Clinicopathologic Characteristics of PANDAS in a Young Adult: A Case Report.

Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is an acute onset or exacerbation of neuropsychiatric symptoms following a group A streptococcus infection. It is believed to be a result of autoimmune response to streptococcal infection, but there is insufficient evidence to fully support this theory. Although this disease is primarily thought to be a disease of childhood, it is reported to occur also in adults. PANDAS is a well-defined clinical entity, but the neuropathology of this condition has not been established yet. We describe the clinical course of a 26-year-old female diagnosed with PANDAS. She committed suicide and her brain was biobanked for further studies. We examined the banked tissue and performed special stains, immunohistochemical, and immunofluorescence analyses to characterize the neuropathology of this condition. Histology of the temporal lobes, hippocampus, and basal ganglia shows mild gliosis and Alzheimer's type II astrocytes. Acute hypoxic ischemic changes were noted in hippocampus CA1 and CA2 areas. Immunostaining shows increased parenchymal/perivascular GFAP staining and many vessels with mild increases in CD3-, CD4-, and CD25-stained lymphocytes in the basal ganglia. The findings suggest that CD4- and CD25-positive T cells might have an important role in understanding the neuroinflammation and pathogenesis of this condition. The case represents the first neuropathological evaluation report for PANDAS.

Deuterium metabolic imaging and hyperpolarized 13C-MRI of the normal human brain at clinical field strength reveals differential cerebral metabolism.

Deuterium metabolic imaging (DMI) and hyperpolarized 13C-pyruvate MRI (13C-HPMRI) are two emerging methods for non-invasive and non-ionizing imaging of tissue metabolism. Imaging cerebral metabolism has potential applications in cancer, neurodegeneration, multiple sclerosis, traumatic brain injury, stroke, and inborn errors of metabolism. Here we directly compare these two non-invasive methods at 3 T for the first time in humans and show how they simultaneously probe both oxidative and non-oxidative metabolism. DMI was undertaken 1-2 h after oral administration of [6,6'-2H2]glucose, and 13C-MRI was performed immediately following intravenous injection of hyperpolarized [1-13C]pyruvate in ten and nine normal volunteers within each arm respectively. DMI was used to generate maps of deuterium-labelled water, glucose, lactate, and glutamate/glutamine (Glx) and the spectral separation demonstrated that DMI is feasible at 3 T. 13C-HPMRI generated maps of hyperpolarized carbon-13 labelled pyruvate, lactate, and bicarbonate. The ratio of 13C-lactate/13C-bicarbonate (mean 3.7 ± 1.2) acquired with 13C-HPMRI was higher than the equivalent 2H-lactate/2H-Glx ratio (mean 0.18 ± 0.09) acquired using DMI. These differences can be explained by the route of administering each probe, the timing of imaging after ingestion or injection, as well as the biological differences in cerebral uptake and cellular physiology between the two molecules. The results demonstrate these two metabolic imaging methods provide different yet complementary readouts of oxidative and reductive metabolism within a clinically feasible timescale. Furthermore, as DMI was undertaken at a clinical field strength within a ten-minute scan time, it demonstrates its potential as a routine clinical tool in the future.

Role of tonsillectomy and adenoidectomy in parental satisfaction of treatments for PANDAS.

OBJECTIVE: To examine caregiver satisfaction with treatments for pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) and how symptom frequency changes over time. METHODS: A list was created for PANDAS subjects seen at the Georgetown Pediatric Otolaryngology clinic from 2015 to 2018. Questionnaires were distributed to caregivers able to be contacted; 62% responded (n = 60). Subjects were placed in groups based on treatments reported: tonsillectomy and adenoidectomy (T&A, n = 28), T&A and intravenous immunoglobulin (IVIG, n = 22), or nonsurgical treatment(s) (n = 10). Caregivers reported frequencies for each of 10 associated symptoms from time of treatment to 12 months and also expressed their satisfaction with treatment. RESULTS: Patients were treated with antibiotics (n = 60, 100%), T&A (83.3%), IVIG (40%), Rituximab (15%), steroids (20%), and/or plasma exchange (10%). Caregivers for 66% (n = 33) of surgical patients identified T&A as the most effective treatment, and 80% would choose the operation again. No difference in median caregiver satisfaction level was found among the groups (n = 0.196). There was no significant difference in frequency for any of the symptoms (all p > 0.05) except choreiform movement (p = 0.0296). CONCLUSION: Caregivers reported a decreasing frequency of symptoms over time regardless of treatment and had no difference in satisfaction. T&A was the most preferred treatment and the most impactful on symptoms for surgical patients. Given the challenges of immunologic therapies, T&A in combination with antibiotics should be considered as an early intervention for PANDAS.

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II-Use of Immunomodulatory Therapies.

Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines. Results: Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be "tincture of time" combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab. Conclusions: These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells.

Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus Immunology: A Pilot Study.

OBJECTIVE: To elucidate specific cytokine and chemokine markers in patients diagnosed with pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS). STUDY DESIGN: Prospective cohort study. STUDY SETTING: Academic university hospital. METHODS: Tonsil tissue was collected from 24 patients and organized into 3 groups: experimental PANDAS cohort (12 patients), group A beta hemolytic streptococcus control cohort (6 patients), and obstructive sleep apnea control cohort (6 patients). Each tissue sample was extracted with MSD Tris lysis buffer, and protein lysates were analyzed for human chemokines and cytokines by the Human Cytokine 30-Plex Assay on the Mesoscale System. RESULTS: We identified a significant difference in expression regarding the 8 following cytokines when comparing the experimental PANDAS, group A beta hemolytic streptococcus, and obstructive sleep apnea control cohorts: tumor necrosis factor-α and eotaxin-3. In addition, our group also identified a significant reduction in the expression of interleukin (IL)-8, interferon inducible protein-10, IL-17a, interferon-γ, IL-10, and IL-12 across the aforementioned groups. CONCLUSIONS: Patients diagnosed with PANDAS appear to maintain significantly different concentrations of cytokines when compared with patients afflicted by chronic group A beta hemolytic streptococcus infections and obstructive sleep apnea. As a result, one could potentially use the described characterization of immunologic markers as a basis for future mechanistic and epidemiological studies.

Ultrastructural features of neuroblastic tumours in relation to morphological, and molecular findings; a retrospective review study.

BACKGROUND: Neuroblastoma is the most common solid tumour of infancy and is responsible for 15% of childhood cancer deaths. Presence of amplified MYCN in neuroblastoma is associated with poor prognosis and rapid tumour progression. The aim of this study was to examine and compare the ultrastructural features of high-risk MYCN amplified neuroblastomas, with lower-risk non-MYCN amplified tumours. METHODS: This was a retrospective study evaluating archival diagnostic tissue samples, in which Fluorescence in-situ hybridisation (FISH) had been used at diagnosis to establish MYCN status. 22 (11 MYCN amplified tumours and 11 non-MYCN amplified) tumours of similar light microscopic appearance (poorly differentiated neuroblastoma) were then selected for ultrastructural examination. RESULTS: There is a relationship between ultrastructural features in neuroblastoma and MYCN status, although with marked overlap between groups. MYCN amplified tumours generally exhibited a 'less differentiated' ultrastructural phenotype, with significantly smaller neurotubules (NT) in the cell body (p < 0.002). Non-MYCN amplified tumours show increased features of neuronal differentiation, with fewer neurosecretory granules (NSG) and NT in the cytoplasm. CONCLUSIONS: MYCN amplification is associated with a less differentiated ultrastructural phenotype, and lack of MYCN amplification with relative ultrastructural neuronal differentiation.