Acute Confusional State

Acute confusional state, previously called acute organic brain syndrome (OBS) or encephalopathy, is defined as a disturbance of consciousness or level of arousal characterized by reduced ability to focus, maintain, or shift attention to external stimuli, and accompanied by disturbances of cognition, mood, affect, and/or behavior.⁵ This condition has been termed delirium in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM IV) and the International Classification of Diseases, ninth revision (ICD-9) diagnostic classifications. Disorganized thinking, loss of orientation, agitation, and delusions can be present. Symptoms may fluctuate or progress. An ominous sign is progression to a reduced level of consciousness, such as stupor or coma. Acute confusional state is one of the most common presentations observed in 4% to 7% of all patients with NP-SLE and up to 30% of patients hospitalized for NP-SLE.¹⁵ Vasculitis, leukothrombosis, and autoantibodies have all been described as causes of acute confusion. Notably, this presentation is also common in patients with SLE who have had NP disturbances caused by cerebral infections, hypertension, medications, thrombotic thrombocytopenia purpura (TTP), and metabolic disturbances, which must always be excluded.

Cognitive Dysfunction

Cognitive dysfunction (previously called chronic OBS or encephalopathy) can range from mild cognitive impairment to dementia, in which neuropsychological testing reveals abnormalities in multiple domains of attention, reasoning, memory, language, visual-spatial processing, psychomotor speed, and executive function.⁵ The recommended 1-hour ACR neuropsychological battery of tests is a standardized, validated instrument (sensitivity 80%, specificity 81%) to document cognitive dysfunction, but it must be administered by a trained neuropsychologist.¹⁶ Other screening tests are also available. Over 80% of patients with lupus have subjective complaints of cognitive difficulties, and multiple secondary causes must be excluded (see Box 28-1). As expected, up to 87% of patients with a history of primary NP-SLE events have objective cognitive deficits on NP testing.¹⁷ However, mild cognitive dysfunction (e.g., lupus fog) has also been documented in patients with SLE without a history of NP-SLE. A review of 14 cross-sectional studies of cognitive function in SLE without overt neuropsychological symptoms revealed subclinical cognitive impairment in 11% to 54% of patients.¹⁸ This dysfunction includes various deficits, because no specific SLE pattern of abnormalities is observed. Most studies, however, show deficits in areas of verbal learning or memory, attention and mental flexibility, and visual-spatial skills. In the majority of patients, these abnormalities are subclinical and do not significantly affect the quality of life. In a 5-year prospective study involving 47 patients with SLE, Hanly and colleagues¹⁹ reported that only 21% had cognitive impairment on neuropsychological tests at baseline. On follow-up testing, 19% of patients resolved their cognitive dysfunction without therapy, whereas 17% either maintained their cognitive impairment or developed new cognitive abnormalities. Those few patients who showed cognitive decline on serial testing were those who developed clinically overt NP events during the study period. Other investigators have confirmed that cognitive performance remains stable over time in the majority of patients with mild deficits on testing and does not predict the subsequent development in NP-SLE.²⁰

The pathogenesis of cognitive dysfunction in SLE is unknown, but several clinical associations have been reported. Most studies have demonstrated an association between cognitive impairment and active or past NP-SLE events, but they have not shown an association with global SLE disease activity or corticosteroid use.²⁰ Some studies support but others discount that psychological distress can affect cognitive performance. An association has been reported between cognitive abnormalities and certain autoantibodies in the serum or cerebrospinal fluid (CSF) or both. The strongest agreement is the association between cognitive dysfunction, cognitive decline, and persistently positive antiphospholipid antibodies.²⁰ Recently, Diamond and colleagues²¹ reported that a subset of anti–double-stranded DNA (anti-dsDNA) antibodies that cross react with the anti-N-methyl-D-aspartate receptor subunit 2A (NR2A) and anti-N-methyl-D-aspartate receptor subunit 2B (NR2B) of the N-methyl-D-aspartate receptor (NMDAR) is associated with diffuse CNS manifestations including cognitive dysfunction and emotional distress particularly when present within the CSF. This association is notable as this subset of NMDARs is increased in both the hippocampus (learning and memory) and the amygdala (fear-conditioning response). They are receptors for glutamate, the major excitatory neurotransmitter of the brain. Binding of the anti-NMDAR antibodies to their cognate antigen enhances calcium influx into the neuron, resulting in mitochondrial stress, caspase activation, and apoptosis, which could result in cognitive deficits and other NP manifestations. Finally, no association has been found between mild cognitive impairment and antiribosomal P or antineuronal antibodies.²⁰

Many patients with SLE (up to 87%) with a history of NP-SLE have significant cognitive dysfunction on neuropsychological testing.¹⁷ Cerebral atrophy and the number and size of white matter lesions or strokes on magnetic resonance imaging (MRI) correlate with the severity of cognitive dysfunction. Some patients progress to dementia (3% to 5%) with global cognitive dysfunction marked by impairment in short- and long-term memory and disturbances in judgment, abstract thinking, and other high cortical functions. The degree of cognitive impairment may be severe, interfering with the patient’s ability to live independently. Dementia can be the result of active NP-SLE, of scarring from previously active NP-SLE, or of multiple infarctions from antiphospholipid antibodies.²²

Most studies of cognitive impairment have used adult study subjects with SLE but not pediatric patients, because no validated battery of neuropsychological tests for children with SLE has been available. Recently, a pediatric version of the Automated Neuropsychological Assessment Metrics (P-ANAM) had initial validation in a pediatric lupus population and showed neurocognitive impairment in 16 of 27 (59%) childhood patients with lupus without a history of NP-SLE.²³ The future impact of cognitive dysfunction on a child’s academic achievement and activities of daily living is unknown but is likely to be significant as the maturing adolescent brain is more vulnerable to disease-associated injury. An additional concern is the potential effect of maternal antineuronal antibodies such as anti-NMDAR on a fetus whose brain lacks a competent blood-brain barrier for much of gestation.

Headache

Headaches are common in patients with SLE, occurring in 24% to 72% of patients.^2–47 Migraine and tension headaches make up the majority. Because of the high prevalence of headache in the general population (40%), the association between headache and SLE is controversial.²⁴ However, some investigators have described a unique headache as a manifestation of primary NP-SLE. This headache is characterized by an acute presentation during a lupus flare, frequent association with other neurologic complications and abnormal laboratory tests, and resolves with corticosteroid therapy as the lupus disease activity improves. Additionally, previous studies have suggested that migraine headache in patients with SLE is associated with Raynaud phenomenon, antiphospholipid antibodies, and/or thrombotic events. However, controlled studies of over 275 patients have failed to confirm these observations.²⁵ Despite the lack of confirmation, many clinicians will administer a 2-week trial of low–molecular-weight heparin to determine whether treatment-resistant headaches improve in a patient with antiphospholipid antibodies.

Benign intracranial hypertension (i.e., pseudotumor cerebri) can occasionally occur in patients with NP-SLE.²⁶ Patients’ presenting signs include refractory headaches, papilledema, and no focal neurologic symptoms. Lumbar puncture reveals increased intracranial pressure (greater than 200 mm H₂O), normal protein, and no white blood cells in the CSF. Although pseudotumor cerebri can occur in adults, most patients are young, adolescent women with severe SLE. Several patients had rapid corticosteroid withdrawal and one half had cerebral venous sinus thrombosis as a result of hypercoagulability (e.g., nephrotic syndrome, antiphospholipid antibodies) as a potential cause of pseudotumor cerebri. In addition to pseudotumor cerebri, CNS vasculitis, cerebral vein thrombosis, intracranial hemorrhage, and aseptic meningitis can be the result of lupus and manifest with headache. Non-lupus secondary causes must always be ruled out in all patients before ascribing a severe headache to primary NP-SLE. The most common or important secondary causes include severe hypertension, infection, nonsteroidal antiinflammatory medications (e.g., aseptic meningitis), antimalarial therapy, sleep apnea, cerebral venous sinus thrombosis, and subdural hematoma.

Aseptic Meningitis

Aseptic meningitis in SLE is rare (<1%). Patient symptoms include fever, headache, meningeal signs, and CSF pleocytosis with normal CSF glucose and protein less than 100 mg/dL.¹ The pleocytosis is most commonly less than 200 to 300 cells/mm³ and predominantly lymphocytes. Rarely, significantly higher cell counts with a neutrophil predominance can occur in patients who are severely ill. Infectious meningitis of any cause, subarachnoid hemorrhage, carcinomatous meningitis, sarcoidosis, and medication effects from nonsteroidal antiinflammatory drugs (e.g., ibuprofen, others), as well as from intravenous gamma globulin and azathioprine, must be excluded. The cause of aseptic meningitis in NP-SLE is unclear, but patients usually respond to corticosteroid therapy.

Cerebrovascular Disease

Cerebrovascular disease (CVD) occurs in 5% to 18% of patients with SLE and can affect any area of the brain.^27–29 Ischemic strokes account for 80% of the CVD observed. The age- and sex-adjusted relative risk for stroke is reported to be up to eight times that of the general population. Acute presentations include transient ischemic attacks (TIAs), hemiplegia, aphasia, cortical blindness, or other deficits of cerebral function. Strokes usually occur within the first 5 years of the onset of SLE; and between 13% and 64% of patients who have had a stroke will have a recurrent stroke, resulting in significant morbidity and a 12% to 28% mortality rate.^27,30

Strokes can be from large- or small-vessel disease. Large-vessel strokes can be the result of vasculitis, thrombosis from a coagulopathy, and cardiogenic emboli.³¹ Small-vessel strokes and TIAs can be from vasculitis, noninflammatory vasculopathy, leukothrombosis, emboli, and antiphospholipid antibody–associated thrombosis. Patients with stroke from antiphospholipid antibodies frequently have evidence of livedo reticularis (Sneddon syndrome). Hemorrhagic strokes from intraparenchymal or subarachnoid bleeding also can occur. In any patient with SLE who has had a stroke, both hypertension and accelerated atherosclerosis must also be considered.

Several risk factors for strokes in patients with SLE have been identified including advanced age, previous stroke or TIA, cigarette smoking, hypertension, dyslipidemia, diabetes mellitus, antiphospholipid antibodies, cardiac valvular disease, and a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of >6.^8,29 Clinical experience suggests that the use of the specific cyclooxygenase-2 inhibitors in patients with SLE who have these risk factors may contribute to the risk of subsequent clotting, especially in patients with antiphospholipid antibodies. Control of hypertension, of elevated cholesterol and blood glucose levels, as well as smoking cessation, must be part of the treatment plan to prevent stroke or the recurrence of stroke.

The diagnosis of CVD is made clinically and supported by neuroimaging studies. A computed tomographic (CT) scan of the brain is capable of detecting cerebral hemorrhage and large infarctions, making it a useful study in screening patients with SLE who have acute neurologic deterioration. Cranial MRI with contrast is superior to CT scanning in detecting smaller and frequently transient lesions. An MRI typically shows hyperintense gray and white matter lesions on T2-weighted images, which account for the patient’s clinical symptoms. Additional lesions in clinically silent areas are also frequently observed. Magnetic resonance angiography (MRA), carotid Doppler ultrasound, and echocardiogram are noninvasive procedures that can be useful in detecting large-vessel vasculitis, thrombosis, or sources of emboli, leading to vascular occlusion and stroke. Angiograms are more likely to show abnormalities in patients with large infarctions. CSF examination may show pleocytosis and high protein in patients with cerebral vasculitis or blood in patients with subarachnoid hemorrhage. Otherwise, the CSF examination is usually normal or demonstrates nonspecific abnormalities, such as a few cells or high protein or both.

Treatment of strokes in patients with SLE is based on the suspected pathogenesis.⁸ Patients with suspected vasculitis are treated with corticosteroids and cytotoxic drugs, whereas those with a coagulopathy or cardiac emboli are treated with anticoagulation therapy. Treatment of patients with strokes as a result of a noninflammatory vasculopathy is difficult since the pathogenesis of these vascular lesions is unclear. Although not proven to reduce stroke in patients with SLE, most clinicians prescribe aspirin or other platelet inhibitors and aggressively treat stroke risk factors. The value of corticosteroids in these patients is uncertain and could potentially contribute to stroke risk by increasing hypertension, cholesterol, and blood glucose. Patients, however, are often given corticosteroids to control other accompanying lupus manifestations.

Myelopathy

Patients with SLE with spinal cord myelopathy present with progressive or sudden weakness or paralysis (e.g., paraplegia, quadriplegia), bilateral sensory deficits, and impaired sphincter control.³² Myelopathy occurs in approximately 1% of patients and can be the initial presentation of SLE. Most patients (80%) are young women between 20 and 40 years of age, although childhood cases have also been reported. CSF is abnormal in the majority of patients, including elevated protein (greater than 80%), pleocytosis (50% to 70%), and decreased glucose levels less than 30 mg% (50%). An MRI of the spinal cord can help confirm the diagnosis and exclude other causes of spinal cord compression, which may benefit from surgery. An MRI of lupus myelopathy typically shows edema with abnormalities of T2-weighted images (up to 93%), which may be accompanied by spinal cord enlargement in 75% of patients. Any level of the spinal cord can be involved. Notably, some patients (up to 30%) may have a normal MRI, especially if the examination is delayed (longer than 5 days) or if the patient has received treatment. The differential diagnosis includes compressive myelopathy (e.g., tumor, abscess, hematoma), epidural lipomatosis, vertebral compression fracture, anterior spinal artery syndrome, infection (e.g., herpes zoster, tuberculosis, polyoma virus including John Cunningham (JC) virus), sarcoidosis, and Guillain-Barré syndrome.

The cause of lupus myelopathy is multifactorial. Vasculitis during an acute exacerbation of lupus leading to ischemic necrosis of the cord has been pathologically documented in a few cases. Some investigators have reported that patients with SLE with myelopathy frequently have antiphospholipid antibodies and clots, whereas other investigators have not. Recently, anti–neuromyelitis optica (NMO) IgG antibodies have been associated with transverse myelitis.³³ The antigenic target of these antibodies is aquaporin-4, which is the most abundant water channel in the CNS. These patients have several features in common, including the development of longitudinally extensive transverse myelitis involving at least three vertebral segments on MRI. This development is distinct from other causes of myelopathy that typically involve a single segment. Additional features that may be present include optic neuritis, coexistent Sjögren syndrome, and anti–Sjögren syndrome antigen A (anti-SSA/Ro) antibodies.³⁴ Identification of this subset is important because the presence of anti–neuromyelitis optica IgG (anti-NMO-IgG) antibodies indicates a severe disease course with frequent relapses.

Lupus myelopathy tends to have a poor prognosis. Several reports have emphasized that pulsed methylprednisolone and cyclophosphamide may improve the prognosis of these patients. This therapy must be used early, because 50% of patients will reach their peak severity of myelopathy symptoms within 3 to 5 days of onset. Early use of aggressive therapy has resulted in the reversal of symptoms and stabilization in the majority of patients with 50% having a complete recovery and 29% having a partial recovery.³² Rituximab has also been successfully used.³⁴ In patients with significant titers of antiphospholipid antibodies, anticoagulation therapy should probably be used, although studies are limited. Recurrences of myelopathy, particularly in patients with anti-NMO-IgG antibodies, are common (50% to 60%). Rehabilitation measures to prevent pressure sores; preserve range of motion, strength, and mobility; and institute appropriate bladder management should be initiated early.

Movement Disorders

Chorea, hemiballismus, cerebellar ataxia, and parkinsonian-like rigidity or tremors are rare manifestations. Chorea is the most common, occurring in <1% (adults) to 4% (pediatric) of patients with SLE.³⁵ Chorea is characterized by rapid, brief, involuntary, and irregular movements and may be generalized or limited to the extremities, trunk, or face. Choreoathetosis is diagnosed when chorea is accompanied by slow, writhing movements of the affected extremity. Chorea occurs most commonly in young women, children, and during pregnancy (chorea gravidarum) or the postpartum period. It may be the initial presentation of SLE or precede other manifestations of SLE by years. Chorea usually occurs early in the course of SLE, tends to be unilateral, can be recurrent (35%), and is frequently associated with other NP-SLE symptoms such as strokes. Antiphospholipid antibodies are frequently found and may be responsible for basal ganglia infarction. The CSF examination is usually unremarkable. The symptoms of chorea usually last for several weeks but rarely can last for up to 3 years.

A long differential diagnosis of illnesses is rarely associated with chorea. Sydenham chorea, secondary to rheumatic fever, is the most common and can be ruled out by obtaining antistreptococcal antibodies (anti-DNase B). However, the onset of chorea in a young woman with a positive antinuclear antibody (ANA) test result should strongly suggest SLE. The recommended treatment of chorea has been corticosteroids and dopamine antagonists. Some patients spontaneously recover, whereas others fail to respond to immunosuppressive therapy. Cervera and others³⁵ have recommended aspirin or anticoagulation therapy in patients with chorea and antiphospholipid antibodies.

Infarction of the subthalamic nucleus can result in hemiballismus.¹ It rarely has been reported in SLE. Ballismus may be steroid responsive or related to antiphospholipid antibodies. Cerebellar ataxia is reported in less than 1% of patients with SLE.¹ Patients have an inability to stop or end purposeful movements. The abnormalities may involve the trunk or extremities. Nystagmus is common. The cause is uncertain, but some cases may be caused by cerebellar or brainstem infarction, antiphospholipid antibodies, or associated with Purkinje cell antibodies. In patients with cerebellar atrophy associated with antibodies against Purkinje cells, a paraneoplastic syndrome must be ruled out before attributing it to NP-SLE.

Tremor of all types has been reported in up to 5% of patients with SLE during the course of their disease.¹ However, parkinsonian-like symptoms caused by alterations of the substantia nigra are an extremely rare manifestation of NP-SLE. Patients present with behavioral alterations (e.g., irritability, apathy), rigidity and progressive bradykinesia, and/or akinetic mutism. Single-photon emission CT (SPECT) cerebral scanning can detect decreased regional cerebral blood flow to the basal ganglia. Treatment with dopamine-agonist drugs can lead to recovery.

Demyelinating Syndrome

Syndromes similar to multiple sclerosis (MS), sometimes called lupoid sclerosis, have rarely (<1%) been described in patients with SLE.³⁶ Interestingly, both MS and NP-SLE share many features including clinical presentation, Lhermitte sign, a positive ANA test result (2% to 27% of patients with MS), abnormal CSF with elevated IgG index and oligoclonal bands, and abnormal brain MRIs. Whether both diseases can coexist in one patient or whether lupoid sclerosis is simply an unusual presentation of NP-SLE is unclear. Notably, antiphospholipid antibodies have been demonstrated in a number of patients with an MS-like illness, suggesting these antibodies may be pathogenic in lupoid sclerosis and transverse myelitis.

Another MS-like presentation is Devic disease (NMO-spectrum disorder).^33,34 These patients present with optic neuritis and longitudinally extensive transverse myelitis either simultaneously or separately. They have anti-NMO-IgG antibodies (75%); however, unlike patients with MS, they frequently have anti-SSA/Ro antibodies (see previous discussion under “Myelopathy”). Patients with SLE with antiphospholipid antibodies can mimic this presentation with optic nerve and spinal cord infarction.

The therapy of patients with lupoid sclerosis differs from MS therapy. Both patient populations may respond to immunosuppressive therapy. However, patients with SLE who have lupoid sclerosis or optic nerve or spinal cord infarction caused by vascular occlusion from antiphospholipid antibodies are best treated with anticoagulation therapy. Patients with SLE with NMO-spectrum disorder should receive aggressive immunosuppressive therapy.

Seizures

Seizures occur in 7% to 20% of patients with SLE. They may occur before the development of other symptoms of SLE or at any time during its course.³⁷ Generalized major motor (67% to 88%) and partial complex seizures are most common, although any kind of seizure can occur. Seizure episodes are usually self-limited, although status epilepticus can occur and frequently signals a preterminal event. Seizures may occur in isolation or accompany other neurologic symptoms.

The cause of seizures in NP-SLE is multifactorial. Antineuronal antibodies, focal ischemia, and infarctions caused by vascular occlusion from thrombosis and emboli, hemorrhage, and cytokine or neuroendocrine effects on the seizure threshold have all been implicated. Several studies have shown an association between antiphospholipid antibodies and seizures in patients with SLE.³⁸ An increased risk of seizures, seizures with strokes, and recurrence of seizures exists in patients with higher titers of antiphospholipid antibodies. Some investigators have demonstrated a direct effect of these antibodies on neurons, possibly leading to neuronal dysfunction and seizure by a nonthrombotic mechanism.³⁹ However, most seizures in patients with antiphospholipid antibodies are probably the result of cerebral ischemia from cerebral microinfarctions. Secondary causes of seizures include infections, medication effects, metabolic disturbances, hypoxemia, and hypertension, which must be ruled out in all patients with SLE who have seizures.

Most patients with a single seizure do not need anticonvulsant medications. Risk factors for recurrent seizures requiring anticonvulsant therapy include focal neurologic signs, abnormal brain MRI, and an epileptiform electroencephalogram (EEG). Although some anticonvulsant medications have been shown to cause a positive ANA test result and rarely clinical SLE, this presentation is no reason to withhold these medications when they are indicated for patients with established lupus. Seizure control is important since recurrent seizures increase the vulnerability of neurons to additional injury. Consequently, corticosteroids and other immunosuppressive medications should be used in patients with status epilepticus, recurrent seizures, or other neurologic manifestations. Patients with SLE with high-titer antiphospholipid antibodies and seizures should also receive anticoagulation therapy, especially if the brain MRI shows areas of microinfarction.