Research

J Schnell, M Bond, N Moll, E Weidinger, B Burger, R Bond, A Dietrich, PJ. Hoekstra, A Schrag, D Martino, M Schwarz, U-X Meier, N Müller. Brain, Behavior, and Immunity. Vol 99, 2022. DOI: 10.1016/j.bbi.2021.10.012

• M. pneumoniae IgG positivity was not associated with the presence of CTD.
• M. pneumoniae IgG positivity was not associated with the first onset of tics.
• M. pneumoniae IgG positivity was significantly associated with higher tic severity.

“It is possible that M. pneumoniae infection influences tic severity in CTD or, that having more severe tics, increases the risk of infection. However, it is more likely that the association observed in this study reflects a propensity toward enhanced immune responses in people with CTD and that, rather than a causal relationship, infection and greater tic severity are indirectly linked via shared underlying immune mechanisms.”

Sizgoric MK, Kovac Sizgoric M, Miculinic A, et al. Clinical manifestations of patients with PANDAS in patients followed up at Srebrnjak children’s hospital in 5-year period. Archives of Disease in Childhood 2021;106:A169. Article

Clinical:
– 20 children, 16 (80%) male, 4 (20%) female, aged 3 to 11 years (median age 6.5)
-Elevated levels of antistreptolysin titers 19 of 20 (95%). Anti-DNAse-B levels were tested in 7 patients and was elevated in 4 (57%)
-Neuroimaging studies (N=12 or 60%) – no specific findings found
-Family history of tics and autoimmune disorders was positive in N=5
(25%)

Symptoms:
-All patients had OCD and tics with acute onset of symptoms
-Attention disorders N=17 (85%)
-Sleeping difficulties N=4 (20%)
-Speech difficulties N=5 (25%)
-Decline in school performance N=10 (71%)

Treatment:
-15 (75%) patients given first-line antibiotics. In 5 (25%) patients a full regression of symptoms was registered, 10 (50%) had partial improvement, 5 (25%) had no response.
-7 (35%) were given IVIG after initial antibiotic treatment with incomplete regression. Tics persisted in 11 patients and 4 had tics with behavioral difficulties. In 7 patients treated with IVIG we proceeded with parenteral antibiotics because of partial symptom regression and 2 were given corticosteroids (still followed).

A Krouse, H Li, JA Krenzer, WN Rose. Plasmapheresis, Rituximab, and Ceftriaxone Provided Lasting Improvement for a 27-Year-Old Adult Male with PANDAS. Dept of Pathology, University of Wisconsin Hospital. Article

• At 17 – developed sudden psychosis and confusion after GAS infection. Had elevated anti-streptolysin O (ASO) titers. Did not present with typical symptoms of PANDAS – OCD and/or tic-like symptoms were not observed. A tentative diagnosis of PANDAS was given. Treated with antipsychotics, antibiotics, tonsillectomy, and IVIG which resulted in remissions and relapses of his neuropsychiatric symptoms.
• At age 27 – received a trial of therapeutic plasma exchange (TPE), rituximab, and ceftriaxone. Eventually resulted in sustained benefit and minimal fluctuations of his clinical symptoms.

de Oliveira, K.C., Camilo, C., Gastaldi, V.D. et al. Brain areas involved with obsessive-compulsive disorder present different DNA methylation modulation. BMC Genom Data 22, 45 (2021). DOI:10.1186/s12863-021-00993-0

• Confirms involvement of previously associated genes and biological processes in OCD as well as reports differences related to specific brain areas
• Findings point to a role of cellular communication, inflammatory processes and behavior mediated by DNA methylation in OCD brain tissues.
• Findings were related to the immune system, reaffirming the current literature findings about its involvement with OCD.
• Changes in DNA methylation are involved with OCD and further studies are needed to characterize alterations in different paths in each brain area.

Dolce, J.L., LaRusso, M.D. & Abadia-Barrero, C. Disruptions and Adaptations in Family Functioning: A Study of Families’ Experiences with PANS/PANDAS. J Child Fam Stud (2021). DOI:10.1007/s10826-021-02101-3

• Examined family functioning utilizing online parent forums and nine semi-structured interviews with PANS/PANDAS families.
• Unpredictability & relapsing-remitting nature of neuropsychiatric symptoms cause significant disruptions to daily life.
• Financial strain, social isolation, and lack of support from schools and medical institutions transform family functioning.
• Parents’ frequent use of trauma metaphors to describe experience diverges from literature on other chronic illnesses.

Rea I, Guido CA, Spalice A. Clinical Features in Patients With PANDAS/PANS and Therapeutic Approaches: A Retrospective Study. Frontiers in Neurology. Vol. 12, 2021. DOI=10.3389/fneur.2021.741176  

• 62 patients with a clinical diagnosis of PANDAS/PANS.
  • 15 with PANS. 47 with PANDAS
• Mean age at onset of PANDAS/PANS symptoms was 6.2 ± 1.2 years
  • 6.2 for PANDAS. 6.0 for PANS
• Neurological and psychiatric symptoms were mostly evident in both groups with little difference
• 93.5% had vocal tics
• 79% had OCD
• PANS kids had more irritability, aggressivity, and food restriction
• PANDAS kids had 10 times higher levels of anti-streptolysin O and anti-DNAse B
• PANS kid had a higher percentage of metabolic disorders
• Psychotherapy significantly relieved OCD the most and reduced stress in patients and parents
• Antibiotic prophylaxis was the most frequently used (90%) for acute neurological symptoms

• Study links significant childhood infections to developing autism later.
• In mouse models, mice that had an immune response later were no longer able to recognize familiar faces. This study was replicated with a focus on social interactions and the mice whose immune system was activated had increased difficulty communicating.
• A different study reinforces the mouse model that tracked 3.6 million hospitalized children shoeing that hospitalizations due to infections during early childhood can predict a future diagnosis of ASD

Ueda K, Black KJ. Recent progress on Tourette syndrome. Fac Rev. 2021;10:70. Published 2021 Sep 7. DOI:10.12703/r/10-70

“Recent years have seen increasing information about the relationship between tics and comorbidities and about new genetic findings. Inflammatory processes have also been a topic of continued interest.

“The prevalence and characteristics of tics in patients with encephalitis were reviewed in a systematic study, which found that sporadic cases of tics were associated with encephalitis, particularly during a post-encephalitis period, and with basal ganglia involvement⁵⁴. A case-control autopsy study (of nine individuals with TS) using basal ganglia transcriptome by RNA sequencing in the caudate and putamen found disrupted basal ganglia neuronal signaling⁵⁵. The study also found a significant increase in immune and inflammatory transcripts. These results suggest metabolic alterations and inflammatory involvement in TS pathophysiology.”

“Inflammation has been extensively discussed in tic pathophysiology. A recent review article on immunological mechanisms in the pathophysiology of tic disorders argues that innate and adaptive systemic immune pathways and neuroinflammatory mechanisms play an important role in the pathogenesis of at least some patients with TS⁵³.”

“Complementary and alternative medicines—including dietary or nutritional supplements (calcium, magnesium, coenzyme Q₁₀, fish oil, gastrodin, and vitamins B, C, D, and E), chiropractic manipulations, meditation, acupuncture, hypnosis, homeopathy, and biofeedback—have been reported for the treatment of tics^116,117; however, the evidence is limited because of a lack of randomized control studies. The efficacy and safety of a Chinese herbal medicine (5-Ling granule) in the treatment of TS were evaluated in a multicenter, double-blind randomized controlled trial, finding it as effective as tiapride in improving tic symptoms¹¹⁸.”

Delaunay-Vagliasindi S, Seneff S, Coro S & Campbell-McBride N (2021) GAPS Nutritional Protocol as a treatment for PANDAS: A case study. J Orthomol Med. 36(3). 6 September 2021 

“Growing research is calling attention to the role of poor gut health in autoimmune conditions, psychological conditions, and neurological conditions – all of which are relevant to PANDAS. The gut microbiome is a perfect target for treatment as it is flexible and adapts quickly to changes. Currently, the first-line treatments for PANDAS are antibiotics and mood stabilizers. The GAPS Nutritional Protocol aims to heal the gut lining, and restore microbial balance in the gut flora. After 18 months, George saw all his PANDAS-related symptoms disappear – tics, anxiety, hypersensitivity to noise and odours, sleep issues, concentration issues, fine motor issues, digestive issues, restricted eating habits, and quality of eye-contact – to the point where his diagnosis was officially removed. In addition, the abnormal blood test results that were indicative of the PANDAS condition – EO, NEUT, LYMPH, NLR, MPV – were restored to normal ranges after the GAPS intervention.”

Maia A., Barahona-Corrêa B., Oliveira-Maia A.J., Oliveira J. (2021) Immune Dysfunction in Obsessive-Compulsive Disorder: From Risk Factors to Multisystem Involvement. In: Berk M., Leboyer M., Sommer I.E. (eds) Immuno-Psychiatry. Springer, Cham. DOI: 10.1007/978-3-030-71229-7_17

“Immune dysfunction has been proposed as an important component of the pathophysiology of obsessive-compulsive disorder (OCD), motivating innovative research hypotheses with potential clinical interest. In this chapter, we will review published evidence supporting a model for immune dysfunction in OCD as multifactorial, constitutive, and environmental, contributing to illness development, clinical presentation, and multisystem impact. The fact that OCD patients present comorbidity with several systemic illnesses, including auto-immune disorders, and that the majority of recognized risk factors, such as perinatal complications, traumatic life events or childhood infections, induce inflammation, motivated the development of studies trying to achieve a deeper comprehension regarding the association between inflammation and OCD.”

Gagliano A, Puligheddu M, Ronzano N, Congiu P, Tanca MG, Cursio I, Carucci S, Sotgiu S, Grossi E, Zuddas A. Artificial Neural Networks Analysis of polysomnographic and clinical features in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): from sleep alteration to “Brain Fog”. Nat Sci Sleep. 2021;13:1209-1224. DOI: 10.2147/NSS.S300818

• Disordered sleep represents is a cardinal symptom in patients with PANS
• Polysomnography showed abnormality in 17 out of 23 recruited subjects (73.9%).
• 8/17 children (47%) had ineffective sleep
• 10/17 (58.8%) fragmented sleep
• 8/17 (47.1%) periodic limb movement disorder (PLMD)
• 11/17 (64.7%) REM-sleep without atonia (RSWA).
• Most subjects presented more than one sleep disturbance
• Among the 19/23 patients diagnosed with Tic/Tourette disorder, 8/19 (42.1%) show PLMD and 10/19 (52.6%) RSWA

Lyme Borreliosis and Associations With Mental Disorders and Suicidal Behavior: A Nationwide Danish Cohort Study. Brian A. Fallon, M.D., M.P.H., Trine Madsen, Ph.D., Annette Erlangsen, Ph.D., Michael E. Benros, M.D., Ph.D. Published Online:28 Jul 2021 https://doi.org/10.1176/appi.ajp.2021.20091347

“Having more than one episode of Lyme borreliosis was associated with increased incidence rate ratios for mental disorders, affective disorders, and suicide attempts, but not for death by suicide. Individuals diagnosed with Lyme borreliosis in the hospital setting had an increased risk of mental disorders, affective disorders, suicide attempts, and suicide. Although the absolute population risk is low, clinicians should be aware of potential psychiatric sequelae of this global disease.”