Introduction
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of systemic lupus erythematosus (SLE), an autoimmune disease. NPSLE primarily affects the nervous system, leading to a wide spectrum of psychiatric and psychiatric symptoms, from memory problems and mood disorders to severe issues like seizures and disturbances in consciousness. It poses a significant challenge in managing SLE patients due to its poor prognosis and higher mortality rate. The American College of Rheumatology has created diagnostic and classification criteria for NPSLE, assisting medical practitioners in recognizing and treating this disorder.
Treatment for NPSLE typically involves a multidisciplinary approach, including immunosuppressive medications and therapies aimed at managing specific symptoms. In order to improve the patient's quality of life and lessen the effects of this life-threatening condition, early identification and adequate management are essential. Understanding the pathogenesis, epidemiology, and treatment strategies for NPSLE is essential for healthcare providers to provide the best possible care to individuals living with SLE.
What Is the Prevalence of Neuropsychiatric Systemic Lupus Erythematosus?
The prevalence of neuropsychiatric systemic lupus erythematosus can vary widely between different research studies because they employ different methods and criteria for diagnosing this condition. In the past, some studies did not include all possible symptoms of NPSLE in their assessments, resulting in underestimations of its occurrence. However, when more comprehensive and sensitive diagnostic tools are used, which take into account mood disturbances, headaches, and cognitive (thinking and memory) problems, a significant majority of individuals with systemic lupus erythematosus actually exhibit some form of neuropsychiatric symptoms.
These commonly include depression (feeling intensely sad), headaches, and cognitive dysfunction. Less frequently, individuals with SLE may also experience symptoms like seizures, anxiety, acute confusion, stroke, or psychosis. Consequently, the prevalence of NPSLE can range from 80 percent to 90 percent among SLE patients, depending on the specific diagnostic criteria and assessment methods employed in a given study.
What Are the Symptoms of NPSLE?
The reported rates of ‘soft’ symptoms associated with NPSLE, such as depression and cognitive difficulties, exhibit substantial variability due to variations in diagnostic tools employed in research. Notably, depression and cognitive dysfunction emerge as common and early indicators of NPSLE, with cognitive issues often detectable before severe confusion or dementia manifests. However, the widely utilized mini-mental state examination sometimes falls short in identifying less severe cognitive impairments.
-
While comprehensive screening tools that use validated rating scales for mood, cognitive function, headaches, and autonomic function are preferred for assessing NPSLE symptoms, their routine use may face feasibility limitations.
-
There is variability in the suggested diagnostic tools for NPSLE, with some lacking validation and showing differing sensitivity to specific behavioral domains like depression.
-
NPSLE episodes are primarily attributed to the central nervous system, but the involvement of the peripheral nervous system remains unclear.
-
Research indicates that NPSLE symptoms may be fundamental manifestations of central inflammatory disease rather than mere side effects of organ dysfunction or medication.
-
These symptoms can occur before active systemic lupus erythematosus or independently of other disease-related symptoms.
-
Differentiating between the adverse neuropsychiatric effects of steroids and primary central disease manifestations requires well-designed studies.
-
Despite extensive research into 'soft' signs of NPSLE, such as cognitive impairment, their connection to overall SLE remains uncertain, adding complexity to understanding this challenging condition.
What Is the Classification of Neuropsychiatric Systemic Lupus Erythematosus Symptoms?
There is a suggestion that symptoms in different behavioral domains may have distinct underlying mechanisms. This has led to proposals to classify these symptoms into subsets or clusters based on their pathologic similarities, mechanisms, and other criteria.
-
Motor Dysfunction: Motor dysfunction often does not receive attention until severe symptoms like chorea (involuntary movements) or Parkinson 's-like symptoms become apparent. Few studies explore subtle motor signs, but investigating these milder motor deficits may reveal a higher prevalence of measurable motor dysfunction similar to other ‘soft’ neurological signs.
-
Sleep and Circadian Dysfunction: The systematic examination of sleep and circadian (daily rhythm) dysfunction in NPSLE is limited. These issues, although sometimes comorbid with depression and fatigue, are distinguishable from fatigue and depression. Encouraging formal assessments of sleep and circadian symptoms is advisable.
-
Fatigue and Behavior: Fatigue, although not included in the diagnostic criteria, is a common symptom in systemic lupus erythematosus and can significantly affect behavior and functioning. It often does not respond to traditional SLE treatments. In this context, quality-of-life questionnaires frequently include fatigue, making them useful in diagnostic evaluations alongside more comprehensive neurologic and psychological instruments.
Treatment Challenges: The treatment of NPSLE is based on empirical approaches due to the lack of controlled studies. Decisions regarding therapy should consider the nature of the underlying disease process, whether it is inflammatory or thrombotic. Therefore, understanding potential mechanisms becomes crucial in treatment planning.
What Are the Potential Mechanisms of NPSLE?
-
Vascular Events: Cerebrovascular events can lead to central nervous system (CNS) dysfunction. The location and extent of vascular injury are just two examples of variables that affect the kind and severity of neuropsychiatric symptoms. These manifestations are relatively rare in SLE unless they involve headaches within this context.
-
Autoantibodies and NPSLE: Research explores the relationship between autoantibodies (antibodies produced against the body's own tissues) and NPSLE. Different classes of autoantibodies are investigated, including antiphospholipid antibodies, antibodies targeting nuclear and cytosolic antigens, antibodies against lymphocyte cell surface antigens, and brain-reactive antibodies. However, the role of autoantibodies as the primary cause of NPSLE remains uncertain, with weak correlations and inconsistencies in findings.
-
Antiphospholipid Autoantibodies: Antiphospholipid autoantibodies, especially those targeting proteins binding to phospholipids, are associated with thromboembolic or vascular events. However, their connection to cerebrovascular disease is not consistently established.
-
Antiribosomal Autoantibodies: Antiribosomal autoantibodies are linked to some NPSLE symptoms, particularly psychosis. However, their presence does not always correlate with NPSLE, and their role in the disease process remains complex.
-
Cytokines and Chemokines: Cytokines (small proteins involved in immune responses) and chemokines (a type of cytokine) play a role in NPSLE. They can influence neural function and induce various symptoms, including depression and mood disorders. These molecules are linked to affective (emotional) and cognitive (thinking-related) dysfunction.
-
Blood-Brain Barrier (BBB): The BBB is a protective barrier for the central nervous system (CNS). Damage to the BBB can result from various causes, including microthrombi (tiny blood clots), immune-mediated attacks, local cytokine production, serum autoantibody entry, and localization of activated immune cells in the CNS. Evidence suggests compromised BBB integrity in some NPSLE patients, potentially contributing to neuropsychiatric syndromes.
-
How Is NPSLE Managed?
-
Current NPSLE Management: The current approach to managing neuropsychiatric systemic lupus erythematosus has remained largely unchanged for many years, involving corticosteroids and immunosuppressive drugs like Cyclophosphamide and Azathioprine.
-
Alternative Therapies: Some off-label treatments include Mycophenolate, plasma exchange, and Rituximab, which target specific immune cells. However, they primarily address immune responses and do not directly tackle inflammation.
-
Exploring New Approaches: Recent studies suggest that manipulating inflammation ‘stop’ signals, like lipoxins and resolvins, may hold promise as potential therapeutic options for NPSLE.
-
Limited Scientific Evidence: While traditional immunosuppressive treatments are commonly used, their effectiveness in NPSLE is not strongly supported by scientific evidence. Studies often involve small patient groups, lack placebo controls, and may focus on severe but less common NPSLE symptoms. Basic assessments used in these studies might not fully capture the range of NPSLE symptoms.
-
Challenges with Standard Treatments: Some patients do not respond well to standard treatments, and steroids can worsen or induce NPSLE symptoms in certain cases.
-
Belimumab: Belimumab, a new drug approved for lupus, has limited data on its effectiveness in NPSLE. It primarily targets B-cell-mediated mechanisms, and its direct benefit in NPSLE remains uncertain. It is worth noting that clinical trials for Belimumab excluded patients with lupus nephritis and CNS symptoms.
Navigating NPSLE treatment involves considering various factors, including the limited evidence for current therapies and the potential of emerging approaches like manipulating inflammation ‘stop’ signals. Further research is needed to enhance understanding and improve treatment options for this challenging condition.
Conclusion
The revision and standardization of diagnostic criteria for neuropsychiatric systemic lupus erythematosus have significantly advanced research in this area. However, there are still critical areas that require attention. One important aspect is the potential classification of NPSLE into groups of symptoms that share similar underlying causes, responses to treatment, timing of onset, behavioral domains affected, and other relevant criteria.
In particular, understanding the timeline of symptom development would be invaluable in identifying the initial triggers of NPSLE and distinguishing them from the complex secondary mechanisms that can exacerbate the condition. Currently, there are no highly reliable pathological or blood markers for diagnosing NPSLE. Therefore, the significance of implementing well-validated and comprehensive psychological and neurological assessments, including questionnaires, cannot be overstated. These measures are essential for accurate diagnosis and effective management of NPSLE.
