Neuropsychiatric systemic lupus erythematosus - Springer Link

The systemic lupus erythematosus (SLE) patient with neuropsychiatric complaints requires a comprehensive and timely diagnostic approach. Despite the obvious difficulties in diagnosing neuropsychiatric SLE, the neurologic complications of SLE can be approachedin a careful, logical manner with gratifying results.

Neurnpsychiatric Systemic Lupus Erytheinatnsus WILMER L. SIBBITTJR., MD Clinical & Magnetic Resonance Research Center Department of Internal Medicine REX E. JUNG, MS Clinical & Magnetic Resonance Research Center WILLIAM M. BROOKS, PhD Clinical & Magnetic Resonance Research Center Department of Neurosciences University of New Mexico Health Sciences Center Albuquerque, N M

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by intense inflammatory attack on the skin, joints, viscera, and brain. Neuropsychiatric SLE (NPSLE) subsumes all the neurologic and psychiatric complications of SLE and affects up to 75% of SLE patients. 1 Because the total population of SLE patients in the United States may be as high as 2 million, NPSLE represents an important cause of neurologic disease, especially in women. Despite the development of reasonably effective interventions for complications of SLE, the morbidity and mortality of NPSLE remain high as a result of ineffective diagnostic methods, unproven therapeutic options, and u n c e r t a i n t y regarding pathogenesis, course, and outcome, z,3 NPSLE may be characterized by virtually any neurologic and m a n y psychiatric abnormalities, including diffuse encephalopathy, psychiatric disturbances, dementia, delirium, affective disorders, anxiety syndromes, cranial neuropathies, cerebrovascular accidents, transverse myelitis, movem e n t d i s o r d e r s , seizures, h e a d a c h e s , a s e p t i c meningitis, pseudotumor cerebri, and lupoid sclerosis. 1,4,5 Thus, a critical step in the evaluation of a SLE patient with neuropsychiatric manifestations is the definition and classification of the specific central nervous system s y m p t o m s and complaints. Despite these myriad neurologic and psychiatric manifestations, the revised American College of Rheumatology criteria for SLE, established in 1982, recognize only central nervous systemic manifestations (eg, seizure and psychosis} as criteria for a diagnosis of NPSLE. 6 These methods have been useful in providing clinically relevant groupings for scientific study and therapeutic intervention, s; REPRINTS Wflmer L. Sibbitt Jr, MD, Department of Internal Medicine, Division of Rheumatology, University of New Mexico School of Medicine, Albuquerque, NM 87131. Submitted for publication: December 10, 1998. Accepted: December 22, 1998.

ACKNOWLEDGMENT This work was supported by the State of New Mexico through a grant to the Center for Non-invasive Diagnosis, the Fraternal Order of Eagles Auxiliary - New Mexico Chapter, and an R01 (NS 35708) from the National Institutes of Health.

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COMPTHER. 1999;25(4):198-208

In the context of this wide array of symptoms and severity, NPSLE clearly remains a challenging disease to classify reliably. However, definitions and nosology of neuropsychiatric complaints have been standardized recently, and these definitions should be used for both current clinical descriptions and future research in NPSLE {Ad Hoc Committee of Neuropsychiatric Lupus Nomenclature). 8 A useful division of these definitions based on central or peripheral nervous system involvement is shown in Figure 1. In this classification scheme, central NPSLE includes aseptic meningitis, cere-

brovascular disease, psychosis, demyelinating synd r o m e , headache, m o v e m e n t disorder {chorea}, myelopathy, seizure disorders, acute confusional state, a n x i e t y d i s o r d e r , cognitive d y s f u n c t i o n , m o o d disorder, central autonomic disorder, and c e n t r a l cranial n e u r o p a t h y . P e r i p h e r a l NPSLE includes myasthenia gravis and various forms of peripheral neuropathy. Both central and peripheral NPSLE can then be further categorized as active, previously active, acute, or chronic. Each of these forms of NPSLE requires careful clinical interpretation, as follows.

Neuropsychiatric Complications in SLE 1) Neuropsychialric SLE (NPSLE) - Manifestations Caused by SLE 2) Confounding Disease - NeuropsychiatricManifestations Not Caused by SLE

General Classifications of NPSLE Confounding Disease A. Central NPSLE

See Table 1

B. Peripheral NPSLE

Classification of Central NPSLE a) Active and/or Previously Active: b) Acute or Chronic nt

rvo

s

em NPSLE

Aseptic meningitis Cerebrovasculardisease Psychosis Demyelinatingsyndrome Headache Movementdisorder (chorea) Myelopathy Seizure Disorders Acute ConfusionalState AnxietyDisorder Cognitive Dysfunction Mood Disorder Central autonomic disorder Central neuropathy,cranial

-NP LE

Classification of Peripheral NPSLE a) Active and/or Previously Active: b) Acute or Chronic Peripheral Nervous System NPSLE (p-NPSLE) Myasthenia gravis Peripheral neuropathy Acute inflammatorydemyelinatingpolyneuropathy Mononeuropathy,single/multiplex Plexopathy Peripheral neuropathy, cranial Peripheral autonomic disorder Polyneuropathy, unspecified

Figure 1.--Classification of central nervous system neuropsychiatric manifestations in systemic lupus erythematosus. COMPTHER1999;25(4) .

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CENTRAL NPSLE Cerebrovascular Disease. Cerebrovascular disease is a particularly devastating but all too common outcome of NPSLE, 9,1~ and is associated with neuronal loss, demyelination, and heterogeneity of lesions. ~1 Cerebrovascular disease includes cerebral infarct, transient ischemic attack, chronic multifocal disease, subarachnoid and intracranial hemorrhage, or sinus thrombosis. It should be noted that, unlike peripheral blood vessels, the cerebrovasculature is rarely affected by true vasculitis, but rather by a nonspecific vasculopathy without vessel wall necrosis {bland vasculopathy) or thrombosis with fibrin, leukocytes, or platelets. Large lesions noted by MRI or CT--particularly in the motor areas, brain stem, and spinal cord--are associated with grave consequences for function and outcome in NPSLE patients. Small infarcts noted on histopathology are common in NPSLE, but may be clinically important only if they accumulate in great numbers over a period of years, or if they occur in large numbers simultaneously, resulting in seizures, cerebral edema, or death. Acute stroke may manifest clinically as a focal neurologic deficit {ie, dysphasia or central cranial neuropathy}, but may also be accompanied by seizures, central autonomic disorder, movement disorders, coma, or death. Most commonly, cerebral infarction and transverse myelitis in NPSLE are a result of vascular thrombosis, although infarct associated with cardiac emboli, vasculitis, and intracerebral hemorrhage may occur less frequently. Cerebral infarct in SLE can result in major strokes affecting motor, speech, or visuospatial functions, or in r e c u r r e n t minor strokes, which can gradually degrade neurocognitive function to the point of overt dementia {chronic multifocal disease). Cerebral infarction in SLE appears to be related both to the presence of predisposing factors (antiphospholipid antibodies, valvular disease, or acquired factor deficiencies} and to systemic SLE disease activity. Thus, a comprehensive interventional approach to cerebral infarction is required, lz Demyelinating Syndromes and Myelopathy. Demyelinating s y n d r o m e s can occur in SLE and clinically resemble multiple sclerosis. These are characterized by evidence of multiple areas of damage to white-matter tracts seen by magnetic resonance imaging (MRI), transverse myelopathy, optic n e u r o p a t h y , isolated nerve palsies, internuclear ophthalmoplegia, brain stem disease, or other cranial neuropathies. Myelopathy can also occur in isolation and is c h a r a c t e r i z e d by rapidly evolving paraparesis and/or sensory loss with a demonstrable motor and cord level. Myelopathy is less common []

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than cerebral infarction, but has a similar pathoetiology and is particularly devastating because it destroys motor function and grossly impairs function and mobility, la Vasculitis and thrombosis are the most common etiologies. Transverse myelitis must be practically differentiated from multiple sclerosis, epidural abscess, cervical instability, and other cord syndromes. Movement Disorders. Movement disorders are characterized by irregular, involuntary, and jerky m o v e m e n t s that m a y involve any portion of the body in a random sequence [choreal, and may be a result of cerebral infarction. On the other hand, rapidly reversible m o v e m e n t disorders are commonly associated with focal cerebral edema and acute seizures induced by v e r y small infarcts or acute breakdown of blood-brain barrier associated with increased systemic disease activity. Movement disorders may also be related to infarction or edema of distinct nuclei, resulting in choreiform movements, cerebellar ataxia, Parkinsonian movements, tremor, or hemiballismus. Thus, movement disorders resulting from NPSLE must be differentiated from primary movement disorders or those associated with drugs, infections, or toxic exposures. Seizure Disorders. Seizures are a common manifestation of major NPSLE and can be classified as primary generalized seizures (bilaterally symmetrical and w i t h o u t local onset) or partial or focal seizures (Jacksonian, temporal lobe, psychomotor, and other). Primary generalized seizures include tonic-clonic, grand mal, tonic, clonic, atonic, astatic, absence {petit mall, myoclonic. Although conside r a b l e c r o s s o v e r exists, p r i m a r y g e n e r a l i z e d seizures are most commonly associated with diffuse injury to the brain, suggestive of acute cerebral e d e m a , hypoxia, or i s c h e m i a . 7 Partial or focal seizures include simple seizures {without loss of consciousness) and complex seizures {with partial loss of consciousness), as well as secondary generalized tonic-clonic seizures. Partial or focal seizures are often associated with focal lesions, especially active or previous infarct, hemorrhage, vasculitis, or brain abscess. Epilepsy {chronically recurrent seizures occurring in a stereotypic pattern I is common in SLE patients, particularly those with prior cerebral infarction associated with the antiphospholipid syndrome, and requires special attention by the clinician. Thus, in SLE patients with idiopathic seizures, active NPSLE, infarct, abscess, hemorrhage, and antiphospholipid s y n d r o m e should be excluded w i t h appropriate determination of SLE activity as well as cranial imaging (MRI or computed tomography [CT]), cere-

brospinal fluid analysis, and, in selected patients, electroencephalogram. Cognitive Dysfunction. Impaired neurocognitive function is common in NPSLE and has been broadly divided into minor or major deficits in global intellectual function or deficits in specific functions, either of which could be active or inactive, reversible or irreversible. 14,1~Memory, word finding, attention, intelligence, p r o b l e m solving, and m o t o r s p e e d are commonly affected, although there is no specific neuropsychological profile that is characteristic of NPSLE. Referral for neurocognitive testing may be useful to characterize individual cognitive impairment, as well as to track the course and measure functional changes in disease presentation over time. Reversible impairments in cognitive function are usually a manifestation of active NPSLE, while irreversible impairments are associated with the acute and chronic effects of active SLE or, more specifically, the cumulative effects of a few or m a n y focal lesions, particularly in stroke syndromes resulting from antiphospholipid antibodies, hemorrhage, or vasculitis. Dementia is the endstage, irreversible form of impaired neurocognitive function, usually resulting in severe disability, and often precipitating aggressive t h e r a p y and highly supervised care. Dementia in SLE is most often caused by multiinfarct injury associated with the antiphospholipid antibody syndrome (chronic multifocal diseasel. Psychosis, Acute C o n f u s i o n a l State, a n d M o o d a n d A n x i e t y D i s o r d e r s . D i s o r d e r s of t h o u g h t , a t t e n t i o n , and m o o d are c o m m o n in NPSLE. In the past, they have often been classified together under the category of "lupus psychosis," although this is practice is imprecise and inaccurate. Psychosis is not infrequent in NPSLE; it is defined by a severe disturbance in the perception of reality, characterized primarily by delusions and/or hallucinations, often accompanied by disorganized thinking, bizarre ideation, paranoia, or other schizophrenic-like symptoms. Acute confusional state (delirium I is one of the most common manifestations of active NPSLE, and is to be distinguished from psychosis. An acute confusional state is characterized by disturbance of consciousness or level of arousal, including a reduced ability to focus, maintain, or shift attention, and is often accompanied by disturbances of cognition, mood, affect, and behavior developing over hours or days and fluctuating throughout the day. These confusional states include hyper- and hypo-arousal states ranging from delirium to coma. When confusional symptoms progress to somnolence, stupor, or frank coma, the prognosis for survival is poor.

Mood disorders in SLE are also c o m m o n and include major depressive-like episodes, and mood disorder with depressive, manic, or mixed features. Anxiety disorders, including generalized anxiety, panic disorder, panic attacks, and obsessive-compulsive disorders, can occur in SLE and are characterized by a n t i c i p a t i o n of d a n g e r or m i s f o r t u n e accompanied by apprehension, dysphoria, or tension. All the above disorders may be a result of prim a r y psychiatric, affective, or medical disorders unrelated to SLE, reactive disorders secondary to chronic illness, or to NPSLE itself. Other psychiatric disorders, including phobia and myriad minor disorders, also have been noted. Headache. Headache is a difficult diagnostic problem in NPSLE and can represent either a minor manifestation of SLE or serious pathology with potentially fatal consequences. 1 The headache of SLE may be migrainous or nonmigrainous, persistent or intermittent, and responsive or unresponsive to pharmacologic interventions. Classification of h e a d a c h e in NPSLE includes migraine (with or without aura}, tension headache (episodic tensiontype headache}, cluster headache, headache from intracranial h y p e r t e n s i o n (pseudotumor cerebri, benign intracranial hypertension}, and nonspecific intractable headache. True migraine headaches are c o m m o n in SLE, and tend to be severe. However, there is little to suggest that headache is associated with a poorer o u t c o m e or t h a t it r e s u l t s in i n c r e a s e d b r a i n injury16; thus headache should not be used as a surrogate marker for SLE or NPSLE activity. An aggressive t h e r a p e u t i c a p p r o a c h , especially one that e m p l o y s high-dose corticosteroids or cytotoxic agents, is probably not indicated unless other markers of severe SLE disease activity are manifested. With this in mind, it should be noted that an incorrect diagnosis, particularly the failure to detect infection or other secondary causes of headache, could be fatal ITable 1). Thus, lumbar puncture should be considered early if the headache is atypical or persistent. Secondary headache in SLE may be caused by brain abscess, infectious meningitis, nonsteroidal anti-inflammatory drugs INSAIDsJ, antimalarial therapy, cerebral venous thrombosis, hypertension, disease of the sinuses, s u b a r a c h n o i d h e m o r r h a g e , intracerebral hemorrhage, or subdural hematoma. Sterile meningitis is a specific cause of headache that is typically unrelenting, and may be primary or related to NSAIDs. Pseudotumor cerebri and aseptic meningitis may also induce unrelenting headache in SLE. Primary and secondary headaches in NPSLE are difficult to separate in terms of character or COMPTHER. 1999;25(4)

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Confounding Neurologic Disease in SLE

Infection 9 Meningitis {bacterial, fungal, viral, parasitic) 9 Abscess {bacterial, fungal, parasitic) 9 Posterior leukoencephalopathy 9 Systemic infection resulting in delirium Medications 9 Psychotropic drugs (confusion, movement disorders, somnolence) 9 Hydroxychloroquine {headache, dizziness, nervousness, neuromyopathy) 9 NSAID {aseptic meningitis, headaches, dizziness, dysphoria, depression) 9 Azathioprine {aseptic meningitis, cerebral lymphoma) 9 Corticosteroids {depression, mania, nervousness, confusion, psychosis) 9 Anticonvulsants (confusion, movement disorders, somnolence) Fluid/Metabolic Disease 9 Uremia 9 Electrolyte imbalance 9 Dehydration 9 Hypoxia 9 Thyroid disease 9 Malignant hypertension 9 Toxemia of pregnancy Primary Neurologic Diseases 9 Idiopathic epilepsy 9 Hyperpyrexia 9 Multiple sclerosis 9 Antiphospholipid syndrome 9 Other stroke syndromes 9 Central nervous system tumor 9 Migraine 9 Dementia of other causes Primary Psychiatric Disease 9 Manic-depressive illness 9 Schizophrenia 9 Undifferentiated psychosis 9 Anxiety syndromes 9 Obsessive-compulsive disorder

COMPTHER.1999;25(4)

d u r a t i o n and m a y r e q u i r e n e u r o i m a g i n g , cerebrospinal analysis, or removal of medications to exclude causes not directly related to NPSLE or disease activity.

PERIPHERAL NPSLE Peripheral manifestations of NPSLE include myasthenia gravis and peripheral neuropathy, both of w h i c h can be c o n f i r m e d by e l e c t r o m y o g r a p h y . Peripheral neuropathy can be further subdivided into acute inflammatory demyelinating polyneuropathy (Guillain-Barre), mononeuropathy (single/multiplex), plexopathy, peripheral cranial neuropathy, peripheral autonomic disorder, and polyneuropathy. Minor peripheral symptoms can include subjective weakness, paresthesias, spasms, or dysesthesias not documented by neurophysiologic evaluation. Peripheral manifestations of NPSLE, particularly if acute, may be a result of small-vessel vasculitis.

PATHOLOGY AND ETIOLOGY OF NPSLE Despite the dramatic neurologic manifestations, the histopathologic findings of NPSLE are generally minimal, with normal brain and nonspecific changes predominating. 4,~7 Bland vasculopathy-characterized by vascular hyalinization, vessel tortuosity, endothelial proliferation, and perivascular gliosis--is common, but represents a nonspecific finding. Perivascular cuffing with i n f l a m m a t o r y cells may occur, but true vasculitis is rare. Autopsy studies occasionally demonstrate cortical atrophy, gross infarcts, gross h e m o r r h a g e , m i c r o h e m o r rhages, ischemic demyelination, and multiple sclerosis-like demyelination. Fatal NPSLE has been associated with complement-consumption, leukostasis, leukoaggregation, ischemia, and extensive cortical microinfarcts, indicating acute immune-mediated vascular occlusion. TM However, despite the w i d e variety of potential histopathologic findings, none are diagnostic for NPSLE. The poor correlation b e t w e e n pathologic findings and neurologic dysfunction in the majority of NPSLE patients suggests a potent physiologic or neurometabolic aspect to the disease that is not reflected in histopathology. Potential mechanisms of cerebral injury associated with specific forms of NPSLE are noted in Table 2.

DIAGNOSTIC TESTING IN NPSLE Neurocognifive Testing. No single clinical finding or diagnostic test is p a t h o g n o m o n i c for NPSLE; thus, diagnosis of NPSLE rests primarily on clinical history and physical examination with supportive evidence from selected testing. TM Neurocognitive

Potential Pathogenic Mechanismsof NPSLE Focal Injury Cerebral infarction

Possible Mechanisms 9 Large-vessel cerebrovascular occlusion 9 Thrombosis 9 Antiphospholipid antibodies 9 Cardiac emboli 9 Large- or medium-vessel vasculitis

Small infarct

9 Small-vessel cerebrovascular occlusion 9 Thrombosis 9 Platelet thrombi 9 Leukoagglutination 9 Small-vessel vasculitis

Focal edema

9 Focal infarct or ischemia 9 Breakdown of blood-brain barrier 9 Endothelial injury 9 Antiphospholipid antibodies 9 Circulating cytokines 9 Anaphylatoxins 9 Vasculitis

Hemorrhage

9 Vasculitis with vascular rupture 9 Infarct with secondary hemorrhage 9 Abscess with secondary hemorrhage

Diffuse Injury Diffuse cerebral edema

9 Breakdown of blood-brain barrier 9 Diffuse ischemia 9 Diffuse cytokine injury 9 Diffuse injury from antineuronal antibodies

Generalized seizures

9 Diffuse and focal cerebral edema 9 Antineuronal antibodies 9 Neuroexcitotoxins 9 Ischemia or infarction

Psychosis

9 Diffuse cerebral edema 9 Antiribosomal P antibodies 9 Neuroexcitotoxins

testing, although not specific for NPSLE, is often abnormal and has been used to determine the presence of acute and chronic cognitive dysfunction and the response of such to therapy. 14 However, neurocognitive testing is useful for research studies and for objective d e t e r m i n a t i o n of disability in SLE patients. Recent studies have s h o w n substantial relationships b e t w e e n neurocognitive functioning and neuronal metabolic functioning using magnetic resonance spectroscopy, z0,zl The main disadvantages of formal neurocognitive testing in diagnosis of NPSLE are related to the insensitivity in differentiating new from old defects, the increased prevalence of neurocognitive defects in all SLE patients regardless of NPSLE activity, the time and expense of the procedure, and the difficulty of performing neurocognitive testing in very ill patients. Is Moreover, in active major NPSLE, the gross neurologic changes are usually obvious with simple neurologic screening. In minor NPSLE, neurocognitive testing m a y be of greater utility, but minor NPSLE is not generally associated with a poorer o u t c o m e and m a y not d e m a n d extensive evaluation acutely. Imaging and N e u r o p h y s i o l o g i c Studies. It should be recognized that noninvasive diagnostic techniques may be normal or nonspecific even in the presence of florid NPSLE. Thus, the limitations of all imaging modalities should be recognized and accepted by the clinician. Nonetheless, CT and MRI are useful for excluding brain abscess, intracerebral hemorrhage, gross cerebral edema, and cerebral infarction, and for determining the degree of diffuse, chronic brain injury (cerebral atrophy). MRI is generally superior to CT for determining specific forms of chronic brain injury in NPSLE, especially small focal lesions, diffuse white-matter changes, and periventricular white-matter abnormalitiesZZ; however, these changes are usually chronic and should not be misinterpreted as indicating active disease. MRI is especially superior to CT in detecting acute brain injury, including transverse myelitis, focal edema, diffuse edema, recent infarct, and focal or multifocal b r e a k d o w n of the blood-brain barrier. When present, these changes indicate active major NPSLE. Magnetic resonance spectroscopy is an extremely sensitive measure of brain injury in NPSLE, but has difficulty differentiating established from new injury.z3, z4 Magnetic resonance relaxometry is exquisitely sensitive to active NPSLE; however, b e c a u s e of n o n s t a n d a r d i z a t i o n and lack of availability, it remains a research technique.Z. 2s Positron emission tomography (PET) and singlephoton emission computed tomography (SPECT) are COMPTHEe. 1999;25(4)

frequently employed for determining NPSLE activity and may demonstrate focal or multifocal defects in cerebral perfusion, glucose metabolism, or oxygen uptake. To be interpretable, these radionuclide techniques usually must be combined with MRI, CT, or previous radionuclide scans to determine activity. Unfortunately, PET and SPECT, although important research tools, are severely hampered by nonspecificity, the high prevalence of defects in inactive NPSLE, and the frequent inability to distinguish new from old defects. Thus, radionuclide techniques cannot be regarded as reliable techniques to diagnose NPSLE in the acute setting, although the demonstration of reversible changes may be supportive of the post hoc diagnosis of NPSLE. 26 Electroencephalography is useful to determine seizure activity, encephalopathy, or brain death in SLE; however, it is unreliable to specifically diagnose NPSLE or differentiate NPSLE from other central nervous system diseases. Consequently, conventional neuroimaging techniques are not reliable diagnostic modalities for NPSLE. Therefore, it is not recommended that a particular imaging technique in the acute setting be ordered to "rule out NPSLE." Rather, these techniques should be employed to exclude brain abscess and hemorrhage, identify infarct, determine the focus of seizure activity in the setting of suspected epilepsy or acute seizure disorder, and determine whether there is cerebral edema or breakdown in the blood-brain barrier. MRI and magnetic resonance spectroscopy in combination with neurocognitive testing may have special utility to determine the presentation, course, and outcome of cumulative chronic brain injury, n,z3 which may be important for the determination of long-term therapy. A u t o a n t i b o d y Testing. NPSLE has been associated with autoantibodies reactive to neuronal antigens and p h o s p h o l i p i d s c o m m o n to m a n y cell m e m b r a n e s and circulating m a c r o m o l e c u l e s . 17 Antiribosomal P antibodies have been associated with psychosis, antineurofilament, and antineuronal antibodies with diffuse neurologic presentations, and anticardiolipin antibodies with stroke, epilepsy, and focal neurologic deficits. 1,27,28 Autoantibodies reactive with brain may have direct pathologic effects; however, it is also possible that these antibodies are not pathogenic, but are merely a host response to the primary lesion of NPSLE. Thus, the role of autoantibodies in the diagnosis of NPSLE remains controversial, aT However, in a patient with stroke or multi-infarct dementia, the presence of antiphospholipid antibodies may be critical. To screen for these antibodies, []

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prothrombin time {PT), partial thromboplastin time (PTT), international normalized ratio (INR), rapid plasma reagin (RPR) dilute Russel Viper Venom assay, or other lupus anticoagulant test should be performed as well as antiphospholipid (anticardiolipin) a n t i b o d i e s (IgG, IgM). 1,9 If s t r o k e has occurred and these antibodies are present, full anticoagulation acutely with heparin and chronically with warfarin must be considered, recognizing the risk for recurrent stroke without therapy and intracerebral hemorrhage with therapy. The role of other autoantibodies in the diagnosis of NPSLE is controversial. At present, antiribosomal P, antineuronal, and antineurofilament antibodies are not considered diagnostic of NPSLE (although they may be supportive of this diagnosis) and should be regarded as research measurements with uncertain clinical relevance, z7,29,3~

DIAGNOSTIC AND THERAPEUTIC APPROACH TO NPSLE NPSLE r e m a i n s a difficult diagnostic p r o b l e m requiring careful and comprehensive attention by the clinician. Neurologic complaints in an SLE patient can represent minor symptoms of no longterm consequence, or could indicate serious drug effects, confounding neurologic disorders, systemic sepsis, central nervous system infection, or lifethreatening NPSLE. 1,28,3~ Common avoidable diagnostic errors include failure to consider infection, to recognize the antiphospholipid syndrome, or to confirm the presence of SLE; the overtreatment of minor symptoms lespecially headache and minor cognitive dysfunction); and the undertreatment of major NPSLE. 14,3~ All too often, patients with cerebral infarct and antiphospholipid syndrome are misdiagnosed with central nervous system vasculitis and are insufficiently treated with immunosuppression alone, rather than with the primary therapy of anticoagulation. Because SLE patients are at increased risk for complications from both lupus-related and nonlupus-related neurologic disease, the SLE patient with neuropsychiatric complaints requires a comprehensive diagnostic approach. One such approach is shown in Figure 2. First, it must be confirmed that the patient indeed has SLE and not some other disorder. Thus, the patient should fulfill the American College of Rheumatology criteria for SLE.6 Next, a careful history with specific attention to prior neurologic and psychiatric disease, strokes, the use of psychotropic medications, drug abuse, cardiac disease, and symptoms of infection should be taken. A compulsive medical evaluation must be performed

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IMRI or CT, ~ ~ s i~ec Cultures, Urinalysis tion Appropriate Antibiotics and Drainage Metabolic Evaluation #'[present? I l Chest X-ray CSF Analysis C3. C4_ anti-DNA lAte the symptoms related to drugs ~ S t o p offending drug and [or metabolic disorders? .,, F ~ x~ F'~correct metabolic disorder I /

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Is significant systemic SLE disease activity present?

,, Is Stroke or Transverse ~ Myelitis Present? ~ (by MRI or CT)

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~ 1 ) Aspirin 81 mg/d ] Carotid Doppler, Radiocontr~t HAntiphospholipid Syndrome 2) Heparin Initially [ or MR Angiography, Ech~ardio3) Warfarin (INR > 3] graphy, Hypercoagulopathy Panel Cardiac Lesion %]1) Prednisone 1-2mg/kg/d 22 Consider Cyelophosphamide

Iwcuhtis I Is there evidence of blood-brain barrier [ breakdown or cerebral edema on MRI or [ ICS1 ~ analysis? .... I

lis disorder primarily pyschiatric?

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IPrednisonex-2m g,d I Consider Cyclophosphamide 9dTrial of 1) a_ntidepressants,2) andpyschotic ~drugs, and/or 3) low dose prednisone

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Reconsider Diagnosis Consider Cyclophosphamide [ Figure 2.--Evaluation of the SLE patient with neuropsychiatric manifestations. with special attention for physical evidence of SLE disease activity, infection, metabolic disturbance, and neurologic disease. The neurologic complaints must be characterized, and then be classified as major or minor. Major symptoms should be considered a medical emergency and should be evaluated rapidly and treated accordingly. Minor symptoms can u s u a l l y be t r e a t e d s y m p t o m a t i c a l l y and

observed or measured for progression or intractability, at which time they can be further evaluated. The first step in evaluating a patient with major NPSLE or intractable minor NPSLE is to exclude systemic or central nervous system infection, intracerebral hemorrhage, gross cerebral edema, and cerebral infarct. Thus, blood, urine, and sputum should be cultured as indicated. Subsequently, a COMPTHER.1999;25(4)

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cranial CT or preferably a cranial MRI should be performed. If focal lesions are present, contrast should be administered to determine activity, acuity, and blood-brain barrier integrity. W h e n lesions are present, the imaging results should be combined with neurologic and/or neurocognitive examination to determine if this lesion most probably represents edema or infarct. A lumbar puncture should then be performed to further exclude infection; however, if a mass effect is present from brain abscess, intracerebral hemorrhage, massive infarct, or diffuse cerebral edema, either a cisternal puncture or no puncture should be considered, depending on the risk of herniation. In addition to culture for bacteria, fungi, and mycobacteria as indicated, samples should be sent for cryptococcal antigen, cell count, differential, glucose, and protein. Samples should be saved for possible viral studies. C e r e b r o s p i n a l fluid also should be sent for demyelinating evaluation, including total IgG, albumin, myelin basic protein, and oligoclonal bands. Breakdown of the blood-brain barrier, the presence of intrathecal IgG synthesis, oligoclonal bands, or the presence of myelin basic p r o t e i n can be s u p p o r t i v e of the diagnosis of NPSLE, although multiple sclerosis and central nervous system infections must also be considered. For these latter studies, a paired serum sample for IgG and albumin must also be obtained. Cerebrospinal fluid and serum antineuronal, antineurofilament, and antiribosomal P antibodies can be obtained at this point as well and m a y be supportive of the diagnosis; however, they are of unproven diagnostic value and the results are usually not available for timely therapeutic decision making. Once infection is excluded, major NPSLE can be broadly classified as that related to infarct and that not related to infarct. Cerebral infarct in SLE has devastating consequences and should be aggressively evaluated and treated. Multi-infarct dementia and transverse myelitis should be evaluated identically to cerebral infarct, with appropriate modification of the imaging procedure. Cerebral infarct in SLE can be divided into 5 main groups: (1) idiopathic, (2) antiphospholipid antibody s y n d r o m e , (3) embolism from cardiac source, (4) vasculitis, or (5) increased systemic disease activity. Thus, w h e n cerebral infarct is present, evaluation for antiphospholipid antibodies, valvular abnormalities, evidence of vasculitis, and SLE disease activity should be undertaken. Evaluation for active SLE should be taken immediately with appropriate testing, including C3, C4, anti-DNA, CBC, urinalysis, and physical examina-

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tion. Valvular abnormalities require an echocardiogram. If vasculitis is not obvious p e r i p h e r a l l y , carotid Doppler studies and cerebral angiogram can be considered, although these tests are of low yield except in the presence of large- or medium-vessel vasculitis (lupus vasculitis that resembles Takayasu's arteritis or polyarteritis nodosa). If antiphospholipid antibodies or a noninfected cardiac source are identified, chronic anticoagulation with warfarin (INR 3 or greater) should be considered. If increased SLE disease activity or vasculitis (skin, central nervous system, gut, carotids) are present, high-dose corticosteroids (1-2 mg/kg/day) and pulse c y c l o p h o s p h a m i d e (0.5-1 m g / k g / m o n t h ) s h o u l d be c o n s i d e r e d . If the p a t i e n t has both antiphospholipid antibodies and increased disease activity or vasculitis, then both anticoagulation and immunosuppression should be considered. Major NPSLE not related to infarct can be classified as psychosis, acute confusional states, movement disorders, severe headache, and mood disorders--all of which are potentially reversible. T h e s e d i s o r d e r s are o f t e n c h a r a c t e r i z e d b y reversible abnormalities seen on neurocognitive testing, MRI, e l e c t r o e n c e p h a l o g r a m , PET, and SPECT. The pathology of these disorders m a y be due to autoantibodies or vascular injury, resulting in cerebral edema presumably due to breakdown of the blood-brain barrier. Gross blood brain-barrier breakdown can be confirmed by contrasted MRI or CT and more subtle blood-brain barrier b r e a k d o w n by cerebrospinal fluid analysis. In the absence of infarct, antiphospholipid antibodies are not particularly useful in evaluating these patients. Chronic major depression, anxiety syndromes, obsessive-compulsive disorders, and mania may respond to appropriate antidepressants, tranquilizers, and antipsychotic drugs, obviating the need for aggressive corticosteroid therapy. However, because breakdown of the blood-brain barrier is likely to occur as a result of increased systemic disease activity, SLE disease activity should be determined in all patients as described above. If patients demonstrate blood-brain barrier breakdown or increased systemic disease activity, the first therapeutic option for non-infarct NPSLE is high-dose corticosteroids (1-2 mg/kg/day). If neurologic symptoms are serious, do not respond to high-dose prednisone, and infection has been definitely excluded, then high-dose dexamethasone can be used (12-20 mg/day). If systemic disease activity is present or major episodes of NPSLE become recurrent and not responsive to more conservative therapy, cyclophosphamide (0.5-1 mg/kg/month)can be considered.

The approach to minor NPSLE symptoms, especially headache, is necessarily more cautious. Symptomatic treatment with analgesics, psychotropic medications, and psychologic support with careful observation for neurologic progression is the best initial approach. 1,19 However, with any atypical features, headache persistence, or neurologic progression, early CT or MRI and (where available) magnetic resonance spectroscopy and magnetic resonance relaxometry should be performed with a subsequent lumbar puncture to exclude infection, inflammation, and brain edema. 1,7,11 Corticosteroid and immunosuppressive therapy for minor NPSLE, including headaches, should always be justified by other measures of disease activity. 16

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CONCLUSION NPSLE is a treacherous disease in which an ill-considered or simplistic approach can be fatal for the patient and disastrous for the physician. The wide array of physical and behavioral manifestations of NPSLE necessitate considerable clinical judgment, selected application of imaging and laboratory modalities, and careful consideration and consultation before therapy to avoid misdiagnosis and inappropriate over- or undertreatment. The physician must recognize that the initial diagnosis in these patients is often incorrect, and the clinician must therefore remain vigilant to react appropriately with further studies and consultation if the patient is not improving. However, despite the recognized difficulties in diagnosis, the neurologic complications of NPSLE can be approached in a careful, logical manner with gratifying results. CT

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