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CHaPtEr 51 Systemic Lupus Erythematosus 699

Leukopenia NPSLE Nomenclature
Leukopenia, either neutropenia or lymphopenia, occurs in In 1999 a consensus committee established by the ACR developed
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20–40% of patients. Lymphopenia (lymphocytes <1500/mm ) reporting standards, case definitions, and recommendations for
has a reported prevalence of 15–80%, whereas severe lympho- laboratory and imaging studies for 19 neurological, psychiatric,
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penia (<500/mm ) occurs in 4–10% of SLE patients. The and cognitive syndromes. Diagnosis of NPSLE requires the
prevalence of neutropenia, variably defined in the literature as exclusion of infections, metabolic disturbances, bleeding disorders,
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<1800 to <2500/mm , is 20–40%, whereas severe neutropenia malignancy, and medication toxicities. Using this nomenclature,
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(<1000/mm ) is rare (1–4% prevalence). Both neutropenia and NPSLE is common overall, with a prevalence of 57–95%. Individu-
lymphopenia can reflect disease activity; however, associations ally, headache, mood disorders, cerebrovascular events, cognitive
with infection remain controversial. Carli et al. found that dysfunction, and seizures are frequent; polyneuropathy, demy-
associations between leukopenia and major infection lost elinating disease, mononeuritis, myasthenia gravis, chorea, cranial
significance in half of published studies after controlling for neuropathy, myelopathy, and Guillain–Barré syndrome are
confounding factors. 64 uncommon. NPSLE can be further subdivided into syndromes
Autoantibodies are the pathogenic mechanism generally occurring in the anatomically distinct central (CNS NPSLE) and
implicated in the leukopenias. Antineutrophil antibodies directed peripheral (PNS NPSLE) nervous systems.
against membrane components of mature and progenitor cells, Manifestations of CNS NPSLE include focal neurological
resulting in decreased phagocytosis and accelerated apoptosis, are syndromes (stroke, seizures, aseptic meningitis, movement
implicated, as are antibodies against granulocyte–colony-stimulating disorder, myelopathy, demyelinating syndrome) and diffuse
factor (G-CSF) and hyposensitivity of myeloid cells to G-CSF. psychiatric/neuropsychological syndromes (mood and anxiety
Binding of TNF-related apoptosis-inducing ligand (TRAIL) to disorders, psychosis, acute confusional state, cognitive dysfunction,
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TRAIL receptors on neutrophils accelerates neutrophil apoptosis. headaches). PNS NPSLE syndromes include cranial neuropathy,
One of four known TRAIL receptors is unable to transduce the polyneuropathy, mononeuropathy, myasthenia gravis, Guillain–
death signal and functions as a decoy receptor; this receptor is Barre syndrome, plexopathy, and autonomic neuropathy
reduced in SLE patients with neutropenia and is upregulated by (Fig. 51.7).
steroid therapy. Lymphocytotoxic antibodies, particularly to CD4
T cells, increased apoptosis related to Fas and Fas ligand upregula- NPSLE Pathogenesis
tion, and increased serum IL-10 levels have all been implicated Many of the focal CNS NPSLE syndromes occur in association
in the pathogenesis of lymphopenia. B cells expressing the 9G4 with APL antibodies and thrombotic events or, more rarely, with
idiotype found on V H 4.34 heavy chains may be responsible for small-vessel vasculitis leading to intraluminal thrombosis. In
production of antilymphocyte antibodies. contrast, proposed mechanisms for the diffuse CNS NPSLE
Treatment of leukopenia is guided by the clinical scenario, syndromes involve autoantibody-mediated neurotoxicity and
and exclusion of drug effects, malignancy, or myelofibrosis is complicated neuroimmune interactions, resulting in increased
required before attribution to SLE. In the absence of recurrent CNS expression of proinflammatory cytokines with deleterious
infection, leukopenia in SLE rarely warrants treatment, as effects on neuronal and microglial cell function and adult neu-
increased steroids can also contribute to the risk of infection. rogenesis. 67,68 Proposed mechanisms for diffuse CNS NPSLE rely
Severe leukopenia has been treated with G-CSF; however, although in large part on disruption of the blood–brain barrier (BBB)—a
it is rapidly effective, G-CSF has also been associated with disease dynamic interface between the brain and circulating hormones
flare in 30% of cases. and inflammatory molecules. Evidence for BBB disruption in SLE
is supported by reports of an elevated albumin concentration
Thrombocytopenia gradient between cerebrospinal fluid (CSF) and plasma, an elevated
Low platelet counts are seen in approximately 25% of patients, IgG index, and elevated serum levels of proteins whose origins
although severe thrombocytopenia is reported in fewer than are exclusive to the brain parenchyma, such as S100B. Proposed
10%. Immune-mediated consumption is the most frequent cause, mechanisms for BBB disruption in SLE include brain endothelial
but in rare instances thrombocytopenia occurs as a manifestation cell disruption mediated by inflammatory cytokines, chemokines,
of microangiopathic hemolytic anemia, TTP, disseminated complement C5a, antiendothelial cell antibodies, anti-NMDAR
intravascular coagulation (DIC), or as part of the hemophagocytic antibodies, and TWEAK (TNF-like weak inducer of apoptosis). 69–71
syndrome, all of which are associated with high mortality and
morbidity. A pathogenic role for antibodies against platelet
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membrane glycoproteins (IIb/IIIa antigen) is well established.
Other possible mechanisms include antibodies to the thrombo- Central nervous system: BBB Peripheral nervous system
poietin receptor (TPOR), and APL and anti-CD40-ligand antibod-
ies that bind to platelets, resulting in platelet sequestration.
Central and Peripheral Nervous System Diffuse Focal Plexopathy
Neurological and psychiatric manifestations of SLE are diverse Acute confusional state Stroke Mononeuropathy
Myelopathy
Polyneuropathy
and frequently occur irrespective of systemic disease activity. Cognitive dysfunction Seizure disorder Myasthenia gravis
Anxiety disorder
Neuropsychiatric symptoms can be focal or diffuse, peripheral Mood disorders Aseptic meningitis Autonomic DO
or central, isolated or complex, and difficulties with assessment Headaches Movement disorder Polyradiculopathy
and attribution of individual symptoms have hindered progress Psychosis Demyelinating syndrome Cranial neuropathy
in understanding mechanisms for neuropsychiatric disease FIG 51.7 Neuropsychiatric Syndromes in Systemic Lupus
attributable to SLE (NPSLE). Erythematosus.