Abstract

Introduction: The mild encephalitis (ME) hypothesis addresses a separate category of clinically meaningful CNS inflammation of a lower degree compared to classical encephalitis (CE), patients presenting with predominant psychiatric symptoms. Inflammation is a dimensional entity over time and space within various bodily compartments or tissues, triggered by infections, trauma, toxicity, and immune challenges. Low level grade brain inflammation (LLNI) should be causally involved in ME. Main candidates of ME were severe psychiatric disorders of affective and schizophrenic type, including prodromal stages, acute exacerbations. Short-lived CE in small localized sites within the brain would match with ME. Clinical assessment of ME depends strongly upon the methods used to identify neuroinflammation. The international consensus that both categories, of encephalitis and of encephalopathy, can associate with neuroinflammation, demonstrates the present theoretical and practical dilemma.

Autoimmune Encephalitis (AE) and Limbic Encephalitis (LE): New insights into CE and LE pathophysiology emerged from the identification of neuronal autoantibodies, e.g. NMDAR antibodies. More and more neuronal autoantibodies become detected. AE cases present varying and various clinical syndromes including epilepsies. In some cases of AE defined autoantibodies maybe missing in the blood or CSF. Overall the threshold for the clinical diagnosis of LE, CE, and AE was lowered through improved laboratory methods. This recent development matches predictions of the ME hypothesis that with improved diagnostic methods a better clinical assessment of LLNI and ME will be possible and the definition of borders between CE and hypothetical ME may change.

Utility and Limitations of Clinical Categorization: Behind the preferred strict categorization in the clinical field stands the important goal to obtain reliable guidelines for therapeutic management, which implies that dimensional aspects of a disease may be neglected. Present brain imaging is rather insensitive to detect LLNI, CSF investigation is the most sensitive approach, but protein concentrations in CSF are much lower than in the blood and the involvement of complicated CSF flow patterns makes interpretation difficult. Experimental models clearly support the view that grading of neuroinflammation into severity levels is needed. In addition topology is relevant for defining cause–response relationships. Definition of neuroinflammation differs between various research fields and clinical fields. Nevertheless with improved diagnostic approaches to ME, especially by CSF diagnostics, a clinical diagnosis of LLNI is becoming feasible. Idealized types of CE and ME in a dimensional scheme (severity by time) are presented.

Some Historical Remarks on Etiology Research in Psychiatric Disorders: The initial hypothesis around 1857 that syphilis might represent an important risk factor for general paresis (GP) was accepted only about 70 years later. Very important was the progress in laboratory diagnosis and introduction of lumbar puncture (with CSF analysis). Nevertheless up to now we cannot exactly explain why, after often long latency of years, GP may develop in a subgroup of the infected. Many infections are characterized by low overall pathogenicity (number of diseased per number of infected).

Multiple Interacting Systems and Factors: Severe psychiatric disorders are complex diseases with many contributing factors to be considered: certainly genes, age (of onset), timing, infection, autoimmunity, stress, and possibly chance. The overall scenario is similar to systemic autoimmune disorders a considerable subgroup of such patients suffering from comorbid psychiatric symptoms including severe psychosis. Respective pathomechanisms are only partially known yet. CSF analysis is the most sensitive diagnostic approach to neuroinflammatory disorders. With modern methods in about 70 % of cases with affective or schizophrenic spectrum (including bipolar) disorders various CSF abnormalities were found, demonstrating some LLNI process or immune activation in the intrathecal spaces, but also crosstalk between the periphery and the brain.

Brain Barriers and Systemic Crosstalk: Systemic inflammation can directly influence brain functions and elicit defined symptoms like sickness behavior. Neuroinflammation is primarily likely to change brain functions. Insights from experimental neuroimmunology show that chronic neuroinflammation develops when acute inflammation is not actively resolved. The choroid plexus (CP) represents an interface between blood and CSF spaces; immune cells are recruited and educated at the CP. The blood–brain barrier (BBB) and the blood–CSF barrier (BCSFB) are to be differentiated. CSF flow is pulsating forth and back with a flow distance up to 10 cm per pulse on certain sites. CSF cells are distributed by CSF flow and can follow the CSF outflow pathways (PCOP) through cribriform plate and along brain nerves and spinal nerves. Crosstalk between CNS immunity and systemic immunity is taking place at these barriers and the PCOP.

Outlook: Subgroups of severe psychiatric disorders present some neuroinflammatory process, which may at least contribute to, if not causally underlie, a variety of severe psychiatric disorders. LLNI pathogenesis remains incompletely understood. ME theory fits with epidemiological and clinical aspects, including the proven risk increase during lifetime by infections and autoimmune disorders, also head trauma. It remains a challenge to clinically assess and differentiate LLNI processes by neuroimaging, CSF investigation and new methods. Psychiatric research should focus on etiopathogenetic research including the ME theory.