Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting as cortisone sensible psychosis with reversible leukoencephalopathy.

INTRODUCTION: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a frequently discussed neuropsychiatric syndrome with elevated thyroid antibodies in the context of various clinical neuropsychiatric phenotypes. MRI abnormalities are usually nonspecific and treatment can be complex. CASE STUDY: We present a case of a woman in her sixties with SREAT whose psychosis kept worsening under cortisone tapering. After three years with cortisone side effects, therapy was changed to plasmapheresis and rituximab treatment with an excellent initial response, subacute unexplained deterioration with extensive leukoencephalopathy on MRI shortly after, and full recovery with regression of leukoencephalopathy afterwards. DISCUSSION: SREAT varies in clinical and diagnostic presentation. Its precise pathophysiology is unknown, as are the best treatment protocols. The case illustrates that some patients with SREAT syndrome might end up in constellations, in which it proves difficult to wean off steroid treatment and illustrates treatment alternatives such as plasmapheresis and/or rituximab. In addition, it highlights leukoencephalopathy as possible MRI finding in the context of SREAT. Further research is necessary to fully comprehend the (potentially different) pathomechanisms and courses of SREAT.

Autoantibodies in patients with obsessive-compulsive disorder: a systematic review.

Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are high. Emerging evidence suggests that biological components, especially autoimmune processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. The following search strategy was used to search PubMed: "(OCD OR obsessive-compulsive OR obsessive OR compulsive) AND (antib* OR autoantib* OR auto-antib* OR immunoglob* OR IgG OR IgM OR IgA)". Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2], paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and "anti-brain" structures) and four with autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome, one with neuropsychiatric lupus, and one with anti-phospholipid autoantibodies). Six patients (67%) benefited from immunotherapy. In addition, eleven cross-sectional studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with inconsistent results, but in six studies an association between autoantibodies and OCD was suggested. In summary, the available case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with OCD compared with healthy controls are needed.

Sarcoidosis and obsessive-compulsive symptoms.

INTRODUCTION: Autoimmune obsessive-compulsive disorder (OCD) in the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) has been observed for decades. The first cases of autoimmune OCD in adulthood were recently described. An association between obsessive-compulsive symptoms (OCS) and systemic autoimmune diseases in the form of connective tissue disease has also been reported. However, whether an association exists between OCD and sarcoidosis is unknown. CASE STUDY: Here, the authors present an end 20-year-old female patient with symptoms of OCD in whom an advanced diagnostic work-up revealed inflammatory cerebrospinal fluid (CSF) changes (elevated IgG index, CSF-specific oligoclonal bands, intrathecal IgG synthesis, and a positive MRZ reaction). In tissue-based assays using unfixed mouse brain sections, both serum and CSF showed a distinct antinuclear antibody pattern with perinuclear staining. Electroencephalography identified frontocentral theta spindles. Upon endobronchial-guided lymph node biopsy demonstrating non-caseating lymph nodes in further work-up, sarcoidosis was diagnosed. Levels of the sarcoidosis parameters IL-2-R and neopterin were increased. Under immunotherapy for sarcoidosis, the OCS seemed to improve. DISCUSSION: This case study is paradigmatic, as an association between sarcoidosis and OCD has not been previously reported. After exclusion of alternative causes, the inflammatory CSF changes would be compatible with an inflammatory brain involvement of sarcoidosis. Autoimmune OCD may occur more frequently than is thought, probably also in the context of neurosarcoidosis. This could open up new opportunities through immunotherapies in rare cases with OCD.

Obsessive-compulsive symptoms in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome.

Symptoms of obsessive-compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive-compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology.

Structural and functional retinal alterations in patients with paranoid schizophrenia.

Ophthalmological methods have increasingly raised the interest of neuropsychiatric specialists. While the integrity of the retinal cell functions can be evaluated with the electroretinogram (ERG), optical coherence tomography (OCT) allows a structural investigation of retinal layer thicknesses. Previous studies indicate possible functional and structural retinal alterations in patients with schizophrenia. Twenty-five patients with paranoid schizophrenia and 25 healthy controls (HC) matched for age, sex, and smoking status participated in this study. Both, ERG and OCT were applied to obtain further insights into functional and structural retinal alterations. A significantly reduced a-wave amplitude and thickness of the corresponding para- and perifoveal outer nuclear layer (ONL) was detected in patients with paranoid schizophrenia with a positive correlation between both measurement parameters. Amplitude and peak time of the photopic negative response (PhNR) and thickness of the parafoveal ganglion cell layer (GCL) were decreased in patients with schizophrenia compared to HC. Our results show both structural and functional retinal differences between patients with paranoid schizophrenia and HC. We therefore recommend the comprehensive assessment of the visual system of patients with schizophrenia, especially to further investigate the effect of antipsychotic medication, the duration of illness, or other factors such as inflammatory or neurodegenerative processes. Moreover, longitudinal studies are required to investigate whether the functional alterations precede the structural changes.

Spectrum of Novel Anti-Central Nervous System Autoantibodies in the Cerebrospinal Fluid of 119 Patients With Schizophreniform and Affective Disorders.

BACKGROUND: Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies, such as those against the NMDA receptor. However, the presence of additional anti-central nervous system (CNS) autoantibodies in these patients has not been systematically assessed. METHODS: Serum and cerebrospinal fluid (CSF) from patients with schizophreniform and affective syndromes were analyzed for immunoglobulin G anti-CNS autoantibodies using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue as part of an extended routine clinical practice. After an initial assessment of patients with red flags for autoimmune psychosis (n = 30), tissue-based testing was extended to a routine procedure (n = 89). RESULTS: Based on the findings from all 119 patients, anti-CNS immunoglobulin G autoantibodies against brain tissue were detected in 18% (n = 22) of patients (serum 9%, CSF 18%) following five principal patterns: 1) against vascular structures, most likely endothelial cells (serum 3%, CSF 8%); 2) against granule cells in the cerebellum and/or hippocampus (serum 4%, CSF 6%); 3) against myelinated fibers (serum 2%, CSF 2%); 4) against cerebellar Purkinje cells (serum 0%, CSF 2%); and 5) against astrocytes (serum 1%, CSF 1%). The patients with novel anti-CNS autoantibodies showed increased albumin quotients (p = .026) and white matter changes (p = .020) more frequently than those who tested negative for autoantibodies. CONCLUSIONS: The study demonstrates five novel autoantibody-binding patterns on brain tissue of patients with schizophreniform and affective syndromes. CSF yielded positive findings more frequently than serum analysis. The frequency and spectrum of autoantibodies in these patient groups may be broader than previously thought.

Immunological causes of obsessive-compulsive disorder: is it time for the concept of an "autoimmune OCD" subtype?

Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of "autoimmune OCD" is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for "autoimmune OCD" could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases.

BACKGROUND: Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. METHODS: The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. RESULTS: We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment. CONCLUSIONS: Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

Probable Autoimmune Depression in a Patient With Multiple Sclerosis and Antineuronal Antibodies.

BACKGROUND: In a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed. CASE PRESENTATION: The authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement. CONCLUSION: The present patient suffered from a probable "autoimmune depression" in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

Psychiatric Manifestation of Anti-LGI1 Encephalitis.

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is typically characterized by limbic encephalitis, faciobrachial dystonic seizures and hyponatremia. The frequency with which milder forms of anti-LGI1 encephalitis mimic isolated psychiatric syndromes, such as psychoses, or may lead to dementia if untreated, is largely unknown. CASE PRESENTATION: Here, the authors present a 50-year-old patient who had suffered from neurocognitive deficits and predominant delusions for over one and a half years. He reported a pronounced feeling of thirst, although he was drinking 10-20 liters of water each day, and he was absolutely convinced that he would die of thirst. Due to insomnia in the last five years, the patient took Z-drugs; later, he also abused alcohol. Two years prior to admission, he developed a status epilepticus which had been interpreted as a withdrawal seizure. In his serum, anti-LGI1 antibodies were repeatedly detected by different independent laboratories. Cerebrospinal fluid analyses revealed slightly increased white blood cell counts and evidence for blood-brain-barrier dysfunction. Magnetic resonance imaging showed hyperintensities mesio-temporally and in the right amygdala. In addition, there was a slight grey-white matter blurring. A cerebral [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) examination of his brain showed moderate hypometabolism of the bilateral rostral mesial to medial frontal cortices. Treatment attempts with various psychotropic drugs remained unsuccessful in terms of symptom relief. After the diagnosis of probable chronified anti-LGI1 encephalitis was made, two glucocorticoid pulse treatments were performed, which led to a slight improvement of mood and neurocognitive deficits. Further therapy was not desired by the patient and his legally authorized parents. CONCLUSION: This case study describes a patient with anti-LGI1 encephalitis in the chronified stage and a predominant long-lasting psychiatric course with atypical symptoms of psychosis and typical neurocognitive deficits. The patient's poor response to anti-inflammatory drugs was probably due to the delayed start of treatment. This delay in diagnosis and treatment may also have led to the FDG-PET findings, which were compatible with frontotemporal dementia ("state of damage"). In similar future cases, newly occurring epileptic seizures associated with psychiatric symptoms should trigger investigations for possible autoimmune encephalitis, even in patients with addiction or other pre-existing psychiatric conditions. This should in turn result in rapid organic clarification and-in positive cases-to anti-inflammatory treatment. Early treatment of anti-LGI1 encephalitis during the "inflammatory activity state" is crucial for overall prognosis and may avoid the development of dementia in some cases. Based on this case, the authors advocate the concept-long established in many chronic inflammatory diseases in rheumatology-of distinguishing between an "acute inflammatory state" and a "state of organ damage" in autoimmune psychosis resembling neurodegenerative mechanisms.

Psychiatric Presentation of Anti-NMDA Receptor Encephalitis.

Background: Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is an autoimmune condition characterized by neuropsychiatric symptoms, including epileptic seizures, movement disorders, autonomic instability, disturbances of consciousness, paranoia, delusions, and catatonia. Ovarian teratomas and viral infections, typically Herpes simplex viruses, have previously been demonstrated to precipitate anti-NMDA receptor encephalitis, but in many cases, the trigger remains unclear. The detection of anti-NMDA receptor antibodies in cerebrospinal fluid (CSF), in combination with other CSF, electroencephalography (EEG), or magnetic resonance imaging (MRI) abnormalities, typically leads to diagnostic clarification. Case Presentation: We present the case of a 22-year-old female patient who developed an acute polymorphic psychotic episode 3 days after receiving a booster vaccination against tetanus, diphtheria, pertussis, and polio (Tdap-IPV). Her psychiatric symptoms were initially diagnosed as a primary psychiatric disorder. Her MRI, EEG, and CSF results were non-specific. Anti-NMDA receptor IgG antibodies against the GluN1 subunit were detected in her serum (with a maximum titer of 1:320), but not in her CSF. [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) showed pronounced relative hypermetabolism of her association cortices and a relative hypometabolism of the primary cortices, on the basis of which an anti-NMDA receptor encephalitis diagnosis was made, and treatment with a steroid pulse was initiated. The treatment led to fast and convincing clinical improvement with normalization of neuropsychological findings, considerable improvement of FDG-PET findings, and decreasing antibody titers. Conclusion: The patient's psychiatric symptoms were most likely caused by anti-NMDA receptor encephalitis. Her polymorphic psychotic symptoms first occurred after she had received a Tdap-IPV booster vaccination. Although the vaccination cannot have caused the initial antibody formation since IgG serum antibodies were detected only 3 days after administration of the vaccine, the vaccine may have exerted immunomodulatory effects. MRI, EEG, and CSF findings were non-specific; however, FDG-PET identified brain involvement consistent with anti-NMDA receptor encephalitis. This case shows the importance of implementing a multimodal diagnostic work-up in similar situations. The negative CSF antibody finding furthermore fits to the hypothesis that the brain may act as an immunoprecipitator for anti-NMDA receptor antibodies.

New Variant of MELAS Syndrome With Executive Dysfunction, Heteroplasmic Point Mutation in the MT-ND4 Gene (m.12015T>C; p.Leu419Pro) and Comorbid Polyglandular Autoimmune Syndrome Type 2.

Background: Mitochondrial diseases are caused by dysfunctions in mitochondrial metabolic pathways. MELAS syndrome is one of the most frequent mitochondrial disorders; it is characterized by encephalopathy, myopathy, lactic acidosis, and stroke-like episodes. Typically, it is associated with a point mutation with an adenine-to-guanine transition at position 3243 of the mitochondrial DNA (mtDNA; m.3243A>G) in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene. Other point mutations are possible and the association with polyglandular autoimmune syndrome type 2 has not yet been described. Case presentation: We present the case of a 25-year-old female patient with dysexecutive syndrome, muscular fatigue, and continuous headache. Half a year ago, she fought an infection-triggered Addison crisis. As the disease progressed, she had two epileptic seizures and stroke-like episodes with hemiparesis on the right side. Cerebral magnetic resonance imaging showed a substance defect of the parieto-occipital left side exceeding the vascular territories with a lactate peak. The lactate ischemia test was clearly positive, and a muscle biopsy showed single cytochrome c oxidase-negative muscle fibers. Genetic testing of blood mtDNA revealed a heteroplasmic base exchange mutation in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4) gene (m.12015T>C; p.Leu419Pro; heteroplasmy level in blood 12%, in muscle tissue: 15%). The patient suffered from comorbid autoimmune polyglandular syndrome type 2 with Hashimoto's thyroiditis, Addison's disease, and autoimmune gastritis. In addition, we found increased anti-glutamic acid decarboxylase 65, anti-partial cell, anti-intrinsic factor, and anti-nuclear antibodies. Conclusion: We present an atypical case of MELAS syndrome with predominant symptoms of a dysexecutive syndrome, two stroke-like episodes, and fast-onset fatigue. The symptoms were associated with a not yet described base and aminoacid exchange mutation in the MT-ND4 gene (m.12015T>C to p.Leu419Pro). The resulting changed protein complex in our patient is part of the respiratory chain multicomplex I and might be the reason for the mitochondriopathy. However, different simulations for pathogenetic relevance are contradictory and rather speak for a benign variant. To our knowledge this case report is the first reporting MELAS syndrome with comorbid polyglandular autoimmune syndrome type 2. Screening for autoimmune alterations in those patients is important to prevent damage to end organs.

Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by difficulties in social communication, unusually restricted, repetitive behavior and interests, and specific abnormalities in language and perception. The precise etiology of ASD is still unknown and probably heterogeneous. In a subgroup of patients, toxic environmental exposure might lead to an imbalance between oxidative stress and anti-oxidant systems. Previous serum and postmortem studies measuring levels of glutathione (GSH), the main cellular free radical scavenger in the brain, have supported the hypothesis that this compound might play a role in the pathophysiology of autism. METHODS: Using the method of single-voxel proton magnetic resonance spectroscopy (MRS), we analyzed the GSH signal in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) of 24 ASD patients with normal or above average IQs and 18 matched control subjects. We hypothesized that we would find decreased GSH concentrations in both regions. RESULTS: We did not find overall group differences in neurometabolites including GSH, neither in the dorsal ACC (Wilks' lambda test; p = 0.429) nor in the DLPFC (p = 0.288). In the dACC, we found a trend for decreased GSH signals in ASD patients (p = 0.076). CONCLUSIONS: We were unable to confirm our working hypothesis regarding decreased GSH concentrations in the ASD group. Further studies combining MRS, serum, and cerebrospinal fluid measurements of GSH metabolism including other regions of interest or even whole brain spectroscopy are needed.