CSF diagnostics in severe mental illness can provide information about the background of the illness. The diagnosis and treatment of psychiatric disorders remain challenging. Despite advances in neuroscience and psychopharmacology, many questions remain regarding the causes and mechanisms of these disorders.
In current international classification systems (ICD-10, DSM-5), diagnostic criteria for psychotic disorders (e.g., schizophrenia and schizoaffective disorder) are based on symptomatic descriptions, as no clear biomarkers are yet known. However, when underlying causes of psychotic symptoms such as inflammation, ischemia, or tumors affecting nervous tissue can be identified, a different classification is used (“psychotic disorder with delusions due to known physiological conditions” (ICD-10: F06.2) or psychosis due to medical factors (DSM-5)). Although CSF diagnosis is still considered optional in current diagnostic guidelines for psychotic disorders, biomarkers in CSF could help identify known physiological states. However, in contemporary psychiatry, only a minority of psychiatric inpatients with severe mental illness undergo CSF diagnostics.
There is increasing evidence that a more precise differential diagnosis is beneficial for a subset of patients before psychopharmacological treatment is initiated.
Case reports and studies on psychiatric disorders and MS diagnosis
The Systematic Review of Case Reports and Case Series by Sabe and Sentissi (2022)*1) finds that the mean age of first psychiatric symptoms was 25.8 ± 10.2 years, the mean age of MS diagnosis was 31.2 ± 10.7 years, and the mean delay to MS diagnosis was 2.7 ± 3 years. At MS diagnosis, immunosuppressive therapy for psychotic symptoms was significantly more effective than antipsychotics. Resistance and poor response to antipsychotics, found in most cases (75%), were associated with excellent improvement (95%) in both psychiatric and neurologic symptoms with corticosteroids.
Poor response or resistance to antipsychotic treatment should alert clinicians to the need for differential diagnostic workup. Between the initial diagnosis of psychosis and the diagnosis of multiple sclerosis obtained via subsequent CSF analysis, time is lost in which to treat with immunosuppressive therapy. The quality controls Duotrol Oligo and Duotrol CSQ Advanced enable the correctness of the laboratory analysis.
CSF diagnostics: schizophrenia and psychiatric disorders
A central aspect of CSF diagnostics is the investigation of inflammatory processes in the central nervous system (CNS). Studies have shown that a mild neuroinflammatory response can be observed in the CSF in certain psychiatric disorders, such as schizophrenia and bipolar disorder. These findings suggest that an immune-mediated component may be involved in the pathophysiology of these disorders.
Fundamentals of CSF diagnosis in psychiatric disorders include protein analysis (albumin, IgG, IgA, IgM) and oligoclonal IgG and lactate analysis. Parallel analysis of CSF with serum samples form the basis for interpretation of immunoglobulin patterns in Reiber diagrams and compilation of data in the cumulative CSF data report for the individual patient.
Recent CSF studies in severe mental illness indicate that approximately 79% of treatment-resistant cases with affective or schizophrenic spectrum disorders showed minor CSF abnormalities.*2)
The meta-analysis by Orlovska-Waast et al. (2019) published in Nature summarized various neuroinflammatory markers in schizophrenia and affective disorders. Thus, CSF total protein was elevated in both schizophrenia and affective disorders, CSF/serum ratio of IgG was elevated in schizophrenia, while IgG/albumin ratio was decreased*3).
CSF diagnostics: Detection of oligoclonal bands in MS
Oligoclonal bands (OCBs) are detected in approximately 90% of patients with multiple sclerosis. OCBs have also been detected in up to 21.8% of patients with schizophrenia.*4) This finding suggests intrathecal IgG production in patients diagnosed with schizophrenia. The prevalence of OCBs type 2 or 3 was higher (13.1%) in patients who used drugs and more than twice as high (27.8%) in patients who used cannabis.*5) Metaanalytic evidence shows that the blood-brain barrier (BBB), which is important for CNS homeostasis, is more frequently disrupted in schizophrenia compared to healthy controls. (cf. Orlovska 2019). In the study by Campana et al. (2022), 15.8% were found to have an elevated CSF/serum albumin ratio. However, it remains unclear whether this is a cause or consequence of neurological dysfunction. Nonetheless, gross barrier dysfunction is thought to be associated with neuronal signaling dysfunction, and BBB dysfunction may be associated with glutamatergic and inflammatory abnormalities involved in the development of schizophrenia. Overall, in Campana et al (2022), 42.7% (134/314) of patients with a diagnosis of schizophrenia, showed changes in the CSF.
Fig. 1: Frequencies of CSF abnormalities in severe mental illness related from the studies of Campana et al. (2022) and Orlovska-Waast et al.(2019).
Thus, the current findings suggest that schizophrenia and affective disorders may have CSF abnormalities, including evidence of blood-brain barrier impairment and inflammation. However, the available evidence does not allow for firm conclusions because largely no confounding factors were taken into account. Moreover, few studies have examined the same parameters with healthy controls, and high-quality longitudinal CSF studies are lacking, including the effects of psychotropic medications, lifestyle factors, and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation. A study is currently underway in this regard.*6)
CSF diagnostics: routine CSF analysis can improve treatment outcomes
In summary, an emerging evidence base shows that routine analysis of CSF samples in patients with psychosis reveals markers for inflammatory or infectious causes as well as the presence of autoimmune encephalitis.
A promising approach for the future is the integration of CSF diagnostics into personalized treatment strategies. For example, with the Duotrol CSQ Advanced and Duotrol Oligo cerebrospinal fluid (CSF) controls, which allow monitoring of laboratory-based tests.
By identifying individual biopatterns in the CSF, it may be possible to predict the efficacy of certain therapies and develop personalized treatment plans. This would allow physicians to target the needs of each individual patient and increase treatment outcomes.
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*1) Sabe M, Sentissi O. Psychotic symptoms prior or concomitant to diagnosis of multiple sclerosis: a systematic review of case reports and case series. Int J Psychiatry Clin Pract. 2022 Sep;26(3):287-293. https://doi.org/10.1080/13651501.2021.1973506
*2) Bechter, K. (2016). CSF diagnostics in psychiatry–present status–future projects. Neurology, Psychiatry and Brain Research, 22(2), 69-74. https://doi.org/10.1016/j.npbr.2016.01.008
*3) Orlovska-Waast, S., Köhler-Forsberg, O., Brix, S.W. et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry 24, 869–887 (2019). https://doi.org/10.1038/s41380-018-0220-4
*4) Campana M, Strauß J, Münz S, et al. Cerebrospinal Fluid Pathologies in Schizophrenia-Spectrum Disorder-A Retrospective Chart Review. Schizophrenia Bulletin. 2022 Jan;48(1):47-55. https://doi.org/10.1093/schbul/sbab105
5*) Campana M, Strauß J, Münz S, et al. Cerebrospinal Fluid Pathologies in Schizophrenia-Spectrum Disorder-A Retrospective Chart Review. Schizophrenia Bulletin. 2022 Jan;48(1):47-55. https://doi.org/10.1093/schbul/sbab105
*6) Sørensen, N.V., Orlovska-Waast, S., Jeppesen, R. et al. Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression – a study protocol. BMC Psychiatry 22, 35 (2022). https://doi.org/10.1186/s12888-021-03633-0