We've all been there. An elderly woman with obvious cognitive dysfunction, otherwise well and apyrexial, but with high ESR/CRP, is screened for "autoimmunity". The screen comes back as strongly positive. The patient is positive for ANA, dsDNA, C3, C4, lupus anticoagulant and IgG antibodies to beta-2 glycoprotein I. A question is asked. Does this patient have "cerebral lupus?" Do we give steroids, anticoagulation, or both?
Even experts find it difficult to make such determinations. There is too much soft research, nonspecific tests and grey areas passed off as "evidence" in the literature that confuses rather than resolves the issue. However, there are some hard facts that can be relied on. One must take care to ask the right questions.
1. Lupus vasculitis as a cause of neuro-psychiatric lupus (NP lupus) is uncommon~3% of all cases of NP lupus. Most patients with lupus vasculitis present with fever, severe headache and confusion and may progress to coma. A true emergency. The focus is on ruling out infection and TTP, and immunosuppressing ASAP with high dose steroids and cyclophosphamide.
2. Most cases of dementia related to lupus have stable, non-progressive disease and do not need to be immunosuppressed. Aspirin and statins are the order of the day.
3. Two-thirds of neuro-psychatric manifestations in lupus are due to non-lupus causes. Consider infections, medications (e.g. aseptic meningitis caused by NSAIDs and azathioprine, CVA caused by steroids), posterior reversible encephalopathy syndrome in those with very high BP and visual disturbances, TTP, atherosclerosis (risk factors diabetes, BP, hyperlipidaemia and smoking- all treatable causes), obstructive sleep apnoea (causing headache and fatigue).
4. Lumbar puncture is one of the most useful tests in NP lupus. Neutrophilia and high CSF protein indicates vasculitis (if bacterial meningitis can be ruled out). Anti-phospholipid (APL) syndrome is associated with raised protein but no pleocytosis. Presence of raised protein and mild lymphocytic pleocytosis indicates non-vasculitic active NP lupus (raised protein more common than pleocytosis). Hypoglycorrhachia indicates infection, with the exception of transverse myelitis, where CSF sugar is often low.
5. CSF IgG levels, IgG index, and CSF oligoclonal bands are really useful tests. CSF IgG levels are raised in over 2/3 of patients with NP lupus and a CSF IgG level> 6mg/dl is virtually pathognomonic of active NP lupus, although present in only 40% of cases. A raised CSF IgG index and CSF oligoclonal bands are seen in ~80% of cases with active NP lupus, particularly those with diffuse manifestations such as encephalopathy and psychosis. IgG index and oligoclonal bands will be normal/absent in those with focal symptoms such as hemiparesis caused by APL syndrome or chorea. CSF Q-albumin is not an useful test as it'd be raised in any aetiology that causes breakdown of the blood brain barrier such as stroke.
(IgG index is the ratio of two ratios- CSF IgG/CSF albumin divided by serum IgG/serum albumin. Normal IgG index is less than 0.66)
(Q-albumin is simply the ratio between CSF albumin and serum albumin).
6. Demographics are really important. Lupus patients with chorea and transverse myelitis tend to be young women. Always check ANA in a young woman who develops chorea. A positive ANA makes it more likely than not that she has lupus. APL is overrepresented in these two conditions, and in those with seizures.
7. Always check NMO-IgG in a lupus or Sjogren's patient who develops optic neuritis or transverse myelitis. The antibody is present in 75% of subjects with neuromyelitis optica, and carries an adverse prognosis, with multiple recurrences. Anti-Ro antibodies are often associated.
8. Large vessel stroke in SLE is bad news. Can be caused by APL, hypertension or TTP, the typical patient is 35 years old, 86% have active SLE at the time of stroke, and 40% will die in the short term. Thirteen percent will have recurrent stroke.
9. Recurrent TIAs with small infarcts is more characteristic of APL.
10. MRI is overrated. Although it is the preferred imaging procedure in picking up lesions of NP lupus, these typically appear as small white matter lesions on T2 weighted MRI. These are non-specific and can be found in many subjects with lupus who do not have NP manifestations.
11. Studies on anti-neuronal antibodies, antibodies to NMDAR and anti-ribosomal P antibodies are simply too discordant for these tests to be useful, although the latter is reasonably specific for lupus with severe psychosis or depression.
Even experts find it difficult to make such determinations. There is too much soft research, nonspecific tests and grey areas passed off as "evidence" in the literature that confuses rather than resolves the issue. However, there are some hard facts that can be relied on. One must take care to ask the right questions.
1. Lupus vasculitis as a cause of neuro-psychiatric lupus (NP lupus) is uncommon~3% of all cases of NP lupus. Most patients with lupus vasculitis present with fever, severe headache and confusion and may progress to coma. A true emergency. The focus is on ruling out infection and TTP, and immunosuppressing ASAP with high dose steroids and cyclophosphamide.
2. Most cases of dementia related to lupus have stable, non-progressive disease and do not need to be immunosuppressed. Aspirin and statins are the order of the day.
3. Two-thirds of neuro-psychatric manifestations in lupus are due to non-lupus causes. Consider infections, medications (e.g. aseptic meningitis caused by NSAIDs and azathioprine, CVA caused by steroids), posterior reversible encephalopathy syndrome in those with very high BP and visual disturbances, TTP, atherosclerosis (risk factors diabetes, BP, hyperlipidaemia and smoking- all treatable causes), obstructive sleep apnoea (causing headache and fatigue).
4. Lumbar puncture is one of the most useful tests in NP lupus. Neutrophilia and high CSF protein indicates vasculitis (if bacterial meningitis can be ruled out). Anti-phospholipid (APL) syndrome is associated with raised protein but no pleocytosis. Presence of raised protein and mild lymphocytic pleocytosis indicates non-vasculitic active NP lupus (raised protein more common than pleocytosis). Hypoglycorrhachia indicates infection, with the exception of transverse myelitis, where CSF sugar is often low.
5. CSF IgG levels, IgG index, and CSF oligoclonal bands are really useful tests. CSF IgG levels are raised in over 2/3 of patients with NP lupus and a CSF IgG level> 6mg/dl is virtually pathognomonic of active NP lupus, although present in only 40% of cases. A raised CSF IgG index and CSF oligoclonal bands are seen in ~80% of cases with active NP lupus, particularly those with diffuse manifestations such as encephalopathy and psychosis. IgG index and oligoclonal bands will be normal/absent in those with focal symptoms such as hemiparesis caused by APL syndrome or chorea. CSF Q-albumin is not an useful test as it'd be raised in any aetiology that causes breakdown of the blood brain barrier such as stroke.
(IgG index is the ratio of two ratios- CSF IgG/CSF albumin divided by serum IgG/serum albumin. Normal IgG index is less than 0.66)
(Q-albumin is simply the ratio between CSF albumin and serum albumin).
6. Demographics are really important. Lupus patients with chorea and transverse myelitis tend to be young women. Always check ANA in a young woman who develops chorea. A positive ANA makes it more likely than not that she has lupus. APL is overrepresented in these two conditions, and in those with seizures.
7. Always check NMO-IgG in a lupus or Sjogren's patient who develops optic neuritis or transverse myelitis. The antibody is present in 75% of subjects with neuromyelitis optica, and carries an adverse prognosis, with multiple recurrences. Anti-Ro antibodies are often associated.
8. Large vessel stroke in SLE is bad news. Can be caused by APL, hypertension or TTP, the typical patient is 35 years old, 86% have active SLE at the time of stroke, and 40% will die in the short term. Thirteen percent will have recurrent stroke.
9. Recurrent TIAs with small infarcts is more characteristic of APL.
10. MRI is overrated. Although it is the preferred imaging procedure in picking up lesions of NP lupus, these typically appear as small white matter lesions on T2 weighted MRI. These are non-specific and can be found in many subjects with lupus who do not have NP manifestations.
11. Studies on anti-neuronal antibodies, antibodies to NMDAR and anti-ribosomal P antibodies are simply too discordant for these tests to be useful, although the latter is reasonably specific for lupus with severe psychosis or depression.
12. The old adage about ESR and CRP in SLE is true. ESR tends to be raised in subjects with lupus, while CRP rises with infection or vasculitis. A subject with NP lupus with raised CRP should be suspected to have infection or vasculitis.
13. NP lupus typically occurs in subjects with active lupus, but less commonly, can be the first presentation of the condition.
14. Scan the heart in all patients with NP lupus. Non infective vegetations (Libman sacks endocarditis) on left sided valves can be a source of emboli for subjects with stroke or multi-infarct phenotypes. APL is overrepresented in such subjects.
15. Don't ignore investigations you'd otherwise perform in non-lupus subjects with stroke, young or otherwise. Thus, carotid dopplers in all patients, and serum homocysteine in young patients should be checked. Young patients with recurrent stroke should be screened for patent foramen ovale through bubble contrast echo.
16. Presence of livedo reticularis (Sneddon's syndrome), thrombocytopenia, adverse obstetric history, or a history of clots makes it more likely that APL is the cause. Subjects with arterial clots related to APL tend to have recurrent arterial clots, while those with venous clots tend to have recurrent VTE, albeit at different sites.
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