Approach Considerations
Patients with an acute neurologic presentation generally require an intensive care unit and neuroimaging facilities. Hemodialysis may be needed if acute renal failure occurs. Physician comfort and access to experienced multispecialty consultation are usually more of a problem than medical equipment limitation.
Treatment of systemic lupus erythematosus (SLE) should be provided in cooperation with a consulting rheumatologist. Therapeutic intensity correlates with the severity of an acute attack. Nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptomatic agents are used for less threatening symptoms. Corticosteroids are used in low-dose oral, high-dose oral, or high-dose intravenous (IV) regimens according to the severity of potential organ damage. Long-term steroid therapy may provoke an adrenocortical deficiency state.
Clinical studies supporting this approach were generally performed in lupus nephritis because of its frequency, severity, and quantifiable improvement or deterioration, still, the same treatment approaches are generally applied to other organ systems, including the central and peripheral nervous systems and muscular disease. This overall treatment approach should be familiar to neurologists who are accustomed to the evaluation and treatment of other autoimmune conditions such as multiple sclerosis, myasthenia gravis, or polymyositis.
A logical approach to the treatment of cerebral lupus is to build a treatment strategy around the various possible pathogeneses: (1) ischemia due to thromboses secondary to the antiphospholipid syndrome, (2) small-vessel noninflammatory proliferative vasculopathy due to cell-mediated immune mechanisms, and (3) antibody-mediated damage to the spinal cord and optic nerve—akin to Devic disease. [41]
Seropositive findings for neuromyelitis optica (NMO)–immunoglobulin G (IgG) antibody occurring with SS/SLE (Sjogren syndrome/SLE overlap) or non–organ-specific antibodies favors coexisting NMO (Devin syndrome) rather than a vasculitic process. Antibodies against the aquaporin 4 channel is an important evaluation for this common confusing situation. [42]
The standard treatment for the non-thrombotic syndromes associated with systemic lupus erythematosus (SLE) is immunosuppression, first with corticosteroids and with early recourse to cyclophosphamide. A Cochrane Database Systematic Review found no randomized controlled trials comparing these two treatments and concluded there was no evidence of a treatment advantage of cyclophosphamide. [43]
Medical Care
Corticosteroids
High-dose intravenous (IV) corticosteroid regimens consist of methylprednisolone 1-2 g daily for 3-6 doses, followed by oral prednisone 60 mg daily, then tapering according to clinical recovery. Less threatening flare-ups may be treated with as much as 100 mg or as little as 10 mg prednisone orally (PO) daily (QD) (or other agents in equivalent dosage), again tapering gradually according to clinical symptoms, with an increase of 10-20% during the taper if clinical disease flares again.
Tapering to an every-other-day steroid regimen reduces adverse effects substantially but probably will not be successful until the clinical disease is relatively stable. In acute high dosage, steroids may provoke status epilepticus, psychosis, hypokalemia, hyperglycemia, or hypertension and clinical evidence of any intercurrent infection may be reduced.
With chronic use, steroids cause familiar adverse effects including weight gain, diabetes mellitus, cataracts, immunocompromise, and osteoporosis. Calcium supplementation (1 g daily for men or premenopausal women, 1.5 g daily for postmenopausal women) should be initiated early and continued even when steroids are tapered successfully to every other day (qod).
Thrush and herpetic outbreaks may be treated symptomatically or prophylactically.
Antimalarial agents
The discovery that Toll-like receptor signaling and interferon-alpha abundance are central elements of the systemic lupus erythematosus (SLE) disease process has led to a new appreciation for hydroxychloroquine as an essential baseline medication. Modulation of the immune system via B-cell depletion is entering clinical practice.
Antimalarials, especially hydroxychloroquine in a dosage of 100-400 mg daily, are used as alternatives to steroids or as supplements to accelerate steroid taper. These agents have not been studied in central or peripheral nervous system disease. Antimalarials generally require months to become effective, and, therefore, they are not used in the acute treatment of organ-threatening disease.
Cytotoxic agents
Various steroid-sparing strategies have evolved for long-term use in systemic lupus erythematosus (SLE), including cyclophosphamide 0.5-2 mg/kg/d, azathioprine 1-2 mg/kg/d, and methotrexate 10-15 mg given once weekly with folate rescue, permitting gradual reduction or elimination of chronic steroid therapy. Higher dose ranges or dosing based on body surface area may be used for these medications based on the experience of individual clinicians.
All chronic cytotoxic regimens present substantial risks and should be followed only by physicians familiar with these agents. In acute, life-threatening illness, one option is to initiate cyclophosphamide PO or a single dose of 8-20 mg/kg IV, along with IV methylprednisolone. [44]
Jonsdottir et al reported that the majority of patients improved following rituximab plus cyclophosphamide. [45] The differential downregulation of anti-DNA of the immunoglobulin (Ig) G and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that greater absolute numbers of CD19+ cells at baseline predict a less impressive clinical and serologic response suggests that more flexible dosing could be advantageous.
Investigational pharmacologic approaches
Mycophenolate mofetil is an effective and safer alternative to cyclophosphamide for patients with lupus nephritis. Other therapeutic approaches under development include anti-cytokine therapies, costimulatory blockade, antigen-specific immune modulation, and hematopoietic stem cell transplantation. [46]
Epratuzumab, a monoclonal antibody against the B-cell surface antigen CD22, and atacicept, a chimeric molecule formed by a receptor for B-cell–activating factor and a proliferation-inducing ligand with immunoglobulin G (IgG), have both been promising in initial small trials; larger clinical trials are underway. [47] Clinical trial data have shown that B-cell targeting therapies are beginning to fulfill their promise as treatments for systemic lupus erythematosus (SLE), and there are good reasons to hope for further progress in the near future.
Anifrolumab, a type I interferon receptor antagonist has shown some success in SLE patients in phase IIb trials. In the future, type I interferon inhibition may be used in the treatment of NPSLE patients with a strong type I interferon signature. [48]
Management of Devic Syndrome
The treatment of Devic syndrome (neuromyelitis optica) in isolated myelopathy or optic neuropathy associated with the antiphospholipid syndrome (APLS) or lupus needs further study. In view of their lack of pathologic similarity to classical multiple sclerosis, treatments such as interferon-beta cannot be justified. Also, there is no hard evidence to support the use of anticoagulation, in the absence of evidence for progressive ischemia of isolated anatomic sites. Therefore, therapy is generally aimed at circulating pathogenic antibodies, with steroids and cyclophosphamide. Plasma exchange has proven effective in non-lupus Devic disease. Because of the analogy with non-lupus Devic disease, plasma exchange is also an attractive alternative in systemic lupus erythematosus (SLE)–Devic disease. [49]
Myopathy/Polyneuropathy Management
Generally, mild myopathy or polyneuropathy may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptomatic medications (e.g., anticonvulsants, tricyclics [TCAs], other medications used for neurogenic or musculoskeletal pain). Symptoms may be caused by medications (e.g., steroids, antimalarials) or other etiologies in addition to systemic lupus erythematosus (SLE). If alternative explanations are unlikely and symptoms are more bothersome, low- to medium-dose prednisone may be tried, possibly with a longer-term transfer to antimalarial therapy.
Polyradiculopathy Management
If a patient with systemic lupus erythematosus (SLE) presents with acute polyradiculopathy resembling Guillain-Barré syndrome or chronic relapsing polyradiculopathy resembling chronic inflammatory demyelinating polyneuropathy, treatment with intravenous immunoglobulin (IVIg) in conventional doses should be considered. When IVIg is unavailable or poorly tolerated, plasma exchange should be considered as an alternative. Unfortunately, few therapeutic studies exist on these rare presentations of SLE.
Management of Seizures
Seizures are common sequelae of systemic lupus erythematosus (SLE) and may result from acute or chronic disease. Acute electrolyte disturbance, response to high-dose steroids, or other acute disturbance may only require temporary anticonvulsant treatment, whereas more chronic epileptogenic foci may require lifetime prophylaxis.
Anticonvulsants may be used in a conventional fashion, emphasizing medications most effective for focal onset or secondarily generalized seizures. Phenytoin and other agents associated with drug-induced lupus are unlikely to actually increase disease activity in SLE, but chronic use may cause diagnostic confusion for physicians.
Management of APLS
Treatment of the antiphospholipid syndrome (APLS) remains controversial, with therapy based predominantly on anecdotal experience. Although many authorities recommend full anticoagulation with warfarin (Coumadin) (despite there being no randomized clinical trial to prove this), others support antiplatelet therapy initially, with stronger measures reserved for repeated stroke, progressive myelopathy, or other clear-cut, clinical treatment failure.
It is clear that aiming for an international normalized ratio (INR) of 2.0–3.0 is as good at reducing the risk of further events as more intensive anticoagulation. [50] This could be done possibly in conjunction with immunosuppressant therapy to suppress the production of the antibody.
Activity
If neurologic signs or symptoms present in a patient with SLE that is well established, the need for additional consultations beyond the treating internist or rheumatologist is determined by the presence and severity of concomitant organ disease.
Like the neurologic vasculitides, cerebral lupus is best managed jointly by neurologists, clinical immunologists, nephrologists, rheumatologists, and primary care physicians.
Consultations
Generally, new-onset systemic lupus erythematosus (SLE) diagnosed based on neurologic symptoms should be managed in conjunction with a rheumatologist or internist.
If neurologic signs or symptoms present in a patient with SLE that is well established, the need for additional consultations beyond the treating internist or rheumatologist is determined by the presence and severity of concomitant organ disease.
Cerebral lupus, like the neurologic vasculitides, is best managed jointly by neurologists, clinical immunologists, renal physicians, rheumatologists, and primary physicians.
Long-Term Monitoring
The overall outcome of central nervous system (CNS) lupus, quality of life, and prognosis can be enhanced with close follow-up and coordination between the individual's neurologist, rheumatologist, and primary care physician. Neurologists and rheumatologists usually do not act as primary care physicians and leave healthcare maintenance to practitioners who need to be reminded to screen for various comorbidities associated with inflammation and medication complications. Rheumatologists need to take the responsibility to ensure that their patients with lupus have optimal primary care access, which includes a working relationship with them. [51]
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This axial, T2-weighted brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with longstanding systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. The distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to the distribution.
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Serum Chemistry Studies
- Hepatocellular and Muscle Enzyme Levels
- Antinuclear Antibody Test
- Lupus Anticoagulant Test
- CSF Studies
- Brain Imaging Studies
- Spinal Imaging Studies
- Echocardiography and Ultrasonography
- Electroencephalography
- EMG and Nerve Conduction Studies
- Biopsies and Histologic Features
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- Treatment
- Medication
- Questions & Answers
- References
