Chapter 86 Neurologic Manifestations of Rheumatic Disorders of Childhood
The rheumatic disorders of childhood include a wide variety of conditions ranging from simple arthritis to complex multisystem autoimmune diseases. The presence and the degree of nervous system impairment vary widely, depending on the diagnosis and course of the disorder. Manifestations of neurologic disease may precede the onset of any other symptoms or occur much later. The current classification of the chronic rheumatic disorders is shown in Box 86-1 [Petty et al., 2004; Dannecker and Quartier, 2009; Horneff and Burgos-Vargas, 2009]. Examples of autoantibodies found in the various rheumatic diseases are given in Table 86-1.
Box 86-1 Classification of the Rheumatic Disorders of Childhood
(Modified from Cassidy JT, Petty RE. Textbook of pediatric rheumatology, 4th edn. Philadelphia, 2001, WB Saunders.)
Table 86-1 Autoantibodies in Pediatric Rheumatic Diseases
| Antibody | Clinical Finding |
|---|---|
| ANA | 97% SLE, but also positive in MCTD, SSc, 10–85% JDMS, 20–88% JRA, SS, and 2–5% of controls |
| Anti-ds-DNA | 30–70% SLE, rarely in other CTDs |
| Anti-Sm | 30% SLE |
| Anti-RNP | MCTD, also in SLE |
| Anti-SSA/Ro | 25% SLE, 75% SS |
| Anti-SSB/La | 10% SLE, 40% SS |
| Anti-histone | 50% SLE, >90% DILS |
| Anti-centromere | 44–98% CREST syndrome |
| Anti-Scl-70 | 27% SSc |
| Anti-c-ANCA | >90% Wegener’s granulomatosis |
| Anti-p-ANCA | 10% Wegener’s granulomatosis, 70% CSS, 75% UC, 20% Crohn’s disease, 30% SLE |
| Anti-NR2 NMDAR | 10% SLE |
| RF A | 20% polyarticular JRA, 50% SS; 10–30% SLE, MCTD |
| LAC | Correlates with thromboembolic risk in SLE |
| aCL | Correlates with thromboembolic risk in SLE, malignancy; variable in many other diseases |
aCL, anticardiolipin antibody; ANA, antinuclear antibody; c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; CREST, calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia; CSS, Churg–Strauss syndrome; CTD, connective tissue disease; DILS, drug-induced lupus syndrome; ds-DNA, double-stranded (native) DNA; JDMS, juvenile dermatomyositis; JRA, juvenile rheumatoid arthritis; LAC, lupus anticoagulant; MCTD, mixed connective tissue disease; NMDAR, N-methyl-d-aspartate receptor; p-ANCA, perinuclear staining antineutrophil cytoplasmic antibody; RF A, rheumatoid factor A; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith; SS, Sjögren’s syndrome; SSc, systemic scleroderma; UC, ulcerative colitis.
(Adapted from Okano Y. Antinuclear antibody in systemic sclerosis [scleroderma]. Rheum Dis Clin North Am 22:709, 1996; Moder KG. Use and interpretation of rheumatologic tests: A guide for clinicians. Mayo Clin Proc 71:391, 1996; Bylund DJ, McCallum RM. Vasculitis. In: Henry JB, editor: Clinical diagnosis and management by laboratory methods, Philadelphia, 1996, WB Saunders.)
Neurologic manifestations of rheumatic disorders can arise in both primary and secondary fashion [Benseler and Schneider, 2004]. That is, the antibodies or cellular immune elements responsible for the underlying disease can attack and injure directly or can cause the malfunction of nerves, muscle, brain, spinal cord, and sensory organs. On the other hand, innocent bystander effects of such rheumatic disease accompaniments as the hypercoagulable state, inflammation of the blood vessel wall, and immune complex deposition and side effects of medications used in the treatment of rheumatic disease also take their toll on the nervous system. These neurologic signs and symptoms are often multifactorial in origin, and their treatment may involve approaches to the proximate underlying disease and the more distal symptomatic manifestations.
Rheumatic disease underlies a small but tangible fraction of neurologic syndromes of childhood. For example, vasculitis of infectious or rheumatic origin accounts for approximately 4 percent of childhood stroke [Williams et al., 1997], and more than 50 percent of children with arterial ischemic stroke exhibit focal or multifocal cerebral arteriopathy [Dlamini and Kirkham, 2009]. Rheumatic disease should be considered as a possible etiologic factor in neurologic syndromes of childhood when these syndromes are accompanied by persistent fever, weight loss, myalgias, arthralgias, meningeal signs, or multiple nonanatomically contiguous neurologic deficits [Carvalho and Garg, 2002].
Juvenile Idiopathic Arthritis (Chronic Arthropathies)
The key neurologic and laboratory findings in chronic arthropathies are summarized in Table 86-2 [Dannecker and Quartier, 2009].
Table 86-2 Key Neurologic and Laboratory Findings in the Chronic and Reactive Arthropathies
| Disease | Neurologic Findings | Laboratory Findings |
|---|---|---|
| Systemic juvenile idiopathic arthritis | Encephalopathy, seizures, macrophage activation syndrome (Reye-like syndrome), neuropathies | Elevated WBC and ESR, anemia, DIC, elevated CSF protein and cell count, marked increase in ferritin and LDH |
| Inflammatory bowel disease | Myasthenia gravis, myopathy, neuropathy, seizures, cognitive changes | Elevated ESR, microcytic anemia, melena |
| Acute rheumatic fever | Chorea, personality changes, seizures | Positive ASO titers, elevated ESR and CRP, abnormal EKG |
| Lyme disease | Early infection: aseptic meningitis, headache, chorea, cranial nerve palsies, late neuroborreliosis myelitis, MS-like symptoms, subtle encephalopathy, radiculopathy, mononeuritis multiplex | Positive IgG Lyme titer by ELISA, protein by Western blot in serum, positive PCR in CSF |
ASO, antistreptolysin O; CRP, C-reactive protein; CSF, cerebrospinal fluid; DIC, disseminated intravascular coagulation; EKG, electrocardiogram; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; LDH, lactate dehydrogenase; MS, multiple sclerosis; PCR, polymerase chain reaction; WBC, white blood cell count.
The neurologic manifestations and sequelae of juvenile idiopathic arthritis (previously described as juvenile rheumatoid arthritis) and its treatment vary greatly with the subtype of arthritis. Children with pauciarticular or polyarticular disease have only rarely been diagnosed with central nervous system (CNS) disease, but approximately 20 percent of those with pauciarticular and 5 percent of those with polyarticular disease develop uveitis [Duzova and Bakkaloglu, 2008]. In contrast, only 1 percent of children with systemic-onset disease develop uveitis [Rosenberg, 2002]. Approximately 6 percent of children with systemic arthritis develop nervous system symptoms that most often involve the CNS.
Neurologic Manifestations
Systemic Juvenile Idiopathic Arthritis
Acute encephalopathy
The most common form of acute encephalopathy in children with systemic juvenile idiopathic arthritis is macrophage activation syndrome. Symptoms include unremitting fever, rheumatoid rash, seizures, encephalopathy, hepatosplenomegaly, and lymphadenopathy, as well as cardiac, pulmonary, and renal failure. Laboratory studies demonstrate varying degrees of cytopenia, low albumin, elevated D-dimer, and elevated ferritin and lactate dehydrogenase. Elevation of liver enzymes and serum triglycerides is common. Acutely, the sedimentation rate may fall [Ravelli, 2002]. Initial reports of this catastrophic complication implicated the use of acetylsalicylic acid, indomethacin, and gold, but the macrophage activation syndrome has occurred after ingestion of many nonsteroidal anti-inflammatory drugs, including sulfasalazine, and in the context of no drug intake [Bray and Singleton, 1994; Avcin et al., 2006]. Immediate treatment with steroids is associated with resolution in most cases. In steroid-resistant cases, cyclosporine A and etanercept have been reported to be effective [Cortis and Insalaco, 2006; Stabile et al., 2006; Makay et al., 2008].
In one series of patients, acute hepatic dysfunction, metabolic alterations (including hyponatremia), intracranial hemorrhage, and acute encephalopathy have been described with and without disseminated intravascular coagulation [Hadchouel et al., 1985]. Clinical features are suggestive of a Reye-like syndrome, although cerebral edema, hyperammonemia, and hepatic microvascular fatty infiltration have not been observed. Elevated cerebrospinal fluid protein and cell count were common. These patients demonstrated generalized electroencephalographic (EEG) slowing, and the neurologic symptoms in 5 of 7 children were attributable to a metabolic encephalopathy associated with hyponatremia. These five children responded well to high-dose corticosteroids. The remaining two children died from disseminated intravascular coagulation [Hadchouel et al., 1985]. In another series of children with systemic juvenile idiopathic arthritis without disseminated intravascular coagulation, an acute encephalopathy associated with generalized and focal seizures, altered states of consciousness, abnormal ictal and interictal EEG, and moderate elevation of cerebrospinal fluid protein and cells has been reported [Lang et al., 1974]. Perivascular infiltrates of inflammatory cells within the brain parenchyma have been documented in several children with acute encephalopathy. In one patient, cerebrospinal fluid immune complexes were associated with parenchymal perivascular mononuclear cell infiltrates, suggesting an autoimmune basis of this complication [O’Connor et al., 1980]. A more recent case report and review [Ueno et al., 2002] points out that acute necrotizing encephalopathy is characterized by multifocal gray-matter lesions in the thalamus, brainstem tegmentum, and cerebellar dentate nucleus during the acute phase, while Reye’s syndrome presents primarily with cerebral edema.
Two reports have been published in which there was an association of true Reye’s syndrome with chronic administration of acetylsalicylic acid in several patients with juvenile idiopathic arthritis, when acetylsalicylic acid was the drug of choice for the treatment of chronic childhood arthritis [Silverman et al., 1983; Young et al., 1984]. No reports of Reye’s syndrome in children with juvenile idiopathic arthritis have emerged since the use of acetylsalicylic acid in children has declined in the United States; furthermore, this complication has not been reported with the use of newer nonsteroidal anti-inflammatory drugs, such as naproxen.
Neuropathies
Motor and sensory neuropathies have been reported in children but are far more common in adults. As such, mononeuritis multiplex, the most common neuropathy in adults with rheumatoid arthritis, is seldom, if ever, present in children. Neuropathologic studies of adult rheumatoid arthritis patients with peripheral neuropathy have demonstrated vasculitis involving both the leptomeninges and the underlying parenchyma, with infarction of adjacent neuronal tissue. The resulting axonal neuropathy may be associated with demyelination caused by vascular occlusion of the vasa nervorum [Peyronnard et al., 1982].
Mood disturbances
Reports of psychologic studies of children with juvenile idiopathic arthritis remain uncertain about both the relative frequency of psychologic disorders and the relation of age and severity of arthritis to psychologic symptoms [Baildam et al., 1995; Ungerer et al., 1988]. Premorbid family dynamics – specifically, maternal personality – may contribute to subsequent psychologic disorders in the child with juvenile idiopathic arthritis [Vandvik and Eckblad, 1991]. Depression and difficulty with concentration may be secondary to drug interventions, including nonsteroidal anti-inflammatory drugs and sulfasalazine.
Myositis
Approximately 33 percent of children with juvenile idiopathic arthritis have mild elevations of creatine kinase without weakness [Rachelefsky et al., 1976]. Proximal muscle weakness and biopsy-confirmed myositis are extremely rare, although intermittent myalgias are common, especially in systemic juvenile idiopathic arthritis. Myositis has been localized with magnetic resonance imaging (MRI) in a patient with myalgias and elevated muscle enzymes in systemic juvenile idiopathic arthritis [Miller et al., 1995]. Of note, children with Duchenne’s muscular dystrophy, paraplegia, poliomyelitis, and cerebral palsy may have skeletal changes, such as apparent overgrowth of the epiphysis, periarticular osteoporosis, and joint-space narrowing, similar to juvenile idiopathic arthritis [Richardson et al., 1984].
Pauciarticular Juvenile Idiopathic Arthritis (Oligoarthritis)
Iridocyclitis and uveitis
Although prior literature suggests that iridocyclitis and uveitis are more common in children with oligoarthritis than in children with polyarthritis, newer studies found equivalent incidence in the two groups [Ravelli et al., 2005; Saurenmann et al., 2010]. Patients with a positive antinuclear antibody have a higher incidence than those with a negative antinuclear antibody. In girls, but not in boys, incidence increases with age and with duration of clinical disease. In antinuclear antibody-positive girls with juvenile idiopathic arthritis diagnosed before age 2 years, the incidence after a mean follow-up time of 6.9 years was 46 percent; the analogous figure for the entire cohort of 1047 children with juvenile idiopathic arthritis was 11.7 percent [Saurenmann et al., 2010].
Psoriatic, Enthesitis-Related, and Undifferentiated Syndromes
Although primarily an intestinal disorder, inflammatory bowel disease may present with arthritis and neurologic symptoms. Published studies indicate that approximately 3 percent of children with inflammatory bowel disease had neurologic involvement during the course of the disease, including one child with myasthenia gravis and others with myopathy, peripheral neuropathy, venous sinus thrombosis, recurrent strokes, myelopathy, cranial neuropathy, seizures, headache, confusional states, meningitis, and syncope [Bridger et al., 1997; del Rosario et al., 1994; Lossos et al., 1995]. A syndrome has been described that includes ileocolonic lymphoid nodular hyperplasia, mild enterocolitis, and developmental delay with autistic features [Wakefield et al., 1998]. Although initial reports and reviews suggested that this disorder is associated with detection of measles virus in the intestinal mucosa of these children [Martin et al., 2002], causality has not been demonstrated [Murch et al., 2004] and subsequent studies make this association highly unlikely [Hornig et al., 2008]. Other than inflammatory bowel disease, the enthesitis-related syndromes have not been described with neurologic findings.
Between 5 and 6 percent of patients with inflammatory bowel disease, psoriatic arthritis, and other enthesitis-related arthritides develop inflammation of the uveal tract [Girardin et al., 2007]. These patients may experience acute episodes of uveitis with eye redness, pain, photophobia, and blurred vision. Prompt attention is required, and treatment with topical ophthalmic corticosteroids usually clears the inflammation. More recent studies and speculation have focused on the inverse situation: that is, the modulation of gastrointestinal inflammation by the nervous system and its chemical messengers [Anton and Shanahan, 1998; Murch, 1998]. It has become clear that both macrophages and lymphocytes bear receptors for various neuropeptides and CNS-relevant cytokines, growth factors, and hormone-regulating factors. Furthermore, substance P has emerged as an important mediator, not only of sensory signaling but also of mucosal inflammation. Finally, the absence of significant pain in patients with severe inflammatory bowel disease and consequent mucosal erosion has been linked to altered cortical localization of pain perception, as determined by positron emission tomography [Anton and Shanahan, 1998].
Neuropathology
Neuropathologic studies of children with systemic-onset juvenile idiopathic arthritis who have had neurologic complications are rare. Investigations of adults with classic rheumatoid arthritis complicated by CNS disease document the presence of rheumatoid nodules in the cranial and spinal dura, falces, leptomeninges, parenchyma, and choroid plexus [Kim, 1980]. Because adult-type (i.e., polyarticular) rheumatoid arthritis is relatively uncommon in children, these manifestations have not been reported but may occur in older children with seropositive (rheumatoid factor-positive) juvenile idiopathic arthritis who have the same disease as their adult counterparts.
Management
The treatment of juvenile idiopathic arthritis is dictated by the subtype of the disease. Pauciarticular juvenile idiopathic arthritis is usually managed with either nonsteroidal anti-inflammatory drugs, such as naproxen and tolmetin sodium, or steroid intra-articular joint injection. Iridocyclitis usually responds successfully to topical ophthalmic corticosteroids. Polyarticular juvenile idiopathic arthritis is initially treated with nonsteroidal anti-inflammatory drugs; however, the risk of chronic inflammation of multiple joints may require the use of second-line agents, such as methotrexate. If methotrexate fails, a drug blocking tumor necrosis factor-α, such as etanercept or infliximab, is used. Systemic juvenile idiopathic arthritis may be managed with nonsteroidal anti-inflammatory drugs alone but often requires steroids for control of systemic symptoms. Second-line drugs, such as methotrexate, are often needed to control arthritis [Cassidy and Petty, 2001]. Once again, etanercept or infliximab is used for disease poorly responsive to prednisone and methotrexate [Quartier et al., 2003]. High-dose methylprednisolone, intravenous immunoglobulin, and cyclophosphamide have been used in recalcitrant disease [Shaikov et al., 1992; Silverman et al., 1994; Uziel et al., 1996]. Anti-tumor necrosis factor-α therapies, paradoxically, have been associated with worsening or even emergence of new cases of multiple sclerosis [Sicotte and Voskuhl, 2001].
Because of the chronic nature of juvenile idiopathic arthritis, some children have psychological problems, including depression, anger, adjustment disorders, and troubles with peer and family relations. Counseling of the patient and family is beneficial [Baildam et al., 1995; Quirk and Young, 1990]. In addition, the importance of physical and occupational therapy cannot be overemphasized [Rhodes, 1991].
Periodic Fever Syndromes
Neonatal-Onset Multisystem Inflammatory Disease or Chronic Infantile Neurologic Cutaneous and Articular Syndrome
Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular (CINCA) Syndrome is an unusual disorder that mimics systemic juvenile idiopathic arthritis. It has its onset during the first year of life, whereas systemic-onset juvenile idiopathic arthritis is a disease of toddlers and children. Clinical manifestations include hectic fever, intermittent rash, lymphadenopathy, hepatosplenomegaly, uveitis, cognitive and developmental delay, chronic meningitis, hydrocephalus, seizures, papilledema, and deforming arthropathy with periosteal changes and bony overgrowth [De Cunto et al., 1997]. Almost all patients have chronic meningitis from infancy and hydrocephalus, and ventriculomegaly can present in utero. Seventy-five percent of patients with CINCA develop progressive sensorineural hearing loss and many progress to deafness; ocular complications occur at an average age of 4 years and include optic nerve changes, uveitis, and corneal stromal keratopathy [Montealegre Sanchez and Hashkes, 2009]. Other neurological sequelae include seizures, abnormal interictal EEG, transient hemiplegia, cerebral atrophy, and an open fontanel. Long-term prognosis is poor [Prieur, 2000].
Familial Mediterranean Fever
Familial Mediterranean fever is inherited as an autosomal-recessive trait as a result of mutations in the MEFV gene. Over 180 individual mutations have been described. Non-neurological symptoms include fever, abdominal pain, peritonitis, pleuritis, and arthritis [Ozdemir et al., 2010]. Myalgias after exertion are common. Headache, febrile seizures, aseptic meningitis, and posterior reversible leukoencephalopathy have been described, as has progressive sensorineural deafness [Montealegre Sanchez and Hashkes, 2009; Ulasli et al., 2010].
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome has an unclear etiology; it is characterized by febrile episodes persisting for 4 –6 days, separated by afebrile periods lasting 4 weeks to 4 months. Headache can occur during febrile episodes. Recurrent aseptic meningitis accompanied by a generalized tonic clonic seizure has been described in a patient with PFAPA syndrome [Frye, 2006].
Hyper-IgG (Autoimmune Lymphoproliferative) Syndrome
This genetic syndrome is thought to result from abnormal regulation of apoptosis of mature lymphocytes. Proliferation of lymphocytes can present with splenomegaly, skin rashes, enlarged lymph nodes, and autoimmune hemolytic anemia. Neurological symptoms connected with this syndrome are the result of its association with other autoimmune phenomena, including Guillain–Barré syndrome [Sneller et al., 2003].
Arthritis Associated with Infectious Agents
Acute Rheumatic Fever
Acute rheumatic fever is an inflammatory illness that follows group A beta-hemolytic streptococcal pharyngitis. The syndrome affects the heart valves, joints, CNS, skin, and subcutaneous tissues. Common clinical manifestations include migratory polyarthritis, fever, carditis, and, less frequently, Sydenham’s chorea, subcutaneous nodules, and erythema marginatum. The modified Jones criteria, which were last revised in 1992, are used to confirm the diagnosis of acute rheumatic fever and call for the presence of a combination of two major and one minor criteria, or one major and two minor criteria, as well as antibody evidence of preceding streptococcal infection (Box 86-2). In the case of isolated Sydenham’s chorea, demonstration of preceding streptococcal infection may not always be possible, and in these cases is not a requirement for the diagnosis of acute rheumatic fever [Dajani et al., 1992].
Box 86-2 Jones Criteria for Diagnosis of Acute Rheumatic Fever (Revised 1992)
* Prior episodes of acute rheumatic fever are not criteria; if a patient has had a prior attack of acute rheumatic fever, a new attack may be difficult to diagnose on the basis of changing carditis. In this setting, proof of recent streptococcal infection and either one major or one minor criterion may allow a presumptive diagnosis. Proof of recent streptococcal infection is necessary, except for isolated chorea.
(Adapted from Dajani, et al. and The Special Writing Group. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update, JAMA 268:2069, 1992.)
Neurological Manifestations
Sydenham’s chorea
Clinical Manifestations
Involuntary, distal, purposeless, rapid movements; hypotonia; weakness; and emotional lability characterize Sydenham’s chorea. It may be associated with other manifestations of rheumatic fever, or “pure” chorea may appear as the sole manifestation of the disease. Isolated chorea represents 20–30 percent of acute rheumatic fever cases and occurs long after the pharyngitis has resolved, which makes the association with streptococcal infection difficult to demonstrate. Indeed, laboratory evidence of preceding streptococcal infection could not be demonstrated in 35 percent of children with Sydenham’s chorea [Ayoub and Wannamaker, 1966]. Although the onset may be explosive, Sydenham’s chorea may develop slowly and insidiously. Chorea may be misdiagnosed as an emotional disorder or as tics with irritability and decreased attention span. Chorea may also be confused with a CNS degenerative process, but this is more common in adults than in young children.
In adolescents, chorea occurs almost exclusively in females and may, on rare occasions, be associated with hemichorea or hemiparesis. The hemiparesis, which may be the initial manifestation of the disorder, has an unusual form of flaccidity combined with hypotonia and slow relaxation of deep tendon reflexes. Choreiform movements are abrupt and erratic without being rhythmic or repetitive, and usually subside during sleep. Face, hands, and feet are most commonly affected; facial movements include grimacing, frowning, grinning, and pouting. Children commonly are unable to sustain prolonged hand contraction, resulting in the “milkmaid” sign. In other patients, emotional lability, personality changes, restlessness, hyperactivity, irritability, and episodes of anger and tearfulness may herald the onset of chorea. Occasionally, typical “spooning” is observed with hyperextension of the hands [Stollerman, 1985]. Choreiform movements usually subside in 2–4 months but may persist for 1 year or more. Chorea and arthritis do not usually accompany each other in acute rheumatic fever; however, carditis frequently develops as the chorea is improving.
Laboratory Findings
Laboratory studies include serologic documentation of antecedent streptococcal infection with an antistreptolysin-O titer, demonstration of a prolonged PR interval on electrocardiogram, elevated C-reactive protein or erythrocyte sedimentation rate, and leukocytosis. Although throat culture may show group A beta-hemolytic streptococci, an elevated or increasing antistreptolysin-O titer is required. An elevated anti-DNase-B increases the sensitivity of an antistreptolysin-O titer alone from 80 to 95 percent and may be necessary, especially in isolated chorea, in which sensitivity may only be 65 percent. To exclude other conditions manifesting with chorea, patients may need additional diagnostic studies, including serum ceruloplasmin, thyroxine, calcium, and antinuclear antibody titers. In patients with Sydenham’s chorea, EEGs may demonstrate diffuse paroxysmal features and generalized or posterior slowing [Ganji et al., 1988]. Cerebrospinal fluid examinations and neuroimaging are rarely necessary. Of interest is the finding of antineuronal antibodies in the cerebrospinal fluid of patients with chorea [Swedo, 1994]. The specificity of these antibodies is not well known, and they are frequently documented in patients with CNS lupus [Bluestein, 1997].
A 3-year-old child with chorea was reported as having the first example of a persistently abnormal MRI, showing a cystic abnormality in the caudate and putamen [Emery and Vieco, 1997]. Subsequent longitudinal radiologic studies of patients with Sydenham’s chorea demonstrated that, although the majority of patients with this disorder have a normal brain MRI, those with abnormalities during the symptomatic period often continue to demonstrate these same abnormalities when the disease is clinically quiescent or resolved [Faustino et al., 2003]. Most patients with MRI abnormalities demonstrate abnormal signal intensity or cystic changes in the caudate nuclei; subcortical foci and multiple peripheral white matter foci of abnormal signal have also been reported [Emery and Vieco, 1997; Faustino et al., 2003; Robertson and Smith, 2002].
Neuropathology
Neuropathologic findings in acute rheumatic fever are rare. Rheumatic proliferative endarteritis is limited to the small cortical and meningeal vessels, with spotty patches of gray-matter degeneration [Halbreich et al., 1976].
Treatment
All patients with acute rheumatic fever, including those whose only manifestation is chorea, should receive a 10-day course of penicillin or erythromycin. Prophylaxis with penicillin or sulfadiazine should be started immediately and continued at least until adulthood because of frequent reinfection and the risk of rheumatic heart disease with subsequent streptococcal pharyngitis. More specifically, when residual valvular disease exists, prophylaxis should continue for at least 10 years after the last episode and at least until age 40. If there is no residual valvular disease, the duration of treatment beyond 10 years or into adulthood is not clearly defined. When Sydenham’s chorea is diagnosed and there is no valvular disease, the duration of prophylaxis should be at least 5 years or until age 21, whichever is longer [Dajani et al., 1995].
Children who develop chorea as the sole manifestation of acute rheumatic fever during the initial episode of illness have an approximate 50 percent risk of developing rheumatic heart disease with subsequent infection [Aron et al., 1965]. In addition, studies have suggested that, in certain chorea-prone patients, recurrence of Sydenham’s chorea may follow either undetectable streptococcal infection or another infectious trigger [Berrios et al., 1985].
Sydenham’s chorea has been treated successfully with chlorpromazine, haloperidol [Shenker et al., 1973], phenobarbital, diazepam, valproic acid [Daoud et al., 1990], and corticosteroids [Green, 1978]. In mild cases, cyproheptadine may be effective. Other agents, such as clonidine, pimozide [Shannon and Fenichel, 1990], and corticosteroids [Barash et al., 2005], may be beneficial in refractory cases. Complete recovery can be expected within 2–6 months, although some children may have residual motor, visuomotor, or cognitive dysfunction and a variety of neuropsychiatric manifestations [Bird et al., 1976; Faustino et al., 2003; Leonard et al., 1993; Stehbens and MacQueen, 1972; Swedo et al., 1989].
In some children with Sydenham’s chorea, atlantoaxial subluxation may occur during the acute episode of chorea, with symptoms of neck stiffness, decreased mobility, and pain [Coster and Cole, 1990]. In such patients, differentiating this complication from juvenile rheumatoid arthritis may require further clinical and laboratory evaluation and specific orthopedic intervention. In rare instances, recurrences of chorea may occur in patients without evidence of rheumatic cardiac involvement decades after the childhood onset of symptoms [Gibb and Lees, 1989].
Post-Infectious Tourette’s Syndrome and PANDAS
Chorea, obsessive-compulsive disorder, tic disorder, and Tourette’s syndrome may all have a common autoimmune pathway. It has been reported that some children with chorea have obsessive-compulsive disorder, and that the obsessive-compulsive disorder resolves before or simultaneously with the resolution of the chorea [Swedo et al., 1993, 1998]. Additionally, an increased prevalence of obsessive-compulsive disorder has been noted in children with tics and Tourette’s syndrome. An increased prevalence of antineuronal antibodies, as well as increased levels of antistreptococcal antibodies, has been reported in all four of these diseases. It has been shown that, in patients with chorea, obsessive-compulsive disorder, or tic disorder, there is an increased incidence of the histocompatability locus antigen marker D8/17, which has been reported more frequently in rheumatic fever patients [Allen et al., 1995; Murphy et al., 1997; Swedo, 1994; Swedo et al., 1997]. The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been suggested for some of these conditions in which there is a combination of behavioral problems, obsessive-compulsive behavior, and tics when associated with an antecedent group A beta-hemolytic streptococcal infection [Garvey et al., 1998]. Some studies refute the connection between group A beta-hemolytic streptococcal infection and obsessive-compulsive disorder with tics, citing evidence that, although children with Sydenham’s chorea have behavioral difficulties, they do not have an increased incidence of obsessive-compulsive disorder [Faustino et al., 2003]. In addition, a more recent series of studies compared antibody profiles in patients with obsessive-compulsive disorder alone, obsessive-compulsive disorders with PANDAS, or obsessive-compulsive disorder with chronic tic disorder, respectively, and PANDAS, Tourette’s syndrome, and controls, respectively, and found no difference among them in either anti-brain antibodies or anti-streptolysin O antibody titers [Morris et al., 2009; Gause et al., 2009].
Other Central Nervous System Manifestations
Rarely, acute rheumatic fever may be accompanied by other neurologic problems, such as meningoencephalitis, encephalitis [Benda, 1948], seizures [Goldenberg et al., 1992], pseudotumor cerebri [Mitkov, 1961], papilledema [Chun et al., 1961], diplopia [Schieken et al., 1973], central retinal occlusion [Ling et al., 1969], transient intellectual loss [Gatti and Rosenheim, 1969], and acute psychosis [Wertheimer, 1961]. Combined, these complications occur in 3–5 percent of all patients.
Lyme Disease
Lyme disease is an important cause of neurologic symptoms in children. The illness follows a tick bite and occurs in endemic areas during the summer months. The clinical course of Lyme disease is marked by stages similar to the course of syphilis, another spirochetal infection. The early stage begins with the tick bite and includes a flulike illness and the appearance of an oval, expanding rash at the site of the tick bite. At this stage, systemic infection with Borrelia burgdorferi may be documented by culture. Within several weeks, the patient may develop early neurologic manifestations, which most commonly include facial nerve palsy and aseptic meningitis, but can also include other cranial neuropathies or transverse myelitis and can represent direct invasion of the organism into cerebrospinal fluid [Huisman et al., 1999]. Acute sinovenous thrombosis with consequent pseudotumor cerebri has been reported, as well [Ansari et al., 2002]. The illness resolves spontaneously, but the resolution may be hastened by antibiotic treatment (amoxicillin or erythromycin in children younger than 9 years old and tetracycline in children age 9 years or older for 10–30 days).
Weeks to months later, the patient who was not treated with antibiotics may develop episodic arthritis of the large joints, primarily the knee. Characteristically, the knee becomes acutely effused, but not particularly tender or hot. The often dramatic joint swelling lasts for several days and resolves but returns multiple times if treatment with antibiotics is not started. The diagnosis may be confirmed after the first few weeks with a positive serum IgG titer against B. burgdorferi. Western blotting may be used to confirm the diagnosis if the titer is equivocal [Steere, 1989]. Polymerase chain reaction amplification of the B. burgdorferi genome in the cerebrospinal fluid is available, as well [Ansari et al., 2002].
Years after the acute infection, some patients develop late neuroborreliosis. In children, this rare complication may manifest as a subtle encephalopathy with stuttering and memory disturbances. Adults may develop a multiple sclerosis-like illness, optic neuritis, seizures, and chronic meningitis. The diagnosis of late neuroborreliosis is confirmed by the demonstration of an elevated intrathecal IgG titer compared with serum titer. Treatment with intravenous ceftriaxone for 1 month to penetrate the blood–brain barrier is indicated, but the response is variable. There is no evidence that treatment lasting longer than 4 weeks is of additional benefit [Bingham et al., 1995; Logigian et al., 1990; Szer et al., 1991].
Reiter’s Syndrome
Reiter’s syndrome is one of several spondyloarthopathies. It is characterized by arthritis, uveitis, and urethritis. Progressive myelopathy [Kim et al., 2007], cerebral vasculitis [Niederwieser et al., 2001], axonal polyneuropathy [Cuchacovich et al., 1991], and seizures [Fishel et al., 1995] have been reported as rare neurological complications in adults with Reiter’s syndrome.
Connective Tissue Disorders
The key neurologic and laboratory findings in connective tissue disorders are summarized in Table 86-3 [Tan, 1986].
Table 86-3 Key Neurologic and Laboratory Findings in Connective Tissue Diseases
| Disease | Neurologic Findings | Laboratory Findings |
|---|---|---|
| SLE | Encephalopathy, chorea, seizures, aseptic meningitis, psychosis, behavioral or cognitive dysfunction, headaches, strokes, neuropathy, myelitis | Elevated ANA, low C3 and C4, pancytopenia, hematuria, proteinuria, autoantibodies, LAC, elevated aCL |
| Scleroderma: coup-de-sabre deformity | Seizures, blurred vision, bulbar palsy, optic neuritis, trigeminal neuropathy | Elevated ANA and rheumatoid factor |
| Mixed connective tissue disease | Same as SLE | Same as SLE plus elevated anti-RNP, elevated CK |
| Sjögren’s syndrome | Encephalopathy, optic neuritis, aseptic meningitis, recurrent paresis, myelopathy, neuropathy, autonomic dysfunction | Positive ANA, rheumatoid factor, antibodies to SSA/Ro and SSB/La |
aCL, anticardiolipin antibody; ANA, antinuclear antibody; C3, third component of complement; C4, fourth component of complement; CK, creatine kinase; LAC, lupus anticoagulant; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus.
Systemic Lupus Erythematosus
Revised criteria for the classification of SLE, developed by the American College of Rheumatology (Box 86-3), call for the presence of at least 4 of 11 specific criteria, including a positive test for antinuclear antibody. The antinuclear antibody alone is not sufficient to establish the diagnosis. It must be associated with multiorgan involvement. Arthritis, arthralgia, fever, and photosensitive rash are the most common initial complaints, with renal, cardiac, and neurologic involvement responsible for chronic disability. Lymphadenopathy, hepatosplenomegaly, pleural and pericardial effusions, pulmonary infiltrates, pericarditis, abdominal pain, and even peritonitis may be present at the time of initial evaluation [Cassidy and Petty, 2001; Szer and Jacobs, 1992].
Box 86-3 Revised Criteria for the Classification of Systemic Lupus Erythematosus (1982)
aCL, anticardiolipin antibody; ds-DNA, double-stranded DNA; LAC, lupus anticoagulant; Sm, Smith.
(Adapted from Tan EM, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982; Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, 1997.)
The prognosis for children with SLE has improved dramatically, with an estimated 10-year survival of 85 percent [Cassidy and Petty, 2001; Szer and Jacobs, 1992; Takei et al., 1997].
Neurologic Manifestations
Nervous system involvement in SLE accounts for some of the most frequent manifestations of the disease during childhood [Hiraki et al., 2008; Muscal and Brey, 2010]. Even in SLE patients without overt neuropsychological symptoms, abnormalities have been reported in quantitative EEG studies [Ritchlin et al., 1992]. Early reports suggested that CNS involvement was the second most common cause of death in children with SLE. More recently, the outcome of children with CNS lupus appears favorable, with most showing recovery [Hiraki et al., 2008].
Seizures
Between 20 and 50 percent of children with SLE develop generalized and occasionally focal motor seizures [Parikh et al., 1995; Steinlin et al., 1995; Vieira-Karuta et al., 2008]. Seizures usually occur during the first year of illness and may be the initial manifestation of SLE, but they may occur at any stage. Interictal EEG may show multifocal paroxysmal sharp-wave or slow-wave activity, particularly in the temporal lobes and particularly in patients with recurrent seizures. Patients who present with a single seizure may have a normal interictal EEG [Appenzeller et al., 2004].
Neuropsychiatric lupus
Although the diagnostic criteria for SLE (see Box 86-3; reviewed in Ruiz-Irastorza et al. [2001]) include only two neuropsychiatric syndromes (seizure and psychosis), numerous neuropsychiatric manifestations have been associated with SLE. The prevalence of these complications in children with SLE ranges from 22 to 95 percent, depending on the report [Muscal and Brey, 2010]. This wide range in reported prevalence rates primarily reflects the use of different diagnostic criteria. Nineteen neuropsychiatric SLE (NPSLE) syndromes based on specific case definitions have been defined for adults [American College of Rheumatology Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999; summarized in Muscal and Brey, 2010]. Initial studies that extended these definitions to children and adolescents indicated that neurological manifestations include headache in 72 percent, mood disorder in 57 percent, cognitive dysfunction in 55 percent, seizures in 51 percent, acute confusional state in 35 percent, peripheral nervous system dysfunction in 15 percent, psychosis in 12 percent, and stroke in 12 percent [Sibbitt et al., 2002]. Neuropsychiatric manifestations of SLE are generally classified as either primary – related to direct involvement of the neuropsychiatric system; or secondary – related to complications of the disease and its treatment. The latter includes infections, metabolic repercussions of organ failure (e.g., uremia), and drug-induced toxicity, such as hypertension associated with glucocorticoid use. A more recent study of 256 children with SLE confirmed the higher frequency with which they develop neuropsychiatric symptoms relative to adults with SLE, the association of renal disease in SLE with secondary neurological complications, and, despite this, the excellent (97 percent) overall survival of children with NPSLE [Hiraki et al., 2008].
In about half of the SLE patients with CNS involvement, the neuropsychiatric pathologies are already present at disease onset. Studies have shown that, in about 70 percent of affected children, the CNS manifestations occur within the first year of diagnosis; in the remaining 30 percent, CNS manifestations may not develop for up to 13 years [Harel et al., 2006]. Others have reported a median disease duration of 11 months [Yu et al., 2006] and a mean of 2.5 ± 5.2 years [Fragoso-Loyo and Sanchez-Guerrero, 2007] prior to the development of neuropsychiatric symptoms. About 30–70 percent of affected children have more than one neuropsychiatric symptom [Steinlin et al., 1995]. Onset may be acute or indolent. In some children, neuropsychiatric manifestations appear to be the only presenting symptom of SLE. However, it remains controversial whether neuropsychiatric manifestations can truly appear as an isolated event [Toubi et al., 1995; Harel et al., 2006], or whether there is always some involvement of other organs [Weiner and Allen, 1991]. Numerous autoantibodies have been seen in association with NPSLE, including antineuronal antibodies, antiphospholipid antibodies, anti-NR2 N-methyl-d-aspartate (NMDA) receptor antibody, and antiribosomal P antibody [Levy et al., 2009]. Anti-NR2 subunit NMDA receptor antibodies are found more frequently in SLE patients and their healthy first-degree relatives than in healthy unrelated controls, but there is no difference between SLE patients with and without NPSLE, respectively, or between SLE patients and their healthy first-degree relatives, respectively. This suggests that, while the familial propensity to have antibodies to the NMDA receptor NR2 subunit is associated with the propensity for autoimmune diseases like SLE, there is no association between these antibodies and the neuropsychiatric pathology seen in SLE [Steup-Beekman et al., 2007]. Diagnostic testing for NPSLE is controversial, as traditional imaging techniques, such as MRI, detect only a subset of abnormalities in these patients. Use of neuropsychiatric testing to diagnose neurocognitive impairment is increasingly being used in this population, but remains a challenging area.
Headache
Headaches are common in children and adolescents with SLE [Benseler and Silverman, 2007; Muscal and Brey, 2010]. Headache usually occurs during exacerbation of systemic symptoms and frequently is associated with other neurologic symptoms. Unless objective neurologic symptoms are present, the diagnostic work-up may yield few abnormalities, although evaluation for a hypertensive encephalopathy should be considered [Parikh et al., 1995; Steinlin et al., 1995]. Most patients will respond to increased dosages of corticosteroids.
In two prospective studies of adult patients with SLE, it was found that vascular headache developed in 26 percent of adult patients, and muscle contraction headache in 40 percent [Vazquez-Cruz et al., 1990; Bicakci et al., 2008]. Although a relationship between migraine and SLE has been hypothesized to be the result of cerebrovascular endothelial dysfunction in vasculitis, a recent study failed to demonstrate evidence of such dysfunction [Davey et al., 2010].
Chorea
Chorea occurs in perhaps 5 percent of children with SLE and is the initial symptom in 25–30 percent of patients who present with neurologic symptoms [Herd et al., 1978]. Systemic lupus manifestations often occur within 1 year of onset; rarely, a prolonged latent interval may ensue after the onset of chorea [Parikh et al., 1995; Steinlin et al., 1995]. Approximately 50 percent of children with lupus chorea develop other CNS manifestations, including seizures and neuropsychiatric disturbances. Chorea has also been associated with thromboembolic disease and elevated anticardiolipin antibody [Besbas et al., 1994].
Reye-like syndrome
A Reye-like syndrome associated with acetylsalicylic acid treatment of SLE has been recognized [Hansen et al., 1985]. Salicylate hepatocellular injury appears to be relatively common in patients with rheumatic disorders, but its relation to Reye’s syndrome has raised the possibility of some other etiologic relation between salicylate therapy, various rheumatic disorders, and idiopathic Reye’s syndrome. This syndrome has not been seen with other nonsteroidal anti-inflammatory agents.
Cerebrovascular disease
Although it is unusual for a cerebrovascular syndrome to be the initial manifestation of SLE, approximately 3 percent of children develop cerebrovascular occlusive disease that results in hemiplegia, aphasia, or sensory and visual impairments [Parikh et al., 1995; Steinlin et al., 1995]. Most of these patients have serious renal, cardiac, pulmonary, or hematologic disease with hypertension or thrombocytopenia. Even if there is recurrent hemiplegia, significant recovery may occur. Antiphospholipid antibody has been associated with thrombosis in SLE, especially when lupus anticoagulant is present [Levy et al., 2003]. Microembolic signals in cerebral vasculature have been observed by transcranial Doppler in patients with lupus; patients with antiphospholipid antibodies are more likely to exhibit this phenomenon [Baizabal-Carvallo and Samson, 2009]. Alternatively, thrombotic or thromboembolic disease may be due to a vasculopathy with or without autoimmunity, atheromatous disease, valvular disease, or vasculitis [Bruyn, 1995; West, 1994]. In adults, it has been reported that elevated homocysteine levels increase the risk of atherothrombotic events [Petri et al., 1996].
One case report indicates that perivenous inflammation with secondary calcification may occur in SLE. This postmortem finding was preceded by computed tomography (CT) and MRI evidence of foci of breakdown of the blood–brain barrier, calcifications, and a clinical picture consistent with focal vascular dysfunction and diffuse encephalopathy [Matsumoto et al., 1998].
Multifocal cerebral dysfunction with patchy areas of altered signal intensity on MRI has been interpreted as acute vascular lesions associated with pulse steroid therapy in patients with SLE. This syndrome responds well to substitution of cyclophosphamide for pulse methylprednisolone, and, as such, it is imperative that it be promptly recognized [Tabata et al., 2002].
Hypertensive encephalopathy
Headache, seizures, coma, and focal ischemic CNS injury have been reported as manifestations of hypertensive encephalopathy associated with lupus nephritis [Cassidy et al., 1977]. Recent reports demonstrate in adolescent and adult lupus patients the classic posterior reversible leukoencephalopathy associated with hypertension of a variety of etiologies. Controlling blood pressure and treatment with corticosteroids frequently result in substantial neurologic improvement [Muscal et al., 2010; Bag et al., 2010].
Cranial nerve, brainstem, and spinal cord dysfunction
Ophthalmoplegia, ptosis, diplopia, facial numbness, vertigo, sensorineural hearing loss [Hisashi et al., 1993], vocal cord paralysis [Teitel et al., 1992], and ataxia have been described in children with SLE. Brainstem involvement is usually observed in conjunction with other nervous system symptoms, such as chorea and seizures [Gold and Yahr, 1960].
Approximately 6 percent of children with SLE manifest visual symptoms, which include blurred vision, sudden blindness, and field loss [Brandt et al., 1975]. Retinal hemorrhages, cotton wool exudates, papilledema, optic neuritis, and cytoid bodies have all been reported [Cassidy et al., 1977; Hackett et al., 1974]. Retinal artery occlusion may also occur, with resulting transient or permanent visual loss. Papilledema associated with pseudotumor cerebri caused by either the disease or corticosteroid therapy also has been reported [Green et al., 1995]. If papilledema is present, the possible presence of increased pressure or a mass lesion should be assessed before lumbar puncture is performed [Brandt et al., 1975; Carlow and Glaser, 1974]. Patients with either retinal artery occlusion or papilledema should be treated with high doses of corticosteroids after elimination of structural or occlusive cerebrovascular disease.
Transverse myelopathy that causes both paraplegia and sensory loss as the initial or late neurologic manifestations of SLE has been reported [Andrianakos et al., 1975; Meislin and Rothfield, 1968]. Other studies in adults have shown an association with antiphospholipid antibodies [Kovacs et al., 1993]. In addition, Devic’s disease with neuromyelitis optica (NMO) antibody seropositivity has been reported in patients with lupus [Karim and Majithia, 2009; Nasir et al., 2009]. Early treatment with high doses of corticosteroids, alone or in combination with cyclophosphamide or rituximab, has been used, but improvement was variable [Propper and Bucknall, 1989; Boumpas et al., 1990; Berlanga et al., 1992; Chan and Boey, 1996; Karim and Majithia, 2009; Nasir et al., 2009].
Central nervous system infections
Infection of the CNS in children with SLE is relatively rare [Cassidy and Petty, 2001; Fish et al., 1977; Walravens and Chase, 1976]. Bacterial meningitis, opportunistic bacterial infection, and fungal meningitis (aspergillosis, nocardiosis, and cryptococcosis) have been reported. Brain abscess may be difficult to differentiate from a multifocal vasculitis, but differentiation may be facilitated by using serial CT scans and angiography. Multiple abscesses of the CNS may be relatively silent; if they are suspected, broad-spectrum antimicrobial or antifungal therapy should be instituted after appropriate cultures are obtained.
Lupus aseptic meningitis
The syndrome of lupus aseptic meningitis, accompanied by a sterile cerebrospinal fluid lymphocytic pleocytosis, may be manifested by nuchal rigidity, fever, and headache, and may occur early in childhood lupus. This syndrome has been reported in association with nonsteroidal anti-inflammatory drugs and trimethoprim-sulfamethoxazole use [Escalante and Stimmler, 1992]. Clinical manifestations and cerebrospinal fluid abnormalities may persist for several weeks before resolving spontaneously. Therapy with corticosteroids may improve this condition, but the data are inconclusive because of the self-limited course [Canoso and Cohen, 1975; Keefe et al., 1974].
Peripheral nervous system involvement
Involvement of the peripheral nervous system occurs in approximately 5 percent of children with SLE. Peripheral neuropathies, with symptoms consisting of paresthesias, numbness, and distal weakness, are usually relatively mild in severity and course, although severe forms of acute lumbosacral plexopathies have been reported [Bailey et al., 1956; Jacob, 1963]. Neuropathy manifesting as either mononeuritis multiplex or acute demyelinating polyneuropathy may occur at any time during SLE, may recur, and generally worsens when CNS involvement is greater. Polyradiculoneuropathy may mimic Guillain–Barré syndrome in children; however, this pattern is extremely rare [Norris et al., 1977; Robson et al., 1994].
Myopathy
Myositis is rare in SLE, although myalgias and generalized weakness are common. Myositis can be distinguished from corticosteroid-related myopathy by demonstrating elevated levels of muscle enzymes, electromyography consistent with myopathic and fibrillation activity, and lack of vacuolization in muscle biopsies. One case report demonstrated pyridostigmine-responsive myasthenia gravis complicating childhood SLE [Nishimura et al., 1997]. Although children with myasthenia gravis may have circulating serum antinuclear antibodies, clinical SLE is highly unusual.
Drug-induced lupus syndrome
Many drugs have been reported to induce a lupus-like syndrome in children and adults [Rubin, 1997]. In general, this disorder is milder than spontaneous SLE and occurs with equal frequency in males and females [Totoritis and Rubin, 1985]. Arthritis, pneumonitis, and pericarditis are common, whereas rashes and alopecia are less frequent. Hepatosplenomegaly, lymphadenopathy, and acute pancreatitis may occur in some patients; renal disease appears less often [Rubin, 1997]. Procainamide, hydralazine, and isoniazid are the three drugs that have most commonly induced this syndrome. These drugs share a primary amine or hydrazine portion that is acetylated by the N-acetyl transferase system of the liver in two different phenotypic expressions [Rubin, 1997]. The risk of a drug-induced syndrome appears to be much greater in the “slow” acetylators than in the “fast” acetylators.
Antiepileptic drugs and phenothiazines have also been associated with a drug-induced lupus syndrome. Antiepileptic drugs reported to cause this disorder in children include phenytoin, ethosuximide, carbamazepine, and trimethadione [Rubin, 1997; Singsen et al., 1976]. Although children receiving these drugs are usually asymptomatic, approximately 20 percent of them produce antinuclear antibodies; these children commonly have normal immunoglobulins and serum complement levels, and remain free of a clinical lupus-like syndrome. Antiepileptic medication therefore may be continued [Singsen et al., 1976]. Among patients in whom antiepileptic drugs have been discontinued, the presence of antinuclear antibodies may persist for several years.
Drug-induced SLE has been associated with etanercept therapy in a child with juvenile idiopathic arthritis [Lepore et al., 2003].
Laboratory Findings
Laboratory features of SLE commonly include a positive antinuclear antibody titer, low C3 and C4 levels, leukopenia, direct Coombs-positive hemolytic anemia, hematuria, and proteinuria. Abnormal autoantibodies may include antibody to double-stranded DNA, Sm (Smith), RNP (ribonucleoprotein), Ro (or SSA), La (or SSB), and anticardiolipin. In addition, there may be a paradoxical prolongation of the partial thromboplastin time because of antiphospholipid antibodies. Antibodies to antiphospholipid may also produce a biological false-positive rapid plasma reagin (RPR) or Venereal Disease Research Laboratories (VDRL) test. In adults, a strong correlation between MRI changes and the presence of a positive lupus anticoagulant or anticardiolipin antibody exists, but there is no clear correlation with neuropsychiatric disease [Ishikawa et al., 1994; Manco-Johnson and Nuss, 1995; Molad et al., 1992; Toubi et al., 1995]. Pediatric case reports have also been published showing some correlation between disease and antiphospholipid antibodies, as demonstrated by one of these tests [Steinlin et al., 1995; von Scheven et al., 1996]. Elevated lupus anticoagulant (LAC) appears to confer a significant increased risk of arterial or venous thrombotic events [Galli et al., 2003]. Anticardiolipin IgG fraction and anti-β2-glycoprotein I antibodies may also correlate, but their association is less certain [Galli et al., 2003].
Several mechanisms explaining the pathogenesis of CNS lupus have been reported [Bruyn, 1995]. In most patients with documented CNS lupus, evidence of immune-mediated abnormalities cannot be found, suggesting multifactorial causes of CNS disease. Interestingly, one study found that approximately 75 percent of observed neurologic events were attributed to metabolic, hematologic, or infectious factors rather than to the primary disease process [Kaell et al., 1986]. Serum complement and autoantibody levels may remain normal. The cerebrospinal fluid is often benign, and imaging modalities are of little value, unless there is an ischemic event [Hirohata et al., 1985; Szer and Jacobs, 1992]. However, cerebrospinal fluid examination is often necessary to rule out infectious causes.
In support of a diagnosis of immune disease, studies of cerebrospinal fluid immunoglobulin production have documented elevations of IgG, IgG/albumin ratio, and the cerebrospinal fluid IgG index and the presence of oligoclonal IgG, suggesting accelerated CNS IgG synthesis. Further support for immune-mediated disease may be found in the relatively high incidence of antineuronal and antiribosomal P antibody in some children with SLE [Reichlin, 2003; Silverman, 1996; West et al., 1995]; however, antiribosomal P was not found to be sensitive for neuropsychiatric manifestations of SLE in another series [Press et al., 1996]. In addition, endothelial or vascular injury may be a complement-mediated immunologic insult, because the choroid plexus has been reported as the deposition site of complement and immune complexes; cerebrospinal fluid C4 also appears to be reduced [Hadler et al., 1973; Sher and Pertschuk, 1974]. In addition, cerebrospinal fluid anti-double-stranded DNA complexes and lymphocytotoxic antibodies have been documented in CNS lupus [Bluestein, 1997; Carr et al., 1975]. Serial cerebrospinal fluid C4 complement levels may help to distinguish between neuropsychiatric symptoms caused by corticosteroids and those caused by SLE. A serial decrease in C4 complement level suggests increased disease activity rather than a drug-induced phenomenon. More recent studies demonstrate moderate levels of interleukin-6 in neuropsychiatric SLE. The importance of this finding must be interpreted with caution because significantly high levels of interleukin-6 may be found in CNS infection [Tsai et al., 1994]. At present, cerebrospinal fluid findings cannot reliably confirm the diagnosis of neuropsychiatric symptoms associated with CNS lupus.
False-positive elevation of antistreptococcal antibody titers can occur in lupus chorea and may incorrectly result in the diagnosis of Sydenham’s chorea, unless antinuclear antibody titers are obtained. Serum complement is decreased in lupus chorea, but cerebrospinal fluid complement, anti-double-stranded DNA antibody titers, and immunoglobulin synthesis have not been studied [Kukla et al., 1978]. In adults, a significant correlation exists between chorea and the presence of antiphospholipid antibodies [Asherson et al., 1987]. This association has also been reported in children [Besbas et al., 1994].
In patients with transverse myelopathy, cerebrospinal fluid analysis may demonstrate increased protein concentration, decreased glucose, and a monocytic pleocytosis [Al-Husaini and Jamal, 1985].
Neurodiagnostic Testing
Neuroimaging with either CT or MRI scans is essential for evaluating the patient with SLE who is suspected of having intracranial disease [Carette et al., 1982; Provenzale et al., 1994]. Such studies may show cortical or cerebellar atrophy (Figure 86-1), infarction (Figure 86-2), low-density lesions in the cerebral white matter (Figure 86-3) [Isshi et al., 1994; Muscal et al., 2010], or hemorrhage [Aisen et al., 1985; Kovacs et al., 1993]. MR angiography or venography may detect sinovenous thrombosis [Steinlin et al., 1995]. Cerebral angiography may be helpful in further differentiating arterial thrombotic from embolic disease, but may be normal in children because small vessel arterial changes may not be demonstrable [Jones et al., 1975]. MRI has been used to detect myelopathy in a child as young as 5 years of age [Vieira et al., 2002]. In a meta-analysis of the literature on lupus patients (age 12–53 years) with transverse myelitis affecting four or more spinal segments, MRI demonstrated increased spinal cord T2 signal, most frequently in the cervical to mid-lower thoracic spinal segments [Espinosa et al., 2010]. Single-photon emission computed tomography (SPECT) is a sensitive tool for demonstrating diffuse and multiple perfusion abnormalities in children and adults with CNS events (Figure 86-4). Unfortunately, the usefulness of SPECT is limited. It is not specific for CNS lupus, and longitudinal assessment with this modality correlates poorly with clinical status [Szer et al., 1993]. There is some suggestion that combining SPECT and MRI findings may have some value in identifying and monitoring lupus patients with neuropsychiatric involvement [Castellino et al., 2008].
