LEIDEN, The Netherlands, and SAO PAULO, Brazil—Two newly-published studies may help explain why cognitive and neuropsychiatric changes are so common in patients with systemic lupus erythematosus (SLE).

In the first study, Bart J. Emmer, MD, and colleagues at Leiden University, in The Netherlands, show that the amygdala is selectively damaged in SLE and that the damage is more severe in patients who have autoantibodies against the NMDA receptor (anti-NMDAR).¹ An estimated 30% to 50% of lupus patients have such antibodies.

"[W]e observed more severe changes in patients with SLE with anti-NMDAR antibodies as compared to patients with SLE without anti-NMDAR antibodies, suggesting that these antibodies induce brain damage," Dr. Emmer writes.

In the second study, Simone Appenzeller, MD, and his colleagues at the University of Camapinas, in Sao Paulo, Brazil, show that hippocampal atrophy predicts cognitive impairment in patients with SLE, that it is progressive, and that it is associated with long-term corticosteroid treatment.²

Functional imaging documents amygdala damage

Lupus-related cognitive impairment is progressive and untreatable, although it may sometimes remit. It is not clearly related to underlying disease activity.

Antibodies that cross-react with DNA and with the N-methyl-D-aspartate receptor (NMDAR) can damage or kill neurons. Attempts to correlate presence of these antibodies with measures of psychological function have produced conflicting data. Dr. Emmer's work partly resolves this conflict by documenting a correlation between the presence of the anti-NMDAR antibody and structural damage to the amygdala.

Dr. Emmer's group analyzed diffusion weighted image (DWI) and calculated the apparent diffusion coefficient (ADC), which measures the movement of water molecules. ADC is affected by cellular integrity and reduced by  tissue inflammation, injury, or destruction. Recent studies have shown quantitative correlations between ADC and cognitive impairment in patients with multiple sclerosis.³

The researchers compared imaging and ADCs for 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE and no symptoms attributable to CNS causes, and 12 healthy control subjects.  NP-SLE diagnosis was based on clinical symptoms, most commonly headache (n = 12), cerebrovascular disease (n = 11), seizures (n = 10), cognitive dysfunction (n = 9), and mood disorder (n = 5). Among the 37 patients, 20 had one NP syndrome, 10 had two syndromes, and 7 had three or more syndromes.

The investigators also determined anti-NMDAR antibody status in a subset of 8 patients.

The basic imaging studies showed no differences in forebrain gray or white matter segments in patients with or without SLE, or between the SLE and NP-SLE patients. However, the lupus patients had regional depression of ADC in the hippocampus and amygdala. Mean ADC values showed that the amygdala was significantly more damaged in SLE patients than in controls, regardless of neuropsychiatric involvement.

Four of the 8 SLE patients whose anti-NMDAR antibody status was analyzed were positive for the antibodies, and their amygdala mean ADC values were significantly lower than those for healthy controls. The amygdala and hippocampal mean ADCs were also lower for these four patients than for the four who did not have anti-NMDAR antibodies, but this difference was not statistically significant in this small sample.

Autoantibodies such as anti-NMDAR produced in lupus patients and directly damaging the amygdala would provide the missing link to explain cognitive and other CNS symptoms that arise in the course of the disease.

In an editorial that accompanies the Emmer study, Drs. Betty Diamond and Bruce T. Volpe write, "The regionally specific depressed [function] confined to the hippocampus and amygdala is obviously interesting in view of the high concentration of NMDAR in these regions, and the preliminary studies that show a correlation of depression and cognitive impairment with anti-NMDAR antibodies."⁴ Dr. Diamond is in the department of medicine at Columbia University Medical Center, in New York City. Dr. Volpe is in the department of neurology and neuroscience at Burke Medical Research Institute of the Weill Medical College of Cornell University, in White Plains, New York.

The amygdala damage is viewed as particularly important because of that structure's role in regulating emotions and triggering responses to danger.

"It remains to be determined whether decreased ADC in the context of magnetic resonance structural images that show a normal hippocampus and amygdala represents a marker of neuron stress, as in ischemia, or acute inflammation, as in MS, or both," Drs. Diamond and Volpe write.

MRI shows progressive hippocampal atrophy

In related work, Dr. Appenzeller and colleagues studied 150 SLE patients and 40 healthy volunteers using complete clinical, laboratory, and neurological evaluation as well as magnetic resonance imaging (MRI). They defined atrophy as less than two standard deviations from the mean values of the control group. MRI was reported in 60 patients after a mean follow-up of 19 months.

The investigators report that the hippocampal volumes of SLE patients were significantly smaller than those of controls at baseline (P <.001) and continued to shrink over the 12 to 25 months of follow-up. "At entry, atrophy was identified in 43.9% and at follow-up in 66.7% of patients with SLE. Hippocampal atrophy was related to disease duration (P <.001), total corticosteroid dose (P = .01), and history of central nervous system manifestations (P = .01). Progression of atrophy was associated with cumulative corticosteroid dose (P = .01) and number of CNS events (P = .01)," Dr. Apppenzeller reports.

Hippocampal atrophy was more severe in SLE patients who had cognitive impairment than in those who did not.

"We showed that structural MRI abnormalities may be associated with cognitive dysfunction in patients with SLE and also that hippocampal atrophy is progressive over time. Furthermore, we showed that hippocampal atrophy may be predictive of cognitive impairment in patients with SLE," Dr. Appenzeller concludes.

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References

1. Emmer BJ, van der Grond J, Steup-Beekman GM, et al. Selective involvement of the amygdala in systemic lupus erythematosus. PLoS Med. 2006;3:e49. doi:10.1371/journal.pmed.0030499.
2. Appenzeller S, Carnevalle AD, Li LM, et al. Hippocampal atrophy in systemic lupus erythematosus. Ann Rheum Dis. 2006;65:1585–1589.
3. Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci. 2006;245:111–116.
4. Diamond B, Volpe BT. Antibodies and brain disease: a convergence of immunology and physiology (editorial). PLoS Med. 2006;3:e498. doi:10.1371/journal.pmed.0030498.