Lyme disease, neuropsychiatric symptoms and autoimmunity
As with other chronic infections, the most devastating effects of Lyme disease can occur from the immune system losing tolerance for normal tissue as it cross-reacts while attacking the pathogen. A paper just published in The Open Neurology Journal reviews the body of knowledge on the neuropsychiatric symptoms of Lyme disease and other infections as an immune mediated neurodegenerative disorder, enlarged by a wealth of citations. The author states:
"Disease progression of neuropsychiatric symptoms in Lyme/tick-borne diseases can be better understood by greater attention to psychoimmunology. Although there are multiple contributors that provoke and weaken the immune system, infections and persistent infections are significant causes of pathological immune reactions. Immune mediated effects are a significant contributor to the pathophysiological processes and disease progression."
He expands on neurodegeneration and immune-mediated inflammation such as occurs in Lyme disease, depression and Alzheimer's disease:
"When neurodegenerative diseases are progressive uncontrolled inflammation drives disease progression. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. It has been hypothesized that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. There is evidence with depression, Alzheimer’s disease (AD), schizophrenia and epilepsy to support this position. A meta-analysis of cytokines in major depression including 24 studies reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. A meta-analysis of cytokines in AD which reviewed 86 studies strengthens the clinical evidence that AD is accompanied by an inflammatory response with particularly higher peripheral concentrations of IL-6, TNF, IL-1, transforming growth factor, IL-12 and IL-18 and higher CSF concentrations of transforming growth factor."
Schizophrenia is included in the list of autoimmune neurodegenerative disorders:
"Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients. First-episode psychosis in children is associated with evidence of increased inflammation. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved which support the inflammatory theory of schizophrenia that was formulated over a 100 years ago."
Epilepsy, of course, is also included:
"There is a rapidly growing body of evidence that supports the involvement of inflammatory mediators in epilepsy—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process. Aspects of brain inflammation and immunity were first described and subsequently, it was demonstrated how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death."
The astute clinician must also bear in mind associated phenomena that support the autoimmune inflammatory process in Lyme disease and other neurodegenerative conditions:
"Oxidative stress and oxygen free radicals or activated oxygen has been implicated in diverse environmental stresses and appears to be a common contributor in neurodegenerative diseases...Excitotoxicity and inadequate remethylation leads to increased homocysteine levels which are excitotoxic [33]. Elevated C-reactive protein levels are linked to a decline in executive function and frontal lobe damage...Proinflammatory cytokines include Interferon alpha, IL-1-beta and IL-6. Cytokine activation has been associated with psychiatric symptoms. For example, IL-6 is elevated in the cerebrospinal fluid of suicide attempters and is related to symptom severity, memory deficits and aggressiveness and IL-1-beta is associated with self-inflicted aggressive behavior and fatigue."
Practitioners who are fuzzy on serotonin dynamics will appreciate their review of how infections by parasites and pathogens like Borrelia burgdorferi in Lyme disease pervert the metabolism of serotonin in such a way that serotonin support can worsen depression. Clinicians who attempt to modulate serotonin with either reuptake inhibitors or precursor therapy must be aware of the following:
"Inflammation provoked by parasites impacts the conversion of tryptophan into serotonin. The kynurenine pathway is a major route of L-tryptophan catabolism into serotonin with a number of metabolites that include—kynurenic acid which is an N-Methyl-D-aspartic acid (NMDA) antagonist (neuroprotective, unless excessive), quinolinic acid which is a NMDA agonist (neurotoxic). In an inflammatory state there is decreased serotonin & a shift to quinolinic acid rather than kynurenic acid. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine and which is stimulated by proinflammatory cytokines, is implicated in the development of interferon--induced depressive symptoms, first by decreasing the serotonin availability to the brain and second by the induction of the kynurenine pathway resulting in the production of neurotoxic metabolites. In persistent infections associated with persistent inflammation, chronic activation of TNF-alpha stimulates interferon-gamma, which overactivates IDO, the rate-limiting enzyme for catabolism of tryptophan in the brain. Overactivated IDO causes neurotoxicity, and immune suppression of cytotoxic T cells."
So attempting to increase serotonin under these conditions is prone to backfire. Moreover...
"Underactivation of IDO is known to cause autoimmune reactions, but it has recently been discovered that overactivated IDO causes autoimmune B cell antibody production. CSF quinolinic acid is significantly elevated in a number of CNS infections including Borrelia burgdorferi (Bb), infection—dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function; a receptor involved in learning, memory, and synaptic plasticity; may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients."
The author also comments on the polar character of the immune imbalance associated with Lyme disease:
"Some immune mediated pathophysiology seen in Lyme/Tick-Borne Diseases (LYD/TBD) is a failure to shift from Th1 to Th2. Persisting immune activation causes the cytokine storm in chronic Lyme. In these patients, the innate immune system is not turned off by a series of specific immune peptides...The magnitude of IL-6 in human serum and CSF has been shown to correlate with disease activity in neurologic Lyme disease. Elevated levels of IL-6 can cause symptoms of fatigue and malaise, common to many infectious conditions as well as Lyme disease. Borrelia species induce activation of IL-17 production. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis CSF CXCL13 and can be used as a diagnostic marker for infection."
Persistently elevated IL-17 is an insignia of autoimmunity.Lyme disease neuropsychiatric phenomena are similar to psychiatric morbidities following strep infection:
"Paraneoplastic limbic encephalopathies and pediatric autoimmune diseases associated with strep (PANDAS) are good models to understand the effects of autoantibodies directed against intracellular neuronal antigens and the associated psychiatric symptoms. In paraneoplastic and nonparaneoplastic limbic encephalitis, voltage-gated potassium channel limbic encephalitis, Hashimoto’s encephalopathy, anti-NMDA and other glutamate receptor encephalitis, encephalitis associated with gamma-aminobutyric acid signaling and systemic lupus erythematosus neurons are excited to death by autoantibodies resulting in neurotoxicity. PANDAS is an interaction of a Streptococcal infection in a genetically susceptible individual at a young age which can result in obsessive compulsive disorder, tics and sometimes attention span difficulties. PANDAS is often comorbid with LYD/TBD and the broader categorization has been referred to as pediatric infection-triggered autoimmune neuropsychiatric disorders. Symptom flares follow a strep infection and correlate with increased antibody production."
Specifically, antigens on the surface of Borrelia can trigger an immune inflammatory response that cross-reacts with the host's neuronal tissues:
"Lyme surface antigens can cause molecular mimicry and associated autoimmune symptoms. Bb spirochetes surface glycolipids may elicit cross-reactive antibodies and IgM Bb flagella antibodies cross-reacted with neuronal antigens. Anti-neural antibody reactivity has been demonstrated in patients with a history of Lyme borreliosis and persistent symptoms. Anti-neural antibody reactivity was found to be significantly higher in the Lyme patients with prior treatment and persistent symptoms (PLS) group than in the post-Lyme healthy and normal healthy groups. Immunohistochemical analysis of PLS serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. The presence of anti-neural antibody reactivity in patients with PLS demonstrates ‘objective immunologic abnormalities’ and underscores the pathophysiologic nature of PLS and discredits the psychosomatic theory advanced by some as the cause of persisting symptoms."
He also considers the autoimmune dimension of autism spectrum disorders (ASD):
"There has been recent attention to the association between chronic infections, LYD/TBD and autism spectrum disorders (ASD). Immune reactivity associated with these infections in the mother, fetus and child appear to adversely affect developing neural tissue and contribute to the pathophysiology associated with autism spectrum disorders. Possible pathophysiological mechanisms include both inflammatory processes as well as autoantibodies to developing neural tissue...Individuals with autism show increased pro-inflammatory cytokines in the brain, as well as activation of microglia. Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers...Autoantibodies targeting brain proteins have been discovered in both children with autism and their mothers and circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism...In addition, antibodies that react to the 36, 37, 39, 61 and/or 73 kDa bands on Western Blot testing are associated with provoking an immune reaction and contribute to causing autism. Reactivity to these bands is also associated with Borrelia burgdorferi and to a lesser degree to Bartonella henselae, Bartonella quintana, Mycoplasma, Chlamydia pneumonia and Streptococcus pneumoniae."
Besides a reminder of factors that practitioners must bear in mind when managing Lyme disease or post-Lyme disease conditions, the author has covered important points for psychiatric disease in general. Readers may wish to see some of the 64 citations referenced in this paper by clicking on the link above. The author concludes:
"When looking at the clinical and basic science research on the subject articles it is apparent that persistent infection and associated inflammation and molecular mimicry mechanisms are associated with gradually increasing encephalopathy and gradually increasing mental symptoms. Cognitive symptoms begin as executive dysfunction and mild cognitive impairments and may gradually progress to dementia while emotional symptoms begin with insomnia, reduced frustration tolerance, irritability and dysthymia and may progress to anxiety disorders, depression, impulsivity and personality disorders and subsequently psychosis and/or suicidal and homicidal tendencies. Many of the neurological, cognitive and psychiatric symptoms associated with LYD/TBD appear to be mediated by immune mechanisms."