Systemic lupus erythematosus (CNS manifestations)

Central nervous system manifestations of systemic lupus erythematosus (CNS lupus), also known as neuropsychiatric systemic lupus erythematosus (NPSLE), describe a very diverse range of neuropsychiatric manifestations that are secondary to systemic lupus erythematosus (SLE) in the central nervous system (CNS). Additionally, SLE may co-exist with neuromyelitis optica spectrum disorder (NMOSD) ²³.

For a general discussion, and for links to other system specific manifestations, please refer to the article on systemic lupus erythematosus. 

Epidemiology

Neuropsychiatric manifestations occur in up to 80% of patients with SLE ¹.

Clinical presentation

The American College of Rheumatology (ACR) defines 19 distinct clinical central and peripheral neuropsychiatric syndromes that can occur in SLE, twelve of which are due to CNS involvement ^2-7,22. These syndromes can precede other symptoms of SLE or may occur at any point during the course of the disease, thus, the clinical presentation is extremely variable ^2-7.

Neurological

• seizure disorders

  • seizures and epilepsy are the most common neurological feature of SLE, occurring in up to 20% of all patients ⁴

  • etiology of seizures is uncertain, but may accompany vasculitis or may be due to a low-grade autoimmune encephalopathy ^3-5

  • presentation may be of generalized or focal seizures ^3-6

• cerebrovascular disease

  • stroke is a relatively common feature of SLE, with rates of up to 19% having been reported ⁸

  • it can manifest as both vaso-occlusive disease, such as ischemic stroke, transient ischemic attack (TIA), and dural venous sinus thrombosis, along with intracerebral hemorrhage ^3,4,8

  • risk factors for stroke due to SLE include anti-phospholipid antibodies (present in up to 55% of SLE patients), cerebral vasculitis (lupus angiitis), hypertension, accelerated atherosclerosis (e.g. due to prolonged corticosteroid use), cardiac valvular disease (e.g. Libman–Sacks endocarditis), thrombocytopenia, and age ^3-5,8,22

  • patients present with features identical to those without SLE, and therefore the clinical presentations are discussed elsewhere (see ischemic stroke, transient ischemic attack, dural venous sinus thrombosis, and intracerebral hemorrhage) ^3-5,8

    • an exception is when due to cerebral vasculitis, a clinical syndrome of headache, fever, and psychiatric symptoms is usually present in addition to those of the stroke ⁴

• demyelinating syndrome

  • although included in the initial ACR definition, it is now thought that "myelopathy" (see below) encompasses this appropriately, and presentations truly akin to multiple sclerosis, once termed "lupoid sclerosis", are unlikely to be associated with SLE at all ³

• myelopathy

  • myelopathy is an umbrella term for transverse myelitis, optic neuritis, and neuromyelitis optica spectrum disorder (NMOSD), and is considered to be a rare feature of SLE ^3-5,22

  • may be due to small vessel disease, vasculitis or demyelination ^3-5,22

  • patients present with features identical to those without SLE, and therefore the clinical presentations are discussed elsewhere (see transverse myelitis, optic neuritis, and neuromyelitis optica spectrum disorder) ^3,4

• headache

  • although included in the initial ACR definition, the causative role that SLE plays in inducing migraine or idiopathic intracranial hypertension (both conditions that have classically been associated with SLE) has since come into doubt ^3,4

  • regardless, up to 40% of patients with SLE experience at least one severe headache per year, which may or may not have other migrainous features or features of idiopathic intracranial hypertension, as per non-SLE patients with migraine ^3,4

• movement disorder

  • movement disorders are rarely described in association with SLE ^3-5

  • it is thought that infarction or neuronal antibodies may play a role in the etiology of these movement disorders in SLE ^3-5

  • the most common manifestation is chorea, which has been found to occur in approximately 1% of patients, however isolated cases reports of other movement disorders such as hemiballismus and parkinsonism have been described and attributed to SLE ^3-5

• aseptic meningitis

  • aseptic meningitis is considered to be a very rare feature in SLE, and most cases can be attributed to previous myelopathy, vasculitis, or therapeutic drugs (e.g. non-steroidal anti-inflammatory drugs) ^3,4

  • it presents with classic signs of meningeal irritation (see meningitis) but without positive bacterial cerebrospinal fluid cultures ^3,4

Psychiatric

• psychosis

  • psychosis is a classic psychiatric manifestation of SLE but only occurs in approximately 5% of patients ⁴

  • the etiology remains uncertain, however patients are more likely to be positive for anti-ribosomal P antibodies and anti-NMDA receptor antibodies; vasculitis can also present with psychosis ^5,9

  • as with other presentations of psychosis, it is clinically characterized by delusions and hallucinations ^3,4

• acute confusional state

  • although many studies use psychosis and "acute confusional state" synonymously, the ACR defines it instead as being a delirium ^3,4

  • the etiology again is uncertain and thought to be multifactorial, with small vessel dementia being a significant contributor; vasculitis can also present with delirium ^3-5

  • as with other presentations of delirium, acute confusional states in SLE can vary from mild disturbances of consciousness to coma, encompassing a range of hypoaroused and hyperaroused states ^3,4

• cognitive dysfunction

  • cognitive dysfunction is very common in SLE, occurring in up to 80% of patients, although severe dysfunction resulting in dementia is rare ¹⁰

  • the etiology is uncertain and is again, thought to be multifactorial ⁵

• mood disorder

  • many mood disorders, such as depression, have been reported in SLE ^3,4

  • although generally thought to be non-melancholic in nature, brought upon by the patient’s reaction to managing their chronic illness, there may be other factors involved such as positive anti-ribosomal P antibodies or anti-NMDA receptor antibodies ^4,5

• anxiety disorder

  • similar to mood disorders in SLE, anxiety is generally thought to be brought upon the patient’s reaction to managing their chronic illness, but there may be other factors involved such as positive anti-ribosomal P antibodies or anti-NMDA receptor antibodies ^3-5

Pathology

The pathogenesis of SLE is uncertain but is thought to be multifactorial involving genetic, hormonal, immunological, and environmental factors ⁴. The specific etiologies of the neuropsychiatric CNS manifestations of SLE have been discussed above, but are also generally uncertain.

Radiographic features

As with the clinical features, CNS lupus has an extremely varied radiographic presentation ^11-15. Although not every described neuropsychiatric syndrome of CNS lupus has radiographic features, those that do, mainly the cerebrovascular disease and myelopathy, tend to be non-specific ^11-15. Therefore, all of these manifestations in CNS lupus are radiographically indistinguishable from their appearance due to other etiologies ¹¹.

Cerebrovascular disease

• small vessel disease and cerebral atrophy

  • most common feature and seen in up to 25% of cases ¹¹

  • CT: small vessel dementia is characterized by diffuse symmetrical hypodensities ^11-14

  • MRI: small vessel dementia is characterized by subcortical and periventricular white matter lesions on T2-weighted sequences ^11-14

• ischemic stroke

  • another common feature that may affect any vascular territory, including lacunar strokes ^12,22

  • CT: hypodense lesion ^11-14,22

  • MRI: varying intensity (see ischemic stroke) ^11-14

• intracerebral hemorrhage

  • very rare ²²

  • ​CT: acutely hyperdense with hypodense perihaematomal edema ^11,13,22

  • MRI: varying intensity (see aging blood on MRI) ^11,13,22

• dural venous sinus thrombosis

  • ​CT: hyperdense sinus reflective of thrombosis ¹¹

  • MRI: variable appearance (see dural venous sinus thrombosis) ¹¹

  • angiography: filling defect in affected venous sinus ¹¹

• cerebral vasculitis (lupus angiitis)

  • may be a cause of ischemic stroke and/or intracerebral hemorrhage (including cerebral microhemorrhage) ²², but may also present as its own syndrome as aforementioned

  • CT: multiple scattered hypodensities ¹⁶

  • MRI: non-specific white matter hyperintensities on T2-weighted sequences ^16,22, there may or may not be gadolinium-enhancing lesions on T1-weighted sequences ²²

  • angiography: focal segmental vascular narrowing and beading may be seen ^12,16

^​Myelopathy

• transverse myelitis (lupus myelitis)

  • may be a standalone feature or be present with other features of NMOSD ^11,17

  • CT: variable enlargement of the cord and variable enhancement ^11,17

  • MRI: cord lesions that are hyperintense on T2-weighted sequences with variable enhancement ^11,17

• optic neuritis

  • may be a standalone feature or be present bilaterally with other features of NMOSD ^17,22

  • CT: often unremarkable ¹⁷

  • MRI: optic nerve lesion that is hyperintense on T2-weighted sequences and enhancing post-gadolinium administration ^17,22

• other features of neuromyelitis optica spectrum disorder (NMOSD) may also be present ²²

Other manifestations

• aseptic meningitis

  • ​CT: may be normal ¹⁸

  • MRI: leptomeningeal enhancement that may be either focal or diffuse ¹⁸

• posterior reversible encephalopathy syndrome (PRES)

  • although not described in the ACR criteria, PRES may develop secondary due to hypertension (e.g. lupus nephritis, corticosteroid use) and other complications of SLE (e.g. TTP) ^11,19,22

  • CT: most commonly hypodensity in the occipital and parietal regions ¹¹

  • MRI: affected regions are hypointense on T1-weighted sequences, hyperintense on T2-weighted sequences, and may have variable enhancement ^11,22

• anti-NMDA receptor encephalitis

  • although not described in the ACR criteria, anti-NMDA receptor antibodies have been associated with psychiatric symptoms of CNS lupus, and resultant anti-NMDA receptor encephalitis has also been rarely described ^20,22

  • MRI: non-specific T2-weighted hyperintensities in the medial temporal lobe, cerebral/cerebellar cortex, basal ganglia, and brainstem ^20,22

Treatment and prognosis

Treatment is highly variable and is often symptomatic depending on the specific neuropsychiatric manifestation exhibited ⁶, but may involve intensive immunosuppression.

Complications

Central nervous system complications arising from intensive immunosuppression of systemic lupus erythematosus include ^12,22:

• progressive multifocal leukoencephalopathy

• primary CNS lymphoma

• drug–induced toxic leukoencephalopathy (e.g. methotrexate-related leukoencephalopathy)

• brain abscess