Neuropsychiatric systemic lupus erythematosus –  dia­gnosis and treatment

Overview

Neuropsychiatric involvement in systemic lupus erythematosus (SLE), known as neuropsychiatric lupus (NPSLE), is one of the most common, variable, and simultaneously least pathophysiologically understood forms of organ involvement in SLE. It represents a rather heterogeneous group of 19 syndromes, which according to the American College of Rheumatology (ACR), can be classified into diffuse neuropsychiatric syndromes (affective disorders, anxiety disorders, cognitive dysfunctions, psychoses, acute confusional states), central nervous system syndromes (headaches, cerebrovascular diseases, epileptic seizures, demyelinating diseases, aseptic meningitis, myelitis, movement disorders), and peripheral nervous system syndromes (mononeuritis simplex/multiplex, cranial neuropathies, plexopathies, polyneuropathies, myasthenia gravis, autonomic disorders, Guillain-Barré syndrome). NPSLE affects up to 80% of SLE patients, including mild forms, and is more frequently manifested at disease onset. Some forms have a severe negative impact on the patient‘s prognosis. The pathogenesis of NPSLE has not yet been fully elucidated, but it is certain that both inflammatory and non-inflammatory (ischemic, thromboembolic) mechanisms contribute in varying proportions. Involvement of the nervous system may also be related to complications from other organ involvement in the context of SLE or its treatment. The diagnosis of NPSLE is based on clinical examination (neurological, psychiatric, and possibly clinical psychological), supplemented by brain MRI and typically also cerebrospinal fluid analysis. Additional examinations are indicated depending on the type of involvement (electrophysiological studies, etc.). The management strategy for NPSLE depends on the type and severity of neuropsychiatric involvement, the predominant pathophysiological mechanism, SLE activity, and the presence of other organ involvement. In inflammatory forms of NPSLE, immunosuppressive therapy is indicated, while ischemic and thromboembolic forms are treated with anticoagulation or antiplatelet therapy. Symptomatic medications are also administered according to the type of involvement (analgesics, anticonvulsants, antidepressants, antipsychotics, etc.). Broader experience with biologic or targeted therapies for NPSLE is currently lacking.

Keywords:

Systemic lupus erythematosus – neuropsychiatric lupus – NPSLE – NPSLE diagnosis – NPSLE therapy

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) continues to pose a significant practical problem for clinicians, both in terms of diagnosis and treatment. Although the prognosis for patients with NPSLE has improved significantly in recent decades, it remains the second most serious organ manifestation of lupus after lupus nephritis, with considerable morbidity and mortality [1]. In 1999, the American College of Rheumatology (ACR) proposed a definition of a total of 19 neuropsychiatric syndromes that may be manifestations of NPSLE, including 12 central and 7 peripheral NPSLE syndromes [2] (Table 1). This publication is the first in Czech literature to comprehensively present the current knowledge on the diagnosis of this disease, including recent experiences and possible pitfalls in practice. It also deals with new perspectives on its pathogenesis. A significant part is devoted to treatment –⁠ both the recommended procedures of European and American professional societies and new therapeutic options, including experimental approaches.

 

Epidemiology

The prevalence of NPSLE varies considerably according to different authors and the latest criteria used, ranging from 37% to 95% [3]. This wide range reflects the approach to individual manifestations of NPSLE. Some authors suggest excluding clinically less severe non-specific syndromes that often occur in the general population and whose causal relationship with NPSLE is at least questionable, such as headaches or anxiety disorders. However, even after excluding these less severe forms, the prevalence of NPSLE remains high –⁠ around 20% [4]. None of the NPSLE syndromes are specific to lupus, and it is always necessary to rule out other causes that may contribute to the development of neuropsychiatric impairment (comorbidities –⁠ primary atherosclerosis, metabolic diseases, toxic or drug-induced damage, neuroinfections, etc.). Some syndromes, such as myasthenia gravis or Guillain-Barré syndrome, are likely to be autoimmune comorbidities with a different immunopathological mechanism than a direct manifestation of NPSLE.

 

Pathogenesis

Inflammatory and non-inflammatory (thromboembolic) mechanisms play a role to varying degrees in the development of neuropsychiatric involvement in SLE.

Autoimmune inflammation can lead to brain dysfunction through the action of inflammatory mediators or autoantibodies that penetrate the CNS through a damaged blood-brain barrier or are produced intrathecally; the role of autoantibodies may not be decisive in some cases. Neuronal dysfunction and structural changes in the CNS can be induced directly by these chemokines, cellular immunity, or indirectly through the activation of other cells, such as microglia [5].

Elevated levels of certain proinflammatory cytokines, primarily interleukin-6 (IL-6) and others (IL-8, IP-10, MCP-1 [monocyte chemoattractant protein-1],  G-CSF [granulocyte colony stimulating factor]), with their levels in the CSF being several times higher than their serum levels, which were normal [6].

The role of autoantibodies is supported by a number of observations. It is therefore assumed that an important factor is a disorder of the blood-brain barrier, which allows autoantibodies to penetrate the CNS. However, autoantibodies can also be produced intrathecally [7].

Different occurrences of systemic antibodies have been described in patients with NPSLE, but none are specific and sufficient for the diagnosis of NPSLE. Antibodies against ribosomal P protein (anti-rP), which have been detected in the serum and cerebrospinal fluid of patients with NPSLE, are highly specific for lupus and are associated mainly with neuropsychiatric syndromes (depression, psychosis, acute confusion) [8,9]. The role of anti-NMDAR (anti-N-methyl-D-aspartate receptor) antibodies in NPSLE is unclear [10].

Antiphospholipid antibodies (aPLA) are part of the picture of antiphospholipid syndrome, which is defined by the occurrence of thromboembolic events or pregnancy disorders; these antibodies can therefore cause, for example, thrombotic CMP, but are also associated with a number of other syndromes, such as chorea gravidarum [7,9].

Antibodies against aquaporin 4 (anti-AQP4) occur in antibody-mediated demyelinating diseases from the spectrum of neuromyelitis optica spectrum disorders (NMOSD), which occur more frequently in patients with SLE than in the general population [9].

Non-inflammatory mechanisms that can cause ischemic CNS lesions due to vascular occlusion include thromboembolic events in the context of antiphospholipid syndrome, vascular damage to large and small intracranial vessels mediated by autoantibodies, immune complex deposition, complement binding, and, last but not least, accelerated atherosclerosis [5].

Accelerated atherosclerosis can lead to early cerebrovascular disease. The risk of premature atherosclerosis is further increased by traditional factors such as smoking, dyslipidemia, older age, obesity, arterial hypertension, as well as factors specific to lupus (duration of disease, higher damage score, cumulative dose of glucocorticoids (GC), and low vitamin D levels) [5].

 

Clinical presentation and classification

The clinical picture of NPSLE is highly variable and includes at least 19 central and peripheral syndromes that may be associated with SLE. NPSLE is thus the second most diverse organ involvement in lupus after skin involvement, but none of these 19 syndromes is specific to SLE, and other causes or conditions that may lead to the neurological symptoms described must always be ruled out.

Neuropsychiatric syndromes are divided into central and peripheral according to the location of the lesion. They can arise and progress acutely or chronically, and can often be the first manifestation of SLE; they are very often combined. According to the presumed pathogenesis, neuropsychiatric syndromes can be divided into inflammatory (aseptic meningitis, myelitis, psychosis, cranial and peripheral neuropathy) and non-inflammatory (cerebrovascular disease); however, the causes are very often combined [11].

Risk factors for the development of NPSLE include high SLE activity, advanced health impairment, previous or concurrent manifestation of another NPSLE, and the presence of aAPLA [11].

 

Diffuse neuropsychiatric syndromes

Affective and anxiety disorders are very common in SLE, with depression occurring in approximately 25% of cases and anxiety disorders in approximately 37% [12,13]; however, the incidence of disorders that can be considered a direct manifestation of SLE is much lower (approximately 5%) [1].

Acute confusion –⁠ this is a sudden qualitative disturbance of consciousness with reduced attention. It is associated with elevated IL-6 levels and the presence of anti-NR2 (N-methyl D-aspartate receptor) and anti-Sm antibodies in the cerebrospinal fluid [14–16]. Non-specific focal changes in white matter may be visible on brain MRI, which are associated with anti-Sm antibodies and higher mortality [17].

Psychosis is rare (2.3%) [18], while psychoses induced by high-dose GK therapy are more common. Psychoses occur at the onset of the disease, may precede the manifestation of SLE, and are associated with anti-P antibodies, antineuronal antibodies, and high disease activity [19–21]. Their prognosis after treatment is good.

Mild to moderate cognitive dysfunction is a common finding in patients with SLE, with a prevalence of 14–95%, and is more common in patients with manifest NPSLE [22]; severe forms of cognitive dysfunction are rarer (3–5%) [23]. In our cohort of SLE patients (n = 100), we observed mild cognitive dysfunction in 35% of patients and moderate to severe cognitive dysfunction in 57% of patients. In patients with cognitive dysfunction, we observed a higher incidence of aPLA and antiphospholipid syndrome (APS) [24]. The most common disorders are attention, visual memory, verbal memory, and psychomotor speed. Risk factors for cognitive dysfunction include positive antiphospholipid antibodies, impaired health, concurrent cerebrovascular disease, and the presence of vasculopathy lesions on MRI [11,24,25].

 

Central nervous system syndromes

Headache is the most common but very nonspecific syndrome, with a reported prevalence of around 60% [1]. All types of primary headaches (migraine, tension headache, cluster headache) can occur in SLE and are clinically indistinguishable from primary headaches. A specific type of cephalalgia for SLE has not yet been defined. The previously described lupus cephalalgia, defined as severe headache that does not respond to common analgesics but subsides after corticosteroid therapy, is very rare. In the differential diagnosis, other more serious causes of headache (venous sinus thrombosis, aseptic meningitis, neuroinfection, etc.) must always be ruled out.

Cerebrovascular disease is also one of the most common manifestations of NPSLE, occurring in 3–20% of patients, with a mortality rate of up to 15% [26,27]. They can arise through various predominantly non-inflammatory mechanisms (thromboembolic in the presence of antiphospholipid antibodies, cardioembolic in Libman-Sacks endocarditis), but lupus vasculitis of the CNS is very rare (< 1% of patients with SLE), post mortem vasculitic changes are observed in SLE in less than 10% of cases [1,28].

Risk factors include the presence of antiphospholipid antibodies, particularly lupus anticoagulant, the degree of damage accrual, and classic risk factors for atherosclerosis, especially arterial hypertension [1]. Cerebrovascular disease can also be caused by premature atherosclerosis, in which case it is more likely to be a comorbidity accompanying SLE.

MR imaging reveals nonspecific focal changes predominantly in the white matter.

Epileptic seizures may be a manifestation of SLE, but there are several possible causes. Epileptic seizures in SLE are often acute symptomatic (e.g., as part of acute stroke, metabolic disturbance, drug-induced), with a low risk of recurrence once the triggering cause is removed. Another group consists of patients in whom epilepsy is already a consequence of structural changes in the brain after these events (e.g., structural epilepsy after a stroke). However, even after excluding these patients, the risk of epilepsy of unknown cause in patients with SLE is higher than in the general population. It remains unclear whether these cases without any other explanatory cause are a form of autoimmune epilepsy or whether the seizure threshold is lowered for another reason. Their prevalence in SLE is approximately 15%, and they are more common in younger individuals and at the onset of the disease [29]. These are usually isolated seizures, mostly tonic-clonic convulsions (67–88%), less often focal [11]. Risk factors include high SLE activity and the presence of autoantibodies (e.g., aPLA, anti-P protein) [30].

Demyelinating diseases of the CNS are also rare, occurring in < 1% of patients with SLE [1].

NMOSD with AQP4 antibody positivity is found in up to 27% of patients with SLE with manifestations of demyelinating disease.

In addition to NMOSD, patients with SLE may also develop MS. This may be the first symptom of the disease, making it very difficult to distinguish between SLE and NPSLE at the onset of the disease. Both diseases often affect young women of childbearing age, and it is possible for both to occur simultaneously. There is no reliable diagnostic test; patients should be examined for other possible manifestations of SLE (exanthema, arthritis, nephritis, hematological abnormalities, etc.), possibly APS (CMP, thromboembolic events), and the presence of specific autoantibodies. Minor multiple changes on brain MRI can be detected in patients with SLE, APS, and (MS), but elongated, ovoid lesions and "black holes" in T1-weighted images are more typical of MS [31]. The diagnosis of MS is further supported by the absence of other manifestations of SLE and the presence of IgG oligoclonal bands in the cerebrospinal fluid.

Antinuclear antibodies, which are present in virtually all patients with SLE, can also be found in patients with MS (up to 80%), but antinuclear antibody (ANA) titers are higher in patients with NPSLE. Antiphospholipid antibodies may also be present in MS (up to 44%) [32]. Antibodies specific to SLE (anti-dsDNA, anti-Sm) are of differential diagnostic significance [33].

When evaluating brain MRI findings, it should be borne in mind that non-specific focal changes in white matter may be visible on brain MRI in patients with SLE with or without APLA, and only one of their causes may be demyelination. Overestimating their significance can lead to misdiagnosis, and for the diagnosis of demyelinating disease, it is necessary to meet the diagnostic criteria for demyelinating diseases using specific biomarkers, such as antibodies against AQP4 in NMOSD or newer MR markers highly specific for MS, such as the presence of a paramagnetic rim or central vein sign.

Aseptic meningitis in SLE is extremely rare (prevalence 0.6%), and all other causes must be ruled out, especially infection or drug-induced aseptic meningitis [34]. Aseptic meningitis manifests as fever, headache, and lymphocytic or polymorphonuclear pleocytosis in the cerebrospinal fluid with negative microbiological examination.

Myelitis is another rare neurological manifestation, occurring in 1–2% of patients with SLE [35].

It is a typical example of a different pathophysiological mechanism. It may be a consequence of antibody-mediated astrocytopathy in NMOSD, but myelitis can also be caused by other immunopathological processes resulting from SLE. Myelopathy may also be caused by spinal cord ischemia or vascular involvement in SLE [11].

Extrapyramidal movement disorders are rare. The most common of these is chorea, but parkinsonism, ataxia, and others may also manifest in SLE. Chorea occurs in 1–4% of patients, is more common in juvenile lupus and in women [1], and may develop during pregnancy. It is more common at the onset of the disease, but may also precede the manifestation of SLE [1]. It is associated with APS or the presence of aPLA [36].

Thrombosis of cerebral venous sinuses is also rare (< 1% of patients with SLE) and is significantly associated with APS and SLE activity [37]. The transverse sinus is most commonly affected. The leading symptom is headache, but nausea and vomiting, convulsions, visual disturbances, and mental status changes are also common. The diagnosis is confirmed by venous angiography.

Posterior reversible encephalopathy syndrome (PRES) is a rare disorder with an incidence of < 1% in SLE. It is more common in younger women with active SLE, with kidney involvement, lymphopenia, dyslipidemia, and arterial hypertension. It can also be drug-induced. It usually manifests with transient symptoms of encephalopathy, headaches, epileptic seizures, and focal neurological deficits [38,39]. PRES manifests on brain MRI as vasogenic edema, especially in the posterior part of the cerebral circulation, and is bilateral and symmetrical. It is probably caused by dysfunction of autoregulation of cerebral blood flow, leading to breakdown of the blood-brain barrier [1]. The prognosis is good with proper treatment and control of arterial hypertension.

Isolated optic neuropathy without myelitis is rare in SLE (approximately 1%). It is more often caused by an ischemic process leading to demyelination and axonal necrosis than by primary inflammatory demyelination, which is supported by its association with APLA antibodies. Isolated optic neuropathy manifests as central scotoma, decreased visual acuity, eye and orbital pain, and can sometimes lead to amaurosis. Unilateral involvement is typical, and isolated optic neuritis can also manifest as retrobulbar ischemic optic neuritis or papillitis [40,41].

Idiopathic intracranial hypertension is also rare (1% of patients with SLE) [42]. Typical symptoms include headache, nausea, vomiting, papilledema, visual disturbances, and lesions of the VI cranial nerve. Native brain MRI is usually normal, as is cerebrospinal fluid analysis, but high opening pressure may be observed during lumbar puncture. The diagnosis is based on Dandy's criteria [43]. The development of idiopathic intracranial hypertension in SLE is associated with the discontinuation of GK, hypercoagulable states, SLE activity, and, according to some authors, also with anti-Ro antibodies [1].

 

Peripheral nerve syndromes

Peripheral neuropathies occur in 1–14% of patients with SLE, with NPSLE accounting for about two-thirds of cases [44].

The most common are peripheral polyneuropathies, which can be axonal, demyelinating, or mixed, sensory, or sensorimotor [44], but thin fiber neuropathies have also been described [45]. Peripheral neuropathies occur in both low and high SLE activity and are more common in older patients, arterial hypertension, and livedo reticularis [46]. For each peripheral neuropathy, other causes must be ruled out, such as diabetes mellitus, drug-induced damage, vitamin deficiency, etc. EMG is of fundamental importance in diagnosis.

Mononeuritis simplex/multiplex occurs in approximately 1.2% of patients with SLE [44] and manifests as involvement of one or more nerve roots, sensorimotor deficits in the limbs, more often in the lower limbs. The cause is vasculitis vasa nervorum, which can be verified by biopsy.

Cranial neuropathy is observed in 1.7–2.4% of patients with SLE [47] and is more common in patients with SLE and concomitant peripheral neuropathy, occurring in approximately 10% of cases [48]. The III, V, and VII cranial nerves are most commonly affected [44]. The condition manifests itself through typical clinical symptoms of the affected nerve (diplopia, neuralgia, paresis, etc.) and can be verified by finding an intensified signal of the affected nerve on MRI. The prognosis is not good, with improvement occurring in only about one-third of patients [1].

Plexopathies affect the entire nerve plexus (brachial, cervical, etc.) and are very rare (0.1–1.2%) [45,46].

Myasthenia gravis is rare in patients with SLE and is often diagnosed before SLE. Approximately 7% of women with myasthenia gravis also meet the criteria for SLE [49]. Typical symptoms include visual impairment, fatigue, and weakness. The diagnosis is supported by evidence of neuromuscular transmission disorder using EMG (repetitive nerve stimulation or single-fiber EMG) and positivity for antibodies against the acetylcholine receptor.

According to various authors, autonomic disorders may occur in 6–93% of patients with SLE; this variability is due to the definition and diagnostic method used [1]. The most common symptoms are dryness in the nasal cavity or, conversely, rhinitis, headaches, migraines, diarrhea, constipation, burning pain in the limbs, hot or cold extremities, sweating disorders, and erectile dysfunction.

Guillain-Barré syndrome can be acute or chronic, lasting longer than 8 weeks. The chronic form is more common in SLE. In addition to clinical examination, electrophysiological examination and cerebrospinal fluid analysis are necessary to establish the diagnosis.

 

Diagnosis of neuropsychiatric impairment in SLE

The diagnosis of NPSLE requires multidisciplinary collaboration between a rheumatologist, neurologist, psychiatrist, and possibly a clinical psychologist, ideally with practical experience with this disease.

If NPSLE is suspected (newly developed neuropsychiatric symptoms in a patient diagnosed with SLE), the attending rheumatologist should clinically examine the patient and supplement this examination with an NPSLE screening questionnaire. At the Institute of Rheumatology, we use a simple screening questionnaire developed by an international working group [50], which we have translated into Czech and validated in a standard manner [51] (Appendix 1). The questionnaire contains a total of 27 questions on the presence of various neuropsychiatric symptoms, the answers are evaluated with a certain number of points, and the result is a weighted score, with values ≥ 17 points indicating the possibility of NPSLE. Patients with a positive screening result should be referred for neurological, psychiatric, or psychological examination.

 

Clinical examination

All patients should undergo a standard clinical neurological or psychiatric examination. Patients with cognitive impairment should also be examined by a clinical psychologist or neuropsychologist. The ACR has proposed a battery of neuropsychological tests for the diagnosis of cognitive dysfunction in SLE, with a sensitivity of 80% and specificity of 81% [2]; validated Czech versions are available for most of these tests.

The further diagnostic process must be determined individually, taking into account the type of neuropsychiatric impairment, but MR brain imaging and cerebrospinal fluid testing are recommended for all patients with suspected NPSLE.

 

Magnetic resonance imaging of the brain

Brain MRI is recommended as the standard imaging method and should be performed in all patients with suspected NPSLE. Hyperintense lesions in the white matter of the brain and cerebral atrophy are common findings in patients with SLE, but they are not specific to lupus. They also occur in patients with and without NPSLE (non-NPSLE). An increased frequency of these focal changes and their greater volume in patients with SLE compared to healthy controls has been described [52,53], and a higher volume of focal changes in white matter has been described in patients with NPSLE compared to non-NPSLE.

Focal changes in the white matter of the brain can be caused by inflammatory and non-inflammatory mechanisms. In an analysis of abnormal MR findings in 325 patients with active NPSLE, 24% of these findings were assessed as being of inflammatory origin, 13.2% of ischemic origin, but most of them (62.8%) were of other origin (non-NPSLE) [54]. However, in inflammatory NPSLE, structural changes on brain MR are more pronounced (smaller total brain and white matter volume) compared to patients with non-inflammatory (ischemic) NPSLE [55]. The presence of lesions in white matter correlates with cognitive dysfunction [52]. However, standard brain MRI still plays an irreplaceable role in the differential diagnosis of other CNS diseases (Fig. 1). The protocol should also include MRA, and there are sequences optimized for imaging the artery lumen ("black blood").

More detailed information is provided by other MR-based imaging methods –⁠ diffusion tensor MRI (DTI), which allows for the evaluation of microstructural changes in white matter by measuring fractional anisotropy, or MR spectroscopy [56–58]. However, these methods are not yet routinely used in everyday practice, although according to the recommendations of the European League Against Rheumatism (EULAR), they should be performed in the event of a negative finding on standard MR [11].

 

Laboratory tests

Routine hematological, biochemical, and immunological tests may reflect the activity of the underlying disease, so we may observe increased erythrocyte sedimentation, changes in blood count (leukocytopenia, hemolytic anemia, thrombocytopenia), active urinary sediment (in active lupus nephritis), and immunological abnormalities –⁠ hypergammaglobulinemia, decreased C3 and C4 complement components, and the presence of various autoantibodies (ANA, anti-dsDNA, anti-Sm, anti-Ro, anti-La, anti-P, antiphospholipid antibodies). Anti-dsDNA antibodies are associated with inflammatory types of neuropsychiatric involvement, while antiphospholipid antibodies are associated with thromboembolic involvement.

To date, no specific serum marker of neuropsychiatric impairment is known, but rarely, autoantibodies against ribosomal protein P associated with diffuse neuropsychiatric syndromes (acute states of confusion, psychosis, severe depressive disorders, etc.) and anti-AQP4 antibodies associated with NMOSD can be found in patients with NPSLE. anti-AQP4, which are associated with NMOSD. Neurofilaments, or rather their light chain, are a promising marker of neuronal damage. Their serum levels are elevated in patients with NPSLE compared to healthy controls and, according to our results, they are able to distinguish NPSLE from lupus without neuropsychiatric involvement [59]. However, their specificity is low, as they may also be elevated in cases of CNS involvement due to organ damage.

 

Cerebrospinal fluid examination

Cerebrospinal fluid examination is also important in the diagnosis of NPSLE, not only to demonstrate CNS inflammatory activity, but also to rule out complications such as neuroinfection in immunosuppressed patients or subarachnoid hemorrhage in patients with vasculopathy. Mild cytological and biochemical abnormalities can be detected in the CSF, which may reflect the presence of inflammatory CNS involvement, destruction of nerve tissue, etc. Intrathecal oligoclonal immunoglobulin synthesis or blood-brain barrier dysfunction may be present. These findings are also not specific to SLE.

Elevated levels of certain proinflammatory cytokines, primarily IL-6, followed by IL-8, IP-10, MCP-1, and G-CSF, can be detected in the CSF of patients with NPSLE, while their serum levels are low [6], or certain autoantibodies (anti-P, antineuronal antibodies) [30].

 

NPSLE diagnostic algorithms

The diagnosis of NPSLE always requires the exclusion of other possible causes of neuropsychiatric symptomatology. Bortoluzzi et al. developed and validated an algorithm for examining patients with NPSLE, which is based on the ACR definition of NPSLE and also includes assessment of SLE activity, imaging methods, and cerebrospinal fluid analysis in an effort to distinguish true neuropsychiatric manifestations of SLE from comorbidities and other diseases [60]. This algorithm evaluates a total of four factors:

1.
the temporal relationship between neuropsychiatric manifestation and SLE diagnosis;

2.
whether it is a minor or nonspecific manifestation;

3.
the presence of confounding or distorting factors (which point to other causes of the condition);

4.
the presence of supporting (favoring) factors, such as various clinical and non-clinical findings, which, on the contrary, indicate the role of SLE (Table 2).

 

Magro-Checa et al. proposed their own algorithm based on a multidisciplinary assessment of each individual case [61].

 

Treatment of neuropsychiatric lupus

The treatment strategy for NPSLE must be designed individually according to the severity of the neuropsychiatric impairment and the presumed pathogenesis (inflammatory vs. non-inflammatory syndromes), and it is also necessary to take into account the overall activity of SLE, associated comorbidities, and other factors.

Treatment of NPSLE, apart from general measures such as correction of risk factors, management of comorbidities, etc., follows three main directions:

1.
specific symptomatic neurological or psychiatric therapy according to the type of impairment (analgesics, anticonvulsants, antidepressants, antipsychotics, etc.);

2.
immunosuppressive treatment for syndromes of inflammatory autoimmune origin (GC in monotherapy or in combination with immunosuppressants);

3.
anticoagulant and antiplatelet therapy for syndromes of non-inflammatory (ischemic or thromboembolic) origin.

 

Specific symptomatic treatment is indicated and administered by a neurologist or psychiatrist. Manifestations that are presumed to be manifestations of autoimmune inflammation (acute states of confusion, psychosis, aseptic meningitis, myelitis, cranial and peripheral neuropathy), or conditions accompanied by high overall SLE activity require immunosuppressive treatment –⁠ GK monotherapy or in combination with synthetic immunosuppressants, or biological drugs. Anticoagulant and antiplatelet drugs are the basis of secondary prevention after ischemic or thromboembolic cerebrovascular events in NPSLE, especially in the presence of APLA [11]. In the coexistence of ischemic and inflammatory NPSLE syndrome, it is advisable to consider a broader therapeutic approach with immunosuppressive and anticoagulant or antiplatelet therapy. A research group at the NPSLE clinic in Leiden has developed an NPSLE treatment algorithm that can be followed, but the final NPSLE treatment strategy must always be individually tailored (Fig. 2) [11,62].

 

Treatment of individual neuropsychiatric syndromes

For mild, non-severe disorders such as headaches, anxiety disorders, or affective disorders, symptomatic treatment (analgesics, anxiolytics, antidepressants) or psychotherapy is sufficient. GK treatment is indicated only for clinically severe or recurrent forms or in cases of high SLE activity.

Epileptic seizures –⁠ long-term anticonvulsant treatment is not necessary in most patients; it is reported that it can be discontinued in up to two-thirds of patients without further seizures [63]. It is always important to investigate the possible causes of epileptic seizures. If epileptic seizures are associated with high inflammatory activity or exacerbation of SLE, treatment with GCs and immunosuppressants may be considered [64]. If ischemic changes are present on brain MRI or APLA is positive, antiplatelet therapy is also recommended; if both of these factors are present (ischemic changes on MRI, APLA+), anticoagulant therapy is indicated [5,11].

Acute states of confusion are very rare in SLE, so other causes (drug-induced states, drug abuse, etc.) must always be ruled out. Acute states of confusion in NPSLE respond very well to therapy with GK and immunosuppressants. In refractory cases, cyclophosphamide, rituximab, IV immunoglobulins, or exchange plasmapheresis may be administered [1,5,11].

Psychosis is a rare manifestation of NPSLE. Similar to acute confusion, other possible causes must be ruled out before treatment begins. Antipsychotics form the basis of therapy. GK and immunosuppressants are indicated only when psychosis is associated with high SLE activity. We proceed similarly in cases of severe depressive disorders [11].

Demyelinating diseases may manifest as a result of NMOSD or MS, which in SLE patients may mimic NPSLE; concurrent diseases are also possible. Treatment of demyelinating diseases is initially started in the induction phase with high doses of GK in monotherapy or in combination with immunosuppressants; in refractory cases, plasmapheresis or rituximab administration may be considered. With regard to long-term immunotherapy, it is necessary to distinguish whether the patient meets the criteria for NPSLE, MS, or NMOSD, because certain immunotherapies carry the risk of worsening the symptoms of the disease if the diagnosis is incorrect, as is the case, for example, with interferon beta, which can worsen the course of both SLE and NMOSD [66].

Recent observations of a small series of patients support the efficacy of belimumab even in demyelinating disease in SLE, where the addition of belimumab to standard treatment led to complete or partial remission in most patients [65].

When SLE and MS are suspected or confirmed to coexist, anti-CD 20 therapy, which has been used successfully in the treatment of both diseases, is the appropriate treatment [11,66].

Myelitis should be treated aggressively and as soon as possible with a combination of high doses of GK and i.v. pulses of cyclophosphamide. The neurological outcomes of late treatment or GK monotherapy are not favorable [67,68]. In the maintenance phase of treatment, we continue with decreasing doses of GK and classic immunosuppressants (mycophenolate mofetil, azathioprine, methotrexate). In patients with antiphospholipid syndrome, it is advisable to add antiplatelet or anticoagulant therapy, but there is currently no evidence for routine use [1]. In patients with suspected transverse myelitis, it is always necessary to rule out spinal cord ischemia, which can mimic rapid-onset my e myelitis but requires a different therapeutic approach, including the possibility of recanalization therapy. Intensive rehabilitation is an essential part of comprehensive care for patients with myelitis, from the beginning and throughout the entire treatment period.

Aseptic meningitis –⁠ after ruling out other causes, treatment consists of GK and immunosuppressants.

Cranial and peripheral neuropathies (mononeuritis simplex/multiplex, plexopathy, polyneuropathy) are treated symptomatically (nonsteroidal anti-inflammatory drugs, gabapentin, pregabalin, carbamazepine); in more severe, acute, or progressive forms, treatment with GCs and immunosuppressants is indicated.

In Guillain-Barré syndrome, we administer GCs; rituximab, IV immunoglobulins, or plasmapheresis may also be indicated [3]. The prognosis is good, with treatment leading to improvement in most patients.

Autonomic disorders are thought to have an inflammatory etiology, so corticosteroid therapy and immunosuppressive treatment are indicated, and in refractory cases, intravenous immunoglobulins or plasmapheresis.

Treatment of myasthenia gravis in patients with SLE does not differ significantly; immunotherapy, which is effective in both diseases, e.g., therapy targeting B lymphocytes, such as rituximab, may be administered with advantage.

Isolated optic neuropathy without myelitis is usually unilateral and caused by ischemia. Treatment is anticoagulant.

Cerebrovascular disease –⁠ primary prevention (acetylsalicylic acid prophylaxis) is recommended in patients with APS or positive APLA, especially when two or more antibodies are positive [69].

Treatment of acute CMP is the same as for patients without SLE [1,11].

Secondary prevention is also similar to that in the general population and consists of controlling cardiovascular risk factors and antiplatelet therapy [1,11].

Chronic anticoagulant therapy is recommended for patients who have had a stroke and have moderate to high aPLA titers; the drugs of choice are warfarin or low molecular weight heparin. Direct oral anticoagulants (DOACs) are not routinely recommended, as there is no evidence of their efficacy in APS; on the contrary, they appear to be less effective than warfarin [70]. They may be considered for venous thrombosis in cases of contraindication or intolerance to warfarin, but are not recommended at all for the prophylaxis of arterial thrombosis. Anticoagulant therapy with warfarin is standard for venous thrombosis, with an INR range of 2–3. For arterial thrombosis, higher doses of warfarin with an INR of 3–4 are necessary, with a transition to low molecular weight heparin or in combination with antiplatelet therapy with low-dose acetylsalicylic acid, hydroxychloroquine, or statins [69].

In cases of high SLE activity and suspected cerebral lupus vasculitis, therapy with GCs and immunosuppressants is indicated.

Cognitive dysfunction should be treated in collaboration with a clinical psychologist (psychotherapy, cognitive rehabilitation). In patients with focal ischemic changes on MRI and positive aPLA, antiplatelet therapy should also be considered. GK administration is reserved only for progressive cognitive dysfunction and conditions with high SLE activity.

 

New treatment options for SLE with neuropsychiatric involvement

New biological and targeted synthetic preparations such as belimumab or anifrolumab are also available for the treatment of SLE, but it is difficult to comment on their efficacy in NPSLE as patients with NPSLE were excluded from clinical trials. Belimumab is effective for moderately active SLE and lupus nephritis, and there have been positive experiences with belimumab in the treatment of NPSLE, but its protective effect on the development or exacerbation of NPSLE has not been proven [71]. Autologous hematopoietic cell transplantation has also been discussed as a treatment for SLE, especially its refractory forms. The highest number of transplants was performed between 1998 and 2001, but it remains a very rare treatment modality; no subanalysis for NPSLE has been performed [72]. Another promising experimental innovation is treatment using CAR (chimeric antigen receptors) T regulatory lymphocytes; however, its potential use in SLE is still in its infancy [73].

 

Conclusion

Neuropsychiatric impairment in SLE has a wide range of clinical manifestations. More than twenty different syndromes have been described in connection with SLE, but none of them are specific to SLE. The diagnosis of neuropsychiatric involvement therefore requires careful clinical and complementary examination and careful differential diagnosis to rule out other causes of the symptoms. The diagnostic process is based on clinical examination (neurological, psychiatric, psychological), imaging (brain MRI), and cerebrospinal fluid examination. Other examination procedures are indicated depending on the type of impairment. In clinical practice, the ACR classification criteria for NPSLE (which require the exclusion of other causes) and the Bortoluzzi algorithm can be followed.

Treatment of NPSLE should be designed individually by an experienced multidisciplinary team (rheumatologist, neurologist, psychiatrist, clinical psychologist) and should be comprehensive. Both inflammatory and non-inflammatory mechanisms may contribute to the development of neuropsychiatric symptoms in SLE, so the treatment strategy should reflect the presumed mechanism of the neuropsychiatric syndrome or syndromes. Treatment with GCs and immunosuppressants is indicated for inflammatory forms, while antiplatelet or anticoagulant therapy is indicated for non-inflammatory thromboembolic forms. In severe forms of inflammatory origin that are refractory to standard therapy, the administration of rituximab may be considered.

The administration of other biological drugs registered for the treatment of SLE (belimumab, anifrolumab) is not yet recommended for active neuropsychiatric involvement due to a lack of data and experience.

 

Grant support

Supported by the Ministry of Health of the Czech Republic project for the conceptual development of research organizations 023728 and the Ministry of Health of the Czech Republic grant project NU21-09-00297.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.

 

 

Central nervous and neuropsychiatric syndromes

Affective disorders

Anxiety disorders

Cognitive dysfunction

Psychoses

Acute states of confusion

Headaches

Cerebrovascular disease

Epileptic seizures

Demyelinating diseases 

Aseptic meningitis

Myelitis

Movement disorders

Peripheral nerve syndromes

Mononeuritis simplex/multiplex

Cranial neuropathy

Plexopathy

Polyneuropathy

Myasthenia gravis

Autonomic disorders

 

 

1. Time of onset of neuropsychiatric symptoms in relation to the time of SLE diagnosis
   1. > 6 months before the onset of SLE                                                 0
   2. Concurrently –⁠ within the first 6 months after SLE diagnosis                     3
   3. later –⁠ 6 months after SLE diagnosis                                    2
2. Minor or nonspecific manifestations
   1. yes                                                                                                     0
   2. no                                                                                                     3
3. Questionable or distorting factors (which point to other possible causes of the condition)
   1. Absent                                                                                               2
   2. one factor present                                                                 1
   3. two or more factors present                                                              0
4. Supporting (favoring factors)
   1. none                                                                                                  0
   2. One factor present                                                                 1

 

Minor or nonspecific manifestations: headaches, mild affective disorders, mild cognitive impairment, polyneuropathy without EMG correlation.

Confounding (distorting) factors are specific to each type of neuropsychiatric disorder, e.g., preexisting neuropsychiatric disease, atherosclerosis and its risk factors, metabolic diseases, drug-induced damage, etc.

Favoring factors are also specific to individual types of impairment, such as high SLE activity, the presence of autoantibodies (aPLA, anti-P-protein, anti-ENA), young age, etc.

SLE –⁠ systemic lupus erythematosus