Summary Highlights and Future Directions

PATRICIA M. MOORE" Deparhnent of Neurology

Wayne State University School of Medicine 4201 St. Antoine

Detroit, Michigan 48201

The multidisciplinary meeting on NP-SLE met and exceeded expectations of providing a venue for discussing current information, revealing persuasive new data and drawing upon relevant advances in neuroscience to stimulate fresh approaches to the evaluation, diagnosis, and therapy of patients with neurologic, behavioral, and psychiatric mani- festations of SLE. Papers from the original speakers, several invited reviews, and selected poster papers are presented in this volume of the Annals. Although all of the presentations were excellent, I will review those that were particularly intriguing or that provide potentially fruitful directions for research.

In the session on cerebrovascular disease in NP-SLE, we asked the questions, What is the evidence that tissue ischemia is a prominent mechanism of the clinical abnormalities in NP-SLE, and, if present, how do we detect it in patients? Although we cannot currently provide definitive answers, a great deal of useful information issued from discussions of two models of ischemia: focal and global. CNS vascular diseases segregate clinically and pathogenically into medium and larger vessel occlu- sions, and pathologic involvement of the microvascular bed. In both experimental studies and human disease, there are distinctions in the clinical presentation, regional localization of cell loss, vulnerability of cells, and the potential for recovery. As Dr. Welch indicated, ischemia from occlusion of large vessels differs in a number of important ways from local or diffuse changes in the microvasculature. Cerebral vessel occlusions usually present with neurologic abnormalities in the distribution of an individual artery. The enduring consequences to the injured tissue depend upon the core changes in K' efflux, Caz+ influx, membrane depolarization, and shifts in cellular water. Acidosis, glutamate release from presynaptic neurons as they depolarize, and further Ca2+ entry into cells are critical factors in initiating irreversible cell death. Newer imaging techniques help us to discern, in vivo, the changes in energy produc- tion, accumulation of lactate, and the subsequent diffusion of water that occurs in the evolution of stroke.

Global ischemia, on the other hand, typically results from a cessation of all flow, such as occurs in cardiac arrest. The histopathologic features differ from focal ischemia largely in the selective vulnerability of the gray matter, including specific sensitivity of neurons in the hippocampus, basal ganglia, and cerebellum. Several investigators commented that although this phenomenon is unusual in SLE, diffuse changes in the

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microvascular bed may initiate a similar pattern of ischemic damage. Dr. del Zoppo explained the unique position of the microvasculature at the interface of brain tissue, inflammatory, and coagulation systems. Normal neuronal function, maintained by metabolic machinery relying on the delivery of nutrients by the microvasculature, is maintained above a critical threshold of blood flow. A coordinated expression of inducible cell membrane adhesion receptors, endothelial cell permeability changes, cytokine expression, activation of leukocytes and platelets, and alterations in micro- vascular structure occurs rapidly. The temporal and spatial expression of receptors is central to the rapid transition from ischemia to inflammation. Prothrombotic events ensuing from the blood elements in primates (platelet-activating factor) and in brain tissue (tissue factor), and induced expression of adhesion molecules by the endothelial cells recruit leukocytes to the injury region. Critical changes in blood flow rapidly induce a cascade of inflammatory and coagulation mediators, increased permeability of endothelium, and exposure of blood elements to tissue parenchyma. Given the dependence of blood flow within the microvasculature on the needs of the tissue, the changes in blood flow itself are not indicative of vascular disease. Given that the microvasculature adjusts its flow in response to the metabolic needs of the tissue, occlusions in the microvascular bed cannot be distinguished from diminished cellular needs secondary to energy failure or local inflammation. Thus, we cannot yet extricate the primary ischemia from a cascade of secondary events in the tissue pathology. The analogy between global ischemia and microvascular disease is, however, not complete, but the shared features should stimulate further work. An in vitro study by Dr. Hsu of the effects of persistent inflammation on the longevity and mode of cell death in cultured endothelial cells (apoptosis analogized to a Scandinavian suicide, as contrasted with necrosis, a Mediterranean murder) provides another potential area to modify ischemia. Clinically, microvascular disease may not present as recognizable strokes but rather as increased vulnerability to other forms of injury, slowly progressive loss of function, or transient neurologic abnormalities, including encephalopathy.

Turning to the histologic events in patients with NP-SLE, Dr. Hess reiterated that, in several postmortem series, histologic evidence of vasculitis is a rare event in the brain. Similarly, immune complex deposition is unusual in the cerebral vessels, probably because of the absence of fenestrated endothelium. By contrast, microvascu- lar occlusions and platelet thrombi appeared relatively often. Although these occlu- sions could be a perimortem event, the presence of perivascular microglia may be a footprint of prior microhemorrhage or previous inflammation. Local, noncomplement- dependent vascular inflammation, such as occurs in the Shwartzman reaction, could explain some of the observed phenomena. In the reviews of the murine models of SLE by Dr. Brey and Dr. Vogelweid, there is histologic evidence of meningeal inflammation and some perivascular immunoglobulin deposition but very rare reports of tissue infarction.

Detection of tissue changes associated with ischemia in human disease is the province of neuroimaging studies. Advances and limitations of the studies are detailed in the presentations by Drs. Welch and Weiner. Both agree that traditional MRI using Tp-weighted images (T2WI) often used for detection of stroke, do correlate with the size of the infarct in experimental models and autopsy studies of human stroke but lack specificity for ischemia. Spontaneously reversible changes in intensity of T2WI occur with other processes altering the diffusion of water, such as recurrent membrane

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depolarization in clinical seizures. Dr. Welch described how the clinical detection of cerebral ischemia is evolving as more precise tools for correlating the effects of blood flow, tissue energy requirements, and water diffusion pathways become avail- able. Welch reviewed the correlations of animal models of focal ischemia with MRI imaging, serial T2-weighted images, diffusion imaging, and proton and phosphorous spectroscopy. Dr. Welch emphasized that newer tools, including diffusion-weighted imaging, allow detection of changes in the apparent diffusion coefficient of water (ADC), a rapidly occurring feature, which, when used in conjunction with T2WI and MR spectroscopy, permits detection of several signatures that correlate well with histologic and recovery data in patients.

Dr. Weiner reviewed the various neuroimaging studies reported in patients with SLE. He affirmed that PET and SPECT do not accurately measure vascular compo- nents of blood flow, nor do the reductions in flow indicate tissue ischemia unless there is also arterial sampling. In MRI and spectroscopy studies, the questions we ask of the studies and the correlations with clinical findings require careful evaluation. The design and interpretation of studies should include careful assessment and knowl- edge of both the limitations of the technique and appropriate questions in the acutely ill and convalescing patient.

In the neuroendocrine section, discussion focused on the dually protective and harmful effects of hormones and cytokines released in response to chronic inflamma- tion as well as the hypothalamic responses to persistent stressful stimuli in vivo and in vitro. Dr. McEwen opened the section with a presentation of the effects of endogenous glucocorticoids (corticosterone in the rodent, cortisol in the human) on the structure and function of hippocampal neurons. Although glucocorticoids are critical for the development of the brain, chronically elevated levels of corticosterone, such as occur in chronic stress, mediate permanent changes in certain aspects of learning and in hippocampal architecture. Although we are limited by the absence of firm information on the passage of two pharmacological preparations, dexamethasone and prednisone, into the human CNS parenchyma, studies by Wolkowitz, and affirmed by Keenan, revealed that corticosteroid preparations can induce profound changes in memory and mood in normal subjects as well as in patients. Upon questioning that a cited study suggested that corticosteroids may improve cognition in patients with SLE, Dr. McEwen responded that some regimens of systemic glucocorticoid therapy may induce a deficiency of glucocorticoids in the CNS. Adequate evaluation of studies claiming improved cognition with prednisone needs careful assessment for the poten- tial that therapy may reflect correction of an iatrogenic cognitive abnormality. Thus, the potential of serious consequences of glucocorticoid therapy on hippocampal function and the paucity of information on access of glucocorticoids to the CNS assigns us the critical task of initiating studies to carefully monitor the efficacy and complications of corticosteroid therapy in patients. Clearly, further information on the effects of corticosteroid therapy on the CNS in patients with SLE is necessary for clinicians to evaluate the benefits and risks of acute and chronic therapy.

Dr. Kelly discussed the production of IL-1 within the CNS and the pleotropic effects of IL-1 as a coordinator of critical body functions. CNS production of IL- 1 results from various stimuli, including seizures, immobilization stress, forebrain ischemia, brain injury, and infections. Centrally administered IL-1 is much more potent than peripheral IL-1 in its role as a mediator of sickness behavior, such as

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malaise, fatigue, listlessness, and the inability to concentrate. The presence of L-1 receptors in the hippocampus and choroid plexus provides additional evidence that IL-1 acts upon brain cells. The striking role of IL-1 as an initial communicator between the brain and immune system was emphasized with data revealing the role of the vagal afferents as a link between the abdominal cavity and brain. This information provides further incentive to explore the role of CNS IL-1 in SLE.

Expanding the role of the brain as a prominent modulator and responder in systemic inflammation, Dr. Harbuz focused upon the temporal changes in expression of hypothalamic secretagogues in a model of an autoimmune disease, adjuvant arthri- tis. In response to systemic inflammation and often mediated by 1L-1, corticotropin- releasing hormone (CRH) is expressed and secreted by the hypothalamus, functioning, largely, to stimulate pituitary secretion of ACTH. Activation of the hypothalamic- pituitary-adrenal (HPA) axis stimulates production of corticosterone that serves to downregulate inflammation at multiple sites in the periphery and central nervous system. In chronic inflammation, persistently elevated corticosterone levels occur. One would anticipate that this is mediated by high levels of CRH expression and production. Paradoxically, the investigators observed that, in the adjuvant arthritis model, initially elevated CRH expression declined over time. Further data revealed that arginine vasopressin (AVP) expression increased. This suggested that the AVP assumes the role of major stimulator of the HPA axis and functions in the adaptation of the HPA axis to chronic inflammatory stress. It appears that this allows the HPA axis to respond to acute stressors even in the setting of chronic stress. They found a similar development in animal models of demyelination and infection. The potential relevance of this to acute and chronic mechanisms of neuronal injury in SLE emerged with the presentation by Dr. Nola Shanks that a similar CRWAVP switch occurred in M l W l p r mice, one of the murine models of SLE. As an editor’s aside, evidence that both CRH and AVP alter aspects of behavior in experimental animals warrants further study.

Dr. Grossman reviewed some of the integrative and regulatory mechanisms of the HPA axis, exploring the idea that the prevailing level of corticosteroid activation sets the threshold for inflammatory processes, varying the signal-to-noise ratio for any given inflammatory locus according to systemic requirements. Further, he ex- plained the role of the hypothalamus as an integrator of the vascular and inflammatory systems, thus opening a pertinent topic in NP-SLE. In local inflammation, the increases in capillary permeability and arteriolar vasodilatation are essential for monocytic diapedesis. However, widespread vasodilatation could lead to a loss of vascular integrity, compromising the regulation of blood pressure. The hypothalamus, acting as a general regulator, subsumes local processes to a central control in order to maintain vital functions. Further, the observations that vasoconstrictor agents stimulated the release of CRH or AVP while vasodilatory agents had the opposite results motivated a series of experiments investigating the effects of the vasodilator, nitric oxide (NO), on CRH release from cultured hypothalamic cells. The observed inhibition of CRH release was substantiated by the pharmacological blockade of NO and coincided with their previous observations in vivo.

In the autoantibody section, Dr. Isenberg reviewed the various roles of autoanti- bodies in autoimmune disease. Information on several autoantibodies implicated in NP-SLE was presented by Drs. Harris, Alarc6n Segovia, Elkon, and Moore. Although

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details of the structure, chemistry, and localization of autoantigens become clearer, there is no evidence, as yet, establishing if and how the autoantibodies cause clinical abnormalities in NP-SLE. Nonetheless, autoantibodies remain an area of interest and retain the potential for clinical relevance in NP-SLE as they are increasingly recog- nized to do in other neurologic disorders. Notably, Dr. Volpe commented that accruing information on the delayed results of neuronal injury may be relevant to cerebral dysfunction in SLE. The topic remains under study.

The section entitled “Stress, Stroke, and Seizures” revealed that current methods of identifying clinical NP-SLE remain fraught with disagreements over terminology, study design, and statistical analysis. Dr. Grant presented lessons from longitudinal studies of patients with AIDS dementia, a disease that also affects young, previously healthy adults. Early patchy, transient abnormalities can be detected by clinical histories, carefully designed neuropsychological testing, and clinical outcome mea- sures. Several pertinent suggestions were given from investigators of AIDS dementia, related to neuropsychological testing in the diagnosis of neurocognitive disorders in NP-SLE: (1) Adequate sample size is critical to determine the nature of the abnormali- ties in diseases prior to reducing the extent of testing; ( 2 ) early determination of the purpose of testing (population studies, longitudinal analysis, or therapeutic trials) improves the quality of the collected data; (3) treatment studies require determination of the anticipated effect (such as diagnosis of cognitive impairment, monitoring neurocognitive changes in relation to therapy, or monitoring adverse effects of a neurocognitive nature), and (4) outcome measures are important to confirm the utility of testing results. The consequences of these statements are substantial. For patients and clinicians caring for the patients to accept diagnosis and treatment options, it is critical to recognize and distinguish among neurocognitive abnormalities, mood disorders, and exacerbations of underlying personality traits. Available tools for establishing the clinical relevance of abnormalities apparent on neuropsychological testing are evaluations of work performance, driving skills, and quality of life scales. These, in fact, are good predictors of outcome.

Animals models of disease do provide information regarding behavioral changes associated with disease. A variety of murine strains spontaneously develop a disease with many similarities to human SLE. Although murine behavior is not analogous to human cognition, many of the changes in behavior, learning strategies, and social interactions do provide information for human studies. Dr. Brey reported several studies of learning and behavioral abnormalities in murine models of SLE. Dr. Vogelwied also described results in a series of behaviorally and motorically impaired pathogen-free animals (reducing the likelihood that an infection is responsible for the changes). Both groups, as well as supporting studies from the literature, relate the onset of neurobehavioral disorders to the appearance of autoimmune abnormalities.

Finally, two excellent talks addressed clinical study design, analysis, and plans for therapy. These intellectually rigorous sessions counseled several approaches to devising mals in disorders without currently adequate nomenclature or evidence of immunopathogenesis. Dr. Kunitz emphasized two issues. First, given the often- mentioned problems with the existing criteria for NP-SLE, modification of the current American College of Rheumatology criteria or a companion scale that more fully describes the NP features is crucial. There are several routes to better characterization of the NP aspects of disease. She recommended evaluating the approaches and results

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of several prospective multicentered trials sponsored by the NINCDS, NIH over the past twenty years. In the area of treatment studies, she provided guidelines for selecting outcome measures when the pathogenic mechanisms are not clearly defined. Both Drs. Kunitz and Peck emphasized the critical features of study design. Dr. Peck reviewed some of the history of pharmaceuticals, including the origins in herbal medicines and the prominent role of serendipitous discoveries. Although the strategies of finding new medications are increasingly rational (based on knowledge of underly- ing mechanisms of clinical abnormalities), information on the actual mechanisms of a pharmacological agent often evolves over time and clinical use. Given the enormous costs of development and clinical trials of new medications, successful identification of promising therapies is likely to develop from using currently available medications and cooperation between academic centers investigating disease mechanisms and pharmaceutical companies with the knowledge and experience in effective testing of medications.