first, second, third, fourth, fifth, or sixth antibody titers are significantly higher than the corresponding first, second, third, fourth, fifth, or sixth normal control titers, respectively, and (2) the measured calcium/calmodulin-dependent protein kinase activity is not significantly higher than the normal control calcium/calmodulin-dependent protein kinase activity. Preferably, step (2) involves carrying out at least five assays on the serum sample, wherein the at least five assays are selected from the group consisting of the first, second, third, fourth, fifth, and sixth assays. More preferable, step (2) involves carrying out all six assays on the serum sample from the group consisting of the first, second, third, fourth, fifth, and sixth assays.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 provides a flowchart illustrating the method of the present invention using PANDAS as an illustrative example.
"FIG. 2 provides a flowchart illustrating the general algorithm used in the present invention using PANDAS as an illustrative example.
"FIG. 3 provides a schematic (but theoretic) illustration of the necessity at least five assays of the present invention to provide a PANDAS diagnosis."
For additional information on this patent application, see: Cummingham,
Keywords for this news article include: Antibodies, Antigens, Neurons, Patents, Therapy, Tubulin, Autacoids, Pediatrics, Tryptamines, Blood Proteins, Immunoproteins, Serum Globulins, Carrier Proteins, Immunoglobulin G, Immunologic Tests, Membrane Proteins, Organic Chemicals, Biological Factors, Dopamine Receptors, Serotonin Receptors, Microtubule Proteins.
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