- Case report
- Open Access
Altered cerebral glucose metabolism normalized in a patient with a pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS)-like condition following treatment with plasmapheresis: a case report
BMC Neurology volume 18, Article number: 60 (2018)
Pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS) is a specific autoimmune response to group-A streptococcal infections in children and adolescents with a sudden onset of obsessive-compulsive disorders or tic-like symptoms. Cerebral metabolic changes of patients have not yet been observed.
We present a case of an 18-year old male with a PANDAS-like condition after developing tic-like symptoms and involuntary movements three weeks after cardiac surgery. The patient had suffered from pharyngotonsillitis before the symptoms started. The anti-streptolysin O (ASO) titer was elevated (805 kU/l). Antibiotic therapy did not improve his condition. Intravenous immunoglobulins and high-dose cortisone therapy had minor beneficial effects on his involuntary movements. 18F-Fluorodeoxyglucose positron emission tomography/ computer tomography (18F-FDG PET/CT) demonstrated pronounced hypermetabolism of the basal ganglia and cortical hypometabolism. The patient was treated with five cycles of plasmapheresis. A marked clinical improvement was observed after four months. Cerebral metabolic alterations had completely normalized.
This is the first report of cerebral metabolic changes observed on FDG-PET/CT in a patient with a PANDAS-like condition with a normalization following immunomodulatory treatment. Cerebral FDG-PET/CT might be a promising tool in the diagnosis of PANDAS.
Acute neuropsychiatric symptoms in children and adolescents can have multiple causes, including autoimmune reactions following a preceding microbial infection.  Pediatric Acute-onset Neuropsychiatric Syndromes (PANS) can be triggered by infection (pediatric infection-triggered autoimmune neuropsychiatric disorders, PITANDS) or have non-infectious metabolic, or environmental triggers.  PITANDS are frequently caused by group A beta-hemolytic streptococcal (GAS) infections , which has been coined pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS) by Susan Swedo and colleagues in 1998.  In PANDAS, it is hypothesized that antibodies directed against streptococcal antigens cross-react with surface proteins of the basal ganglia activating calcium calmodulin-dependent protein kinase II (CaMKII), hence causing altered central dopamine neurotransmission.  Additionally, it is thought that specific strains of S. pyogenes causing a strong immune response must meet a genetic predisposition of infected children that lead to autoimmune reactions with cellular and humoral immune responses.  Most recently, findings of a large-scale study support the PANDAS hypothesis, demonstrating an increased risk of mental disorders, particular OCD (obsessive-compulsive disorders) and tic disorders, in young individuals with GAS throat infections. 
So far, published imaging findings of patients diagnosed with PANDAS are mainly restricted to magnetic resonance imaging (MRI) describing increased volumes of the basal ganglia. [8, 9] One study could demonstrate increased microglia-mediated neuroinflammation in the basal ganglia on positron emission tomography (PET) using a 11C-[R]-PK11195 tracer.  To our knowledge, no data exist on the use of fluorodeoxyglucose (FDG) PET in patients with PANDAS. Here, we report the first case with a PANDAS-like condition that received a FDG-PET/CT before and after treatment with plasmapheresis.
A male, 18-year old patient presented at the Department of Neurology at the Charité – University Hospital Berlin, in February 2016 because of involuntary movements and neuropsychiatric symptoms.
Involuntary movements included orofacial dyskinesias and tic-like symptoms, dysarthric voice accompanied by dysphagia, and hyperkinetic movements of the extremities with jerking and dystonic components that were predominantly present on the left side of his body.
Six months earlier, in August 2015, the patient, who had a congenital bicuspid aortic valve with aortic distension, underwent surgical replacement of the aortic valve and the ascending aorta using a cardiopulmonary bypass system and mild hypothermia. The remaining medical history was unremarkable without pre-existing neuropsychiatric conditions.
Precisely 3 weeks after surgery, the patient experienced the acute onset of an emotional dysbalance, hyperactivity, and loss of concentration accompanied by involuntary movements of his left upper extremity, especially his left hand. Because of further deterioration of the involuntary movements, now extending to his left leg and causing gait instability; worsening of his mood state with increasing aggressiveness at home; sleeping problems with frequent nightmares; and a severe decline in school performance the patient was admitted to a clinic in November 2015. He was reported to have had symptoms of pharyngotonsillitis days before symptoms initially started. The anti-streptolysin O (ASO) titer was elevated at 805 kU/l (reference values: < 200 kU/l). Further laboratory tests including anti-basal ganglia antibodies, CSF analysis, and a cranial CT scan showed unremarkable results.
Assuming a post-streptococcal neuropsychiatric disorder, the patient was treated with high-dose penicillin (3 × 1 Mio. I.E./ d) for three days without any clinical effect. An immunomodulatory therapy with intravenous immunoglobulins (IVIG) with a dose of 2 g per kg of bodyweight (105 g in total) was applied showing a minor, short-lasting improvement of his involuntary movements. He was discharged home on a symptomatic, anti-dopaminergic therapy with tiapride 100 mg TID. Tiapride mildly improved his sleep quality, but induced dizziness during daytime.
On presentation at the Charité several weeks later, the patient showed further psychological deterioration revealing depressive moods, attention deficits, and progressive decline in school performance, threatening his graduation. He described having vivid nightmares and a loss of body weight (5 kg in 2 months, i.e. 9% of body weight). The ASO titer was still elevated at 450 kU/l, whereas anti-deoxyribonuclease B (Anti-DNaseB) titer, autoimmunological parameters, and CSF analyses remained unremarkable. In particular, cerebral autoantibodies (a large panel antibodies including anti-NMDA receptor- and anti-TPO-antibodies) could not be detected neither in serum nor in CSF. Immunohistologically, plasmapheresis eluate of the patient did not reveal any specific or unspecific binding on murine brain tissue. Cerebral magnetic resonance imaging (MRI) showed small bicerebellar and left frontal microbleeds, but no focal lesion or specific pattern of atrophy. Electroencephalography (EEG) displayed diffuse brain dysfunction without further implication.
Comprehensive neuropsychological testing identified a dysexecutive syndrome characterized by a decrease in working memory capacity, attention, and concentration deficits, as well as frequent failure of spontaneous speech. Psychosomatic counseling revealed several underlying family-based conflicts. His mother was described as a controlling person who discounted his symptoms and persistently browsed through his personal belongings. He described himself as sad with fears of separation and being lonely. Suicidal thoughts had occurred two months prior to the second admission. The clinical course of the patient is depicted in Fig. 1.
The differential diagnoses at this time were: 1) Sydenham chorea minor (SC), 2) Pediatric Autoimmune Neuropsychiatric Syndrome after Streptococcal infection (PANDAS) or PANDAS-like condition, 3) antibody-mediated autoimmune encephalitis (e. g anti-NMDA receptor encephalitis) 4) Psychosomatic disorder, 5) Post pump chorea. 
Diagnostic work-up was expanded and a cerebral FDG positron emission tomography/ computer tomography (PET/CT) demonstrated a moderate to severe hypermetabolism of the basal ganglia, especially of the left striatum, whereas the cortex revealed hypometabolic signals (Fig. 2).
The anti-dopaminergic medication was discontinued and an additional IVIG therapy had marginal effects on his symptoms. A series of high-dose cortisone therapy (1 g i.v.) for five days improved his restlessness, muscle strength of his left arm, and quality of sleep, but symptoms persisted. Subsequently, we initiated five cycles of plasmapheresis, and ASO titer significantly decreased (78 kU/l).
Four months later at follow-up, the patient demonstrated a normalized neurological exam with a minimal fine motor skill deficit in his left hand. Neuropsychological disorders had resolved. Follow-up FDG-PET/CT revealed a complete normalization of cerebral glucose metabolism (Fig. 2). The ASO titer remained at normal levels (197 kU/l). The patient’s personality returned to its premorbid state and family-based stress factors had dissolved. He resumed taking psychotherapeutic sessions twice a month.
Discussion and conclusions
We report the case of an adolescent patient diagnosed with a PANDAS-like condition that showed severe striatal hypermetabolism and cortical hypometabolism on FDG PET/CT imaging. Consistent with clinical improvement, glucose metabolism completely normalized four months after immunomodulatory therapy with five cycles of plasmapheresis. To the best of our knowledge, this is the first report of a patient with a PANDAS-like condition demonstrating changes of glucose metabolism before and after treatment.
Opposed to surgical intervention , the beneficial effects of immunomodulatory therapies, such as IVIG and plasmapheresis, in OCD/tic disorder patients have been reported previously. [13,14,15] Although IVIG administration could not demonstrate statistically significant effects compared to placebo in a large clinical trial, the application was safe and well tolerated in all treated patients.  We also did not experience any complication during IVIG or plasmapheresis therapy. Despite the reported benefits, several clinical guidelines do not support the use of immunomodulatory therapies in patients with PANDAS limiting their clinical use.  However, others support its use in severe cases as a second-line therapy after inefficiency of antibiotic treatment. [18, 19]
We assume that a PANDAS-like condition was the most appropriate diagnosis for our patient. According to the published diagnostic criteria on PANDAS, patients must meet the following criteria: 1) abrupt onset of OCD/tic-like symptoms or severely restricted food intake, 2) prepubertal onset of symptoms, 3) acute symptom onset and episodic (relapsing-remitting) course, 4) temporal association between Group A streptococcal infection and symptom onset/exacerbations, and 5) association with neurological abnormalities.  In our case, the patient experienced an acute onset three weeks after cardiac surgery. Additional to orofacial dyskinesia and tic-like symptoms, he demonstrated neuropsychiatric symptoms including obsessional fears, separation anxiety, depressive mood, sleep and body weight problems as well as dramatic decline in school performance. Because of the age of the patient and the lack of a positive throat culture, a PANDAS diagnosis is not justified. Striatal hypermetabolism was described in SC [21, 22], however, post pump chorea, presenting in children following open-heart surgery, was shown to be associated with hypometabolism of the basal ganglia.  In addition, patients described with post pump chorea developed symptoms within the first two weeks after surgery and were much younger (age < 3 years). Other differential diagnoses such as atypical manifestations of an anti-NMDA receptor encephalitis or Hashimoto’s encephalitis must be mentioned. However, negative antibody titers in both blood and CSF as well as the absence of immunohistological findings on murine brain tissue, and the cerebral distribution of metabolic changes on FDG-PET/CT make these diagnoses unlikely. [24,25,26]
In conclusion, PANDAS is a severe disorder that needs appropriate treatment with immunomodulatory therapy, if antibiotic treatment is not effective and symptoms progress. FDG PET/CT seems to be a valuable diagnostic approach to prove cerebral metabolic alterations in PANDAS. Future cohort studies should assess the sensitivity of FDG PET/CT in diagnosed PANDAS patients and investigate the association of metabolic abnormalities with severity of clinical symptoms.
- ASO :
- FDG PET/CT :
FDG positron emission tomography/computer tomography
- GAS :
group A beta-hemolytic streptococcus
- PANDAS :
Pediatric Autoimmune Neuropsychiatric Disorder after Streptococcal Infection
Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, et al. Autoimmune diseases and severe infections as risk factors for mood disorders. JAMA Psychiatry. 2013;70:812.
Calaprice D, Tona J, Parker-Athill EC, Murphy TK. A survey of pediatric acute-onset neuropsychiatric syndrome characteristics and course. J. Child Adolesc. Psychopharmacol. 2017;27:607–18.
Allen AJ, Leonard HL, Swedo SE. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry The American Academy of Child and Adolescent Psychiatry. 1995;34:307–11.
Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155:264–71.
Cunningham MW, Cox CJ. Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Acta Physiol. 2016;216:90–100.
Cutforth T, DeMille MM, Agalliu I, Agalliu D. CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors. Future Neurol. 2016;11:63–76.
Orlovska S, Vestergaard CH, Bech BH, Nordentoft M, Vestergaard M, Benros ME. Association of Streptococcal Throat Infection with Mental Disorders: testing key aspects of the PANDAS hypothesis in a Nationwide study. JAMA psychiatry. 2017;74:740–6.
Perlmutter SJ, Garvey MA, Castellanos X, Mittleman BB, Giedd J, Rapoport JL, et al. A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Am J Psychiatry. 1998;155:1592–8.
Giedd JN. MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. Am J Psychiatry. 2000;157:281–3.
Kumar A, Williams MT, Chugani HT. Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and Tourette syndrome. J Child Neurol. 2015;30:749–56.
Du Plessis AJ, Bellinger DC, Gauvreau K, Plumb C, Newburger JW, Jonas RA, et al. Neurologic outcome of choreoathetoid encephalopathy after cardiac surgery. Pediatr Neurol. 2002;27:9–17.
Pavone P, Rapisarda V, Serra A, Nicita F, Spalice A, Parano E, et al. Pediatric autoimmune neuropsychiatry disorder associated with group a streptococcal infection: the role of surgical treatment. Int J Immunopathol Pharmacol. 2014;27:371–8.
Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354:1153–8.
Latimer ME, L’Etoile N, Seidlitz J, Swedo SE. Therapeutic plasma apheresis as a treatment for 35 severely ill children and adolescents with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol. 2015;25:70–5.
Vitaliti G, Tabatabaie O, Matin N, Ledda C, Pavone P, Lubrano R, et al. The usefulness of immunotherapy in pediatric neurodegenerative disorders: a systematic review of literature data. Hum Vaccin Immunother. 2015;11:2749–63.
Williams KA, Swedo SE, Farmer CA, Grantz H, Grant PJ, D’Souza P, et al. Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J. Am. Acad. Child Adolesc. Psychiatry2016;55. 860–7:e2.
Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the therapeutics and technology assessment Subcommittee of the American Academy of neurology. Neurology. 2011;76:294–300.
Cortese I, Cornblath DR. Therapeutic plasma exchange in neurology: 2012. J Clin Apher. 2013;28:16–9.
Williams KA, Swedo SE. Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond. Brain Res. 2015;1617:144–54.
E. Swedo S. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS Criteria to Describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr. Ther; 2012. p. 02.
Goldman S, Amrom D, Szliwowski HB, Detemmerman D, Goldman S, Bidaut LM, et al. Reversible striatal hypermetabolism in a case of sydenham’s chorea. Mov Disord. 1993;8:355–8.
Paghera B, Caobelli F, Giubbini R, Premi E, Padovani A. Reversible striatal hypermetabolism in a case of rare adult-onset Sydenham chorea on two sequential 18F-FDG PET studies. J Neuroradiol. 2011;38:325–6.
Medlock MD, Cruse RS, Winek SJ, Geiss DM, Horndasch RL, Schultz DL, et al. A 10-year experience with postpump chorea. Ann Neurol. 1993;34(6):820.
Citak EC, Gücüyener K, Karabacak NI, Serdaroğlu A, Okuyaz C, Aydin K. Functional brain imaging in Sydenham’s chorea and streptococcal tic disorders. J Child Neurol. 2004;19:387–90.
Solnes LB, Jones KM, Rowe SP, Pattanayak P, Nalluri A, Venkatesan A, et al. Diagnostic value of 18 F-FDG PET/CT versus MRI in the setting of antibody-specific autoimmune encephalitis. J Nucl Med. 2017;58:1307–13.
Kelley BP, Patel SC, Marin HL, Corrigan JJ, Mitsias PD, Griffith B. Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. Am J Neuroradiol. 2017;38:1070.
We thank Ute Scheller for helping us to monitor the clinical course of the patient as detailed as possible. We also thank the Dpt. of Radiology and Nuclear Medicine of the Charité, Campus Mitte for performing the FGD PET/CT examinations.
Dr. Nave is participant in the BIH-Charité Clinical Scientist Program funded by the Charité and the Berlin Institute of Health.
Ethics approval and consent to participate
Informed consent was obtained from the patient to present and publish medical data including video material. The local ethics committee of the Charité, Berlin, approved the publication of this report: EA1/138/17.
Consent for publication
The patient and the local ethics committee of the Charité, Berlin, approved the publication of this report: EA1/138/17.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nave, A.H., Harmel, P., Buchert, R. et al. Altered cerebral glucose metabolism normalized in a patient with a pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS)-like condition following treatment with plasmapheresis: a case report. BMC Neurol 18, 60 (2018). https://doi.org/10.1186/s12883-018-1063-y